Cystic Fibrosis Pulmonary Care Materials

COMPLEXITIES OF CYSTIC FIBROSIS PULMONARY CARE

Pamela Sardo, PharmD, BS

Pamela Sardo, PharmD, BS, is a freelance medical writer and licensed pharmacist in 3 states. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS. from the University of Connecticut and her PharmD. from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.

Topic Overview

Cystic fibrosis (CF) is considered a rare disease, according to the National Organization of Rare Diseases, and is one of the most commonly diagnosed genetic disorders. Approximately 30,000 people are living with CF in the United States, with 1,000 new cases diagnosed every year. Pulmonary complications and clinical characteristics, including progressive obstructive lung disease, sinusitis, and infection, among others, contribute to significant morbidity. Although CF is a life-shortening disease, survival has continued to improve due to earlier diagnosis through routine newborn screening, evidence-based guidelines to optimize pulmonary health, and the development of CF-specific interdisciplinary care centers. Pharmacists are well-positioned to engage in shared decision-making regarding treatments for CF pulmonary conditions and to remain aware of the comprehensive safety and efficacy of these treatments. The Cystic Fibrosis Foundation recommends treatments for moderate-to-severe pulmonary disease, including inhaled tobramycin, dornase alfa, ivacaftor, and inhaled aztreonam. Pharmacy technicians' patient-facing roles also contribute to patient care for patients and families presenting with CF. Future improvements in health and quality of life for individuals with CF are likely with the recent development of new therapeutics and ongoing research.

Accreditation Statement

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-23-172-H01-P

Pharmacy Technician  0669-0000-23-173-H01-T

Credits: 1 hour of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $4.99

Estimated time to complete activity: 1 hour, including Course Test and course evaluation

Release Date: October 17, 2023 Expiration Date: October 17, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From October 17, 2023, through October 17, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the common clinical pulmonary manifestations of cystic fibrosis (CF)

Identify laboratory and genetic studies needed to diagnose CF

Recognize the most common presentations of CF-related complications

Describe the current recommendations for long-term maintenance of optimal lung health in CF patients

Disclosures

The following individuals were involved in developing this activity: Pamela Sardo, PharmD, BS. Pamela Sardo was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Introduction

Cystic fibrosis is an inherited, progressive, life-shortening, autosomal recessive disease. Although cystic fibrosis is rare, it is one of the most commonly diagnosed genetic disorders. Early diagnosis from newborn screening, improved lung health therapies, aggressive treatment of respiratory infections, and lung transplantation have led to significant improvements in patient outcomes. Optimizing care includes coordinating services between primary care providers and the interdisciplinary CF care team, including pharmacy staff. This educational module focuses on the pulmonary aspects of the disease.

Epidemiology

The National Organization for Rare Diseases (NORD) designates cystic fibrosis (CF) as a rare disease.1 Cystic fibrosis occurs in all racial and ethnic backgrounds; however, it has the highest incidence in Caucasians.3 Data reveal an incidence of 1:13,500 in people of Hispanic background, 1:15,000 in people of African descent, and 1:31,000 in people of Asian descent.3 Approximately 30,000 people live with CF in the United States, with 1,000 new cases diagnosed yearly.2,4

Pathophysiology

Cystic fibrosis is a multisystem disorder resulting from genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.2 The gene is located on chromosome 7q31.2, which encodes for the CFTR protein.2.

Cystic fibrosis causes problems in the body's cells that make salt, water, and mucus. CFTR controls the flow of water and salt in and out of the body's cells. A primary cause of morbidity and mortality in individuals with CF is the development of progressive impairment of the respiratory system.5

Defects in CFTR lead to absent or malfunctioning chloride channels in the membranes of the lung surface or glandular epithelium. This results in the formation of thick and sticky mucus.2 The disease process causes thick mucus to build up and clog areas in the lungs.2 This first manifestation occurs in the small lung airways. Over time, all airways may be affected.2 The mucus retention leads to chronic lung infections and damaging airway inflammation.

Patients with CF have unique pharmacokinetic and pharmacodynamic profiles related to their disease state. Table 1 discusses these considerations in individuals suffering from CF.

Table 1: Considerations in Patients with Cystic Fibrosis6

Antibiotic dosing in patients with CF is challenging

Difficulties include altered PK, lung tissue penetration of medication is impeded, drug delivery devices vary, patient-specific considerations, and the increasing presence of antimicrobial resistance

CF patients have decreased plasma protein binding of penicillins and most cephalosporins, resulting in increased clearance rates

This increased clearance requires a higher medication dose or a switch to continuous infusion

Higher doses of aminoglycosides and trimethoprim are required

A combination of different classes of antibiotics can be given at the same time to prevent resistance and to achieve synergy, especially in the treatment of Pseudomonas aeruginosa

Inhalation therapy provides higher local antibiotic concentrations in the airways to eradicate bacteria while minimizing systemic exposure and risk of toxicity

Diseased lung areas receive less inhaled antibiotics than healthy areas

The reduced antibiotic coverage may cause patients with more advanced disease to receive higher doses to achieve sufficient drug concentrations

Chronic cough

Coughing up blood

Collapsed lung

A rounding and enlargement of the tips of the fingers and toes (clubbing)

Frequent lung infections with thick phlegm

Heart enlargement

Nasal polyps

Shortness of breath

Inflamed nasal sinuses (sinusitis)

Bronchitis

In the lungs, mucous plugging from dehydrated thick secretions results in inflammation, chronic infection, progressive small airway obstruction, and the development of bronchiectasis.2 This condition is an abnormal, permanent enlargement of the bronchi. Bronchiectasis leads to a decreased ability to clear secretions, causing a cycle of increased rates of infections, which further dilates and damages the airways.2

Screening and Diagnosis

Newborn screening (NBS) is routine and can prevent missed or delayed diagnosis of CF.8 NBS is performed by measuring an immunoreactive trypsinogen (IRT) level in screening neonatal blood.2 If an infant has an elevated IRT level, laboratories perform confirmatory CFTR variant testing. Screening is considered positive if the IRT level remains elevated between the ages of 7 and 14 days of life.2

The next step is that a positive NBS result triggers a notification to a provider. The infant should be referred for further evaluation and sweat testing within 72 hours of a positive screening result.2 The sweat test measures the concentration of chloride that is excreted in sweat after the transdermal administration of pilocarpine.8 Due to defective chloride channels, the concentration of chloride in sweat is elevated in individuals with CF.8

The Cystic Fibrosis Foundation (CFF) consensus guidelines in 2017 summarized that a diagnosis of CF can be made if an individual has a positive newborn screening and clinical features, such as chronic, recurrent sinus issues and pulmonary disease. Diagnosis can also be made by a positive family history of CF and evidence of CFTR dysfunction (e.g., elevated sweat chloride concentration).9

Early diagnosis of an asymptomatic infant with CF allows timely interventions to slow lung disease progression and the provision of psychosocial support to families.2 At least 64% of new CF diagnoses in the US now occur in asymptomatic or minimally symptomatic infants.9

Although there are many positive actions from screening, there are also concerns during the patient and family journey through this process. Possible concerns of NBS include an increased number of medical interventions.2 This can be burdensome to the family. There can be exposure to respiratory pathogens when the family comes to a CF specialty clinic or any care setting. There can be financial hardships due to the cost of CF-related therapies.2

Complications such as exposure to therapies with side effects and caregiver anxiety are also possible.2

Cystic Fibrosis Management

There is no cure for CF so treatment involves management of respiratory symptoms focusing on maintaining lung function and preventing the development of bronchiectasis and parenchymal destruction.10 Early diagnosis from newborn screening, improved lung health therapies, aggressive treatment of respiratory infections, and lung transplantation have led to significant improvements in survival.2 Optimizing care includes coordinating services between primary care providers and the interdisciplinary CF care team, including pharmacy staff.2

In addition to encouraging a smoke-free environment, children with CF are often prescribed multiple therapies, which will likely be lifelong and should be initiated shortly after diagnosis.2 Long-term therapies for children and adults with CF include control of airway infection, airway inflammation, clearance of mucous secretions, and treatments aimed at the genetic defect, where applicable.2,9

Therapies to Manage Lung Health

Clearance of Airway Secretions

Positive expiratory pressure devices help keep the patient’s airway open. Breathing out with moderate force through resistance allows airflow to get beneath mucus obstruction so that it can be coughed out.8

By removing airway mucus, airway clearance therapy (ACT) helps to decrease the respiratory bacterial load along with irritants, leading to improved gas exchange and a decrease in airway obstruction.2 Airway clearance therapy modalities commonly used include manual percussion, positive expiratory pressure devices, and high-frequency chest wall oscillation.11 This is achieved through an inflatable vest that performs chest physical therapy by vibrating at a high frequency.11 Patients should choose

the airway clearance technique that best meets their needs after considering comfort, convenience, flexibility, practicality, and cost.11

Dornase alpha is a recombinant human deoxyribonuclease. It is indicated, in conjunction with standard therapies, for managing pediatric and adult patients with cystic fibrosis (CF) to improve pulmonary function.12 Pulmonologists may use forced vital capacity (FVC) measurements when considering dornase alpha. Forced vital capacity (FVC) is the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. In patients with an FVC ≥ 40% of predicted values, daily administration of dornase alpha has been shown to reduce the risk of respiratory tract infections.

.

Hypertonic saline is a sterile saline solution available in concentrations of 3%, 3.5%, and 7%.13,14 It increases the amount of sodium (salt) in the airways.13 Salt attracts water into the airways, which thins the mucus, making it easier to cough out. Research has shown that inhaling hypertonic saline twice a day results in fewer lung infections.14 It is recommended for individuals 6 years of age and older.14

Mannitol is a sugar alcohol indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years of age and older with cystic fibrosis.15 It should only be used in adults who have passed the mannitol tolerance test.15 Mannitol is available as an inhaled powder that makes it

easier to cough up mucus.15 The mechanism of action is unknown.14 Mannitol can be taken twice a day and comes with a handheld inhaler and blister pack of tablets.14 Most common adverse reactions include cough, hemoptysis, oropharyngeal pain, vomiting, bacteria sputum identified, pyrexia, and arthralgia.15

Chronic Airway Infections

Aggressive management of chronic airway infections prevents lung function decline.16 Nebulized antibiotics such as tobramycin or aztreonam can be used as suppressive therapy for individuals with chronic infection or colonization with organisms.2 This suppressive therapy is administered every other month to decrease the risk of antibiotic resistance.2

Table 2 contains select bacteria commonly identified in patients suffering from CF and antibiotics prescribed to treat the infection. This is not a comprehensive list. Consult the prescribing information for each treatment for comprehensive safety and efficacy information. Culture and susceptibility testing is recommended.

Table 2:* Common Bacteria and Select Antibiotics for Patients with CF6,16-19

*This is not a complete list iv- intravenous po- oral

Chronic Airway Inflammation

Chronic airway inflammation is managed with either high-dose ibuprofen or azithromycin. Although ibuprofen has proven benefits in CF, the risk of gastrointestinal bleeding and the need for monitoring serum levels has limited its use.16 Azithromycin results in improved lung function, a reduced number of pulmonary exacerbations (PEx), and improved quality of life.16 It can also reduce sputum viscosity and airway adhesion of P. aeruginosa.16 The pharmacological mechanism that causes the beneficial effect in CF is unclear.16

The Cystic Fibrosis Foundation recommends the treatments in Table 3 as having substantial benefits for moderate-to-severe disease.16 Other treatments have also yielded successful results. The full prescribing information of each medication should be consulted for comprehensive dosing and safety information.

Table 3:* Pharmacologic Treatment for Cystic Fibrosis8,12,13,20-26

*Treatment may vary based on age, symptoms, severity, comorbidities

^hemoptysis- blood in mucus

ᵞ dyspnea- shortness of breath

† off-label use

Antibiotic therapy and mode of delivery (enteral, inhaled, and/or intravenous) are dictated by the severity of the exacerbation and previous/current respiratory culture results.2 In patients (aged ≥6 years) with chronic presence of Pseudomonas aeruginosa (P aeruginosa) in airway cultures, prophylactic use of antibiotics (tobramycin, aztreonam, and azithromycin) is recommended.27 The use of inhaled tobramycin and aztreonam delivers the drug locally to the lung and decreases the risk of systemic side effects.27

For chronic use, tobramycin is administered by nebulization (300 mg) or dry powder inhalation (112 mg) twice daily for 28 days on and 28 days off.21 It can also be administered IV or IM at a dose of 10 mg/kg/day given in four equally divided doses.20

Aztreonam inhalation solution is an alternative antibiotic for patients with chronic colonization of P aeruginosa.21 Aztreonam 75 mg is administered by nebulization route three times daily for 28 days on and then 28 days off.21 If a patient is chronically using a bronchodilator and mucolytic, the bronchodilator should be used first, followed by the mucolytic, and then the aztreonam.10,21

CFTR Modular Therapies

CFTR modulators are the first therapies to target the basic defect in CF by directly acting on the CFTR protein. They are categorized into 3 types: potentiators, correctors, and amplifiers. Ivacaftor, the first approved modulator therapy, is a potentiator, which helps improve chloride flow through the CFTR protein at the cell surface for patients.23

Correctors, such as lumacaftor and tezacaftor, help the CFTR protein to form correctly to allow the protein to move, or traffic, to the cell surface.24,26 When added to potentiators, correctors such as lumacaftor/ivacaftor or tezacaftor/ivacaftor work to improve the amount of protein that reaches the cell surface for patients.24,26

In 2019, the FDA approved the use of a triple-combination therapy, elexacaftor/tezacaftor/ivacaftor, for individuals with at least one F508del variant.2,25 This triple combination has been shown in clinical trials to show dramatic improvement in key measures of disease, including increased lung function.2,25

Patients should be counseled to take CFTR modulators with fat- containing food. This is another pharmacist counseling opportunity. If the prescriber has not provided a list of fat-containing foods to the patient, the pharmacist is ideally positioned to propose foods such as avocados, cheese, full fat yogurt, nuts, or cooking with olive oil, among other options.29

Pulmonary and Extrapulmonary CF Complications Pulmonary Exacerbation (PEx)

One of the most common complications of CF lung disease is episodic acute worsening of symptoms, referred to as pulmonary exacerbations (PEx). There is no universally agreed definition of a PEx, making it difficult to standardize treatments.30

Pulmonary exacerbations are characterized by increased respiratory symptoms, including coughing, sputum production, and/or wheezing, reduced pulmonary function, or fatigue.2 Pulmonary exacerbations are associated with reduced quality of life, hospitalizations, and decreased survival.30

Treatment typically includes antibiotics, sometimes in combination for synergistic activity and reducing drug resistance.31 Alternative treatments, such as the cephalosporin/b-lactamase inhibitor combinations ceftazidime- avibactam and ceftolozane-tazobactam or others, may be required.31 Increased frequency of ACT to help clear secretions from the airways.2

Hemoptysis

Cystic fibrosis-related hemoptysis is most commonly a result of chronic infection and inflammation, leading to erosion of hypertrophied bronchial arteries into the airways.2 Vitamin K deficiency can contribute to hemoptysis.2

Managing mild to moderate hemoptysis (with volume of ≤240 mL) includes antibiotic therapy and consideration of limiting certain exacerbating therapies, such as ibuprofen, hypertonic saline, dornase alpha, and ACT.2,30 Severe hemoptysis (>240 mL) is considered life-threatening, and discontinuation of anti-inflammatory and airway clearance measures are needed.2 Hemoptysis causes significant distress.30

If severe, patients should be hospitalized and treatment includes IV antibiotics and discontinuation of airway clearance and aerosolized therapies.30 Procoagulant therapies (e.g., tranexamic and aminocaproic acid) have shown benefit with reduced need for hospitalization, shorter length of stay for those patients who are hospitalized, and less need for invasive procedures.30

Pneumothorax

Pneumothorax is a common and life-threatening complication in patients with CF, especially in those who have infections or developed massive

hemoptysis. It is the accumulation of air within the pleural space. It occurs secondary to air trapping.2 High alveolar pressure forces air into the lower pressure interstitial spaces, leading to air leak into the pleural space, resulting in symptoms of acute chest pain and dyspnea.2

Clinical presentation could range from dramatic to mild. Early and aggressive treatment and surgical intervention should be considered after the first episode, provided that the patient is fit for the procedure.32

Therapeutic options include intercostal tube drainage, and video- assisted thoracoscopic surgery (VATS).30 Chronic therapies, including nebulized mucolytics and antimicrobials, should be continued.30 No consensus exists regarding the administration of oral or IV antibiotics.30 CF patients with pneumothorax should neither fly on a plane, nor perform spirometry or lift weights for 2 weeks after the pneumothorax has resolved.32

Chronic Rhinosinusitis (CRS) and Nasal Polyposis

The sinuses can have defective CFTR protein, so chronic sinus disease is common in patients with CF.2 In contrast, the prevalence of nasal polyposis is more variable and increases with age. Rhinosinusitis and nasal polyposis can be intermittent or chronic and result from mucous obstruction of the sinus area.2,33 Clinical presentations may include chronic headache, congestion, or facial pressure.2

Medical management includes saline nasal irrigation to aid with mucus clearance and nasal steroids to decrease inflammation.2,33 Surgical treatment for severe and recurrent disease can improve mucus clearance.33 Ciprofloxacin and azithromycin are the most widely used antibiotics for prophylaxis and exacerbation control.33 Because of their anti-inflammatory activity, leukotriene receptor antagonists are recommended for patients with CRS with nasal polyposis as an alternative to oral corticosteroids, being used in combination with topical corticosteroids.33

Transitioning to Adulthood

Understanding self-care skills and transitioning to adult care should begin in the early teenage years.2 Readiness assessment tools and questionnaires are available for self-management skills. One is the Transition Readiness Assessment Questionnaire (TRAQ).2,34 Discussions should also include educational/vocational plans, behavioral risk counseling, screening for depression/anxiety, and reproductive health and family planning.2,34

Adolescents need opportunities to meaningfully participate in the design and delivery of interventions to improve health.34 Meeting the adult CF team prior to transition can decrease anxiety and concern.34 In preparing for transition, it is important to assess the young person's knowledge of CF, and age-appropriate educational materials should be provided.

Patient Counseling

Patients with CF should exercise as tolerated, wash their hands, and avoid smoke. Instruct patients on the proper techniques to store and handle inhaled, oral and iv treatments, and to protect medications from light and heat, if appropriate. Attention should be paid to refrigeration requirements and ampules should be checked for leaks prior to use.12

If taking tobramycin, advise patients to inform their physician if they experience ringing in the ears, dizziness, or any changes in hearing.20 Advise patients to inform their physician if they have any history of kidney problems

because tobramycin inhalation solution is in a class of drugs that have caused kidney damage.20

Pharmacy technicians should place the auxiliary label on ibuprofen to take with food or milk, look at the patient record for any possible interactions, and make sure the patient and family are not purchasing an over-the-counter (OTC) medication with another nonsteroidal anti-inflammatory (NSAID) or aspirin in it at the same time. Watch for other OTC that may have a risk of GI bleed. Refer your observations to the pharmacist.

Patients should be asked in which order they administer inhaled medications.14 Bronchodilators, for example, are generally used before inhaling hypertonic saline or mannitol. Dornase alfa is generally used before airway clearance procedures.14

Hypertonic saline can damage electrical equipment, such as computers. Advise the patients to take hypertonic saline in a well-ventilated area away from electronics.14 Women with advanced CF contemplating pregnancy should carefully consider the risks in consultation with high-risk obstetrics and CF providers.

There are many support opportunities for families, patients, and clinicians. Table 4 provides select support resources to review and consider sharing.

Table 4: Support Resources

Next Steps

Pulmonary disease continues to account for almost 60% of CF-related mortality.2 Lung transplantation can extend and improve the quality of life of individuals with CF. Recent reports reveal that individuals with CF are experiencing an additional 9.5 years of median survival following lung transplantation.2

Cystic fibrosis research is ongoing. In one study, researchers are striving to identify children at risk of developing CF and to assess children who carry a mutation at risk of CFTR-related disorder (CFTR-RD) but remain asymptomatic during childhood.35 Another study is investigating whether the relatively low number of reported cases of COVID-19 in people with CF (pwCF) is due to enhanced infection prevention practices or whether pwCF have protective genetic/immune factors.36

Summary

Understanding pathophysiology and guidelines for treatment is important to optimize care in individuals suffering from CF. These patients require complex care. Pharmacists should carefully perform drug utilization reviews. Patient counseling is crucial. Pharmacists can provide clinicians, and patients, with the latest clinical practice recommendations and information about their drug therapy, which can help adherence and optimizing outcomes.

Course Test

Which is a common manifestation of cystic fibrosis (CF)?

Red-eyes

Trunk rash

Chronic cough

Bad breath

What is a laboratory test needed to diagnose CF?

Plasma blood glucose (mg/dl)

Low-density lipoprotein (LDL)

Serum potassium (K)

Immunoreactive trypsinogen (IRT)

What is a clinical presentation of pulmonary exacerbations (PEx)?

Increased respiratory symptoms, coughing, sputum production

Wheezing and walking 500 feet before resting

Fatigue and ability to pass the mannitol tolerance test

Hospitalization, but the quality of life is not affected

What is one recommendation for long-term maintenance of optimal lung health in patients with CF?

Clearance of airway secretions

Give tetracycline to children from ages 1-7

Increase sputum viscosity

Give lumacaftor/ivacaftor with fat-free meals

Which bacteria has been isolated in chronic infections that occur in patients with CF?

Achromonius streptus

Pseudomonas aeruginosa

Pseudomonas aureus

Achrostreptus aeruginosa

CF mainly affects which system of the body?

Nervous system

Skeletal system

Respiratory system

Urinary system

Which symptoms in a baby or young child might help identify CF?

Pale stools and ear infections

Skin that appears jaundiced and forced vital capacity (FVC) ≥90%

Frequent wheezing and no mucus

Chronic cough and thick phlegm

Which choice below is a patient counseling opportunity?

Advise that dornase alfa can damage electrical equipment

Exercise as tolerated, wash hands and avoid smoke

Ask about the history of kidney problems with hypertonic saline

Inspect capsules but not ampules for possible leaks

Which complication in CF recommends not flying or lifting weights?

Hemoptysis

Chronic rhinosinusitis

Bacterial infections

Pulmonary exacerbations

Which option below does not reflect pulmonary involvement in CF?

Clubbing and impetigo

Hemoptysis and collapsed lung

Lung infections and nasal polyps

Bronchitis and inflamed sinuses

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