Cystic Fibrosis: Persistent Cough – Symptom Introduction

Cystic Fibrosis: Persistent Cough – Symptom Introduction

1. Overview

Cystic Fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The CFTR protein encoded by this gene is a chloride ion channel primarily responsible for the transport of chloride ions and water across the surface of epithelial cells. CFTR dysfunction leads to abnormal secretions from exocrine glands, producing thick, viscous mucus, which affects multiple organ systems, including the lungs, pancreas, liver, intestines, and sweat glands. Among all affected organs, lung disease is the leading cause of morbidity and mortality in CF patients.

Persistent cough is one of the most common and characteristic respiratory symptoms in patients with cystic fibrosis, often appearing as an initial symptom early in the disease, even in the neonatal or infancy period. This cough is not a simple physiological response but a direct manifestation of the pathophysiological processes in the lungs, reflecting a vicious cycle of impaired airway mucus clearance, chronic infection, and inflammation. The abnormally viscous mucus in CF patients is difficult to expel through normal ciliary movement, leading to airway obstruction, bacterial proliferation, and persistent inflammatory responses. Cough, as the body's defense mechanism to clear foreign bodies and secretions from the airways, becomes frequent and ineffective in CF patients, instead becoming a chronic and destructive symptom. As the disease progresses, the nature of the cough changes, evolving from an initial dry cough or mild wet cough to a persistent, severe wet cough accompanied by a large amount of thick sputum, severely impacting the patient's quality of life and lung function. Therefore, a deep understanding of the etiology, pathophysiology, clinical manifestations, diagnosis, management, and prognosis of CF-related persistent cough is crucial for early identification, effective intervention, and improving long-term patient outcomes.

2. Epidemiology

Cystic fibrosis is one of the most common fatal genetic diseases in Western countries, and its epidemiological characteristics vary significantly worldwide.

Incidence and Carrier Rate:

• Caucasian Population: The incidence of CF is highest in Caucasians, approximately 1/2,500 to 1/3,500 live births. This means that in the Caucasian population, one in every 25 to 30 people is a carrier of the CFTR gene. This high carrier rate explains the relatively high incidence of CF in Caucasians.
• Other Populations: In African Americans, the incidence of CF is approximately 1/15,000 to 1/17,000 live births; in Asian populations, the incidence is even lower, about 1/30,000 to 1/90,000 live births. Nevertheless, CF is not exclusive to Caucasians and has been reported in all races and ethnicities, albeit with different incidence rates. This difference may be related to the gene pools and historical migration patterns of different populations.

Geographical Distribution: The geographical distribution of CF is highly correlated with the distribution of Caucasian populations. Regions such as North America, Europe, and Australia have higher incidence rates. However, with global population mobility and the widespread use of genetic testing technologies, more and more CF cases are being diagnosed in non-Caucasian populations, suggesting that we cannot exclude a diagnosis of CF based solely on ethnic background.

Impact of Newborn Screening: Since the late 1980s, many developed countries have gradually implemented newborn screening programs for CF. Newborn screening typically identifies affected infants early by detecting serum immunoreactive trypsinogen (IRT) levels, combined with CFTR gene mutation analysis. The widespread adoption of newborn screening has significantly changed the epidemiological landscape of CF:

• Early Diagnosis: The vast majority of CF infants can be diagnosed before the appearance of obvious symptoms, with the average age of diagnosis significantly advanced. This enables early intervention, which helps to slow disease progression, improve nutritional status, and lung function.
• Changes in Symptom Presentation: Due to early diagnosis and intervention, the incidence or severity of some traditionally considered typical initial symptoms of CF (such as meconium ileus, growth retardation) has decreased. However, persistent cough, as an early indicator of lung disease, remains a key focus for clinicians.
• Improved Survival Rate: Advances in early diagnosis and multidisciplinary comprehensive treatment have significantly extended the life expectancy of CF patients. In the 1980s, the average life expectancy for CF patients was only in their 20s, whereas now, the median survival age for CF patients in many developed countries has exceeded 40 years and continues to improve.

Epidemiological Characteristics of Persistent Cough:

• Age of Onset: Persistent cough typically appears very early in CF patients, with about half of CF infants developing cough symptoms before 1 year of age, and by school age, almost all CF children will have some degree of chronic cough.
• Disease Burden: Cough is one of the most common symptoms in CF patients and a significant factor contributing to reduced quality of life, sleep disturbances, and social difficulties. As the disease progresses, the frequency and severity of cough are often closely related to declining lung function, worsening infection, and acute exacerbation events.
• Association with Genotype: Certain CFTR gene mutation types (such as F508del homozygotes) are usually associated with more severe phenotypes and earlier onset of lung symptoms (including cough). However, even mutation types with residual CFTR function can develop chronic lung disease and persistent cough.

In summary, the epidemiology of cystic fibrosis is evolving with advances in diagnosis and treatment. Persistent cough, as a core symptom of CF lung disease, its high incidence early in patients' lives and its profound impact on their quality of life, make it an undeniable focus in clinical practice.

3. Etiology/Pathophysiology

The etiology of cystic fibrosis is rooted in gene mutations, while its pathophysiology is a complex multi-system cascade reaction that ultimately leads to lung disease characterized by persistent cough.

3.1 Genetic Basis

• CFTR Gene Mutation: Cystic fibrosis is an autosomal recessive genetic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, located on the long arm of chromosome 7 (7q31.2). Patients must inherit one mutated gene from each parent to develop the disease. If only one mutated gene is inherited, the individual is an asymptomatic carrier.
• CFTR Protein Function: The CFTR protein encoded by the CFTR gene is a member of the ATP-binding cassette (ABC) transporter family, primarily functioning as a chloride ion channel that regulates the transmembrane transport of chloride ions, bicarbonate ions, and water across the surface of epithelial cells. It is expressed in glandular epithelial cells of multiple organs, including the lungs, pancreas, liver, intestines, sweat glands, and reproductive system.
• Mutation Types and Classification: Over 2000 CFTR gene mutations have been identified, which can be classified into six classes based on their impact on CFTR protein function:
  • Class I (No Synthesis): Leads to complete absence of CFTR protein synthesis (e.g., frameshift mutations, nonsense mutations).
  • Class II (Processing Defects): Leads to misfolding of the CFTR protein after synthesis, preventing its transport to the cell membrane surface (e.g., the most common F508del mutation).
  • Class III (Gating Defects): CFTR protein reaches the cell membrane, but its chloride ion channel opening and closing function is impaired (e.g., G551D mutation).
  • Class IV (Conductance Defects): The ability of the CFTR protein channel to conduct chloride ions is reduced.
  • Class V (Reduced Synthesis): The amount of CFTR protein synthesized is reduced.
  • Class VI (Stability Defects): CFTR protein is unstable on the cell membrane and undergoes premature degradation.
  • Different mutation types lead to varying degrees of CFTR protein dysfunction, thereby affecting disease severity and clinical phenotype.

3.2 Respiratory System Pathophysiology (Mechanisms Leading to Persistent Cough) CFTR protein dysfunction in respiratory epithelial cells triggers a series of pathophysiological changes, ultimately forming a vicious cycle that leads to persistent cough and progressive lung damage.

• Airway Surface Liquid (ASL) Dehydration:

  • Normal CFTR protein maintains the appropriate volume and ion composition of the airway surface liquid (ASL) by secreting chloride and bicarbonate ions and inhibiting the absorption of sodium ions by the epithelial sodium channel (ENaC). ASL is a thin layer of fluid covering the airway epithelial cells, divided into a gel layer and a sol layer, and is crucial for ciliary movement and mucus clearance.
  • In CF patients, dysfunctional CFTR protein leads to reduced chloride secretion, while the excessive absorption of sodium ions by ENaC is not inhibited. This causes water molecules to be passively absorbed from the ASL into the epithelial cells, leading to a reduced ASL volume, making it highly concentrated and dehydrated.
  • Dehydrated ASL makes the overlying mucus layer abnormally viscous and less elastic.

• Mucociliary Clearance Dysfunction:

  • The normal mucociliary clearance system relies on the coordinated beating of cilia and the appropriate viscoelasticity of mucus to clear inhaled particles, pathogens, and cellular debris from the airways.
  • In CF patients, the viscous mucus layer adheres tightly to the cilia, even flattening them, preventing effective beating. This leads to severely impaired mucociliary clearance, and secretions in the airways cannot be effectively expelled.
  • Mucus retention in the airways forms mucus plugs, obstructing small airways, leading to distal airway collapse, air trapping, and atelectasis.

• Chronic Bacterial Infection:

  • Retained viscous mucus provides an ideal growth environment for bacteria. At the same time, CFTR dysfunction may directly affect host defense against bacteria, for example, by influencing the secretion of antimicrobial peptides or regulating immune cell function.
  • The respiratory tract of CF patients is highly susceptible to bacterial colonization. Common pathogens include:
    • Early: Staphylococcus aureus, Haemophilus influenzae.
    • Late or Progressive: Pseudomonas aeruginosa is the most destructive pathogen in CF lung disease; once colonized, it is often difficult to eradicate and forms biofilms, making it resistant to antimicrobial drugs.
    • Others: Burkholderia cepacia complex, Non-tuberculous mycobacteria (NTM), etc.
  • Chronic bacterial infection is a key driving factor in the progression of CF lung disease.

• Persistent Inflammatory Response:

  • Chronic bacterial infection and mucus retention continuously stimulate the host immune system, triggering a strong inflammatory response. The inflammatory response in CF patients typically manifests as an overactive neutrophil infiltration.
  • Neutrophils release large amounts of inflammatory mediators (e.g., elastase, myeloperoxidase, cytokines) and DNA. These substances further damage airway epithelial cells and lung tissue, exacerbate mucus viscosity (DNA is an important component of mucus viscosity), and impair ciliary function.
  • The inflammatory response itself also irritates the airways, leading to airway hyperresponsiveness, further aggravating the cough.

• Bronchiectasis:

  • Long-term mucus obstruction, chronic infection, and persistent inflammatory response collectively lead to progressive destruction of the airway wall structure. Elastic fibers and cartilage are degraded, and the airway walls thin and dilate, forming irreversible bronchiectasis.
  • Bronchiectasis further exacerbates mucus clearance dysfunction, as dilated airways lose their normal clearance ability, forming more areas of mucus retention, thus creating a vicious cycle: mucus retention → infection → inflammation → airway damage → bronchiectasis → more mucus retention.

• Stimulation of Cough Reflex:

  • Abnormally viscous mucus, bacteria, inflammatory mediators, and damaged airway epithelial cells in the airways continuously stimulate cough receptors.
  • Cough is a defensive reflex by which the body attempts to clear these irritants. However, in CF patients, due to the excessively viscous mucus and impaired ciliary function, coughing is often inefficient and cannot effectively clear secretions.
  • This ineffective cough becomes frequent and severe, becoming a chronic symptom, and may lead to increased airway pressure, further aggravating airway damage.

In summary, the pathophysiology of CF is a complex vicious cycle initiated by CFTR gene mutations, involving airway surface liquid dehydration, mucociliary clearance dysfunction, chronic bacterial infection, persistent inflammatory response, and bronchiectasis. Persistent cough is a direct clinical manifestation of this series of pathophysiological processes, reflecting the continuous progression of lung damage.

4. Clinical Presentation

The clinical presentation of cystic fibrosis is multi-systemic, but persistent cough, as a core symptom of lung disease, is often the main reason for patients to seek medical attention and an important indicator of disease progression.

4.1 Characteristics of Persistent Cough The cough in CF patients has its unique nature and evolutionary process:

• Early Manifestation: In the early stages of the disease, especially in infants and preschool children, the cough may be intermittent, dry, or mildly wet, often misdiagnosed as a common cold, bronchitis, or asthma. Children may experience recurrent respiratory infections, with cough persisting after each infection.
• Progressive Manifestation: As the disease progresses, the cough becomes more frequent, severe, and persistent. It is usually a wet cough, accompanied by a large amount of viscous, thick sputum.
  • Sputum Characteristics: Sputum is typically white, yellow, green, or brown, especially during infection exacerbations, when it becomes even thicker and purulent. Sputum volume can range from small amounts to hundreds of milliliters daily.
  • Cough Rhythm: Cough often occurs in paroxysms, especially upon waking in the morning, after physical activity, or during nighttime sleep. Patients may require prolonged, severe coughing to expel a small amount of sputum.
  • Associated Symptoms: Severe coughing can lead to chest pain, abdominal pain, vomiting, and even cause rib fractures or pneumothorax.
  • Hemoptysis: With the progression of bronchiectasis and damage to airway wall blood vessels, hemoptysis is a common complication in advanced CF patients. The amount of hemoptysis can range from blood-streaked sputum to massive hemoptysis, the latter potentially life-threatening.
• Impact on Quality of Life: Persistent cough severely affects patients' sleep quality, ability to study and work, social activities, and mental health. Patients may feel fatigued, embarrassed, and frustrated due to the cough.

4.2 Other Respiratory Symptoms In addition to persistent cough, CF patients may also experience the following respiratory symptoms:

• Recurrent Respiratory Infections: Frequent bronchitis, pneumonia, and sinusitis. These infections often persist and require repeated antibiotic use.
• Wheezing and Dyspnea: Airway obstruction and inflammation can lead to wheezing and dyspnea, especially during exercise or infection. Some patients may be misdiagnosed with asthma.
• Nasal Polyps and Chronic Sinusitis: The nasal and sinus mucosa of CF patients are also affected, leading to a significantly higher incidence of chronic sinusitis and nasal polyps than in the general population. Symptoms include nasal congestion, rhinorrhea, facial pain, and reduced sense of smell.
• Clubbing: A sign of long-term chronic hypoxia, characterized by thickening and enlargement of the fingertips or toes, and increased curvature of the nails.
• Barrel Chest: Long-term airway obstruction leads to lung hyperinflation, increasing the anteroposterior diameter of the chest, forming a barrel chest.
• Pneumothorax: Rupture of bullae can lead to pneumothorax, causing sudden chest pain and dyspnea.
• Respiratory Failure: Advanced lung disease can progress to chronic respiratory failure, manifesting as progressive dyspnea, cyanosis, and hypercapnia.

4.3 Non-Respiratory Symptoms CF is a multi-systemic disease, and in addition to respiratory symptoms, it is often accompanied by the following non-respiratory manifestations:

• Digestive System:
  • Pancreatic Insufficiency: Approximately 85-90% of CF patients have exocrine pancreatic insufficiency, leading to malabsorption of fats, proteins, and fat-soluble vitamins (A, D, E, K). Clinical manifestations include steatorrhea (bulky, greasy, foul-smelling stools), abdominal distension, abdominal pain, and malnutrition.
  • Growth Retardation: Due to impaired nutrient absorption and chronic inflammatory consumption, children often exhibit failure to thrive, slow height growth, and even developmental delay.
  • Meconium Ileus: Approximately 10-20% of newborn CF patients present with meconium ileus at birth, characterized by failure to pass meconium after birth, abdominal distension, and vomiting.
  • Distal Intestinal Obstruction Syndrome (DIOS): Occurs in children and adult CF patients due to viscous intestinal contents, leading to partial or complete obstruction of the the ileocecal region or distal colon.
  • Cystic Fibrosis-Related Diabetes (CFRD): Impaired pancreatic endocrine function leads to insufficient insulin secretion, usually developing in adolescence or adulthood.
  • Hepatobiliary Disease: Viscous bile leads to cholestasis, biliary cirrhosis, intrahepatic bile duct dilation, which can progress to focal biliary cirrhosis and even portal hypertension.
• Sweat Glands: CFTR dysfunction leads to elevated sodium chloride concentration in sweat, making the patient's skin taste salty. This is an important diagnostic clue for CF.
• Reproductive System:
  • Male Infertility: Approximately 95% of male CF patients have congenital bilateral absence of the vas deferens (CBAVD), preventing sperm expulsion and causing obstructive azoospermia.
  • Female Subfertility: Female CF patients may experience reduced fertility due to viscous cervical mucus, malnutrition, and chronic lung disease, but they can still conceive.
• Skeletal System: Chronic inflammation, malnutrition, and vitamin D deficiency can lead to osteoporosis and increased fracture risk.
• Others: Arthritis, kidney stones, etc.

The clinical manifestations of CF are highly heterogeneous; even patients with the same genotype may have different symptom severity and affected organs. However, persistent cough, as a hallmark of lung disease, runs throughout the course of CF patients and is a key indicator for assessing disease progression and treatment effectiveness.

5. Diagnosis

The diagnosis of cystic fibrosis requires a combination of clinical symptoms, family history, newborn screening results, and specific laboratory tests. For patients with persistent cough, especially those with high-risk factors for CF, the diagnosis of CF should be actively considered.

5.1 Diagnostic Clues

• Positive Newborn Screening: Many countries have included CF in newborn screening programs. Screening typically detects serum immunoreactive trypsinogen (IRT) levels; if IRT is elevated, further CFTR gene mutation analysis is performed.
• Clinical Symptoms: CF should be highly suspected when any one or more of the following typical symptoms appear:
  • Persistent cough, accompanied by viscous sputum and recurrent respiratory infections.
  • Growth retardation, failure to thrive, steatorrhea.
  • Meconium ileus or distal intestinal obstruction syndrome.
  • Chronic sinusitis, nasal polyps.
  • Male infertility (congenital bilateral absence of the vas deferens).
  • Family history (presence of CF patients or CFTR gene carriers).
  • Salty-tasting skin.

5.2 Confirmatory Tests

5.2.1 Sweat Chloride Test This is the "gold standard" for diagnosing CF, assessing CFTR function by measuring chloride ion concentration in sweat.

• Principle: The CFTR protein is responsible for reabsorbing chloride ions in the sweat gland duct; its dysfunction leads to reduced chloride ion reabsorption in sweat, thus increasing sweat chloride concentration.
• Method: The most commonly used method is pilocarpine iontophoresis, which stimulates sweat gland secretion by local application of pilocarpine, then collects sweat and measures chloride concentration.
• Interpretation of Results:
  • Normal: Sweat chloride concentration < 30 mmol/L.
  • Intermediate: 30-59 mmol/L. Results in this range require further evaluation in conjunction with genetic testing or other auxiliary examinations.
  • Diagnostic: ≥ 60 mmol/L. Usually, two independent test results meeting this standard are sufficient for diagnosis.
• Precautions: The test should be performed by experienced technicians, ensuring sufficient sweat volume is collected (at least 50-75 mg). In the neonatal period, due to immature sweat gland function, the sweat chloride test may yield false negatives; it is usually recommended to perform it after 2 weeks of age or when the weight reaches 2 kg.

5.2.2 CFTR Gene Mutation Analysis

• Principle: Directly detects the presence of pathogenic mutations in the CFTR gene.
• Method: Analyzes the patient's CFTR gene using techniques such as polymerase chain reaction (PCR) and sequencing.
• Role:
  • Diagnosis: Identification of two pathogenic CFTR mutations confirms CF.
  • Guiding Treatment: Certain mutation types (e.g., G551D, F508del) can guide the selection of CFTR modulators.
  • Prognostic Assessment: Certain mutation types are associated with disease severity.
  • Genetic Counseling: Provides genetic risk assessment for the patient's family.
• Limitations: Even with testing for the most common mutations, a small number of patients may carry rare or undiscovered mutations, leading to negative genetic test results despite high clinical suspicion of CF.

5.2.3 Nasal Potential Difference (NPD) Measurement

• Principle: Measures the transepithelial potential difference across nasal epithelial cells, reflecting chloride and sodium ion transport function. CFTR dysfunction leads to abnormal NPD.
• Role: Primarily used for difficult cases with uncertain sweat chloride test results or unclear genetic test results, as well as for research purposes.
• Limitations: Technically complex, performed only in a few specialized centers.

5.2.4 Intestinal Current Measurement (ICM)

• Principle: Measures the response of rectal biopsy tissue to chloride ion secretion stimulation in vitro, assessing CFTR function.
• Role: Similar to NPD, used for diagnosing difficult cases.

5.3 Auxiliary Examinations (Assessing Disease Severity and Complications)

5.3.1 Imaging Studies

• Chest X-ray: May be normal in early stages or show only increased bronchovascular markings. In advanced stages, lung hyperinflation, bronchial wall thickening ("tram-track sign"), atelectasis, mucus plugging, and bronchiectasis may be seen.
• High-Resolution CT (HRCT) Scan: The most sensitive imaging test for CF lung lesions. Can detect early bronchiectasis, bronchial wall thickening, mucus plugging, centrilobular nodules, mosaic perfusion (suggesting air trapping), and bullae. HRCT is valuable in assessing disease progression and guiding treatment.
• Abdominal Ultrasound/CT: Evaluates liver, pancreas, and biliary tract lesions.

5.3.2 Pulmonary Function Tests (PFTs)

• Role: Assesses the degree of airway obstruction, lung volumes, and gas exchange function, and is a key indicator for monitoring CF lung disease progression and treatment effectiveness.
• Common Manifestations:
  • Obstructive Ventilatory Defect: Characterized by decreased forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. FEV1 is the most commonly used indicator for assessing CF lung function.
  • Air Trapping: Characterized by increased residual volume (RV) and functional residual capacity (FRC).
  • Restrictive Ventilatory Defect: Late-stage pulmonary fibrosis or chest wall deformities may lead to restrictive ventilatory defects.
• Precautions: Must be performed when the child can cooperate, usually applicable to children over 6 years old and adults.

5.3.3 Microbiological Examination

• Sputum Culture: Regular sputum cultures (or throat swabs, bronchoalveolar lavage fluid cultures) are performed to identify colonizing pathogens in the airways and guide antibiotic treatment. Common pathogens include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia complex, and non-tuberculous mycobacteria.
• Antimicrobial Susceptibility Testing: Performed on isolated pathogens to select sensitive antibiotics.

5.3.4 Nutritional Assessment

• Growth Indicators: Regular monitoring of height, weight, body mass index (BMI).
• Serum Vitamin Levels: Measurement of fat-soluble vitamin (A, D, E, K) levels.
• Fecal Elastase-1: Assesses exocrine pancreatic function; levels below 200 μg/g stool suggest pancreatic insufficiency.

5.3.5 Blood Glucose Monitoring: Regular screening for cystic fibrosis-related diabetes (CFRD).

By combining the above diagnostic methods, patients with persistent cough, especially those with other typical CF symptoms or high-risk factors, should undergo a comprehensive evaluation to ensure early diagnosis and initiation of standardized treatment.

6. Management/Treatment

The treatment and management of cystic fibrosis is a complex, multidisciplinary, lifelong process aimed at controlling symptoms, preventing complications, slowing disease progression, improving quality of life, and extending life expectancy. For persistent cough, a core symptom, treatment strategies primarily focus on clearing airway mucus, controlling infection, and reducing inflammation.

6.1 Multidisciplinary Team Collaboration CF management requires a multidisciplinary team consisting of pediatricians/adult pulmonologists, gastroenterologists, dietitians, physical therapists, respiratory therapists, social workers, psychologists, genetic counselors, and nurses.

6.2 Airway Clearance Therapies (ACTs) ACTs are fundamental to CF lung disease management, aiming to help patients clear viscous sputum from the airways, reduce airway obstruction, and thus alleviate cough.

• Chest Physiotherapy (CPT): Traditional CPT includes postural drainage, percussion, and vibration. By changing body positions, gravity drains secretions from different lung segments, combined with percussion and vibration to help loosen mucus.
• Mechanical Assisted Secretion Clearance Devices:
  • High-Frequency Chest Wall Oscillation (HFCWO): Patients wear an oscillating vest connected to an air pulse generator, which generates high-frequency oscillations to loosen mucus from the airway walls.
  • Positive Expiratory Pressure (PEP) Devices: Patients exhale through a device with resistance, creating positive pressure at the end of exhalation, which helps open collapsed airways and move mucus towards larger airways.
  • Oscillating PEP Devices (Flutter Valve, Acapella, etc.): Combine PEP with high-frequency oscillation, generating vibrations during exhalation to help loosen mucus.
• Autogenic Drainage (AD): Patients control breathing depth and speed to breathe at different lung volumes to mobilize mucus.
• Active Cycle of Breathing Technique (ACBT): Combines deep breathing, thoracic expansion exercises, and forced expiratory techniques to clear secretions.
• Exercise: Aerobic exercise (e.g., running, swimming) helps increase breathing depth and frequency, promoting mucus clearance.

6.3 Mucolytics Used to reduce sputum viscosity, making it easier to cough up.

• Recombinant Human Deoxyribonuclease (Dornase alfa): Reduces sputum viscosity by hydrolyzing DNA released by neutrophils in sputum. Usually administered once daily by nebulization.
• Hypertonic Saline (7%): Nebulized hypertonic saline can increase the osmotic pressure of the airway surface liquid, drawing water into the airways, thereby diluting mucus and improving ciliary clearance function. Usually administered twice daily by nebulization.

6.4 Antibiotic Treatment Used to treat and prevent respiratory infections, which are a major cause of worsening cough and declining lung function.

• Acute Exacerbation: Based on sputum culture and susceptibility results, sensitive oral, intravenous, or nebulized antibiotics are selected. High doses and long courses are usually required.
• Chronic Suppressive Therapy:
  • Nebulized Antibiotics: For patients with chronic Pseudomonas aeruginosa infection, regular (e.g., 28 days on, 28 days off each month) nebulized tobramycin, aztreonam, or colistin can effectively suppress bacterial growth, reduce the frequency of acute exacerbations, and slow lung function decline.
  • Oral Macrolide Antibiotics: Such as azithromycin, taken orally three times a week, have anti-inflammatory and anti-pseudomonal biofilm formation effects, which can reduce acute exacerbations.
• Prophylactic Antibiotics: Children with early Staphylococcus aureus infection may require prophylactic oral antibiotics.

6.5 Anti-inflammatory Treatment Aims to reduce excessive inflammatory responses in the airways.

• Ibuprofen: High-dose long-term oral ibuprofen has been shown to slow the decline in lung function in children with CF, possibly by inhibiting neutrophil function.
• Corticosteroids: Oral or inhaled corticosteroids are generally not used as routine long-term treatment but may be used short-term during acute exacerbations or in patients with airway hyperresponsiveness.

6.6 Bronchodilators

• β2-agonists (e.g., salbutamol): Administered via nebulizer or inhaler, they relax airway smooth muscles, dilate airways, and improve ventilation. Especially useful for patients with airway hyperresponsiveness or wheezing.

6.7 CFTR Modulators These represent a revolutionary advance in CF treatment, directly targeting the functional defects of the CFTR protein.

• Mechanism of Action:
  • Potentiators: Such as ivacaftor, improve chloride transport by increasing the opening time of the CFTR channel, applicable to patients with gating defect mutations (e.g., G551D).
  • Correctors: Such as lumacaftor, tezacaftor, elexacaftor, help misfolded CFTR protein to fold correctly and traffic to the cell membrane surface, applicable to patients with processing defect mutations (e.g., F508del).
• Combination Therapy: The most effective treatment regimens currently involve the combined use of correctors and potentiators, such as the elexacaftor/tezacaftor/ivacaftor triple therapy (Trikafta/Kaftrio), applicable to patients carrying at least one F508del mutation or other specific mutations.
• Effects: CFTR modulators significantly improve lung function (FEV1), reduce the frequency of acute exacerbations, and improve nutritional status and quality of life. They fundamentally correct CFTR dysfunction, thereby alleviating the underlying cause of persistent cough.

6.8 Nutritional Support

• Pancreatic Enzyme Replacement Therapy (PERT): Pancreatic enzyme preparations are taken with meals to supplement exocrine pancreatic insufficiency and improve the absorption of fats, proteins, and fat-soluble vitamins.
• High-Calorie, High-Fat Diet: Patients are encouraged to consume a high-calorie, high-fat diet to meet their high metabolic demands and compensate for malabsorption.
• Fat-Soluble Vitamin Supplementation: Supplementation with vitamins A, D, E, K.
• Salt Supplementation: Especially in hot weather or after strenuous exercise, salt supplementation is needed to compensate for excessive salt loss in sweat.

6.9 Complication Management

• Cystic Fibrosis-Related Diabetes (CFRD): Insulin therapy.
• Liver Disease: Ursodeoxycholic acid may help improve bile flow.
• Nasal Polyps: Nasal corticosteroid sprays, surgical removal if necessary.
• Hemoptysis: Small amounts of hemoptysis can be managed conservatively; massive hemoptysis may require bronchial artery embolization.
• Pneumothorax: Chest tube drainage; recurrent episodes may require pleurodesis.
• Lung Transplant: For patients with advanced, irreversible lung disease and respiratory failure, lung transplantation is the only curative option.

CF treatment is a dynamic process that requires individualized management based on the patient's age, genotype, disease severity, complications, and response to treatment. The alleviation of persistent cough is one of the important indicators for assessing treatment effectiveness.

7. Rehabilitation/Patient Education

Rehabilitation and patient education for cystic fibrosis are crucial components of comprehensive management, aiming to enhance patients' self-management abilities, improve quality of life, and promote long-term health. For patients with persistent cough, rehabilitation and education are particularly critical as they directly impact adherence to airway clearance and understanding of the disease.

7.1 Rehabilitation Therapy

• Physical Therapy and Exercise Rehabilitation:
  • Purpose: To maintain and improve lung function, enhance cardiorespiratory endurance, promote mucus clearance, and improve posture.
  • Content:
    • Regular Exercise: Patients are encouraged to engage in regular aerobic exercise (e.g., running, swimming, cycling) and strength training. Exercise itself is an effective airway clearance method, aiding deep breathing and coughing to expel sputum.
    • Breathing Exercises: Teaching breathing techniques such as diaphragmatic breathing and pursed-lip breathing to improve ventilation efficiency and reduce the work of breathing.
    • Posture Correction: Correcting poor posture, such as kyphosis, which may result from chronic lung disease, to improve chest wall mobility.
    • Chest Expansion Exercises: Maintaining chest wall flexibility and increasing lung capacity.
  • Individualized Programs: Rehabilitation programs should be tailored to the patient's age, lung function, physical condition, and interests.
• Nutritional Rehabilitation:
  • Purpose: To correct malnutrition, promote growth and development, maintain ideal weight, and enhance immunity.
  • Content:
    • High-Calorie, High-Fat Diet Guidance: Dietitians will develop detailed dietary plans based on the patient's specific situation to ensure adequate energy and nutrient intake.
    • Pancreatic Enzyme Replacement Therapy Adherence Education: Emphasizing the correct method of taking enzyme preparations (with meals, dose adjustment) and their importance.
    • Fat-Soluble Vitamin and Salt Supplementation Guidance: Informing patients about the necessity and dosage of vitamin and salt supplementation.
    • Monitoring and Adjustment: Regularly assessing nutritional status (weight, height, BMI, serum vitamin levels) and adjusting diet and supplementation as needed.
• Psychological Rehabilitation:
  • Purpose: To cope with psychological stress, anxiety, and depression caused by chronic illness, improve mood, and enhance quality of life.
  • Content:
    • Psychological Counseling and Support: Providing individual or group psychological counseling to help patients and families cope with the challenges of the disease.
    • Peer Support: Encouraging patients to participate in CF patient support groups to share experiences and receive emotional support.
    • Coping Strategies: Teaching stress management, relaxation techniques, and positive coping methods for the disease.

7.2 Patient Education Patient education is central to CF management, aiming to ensure patients and families fully understand the disease, master self-management skills, and actively participate in treatment decisions.

• Disease Knowledge Education:
  • Basic Concepts of CF: Explaining the genetic basis of CF, CFTR gene mutations, and the characteristics of multi-system involvement.
  • Pathophysiology of Lung Disease: Detailed explanation of the vicious cycle of mucus clearance dysfunction, infection, and inflammation, and how they lead to persistent cough and lung function decline.
  • Other Organ Involvement: Introducing the mechanisms and clinical manifestations of pancreatic, liver, intestinal, sweat gland, and reproductive system involvement.
• Treatment Plan Education:
  • Airway Clearance Techniques: Detailed demonstration and guidance on the correct operation of various ACTs, emphasizing their importance and regularity. Patients and families need to master these techniques and integrate them into daily life.
  • Medication Treatment: Explaining the mechanism of action, usage, dosage, side effects, and precautions for each medication (antibiotics, mucolytics, bronchodilators, CFTR modulators, pancreatic enzymes, vitamins). Emphasizing the importance of taking medication on time and as prescribed.
  • Expectations vs. Reality of CFTR Modulators: Informing patients about the significant benefits of CFTR modulators, but also clarifying that they are not a "cure" and other conventional treatments still need to be adhered to.
• Infection Control Education:
  • Hand Hygiene: Emphasizing the importance of frequent hand washing to reduce pathogen transmission.
  • Avoiding Cross-Infection: Advising patients to avoid close contact with individuals suffering from respiratory infections. In CF centers, different patients should maintain distance to prevent cross-transmission of specific pathogens (e.g., Pseudomonas aeruginosa, Burkholderia cepacia).
  • Vaccination: Emphasizing the importance of receiving influenza vaccines, pneumococcal vaccines, etc., to prevent common respiratory infections.
• Nutritional Management Education:
  • Dietary Principles: Emphasizing the importance of a high-calorie, high-fat diet and providing specific dietary recommendations.
  • Pancreatic Enzyme Dosing Techniques: Teaching how to adjust enzyme dosage based on food type and quantity, and how to handle missed enzyme doses.
  • Hydration and Salt Supplementation: Emphasizing the importance of adequate fluid intake and salt supplementation in special circumstances.
• Monitoring and Follow-up Education:
  • Symptom Monitoring: Educating patients and families to recognize signs of acute exacerbation (e.g., worsening cough, increased sputum volume, change in sputum color, fever, increased dyspnea, decreased appetite) and seek timely medical attention.
  • Regular Follow-up: Emphasizing the importance of regular comprehensive evaluations at a CF center, including lung function tests, sputum cultures, and nutritional assessments.
• Genetic Counseling: Providing genetic counseling to patients and their families, explaining CF inheritance patterns, reproductive risks, and options such as prenatal diagnosis and preimplantation genetic diagnosis (PGD).
• Transition Care: For adolescent CF patients, structured transition care education is needed to help them smoothly transition from pediatric to adult care and develop the ability to independently manage their disease.

Through comprehensive rehabilitation and patient education, CF patients can better understand and manage their disease, actively cope with the challenges of persistent cough, thereby improving treatment adherence, long-term prognosis, and quality of life.

8. Prognosis

The prognosis of cystic fibrosis has significantly improved over the past few decades, but it remains a progressive, life-threatening disease. Prognosis is influenced by multiple factors, including genotype, age at diagnosis, disease severity, treatment adherence, and the occurrence of complications.

8.1 History and Current Status

• Historical Prognosis: In the 1950s, few children with CF survived past school age. By the 1980s, the average life expectancy increased to the 20s.
• Current Prognosis: With the widespread adoption of newborn screening, advances in multidisciplinary comprehensive treatment (including airway clearance techniques, antibiotics, mucolytics, nutritional support), and the advent of CFTR modulators, the prognosis for CF patients has greatly improved. In developed countries, the median survival age for CF patients has exceeded 40 years and continues to extend. Many patients are able to complete their education, work, and start families.

8.2 Main Factors Affecting Prognosis

8.2.1 Severity and Progression of Lung Disease

• Lung Function: Lung function (especially FEV1) is the most important prognostic predictor for CF. A sustained decline in FEV1 indicates a poor prognosis.
• Chronic Infection: Chronic Pseudomonas aeruginosa infection is closely associated with accelerated lung function decline and poor prognosis. Burkholderia cepacia complex infection usually indicates an even worse prognosis.
• Frequency of Acute Exacerbations: Frequent pulmonary acute exacerbations lead to irreversible decline in lung function, accelerating disease progression.
• Bronchiectasis: Extensive bronchiectasis is a hallmark of impaired lung function and recurrent infections.
• Hemoptysis and Pneumothorax: Severe hemoptysis and recurrent pneumothorax are complications of advanced lung disease and can be life-threatening.

8.2.2 Genotype

• CFTR Mutation Type: Mutations with severe CFTR functional defects (e.g., Class I, II, III mutations, especially F508del homozygotes) are generally associated with more severe phenotypes and worse prognosis. Mutations with residual CFTR function (e.g., Class IV, V mutations) may lead to milder disease, sometimes diagnosed only in adulthood.
• Applicability of CFTR Modulators: Patients who can use CFTR modulators have significantly improved prognoses because these drugs directly correct the functional defects of the CFTR protein.

8.2.3 Nutritional Status

• Body Mass Index (BMI): Good nutritional status (maintaining a healthy BMI) is associated with better lung function and longer survival. Malnutrition weakens immune function and exacerbates lung infections and inflammation.
• Pancreatic Function: Patients with exocrine pancreatic insufficiency are prone to malnutrition if they do not receive adequate pancreatic enzyme replacement therapy.

8.2.4 Age at Diagnosis and Early Intervention

• Newborn Screening: Early diagnosis (through newborn screening) and early initiation of comprehensive treatment can delay the onset and progression of lung disease, improve nutritional status, and thus improve long-term prognosis.

8.2.5 Treatment Adherence

• Patient adherence to airway clearance therapy, medication (antibiotics, mucolytics, CFTR modulators), and nutritional support is a critical factor influencing prognosis. Poor adherence leads to accelerated disease progression.

8.2.6 Complications

• Cystic Fibrosis-Related Diabetes (CFRD): The occurrence of CFRD is associated with accelerated lung function decline and reduced survival.
• Liver Disease: Severe liver disease (e.g., cirrhosis, portal hypertension) increases the risk of complications and mortality.
• Pulmonary Hypertension and Right Heart Failure: Advanced lung disease can lead to pulmonary hypertension and right heart failure, further worsening the prognosis.

8.3 Causes of Death Despite significant improvements in prognosis, the primary cause of death in CF patients remains respiratory failure due to progressive lung disease. Other causes of death include lung transplant complications, severe infections, hemoptysis, and liver complications.

8.4 Outlook With the widespread use of CFTR modulators and the continuous development of new drugs, as well as the exploration of cutting-edge technologies such as gene therapy, the prognosis for CF patients is expected to improve further. The future goal is to make CF a manageable chronic disease, allowing patients to have a near-normal life expectancy and quality of life.

9. Prevention

The prevention of cystic fibrosis is mainly divided into two levels: primary prevention (preventing the occurrence of the disease) and secondary prevention (early diagnosis and intervention to prevent disease progression or reduce its severity).

9.1 Primary Prevention (Preventing Disease Occurrence)

Primary prevention primarily targets couples with a family history of CF or known CFTR gene carriers, aiming to reduce the risk of affected children through genetic counseling and reproductive choices.

• Genetic Counseling:
  • Purpose: To provide individuals with a family history of CF, CF patients and their partners, or couples known to be CFTR gene carriers with detailed information about CF inheritance patterns, recurrence risk, testing options, and reproductive choices.
  • Content: Explaining that CF is an autosomal recessive disorder, and if both parents are carriers, there is a 25% chance of having an affected child, a 50% chance of having a carrier child, and a 25% chance of having a non-carrier child with each pregnancy.
• Carrier Screening:
  • Purpose: To identify asymptomatic CFTR gene carriers, especially in Caucasian populations where the carrier rate is higher.
  • Method: Genetic testing to analyze common CFTR gene mutations. For couples planning a family, carrier screening is recommended; if both are carriers, further reproductive options can be considered.
• Prenatal Diagnosis:
  • Purpose: For high-risk couples where both parents are known CFTR gene carriers, to diagnose whether the fetus has CF during pregnancy.
  • Methods:
    • Chorionic Villus Sampling (CVS): Usually performed at 10-13 weeks of gestation, placental villus tissue is taken for genetic testing.
    • Amniocentesis: Usually performed at 15-20 weeks of gestation, amniotic fluid is drawn for genetic testing of fetal cells.
  • Ethical Considerations: If prenatal diagnosis results are positive, couples can choose to terminate the pregnancy or prepare for the birth of an affected child. This involves complex ethical, moral, and personal choices.
• Preimplantation Genetic Diagnosis (PGD):
  • Purpose: For high-risk couples conceiving through in vitro fertilization (IVF), to perform genetic testing on embryos before implantation into the uterus, selecting embryos that do not carry CFTR mutations or are only carriers for implantation.
  • Method: A small number of cells are taken from early embryos formed by in vitro fertilization for genetic testing.
  • Advantage: Avoids the ethical dilemma of pregnancy termination after prenatal diagnosis.

9.2 Secondary Prevention (Early Diagnosis and Intervention to Prevent Disease Progression or Reduce its Severity)

Secondary prevention aims to minimize the impact of the disease on patient health through early detection and active management.

• Newborn Screening:
  • Purpose: To diagnose CF early before the onset of symptoms.
  • Method: Typically detects serum immunoreactive trypsinogen (IRT) levels; if elevated, further CFTR gene mutation analysis is performed.
  • Benefits: Early diagnosis enables early intervention, including:
    • Early Nutritional Support: Timely supplementation with pancreatic enzymes and fat-soluble vitamins to prevent malnutrition and growth retardation.
    • Early Airway Clearance Therapy: Initiating airway clearance even when symptoms are not obvious helps prevent mucus retention and infection.
    • Early Antibiotic Treatment: Timely detection and treatment of respiratory infections to delay the establishment of chronic infection.
    • Early Application of CFTR Modulators: For eligible patients, early use of CFTR modulators can fundamentally improve CFTR function and significantly slow disease progression.
  • Results: Newborn screening has been shown to improve nutritional status, lung function, and long-term survival in CF patients.
• Prevention of Respiratory Infections:
  • Vaccination: CF patients are advised to receive routine childhood vaccinations on time, and annual influenza vaccines, and pneumococcal vaccines every 5 years, to prevent common respiratory infections.
  • Infection Control Measures: Emphasizing good hand hygiene practices and avoiding close contact with individuals suffering from respiratory infections. In CF centers, different patients should maintain distance to avoid cross-infection.
  • Chronic Suppressive Antibiotics: For patients with established chronic Pseudomonas aeruginosa infection, regular nebulized antibiotics can effectively suppress bacterial growth and reduce acute exacerbations.
• Nutritional Optimization:
  • Pancreatic Enzyme Replacement Therapy: Ensuring patients with exocrine pancreatic insufficiency receive adequate and correct pancreatic enzyme replacement therapy.
  • High-Calorie Diet and Vitamin Supplementation: Maintaining good nutritional status, enhancing immunity, and improving lung function.
• Regular Airway Clearance Therapy: Even during stable periods, regular airway clearance therapy should be maintained to prevent mucus retention and infection.
• Regular Follow-up and Monitoring: Regular visits to a CF center for comprehensive clinical evaluation, lung function tests, sputum cultures, and nutritional assessments, to timely detect and manage disease progression and complications.

Through the comprehensive implementation of primary and secondary prevention measures, the burden of cystic fibrosis on individuals and families can be minimized, and patients' long-term health outcomes can be significantly improved.