Cystic Fibrosis: Disease Introduction

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 located on the apical membrane of exocrine gland cells, responsible for regulating the transport of chloride ions, bicarbonate, and water across the cell membrane. CFTR dysfunction leads to abnormally thick and sticky mucus secreted by exocrine glands, thereby affecting multiple organ systems, particularly the respiratory system, digestive system (pancreas, liver, intestines), sweat glands, and reproductive system.

The clinical manifestations of cystic fibrosis are highly heterogeneous, ranging from mild symptoms to severe life-threatening illness. Its core pathophysiological features are impaired mucus clearance and chronic inflammation, especially in the lungs, which leads to recurrent infections, bronchiectasis, and progressive decline in lung function, eventually progressing to respiratory failure. In the digestive system, exocrine pancreatic insufficiency leads to malabsorption of fats and fat-soluble vitamins, causing malnutrition and growth retardation. Elevated sodium chloride concentration in sweat is a typical feature of this disease and an important diagnostic criterion.

Despite cystic fibrosis being a severe chronic disease, medical advancements, particularly early diagnosis, multidisciplinary comprehensive treatment, and the advent of CFTR modulators, have significantly improved patients' survival and quality of life. In developed countries, the life expectancy of cystic fibrosis patients has extended from childhood in the mid-20th century to the current 40-50 years, or even longer.

Epidemiology

Cystic fibrosis is the most common fatal genetic disease in Caucasian populations. Its global epidemiological characteristics vary by ethnicity and geographical region.

Incidence:

• Caucasian Populations: The incidence of cystic fibrosis is highest in Caucasian populations of Northern European descent, approximately 1/2,500 to 1/3,500 live births. For example, in Ireland, the incidence can be as high as 1/1,350.
• Other Ethnicities: In Hispanic populations, the incidence is approximately 1/4,000 to 1/10,000. In African Americans, the incidence is approximately 1/15,000 to 1/20,000. In Asian populations, cystic fibrosis is relatively rare, with an incidence typically below 1/30,000, or even lower.
• Global Differences: These differences in incidence reflect genetic drift and selective pressure of CFTR gene mutations in different populations.

Carrier Frequency:

• Since cystic fibrosis is an autosomal recessive genetic disorder, patients need to inherit one mutated gene from each parent. Therefore, the frequency of carriers (individuals with only one mutated gene but no symptoms) is much higher than that of patients.
• In Caucasian populations, the frequency of CFTR gene carriers is approximately 1/25, meaning 1 in 25 people is a carrier of cystic fibrosis.
• In other populations, carrier frequencies are correspondingly lower, for example, approximately 1/65 in African Americans and 1/90 in Asian populations.

Age at Diagnosis:

• With the widespread adoption of Newborn Screening (NBS), an increasing number of cystic fibrosis patients are diagnosed shortly after birth, enabling early intervention and thus improving prognosis.
• In regions without newborn screening, diagnosis is usually based on the appearance of clinical symptoms, which may occur in infancy, childhood, or even adulthood.

Gender Distribution:

• There is no significant difference in the incidence of cystic fibrosis between males and females. However, in some studies, female patients may experience a slightly faster decline in lung function than males, and survival rates may be slightly lower, but the specific mechanisms are not yet fully understood.

Overall, cystic fibrosis is a significant public health issue globally, especially in Caucasian populations. Identification of carriers and patients is crucial for genetic counseling and disease management.

Etiology and Pathophysiology

Etiology

Cystic fibrosis is caused by CFTR gene mutations.

• Gene Location: The CFTR gene is located on the long arm of human chromosome 7 (7q31.2).
• Inheritance Pattern: Cystic fibrosis follows an autosomal recessive inheritance pattern. This means that an individual will only develop the disease if they inherit one mutated CFTR gene from each parent. If an individual inherits only one mutated gene, they are an asymptomatic carrier.
• CFTR Protein: The CFTR gene encodes a transmembrane protein, the Cystic Fibrosis Transmembrane Conductance Regulator. This protein primarily functions as a chloride ion channel, involved in the transport of fluid and electrolytes across epithelial cell surfaces. It may also regulate the function of other ion channels (such as the epithelial sodium channel, ENaC) and participate in bicarbonate transport.
• Gene Mutation Types: More than 2000 types of CFTR gene mutations have been identified to date. The most common mutation is F508del (or ΔF508), which results in the deletion of phenylalanine at position 508 of the CFTR protein. The F508del mutation accounts for approximately 70% of global cystic fibrosis cases and is more common in populations of Northern European descent.
• Mutation Classification: CFTR gene mutations are 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., G542X, W1282X).
  • Class II (Processing Defects): Leads to misfolding of the CFTR protein after synthesis, preventing its transport to the cell membrane (e.g., F508del).
  • Class III (Gating Defects): CFTR protein reaches the cell membrane, but its channel gating function is abnormal, preventing normal opening (e.g., G551D).
  • Class IV (Conductance Defects): CFTR protein reaches the cell membrane and opens, but its chloride ion conductance is reduced (e.g., R117H).
  • Class V (Reduced Synthesis): Reduced amount of CFTR protein is synthesized, but its function is normal (e.g., 3849+10kbC>T).
  • Class VI (Stability Defects): CFTR protein has poor stability on the cell membrane and is prematurely degraded.
  • Different classes of mutations lead to varying degrees of CFTR dysfunction, thereby affecting disease severity and clinical manifestations. For example, Class I, II, and III mutations are typically associated with more severe disease phenotypes, while Class IV and V mutations may lead to milder disease or atypical cystic fibrosis.

Pathophysiology

CFTR protein dysfunction is the root cause of all pathophysiological changes in cystic fibrosis. When CFTR protein function is abnormal or absent, the transmembrane transport of chloride ions and bicarbonate is impaired, leading to abnormally thick and sticky secretions from exocrine glands.

1. Respiratory System

• Airway Surface Liquid (ASL) Imbalance: Under normal conditions, the CFTR protein maintains the appropriate volume and pH of the airway surface liquid (ASL) by secreting chloride ions and bicarbonate. CFTR dysfunction leads to reduced chloride ion secretion, while epithelial sodium channel (ENaC) activity is enhanced, resulting in excessive absorption of sodium ions and water. This causes the ASL volume to decrease, becoming dehydrated and viscous.
• Impaired Mucociliary Clearance: The viscous ASL prevents cilia from beating effectively, leading to impaired mucociliary clearance. Bacteria, viruses, and environmental particles become trapped in the airways and are difficult to clear.
• Chronic Infection: Trapped mucus becomes a breeding ground for bacteria. The airways of cystic fibrosis patients are prone to chronic infection by specific pathogens, most commonly Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex. These bacteria form biofilms in the mucus, making them resistant to antibiotic treatment.
• Chronic Inflammation: Persistent bacterial infection and the host's immune response to the infection lead to continuous inflammation in the airways. Neutrophils accumulate in large numbers and release proteolytic enzymes such as elastase, which not only destroy bacteria but also damage lung tissue. The inflammatory response further exacerbates mucus secretion and airway damage.
• Bronchiectasis and Airway Obstruction: Chronic infection and inflammation lead to structural damage of the airway walls, forming irreversible bronchiectasis. Viscous mucus plugs and inflammatory reactions cause small airway obstruction, which in turn leads to gas trapping, atelectasis, and progressive decline in lung function.
• Respiratory Failure: As the disease progresses, lung tissue damage worsens, eventually leading to respiratory failure, which is the most common cause of death in cystic fibrosis patients.

2. Digestive System

• Pancreas:
  • Exocrine Pancreatic Insufficiency: CFTR dysfunction leads to viscous secretions within the pancreatic ducts, blocking them. This prevents pancreatic enzymes (such as lipase, amylase, protease) from entering the intestine, leading to maldigestion and malabsorption of food. Pancreatic duct obstruction can also cause autodigestion and fibrosis of the pancreas, ultimately leading to pancreatic tissue destruction. Approximately 85-90% of cystic fibrosis patients have exocrine pancreatic insufficiency.
  • Endocrine Pancreatic Dysfunction (CF-Related Diabetes, CFRD): Progressive damage to the pancreas also affects islet cells, leading to insufficient insulin secretion and insulin resistance, thus developing into CF-related diabetes. CFRD is a common complication in cystic fibrosis patients, usually appearing in adolescence or adulthood.
• Hepatobiliary System:
  • CFTR dysfunction leads to viscous bile, blocking the bile ducts. This can cause cholestasis, cholangitis, gallstones, and focal biliary cirrhosis. Approximately 5-10% of patients develop multilobular cirrhosis, which may lead to portal hypertension and liver failure.
• Intestines:
  • Meconium Ileus: Approximately 10-20% of cystic fibrosis neonates present with meconium ileus at birth, due to abnormally viscous meconium in the intestine blocking the terminal ileum.
  • Distal Intestinal Obstruction Syndrome (DIOS): In children and adult patients, viscous intestinal contents and undigested food residues can form a fecal mass in the ileocecal region, causing partial or complete intestinal obstruction.
  • Rectal Prolapse: Chronic cough, malnutrition, and difficulty with defecation can lead to rectal prolapse.

3. Sweat Glands

• In normal sweat glands, primary sweat (isotonic) passes through the duct, where the CFTR protein is responsible for reabsorbing chloride ions, and ENaC is responsible for reabsorbing sodium ions, thereby producing hypotonic final sweat.
• In cystic fibrosis patients, CFTR dysfunction leads to the inability of sweat gland ducts to effectively reabsorb chloride ions, and sodium ion reabsorption is also affected. Therefore, the sodium chloride concentration in the sweat of cystic fibrosis patients is abnormally elevated, and the skin tastes salty. This is a hallmark diagnostic feature of cystic fibrosis.

4. Reproductive System

• Males: Approximately 95% of male cystic fibrosis patients have Congenital Bilateral Absence of the Vas Deferens (CBAVD), due to the vas deferens failing to develop normally during embryonic development or being blocked and degenerated by viscous secretions. This prevents sperm from being transported from the testes to the urethra, causing obstructive azoospermia and infertility. The testes themselves are usually functional, and sperm production is unaffected.
• Females: The fertility of female cystic fibrosis patients is usually impaired but not completely infertile. Viscous cervical mucus may hinder sperm passage, and chronic disease status and malnutrition may also affect ovulation and endometrial function.

5. Other Systems

• Bone Disease: Cystic fibrosis patients often suffer from osteoporosis and increased fracture risk, which are related to factors such as vitamin D deficiency, chronic inflammation, malnutrition, corticosteroid use, and reduced physical activity.
• Sinusitis and Nasal Polyps: CFTR dysfunction of the nasal and sinus mucosa leads to mucus retention and chronic inflammation, causing chronic sinusitis and recurrent nasal polyp formation.
• Kidneys: Long-term use of certain antibiotics (such as aminoglycosides) may lead to nephrotoxicity.
• Arthritis: A small number of patients may develop CF-related arthritis.

In summary, exocrine gland dysfunction caused by CFTR gene mutations is the fundamental reason for multi-system involvement in cystic fibrosis. Its pathophysiological mechanisms are complex, involving multiple links such as impaired mucus clearance, chronic infection, inflammation, and tissue damage.

Clinical Manifestations

The clinical manifestations of cystic fibrosis are highly heterogeneous, ranging from mild symptoms to severe life-threatening illness, and evolve with age. The severity of symptoms and the extent of organ involvement primarily depend on the type of CFTR gene mutation and the residual function of the CFTR protein.

1. Neonatal Period

• Meconium Ileus: Approximately 10-20% of cystic fibrosis neonates present with meconium ileus at birth, due to abnormally viscous meconium in the intestine blocking the terminal ileum, leading to abdominal distension, vomiting, feeding intolerance, and delayed meconium passage. This is one of the most common initial symptoms of cystic fibrosis.
• Persistent Jaundice: Some neonates may experience persistent cholestatic jaundice.
• Growth Retardation: Even without meconium ileus, some neonates may exhibit low birth weight or poor weight gain after birth.
• Positive Newborn Screening: Many patients are diagnosed in the asymptomatic period through newborn screening (elevated IRT).

2. Infancy and Childhood

• Respiratory Symptoms:
  • Chronic Cough: This is the most common early respiratory symptom, usually a wet, persistent, productive cough, especially worse at night or in the early morning.
  • Recurrent Respiratory Infections: Frequent bronchitis, pneumonia, often accompanied by wheezing.
  • Tachypnea and Dyspnea: As lung disease progresses, tachypnea and dyspnea may occur.
  • Sinusitis and Nasal Polyps: Chronic sinusitis and recurrent nasal polyp formation.
• Digestive Symptoms:
  • Steatorrhea: Due to exocrine pancreatic insufficiency, fat malabsorption leads to large, greasy, foul-smelling stools that float in water.
  • Growth Retardation: Despite good appetite, due to malabsorption of fats and fat-soluble vitamins, there is failure to gain weight, slow height growth, and even malnutrition.
  • Abdominal Distension and Abdominal Pain: Indigestion and excessive intestinal gas can cause abdominal distension and abdominal pain.
  • Rectal Prolapse: Chronic cough and difficulty with defecation can lead to rectal prolapse.
  • Vitamin Deficiencies: Deficiencies in fat-soluble vitamins (A, D, E, K) can lead to night blindness, coagulation disorders, bone abnormalities, etc.
• Other Symptoms:
  • Salty Skin: Parents may notice an abnormally salty taste on the child's skin when kissing, which is a manifestation of elevated sodium chloride concentration in sweat.
  • Clubbing: A sign of chronic hypoxia and progressive lung disease.
  • Edema: Severe malnutrition or hypoproteinemia can lead to edema.
  • Electrolyte Imbalance: In hot weather or after strenuous exercise, excessive sweating can lead to hyponatremia and hypochloremia, causing fatigue, weakness, and even collapse.

3. Adolescence and Adulthood

As age increases, chronic complications and progressive damage of the disease become more prominent.

• Respiratory System:
  • Progressive Decline in Lung Function: Lung function tests show obstructive ventilatory dysfunction, with progressive decline in FEV1 (forced expiratory volume in one second).
  • Bronchiectasis: Imaging studies (e.g., high-resolution CT) show significant bronchiectasis.
  • Hemoptysis: Bronchiectasis and chronic inflammation can lead to hemoptysis, ranging from small streaks of blood to massive hemoptysis.
  • Pneumothorax: Rupture of bullae can cause pneumothorax.
  • Chronic Respiratory Failure: Eventually progresses to chronic respiratory failure, requiring oxygen therapy or even lung transplantation.
  • CF-Related Arthritis: A small number of patients may experience joint pain and swelling.
• Digestive System:
  • CF-Related Diabetes (CFRD): Approximately 30-50% of adult cystic fibrosis patients develop CFRD, requiring insulin therapy.
  • Liver Disease: Hepatomegaly, fatty liver, cholestatic cirrhosis, portal hypertension, and esophageal varices.
  • Distal Intestinal Obstruction Syndrome (DIOS): Intermittent or persistent abdominal pain, abdominal distension, nausea, vomiting, with a palpable mass in the right lower quadrant.
  • Pancreatitis: A small number of patients may experience acute pancreatitis attacks, especially in those with some preserved pancreatic function.
• Reproductive System:
  • Male Infertility: Almost all male patients experience obstructive azoospermia due to congenital bilateral absence of the vas deferens.
  • Female Fertility Decline: Viscous cervical mucus, chronic disease status, and malnutrition can affect female fertility, but pregnancy is still possible.
• Skeletal System:
  • Osteoporosis: Prevalent, increasing fracture risk.
  • Growth Retardation and Delayed Puberty: Persistent malnutrition and chronic inflammation can lead to growth retardation and delayed puberty.
• Psychosocial Issues: The burden of chronic illness, frequent treatments, hospitalizations, and concerns about life expectancy can lead to psychological problems such as anxiety and depression.

In summary, the clinical manifestations of cystic fibrosis are multi-systemic and progressive, requiring comprehensive evaluation and management. Early identification and intervention are crucial for improving patients' long-term prognosis.

Diagnosis

The diagnosis of cystic fibrosis is usually based on clinical manifestations, newborn screening results, sweat chloride test, and gene mutation analysis.

1. Newborn Screening (NBS)

• Purpose: Aims to identify infants with cystic fibrosis early, to initiate treatment as soon as possible and improve prognosis.
• Method: Typically involves measuring Immunoreactive Trypsinogen (IRT) levels in blood spots. Elevated IRT suggests pancreatic duct obstruction, which may be a manifestation of cystic fibrosis.
• Follow-up Steps: If IRT levels are elevated, a second screening step is usually performed, including repeat IRT testing or direct CFTR gene mutation analysis. If screening results indicate high risk, a confirmatory sweat chloride test is required.
• Limitations: Elevated IRT is not specific; other diseases or premature infants may also have elevated IRT. Therefore, a positive NBS result needs to be confirmed by subsequent definitive tests.

2. Sweat Chloride Test

• Gold Standard: The sweat chloride test is the gold standard for diagnosing cystic fibrosis.
• Principle: Uses pilocarpine iontophoresis to stimulate local sweat glands to secrete sweat, then collects the sweat and measures its chloride concentration.
• Interpretation of Results:
  • Positive (Confirmed): Sweat chloride concentration ≥ 60 mmol/L.
  • Intermediate (Uncertain): Sweat chloride concentration 30-59 mmol/L. Results in this range require further evaluation in conjunction with clinical manifestations and gene mutation analysis.
  • Negative (Excluded): Sweat chloride concentration < 30 mmol/L.
• Precautions: The test must be performed by experienced technicians in a certified laboratory, ensuring that a sufficient amount of sweat is collected (usually at least 50 mg). In infancy, sweat gland function may be immature, and repeat testing may be necessary.

3. Genetic Mutation Analysis

• Purpose: To identify specific mutations in the CFTR gene to confirm cystic fibrosis, and to help predict disease severity and guide the selection of CFTR modulators.
• Method: Detects common CFTR mutations or performs full gene sequencing using polymerase chain reaction (PCR), sequencing, or other molecular biology techniques.
• Interpretation of Results:
  • Confirmed: Two pathogenic CFTR mutations are found (one from each parent).
  • Uncertain: One pathogenic mutation is found, or a Variant of Unknown Significance (VUS) is found. In this case, a comprehensive judgment is needed in conjunction with the sweat chloride test and clinical manifestations, or parental genetic testing.
• Limitations: Even if the most common mutations are tested, a small number of patients may carry rare mutations that are not detected. Therefore, a negative genetic test result does not completely rule out cystic fibrosis, especially in patients with typical clinical symptoms and intermediate sweat chloride results.

4. Other Ancillary Tests

• Pancreatic Function Assessment:
  • Fecal Elastase-1: Reduced fecal elastase-1 levels are a sensitive indicator of exocrine pancreatic insufficiency.
  • Fat Absorption Test: 72-hour fecal fat quantification, used to assess the degree of fat malabsorption.
  • Fat-Soluble Vitamin Levels: Measures serum vitamin A, D, E, K levels to assess for deficiencies.
• Pulmonary Function Tests (PFTs):
  • Spirometry: Assesses the degree of airway obstruction, such as FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), and FEV1/FVC ratio.
  • Lung Volume Measurement: Assesses lung hyperinflation and gas trapping.
• Imaging Studies:
  • Chest X-ray: May show lung hyperinflation, bronchial wall thickening, bronchiectasis, atelectasis, or infectious infiltrates.
  • High-Resolution CT (HRCT): More sensitive for diagnosing early bronchiectasis, mucus plugging, parenchymal lung disease, and pulmonary vascular changes.
  • Abdominal Ultrasound: Used to assess liver and gallbladder lesions, such as fatty liver, gallstones, cirrhosis, etc.
• Microbiological Examination:
  • Sputum culture or pharyngeal swab culture: Performed regularly to identify pathogens in the airways, such as Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, etc., to guide antibiotic treatment.
• Nasal Potential Difference (NPD) Measurement:
  • A research diagnostic method that assesses CFTR channel function by measuring the potential difference across nasal epithelial cells. In CF patients, the NPD pattern is abnormal due to impaired chloride ion transport. Primarily used to diagnose atypical CF or patients with unclear genetic test results.

Summary of Diagnostic Criteria: Usually, at least one of the following needs to be met:

1. Positive newborn screening, and positive sweat chloride test, or two pathogenic CFTR mutations found.
2. At least one typical clinical feature of cystic fibrosis (e.g., chronic lung disease, exocrine pancreatic insufficiency, meconium ileus, etc.), and positive sweat chloride test, or two pathogenic CFTR mutations found.
3. A sibling with cystic fibrosis, and positive sweat chloride test, or two pathogenic CFTR mutations found.

For patients with intermediate sweat chloride test results or only one CFTR mutation, a comprehensive judgment is needed in conjunction with clinical manifestations, other ancillary tests, and CFTR function assessment (e.g., NPD).

Management and Treatment

The management of cystic fibrosis is a complex, multidisciplinary, lifelong process aimed at controlling symptoms, preventing complications, slowing disease progression, and improving patients' quality of life and survival. Treatment strategies should be individualized based on the patient's age, disease severity, gene mutation type, and affected organs.

1. Respiratory System Management

Respiratory complications are the main cause of morbidity and mortality in cystic fibrosis patients, so lung management is central to treatment.

• Airway Clearance Techniques (ACTs):
  • Purpose: To help clear thick mucus from the airways, reducing bacterial colonization and inflammation.
  • Methods: Include postural drainage, percussion, vibration, high-frequency chest wall oscillation (vibrating vest), positive expiratory pressure (PEP) devices, autogenic drainage (AD) techniques, and exercise. Patients should perform these daily, or even multiple times a day.
• Bronchodilators:
  • Purpose: To dilate airways and improve ventilation.
  • Medications: Short-acting or long-acting β2-agonists (e.g., salbutamol, formoterol) and anticholinergic drugs (e.g., ipratropium bromide). Usually used before ACTs to help open the airways.
• Mucolytics:
  • Purpose: To thin mucus, making it easier to cough out.
  • Medications:
    • Recombinant human deoxyribonuclease (Dornase alfa, Pulmozyme): Reduces sputum viscosity by hydrolyzing extracellular DNA. Inhaled daily.
    • Hypertonic saline: Inhaled hypertonic saline (3%-7%) can increase the water content of the airway surface liquid, thin mucus, stimulate coughing, and improve mucus clearance. Inhaled daily.
• Antibiotic Therapy:
  • Purpose: To treat acute infections and control chronic bacterial colonization.
  • Acute Exacerbations: Oral, intravenous, or inhaled antibiotics are selected based on sputum culture results and susceptibility testing. Common pathogens include Pseudomonas aeruginosa, Staphylococcus aureus, etc.
  • Chronic Infection Control:
    • Inhaled Antibiotics: For chronic Pseudomonas aeruginosa infection, long-term inhaled antibiotics (e.g., tobramycin, aztreonam) can reduce bacterial load, improve lung function, and decrease the frequency of acute exacerbations.
    • Oral Macrolide Antibiotics: Such as azithromycin, have anti-inflammatory and anti-biofilm effects, and can be used in patients with chronic Pseudomonas aeruginosa infection.
• Anti-inflammatory Drugs:
  • Purpose: To reduce airway inflammatory response.
  • Medications:
    • High-dose ibuprofen: Long-term use can slow the decline in lung function, but kidney function and gastrointestinal side effects need to be monitored.
    • Corticosteroids: Oral or inhaled corticosteroids are usually only used to treat acute exacerbations or in patients with concomitant asthma, due to their numerous long-term side effects.
• CFTR Modulators:
  • Revolutionary Progress: These drugs directly act on the CFTR protein, correcting its functional defects, representing a major breakthrough in cystic fibrosis treatment.
  • Types:
    • Potentiators: Such as ivacaftor, act on CFTR protein gating defects (Class III mutations), prolonging channel opening time and increasing chloride ion transport.
    • Correctors: Such as lumacaftor, tezacaftor, elexacaftor, act on CFTR protein processing defects (Class II mutations, such as F508del), helping it fold correctly and transport to the cell membrane.
    • Combination Therapies: Combinations of potentiators and correctors (e.g., lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor) can significantly improve lung function, weight, and quality of life in patients homozygous or heterozygous for F508del.
  • Selection: The choice of CFTR modulator depends on the patient's CFTR gene mutation type.
• Lung Transplantation:
  • For end-stage, irreversible lung disease, when other treatments are ineffective and life expectancy is limited, lung transplantation is the only option.

2. Digestive System Management

• Pancreatic Enzyme Replacement Therapy (PERT):
  • Purpose: To supplement digestive enzymes lacking in patients with exocrine pancreatic insufficiency.
  • Medications: Enteric-coated microsphere preparations containing lipase, amylase, and protease.
  • Usage: Taken with meals and snacks, dosage adjusted based on the fat content of food and the patient's weight gain.
• Nutritional Support:
  • High-calorie, high-fat diet: Cystic fibrosis patients have increased energy needs due to maldigestion, malabsorption, and chronic inflammation, requiring 120-150% more calories than their peers.
  • Fat-soluble vitamin supplementation: Supplementation with high doses of vitamins A, D, E, K to correct or prevent deficiencies.
  • Salt supplementation: In hot weather or after strenuous exercise, salt should be supplemented to prevent electrolyte imbalance.
  • Enteral nutrition: For severely malnourished patients or those unable to consume enough calories orally, nocturnal nasogastric tube or gastrostomy tube feeding may be considered.
• CF-Related Diabetes (CFRD) Management:
  • Insulin therapy: Treatment for CFRD primarily relies on insulin, as its main pathophysiology is insufficient insulin secretion.
  • Dietary management: Unlike general diabetic patients, CFRD patients still need to maintain a high-calorie diet to meet growth and energy needs.
• Liver Disease Management:
  • Ursodeoxycholic acid (UDCA): Can improve bile flow, reduce cholestasis, and slow the progression of liver disease.
  • Liver transplantation: For patients with end-stage cirrhosis and liver failure.
• Distal Intestinal Obstruction Syndrome (DIOS) Management:
  • Conservative treatment: Oral or nasogastric tube infusion of osmotic laxatives such as polyethylene glycol (PEG), or use of acetylcysteine.
  • Surgery: For patients unresponsive to conservative treatment or with complete intestinal obstruction.

3. Other System Management

• Bone Disease Management:
  • Supplement vitamin D and calcium, encourage weight-bearing exercise.
  • For severe osteoporosis, bisphosphonate therapy may be considered.
• Sinusitis and Nasal Polyps Management:
  • Nasal irrigation, inhaled corticosteroids, oral antibiotics.
  • For stubborn nasal polyps, surgical removal may be necessary.
• Psychosocial Support:
  • Provide psychological counseling, support groups, and education to help patients and families cope with the challenges of chronic illness.
• Fertility Management:
  • Males: For males with congenital bilateral absence of the vas deferens, fertility can be achieved through testicular sperm extraction (TESE) combined with in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
  • Females: Assess fertility, provide fertility counseling.

4. Infection Control

• Cross-infection Prevention: There is a risk of cross-infection of specific pathogens (e.g., Pseudomonas aeruginosa, Burkholderia cepacia complex) among cystic fibrosis patients. Therefore, patients should maintain distance from each other in outpatient and inpatient settings, and strict hand hygiene and respiratory droplet isolation measures should be implemented.

Cystic fibrosis treatment is a continuous learning and adjustment process, requiring close cooperation among patients, families, and a multidisciplinary medical team (including pulmonologists, gastroenterologists, nutritionists, physical therapists, nurses, social workers, psychologists, etc.).

Rehabilitation and Patient Education

Rehabilitation and patient education are indispensable components of comprehensive cystic fibrosis management, aiming to improve patients' self-management abilities, enhance quality of life, and slow disease progression.

1. Rehabilitation

Cystic fibrosis rehabilitation primarily focuses on the respiratory system and nutrition to maintain or improve physical function.

• Physical Therapy and Respiratory Rehabilitation:
  • Airway Clearance Techniques (ACTs): Physical therapists will guide patients and families to learn and master various ACTs, such as postural drainage, percussion, vibration, high-frequency chest wall oscillation, positive expiratory pressure (PEP) devices, autogenic drainage techniques, etc. These techniques require regular assessment and adjustment to ensure their effectiveness and adherence.
  • Respiratory Muscle Training: For patients with respiratory muscle weakness or fatigue, respiratory muscle training is performed to enhance respiratory function.
  • Exercise Rehabilitation: Patients are encouraged to engage in regular physical exercise, such as running, swimming, cycling, etc. Exercise not only aids in airway clearance but also improves cardiopulmonary function, enhances physical fitness, increases bone density, and promotes mental health. Exercise plans should be individualized and conducted under the guidance of the medical team.
  • Posture Correction: Correct postural abnormalities that may result from chronic lung disease, preventing complications such as scoliosis.
• Nutritional Rehabilitation:
  • Nutritional Counseling: Registered dietitians regularly assess patients' nutritional status and provide personalized dietary advice to ensure adequate intake of calories, protein, and fat to support growth and maintain weight.
  • Pancreatic Enzyme Replacement Therapy (PERT) Guidance: Detailed guidance is provided to patients on how to correctly take pancreatic enzyme preparations, including dosage, timing, and pairing with food, to maximize digestive absorption efficiency.
  • Fat-Soluble Vitamin Supplementation Guidance: Inform patients about the importance of fat-soluble vitamin supplementation and correct administration methods.
  • Enteral Nutritional Support: For severely malnourished patients, guide families in the care and management of nasogastric tube or gastrostomy tube feeding.
• Psychological Rehabilitation:
  • Psychological Support: Cystic fibrosis is a chronic, progressive disease, and patients and families often face immense psychological pressure. Psychologists or social workers provide psychological counseling and support groups to help them cope with anxiety, depression, disease burden, and decreased quality of life.
  • Coping Strategies: Teach patients strategies for coping with disease challenges and improve self-efficacy.

2. Patient Education

Patient education is key to empowering patients and families for effective self-management. Educational content should be comprehensive, continuous, and easy to understand.

• Disease Knowledge Education:
  • In-depth understanding of cystic fibrosis: Explain the genetic basis, pathophysiology, characteristics of multi-system involvement, and the natural course of the disease.
  • Symptom Recognition: Teach patients and families to recognize early symptoms of disease exacerbation or complications, such as worsening cough, increased sputum, dyspnea, fever, abdominal pain, etc., for timely medical attention.
• Treatment Plan Education:
  • Medication Adherence: Explain in detail the action, dosage, administration method, potential side effects, and importance of adherence for each medication (including CFTR modulators, antibiotics, mucolytics, bronchodilators, pancreatic enzymes, vitamins, etc.).
  • Airway Clearance Techniques: Ensure patients and families are proficient in and adhere to daily ACTs.
  • Nutritional Management: Emphasize the importance of a high-calorie, high-fat diet, and the necessity of pancreatic enzyme and vitamin supplementation.
  • CF-Related Diabetes Management: For CFRD patients, educate them on blood glucose monitoring, insulin injection, and dietary management.
• Infection Control Education:
  • Hand Hygiene: Emphasize the importance of frequent hand washing to prevent infection.
  • Cross-infection Prevention: Inform patients that they should avoid close contact with other cystic fibrosis patients in healthcare settings or patient gatherings to prevent the spread of specific pathogens (e.g., Pseudomonas aeruginosa).
  • Vaccination: Emphasize timely vaccination against influenza, pneumococcal disease, etc., to prevent common respiratory infections.
• Self-Monitoring and Record Keeping:
  • Home Monitoring: Teach patients to perform home lung function monitoring (e.g., peak flow meter), blood glucose monitoring (for CFRD patients), weight monitoring, etc.
  • Symptom Diary: Encourage patients to record daily symptoms, medication use, and ACTs performance to provide detailed information to doctors during follow-up visits.
• Genetic Counseling:
  • For patients and their families, provide genetic counseling, explaining the inheritance pattern of the disease, carrier screening, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) options.
• Lifestyle Guidance:
  • Physical Exercise: Encourage regular exercise and provide exercise recommendations suitable for the patient's physical condition.
  • Smoking Cessation: Emphasize avoiding smoking and secondhand smoke exposure.
  • Travel Precautions: Provide advice on medication carrying, infection prevention, and medical support during travel.
• Psychosocial Support:
  • Encourage patients and families to seek psychological support, participate in support groups, share experiences, and reduce psychological burden.

Through comprehensive rehabilitation and patient education, cystic fibrosis patients can better understand and manage their disease, actively participate in treatment decisions, thereby improving their quality of life and extending their survival.

Prognosis

The prognosis of cystic fibrosis has significantly improved over the past few decades, primarily due to early diagnosis (newborn screening), advancements in multidisciplinary comprehensive treatment, and the advent of CFTR modulators.

Historical Review and Current Trends:

• In the 1950s, the average life expectancy for cystic fibrosis patients was only a few years, with most children not surviving to school age.
• By the 1980s, the average life expectancy extended to over 20 years.
• Into the 21st century, with continuous improvements in treatment methods, especially in developed countries, the median survival age for cystic fibrosis patients has reached 40-50 years, or even higher. Many patients are able to complete their education, work, and start families.

Key Factors Affecting Prognosis:

1. Severity of Lung Disease: The degree of lung function decline is the most important factor affecting the prognosis of cystic fibrosis. Persistent chronic infection, inflammation, and bronchiectasis ultimately lead to respiratory failure, which is the most common cause of death for patients. FEV1 (forced expiratory volume in one second) is a key indicator for assessing lung function and predicting prognosis.
2. CFTR Gene Mutation Type:
   • Severe Mutations (e.g., Class I, II, III): Usually lead to complete absence or severe impairment of CFTR protein function, associated with more severe disease phenotypes and poorer prognosis.
   • Mild Mutations (e.g., Class IV, V): May retain partial CFTR function, leading to milder disease phenotypes, such as normal pancreatic function (PI), slower progression of lung disease, and relatively better prognosis.
3. Early Diagnosis and Treatment: Early diagnosis through newborn screening and timely initiation of comprehensive treatment (including airway clearance, nutritional support, anti-infective therapy, etc.) can significantly slow disease progression and improve long-term prognosis.
4. Application of CFTR Modulators: The advent of CFTR modulators is a milestone in cystic fibrosis treatment. These drugs can directly correct CFTR protein functional defects, significantly improving lung function, nutritional status, and quality of life, especially for patients carrying specific mutations (e.g., F508del, G551D), greatly altering the natural course and prognosis of the disease.
5. Nutritional Status: Good nutritional status is crucial for maintaining immune function, lung function, and overall health. Persistent malnutrition is associated with poorer prognosis.
6. Infection Control: Chronic infection of specific pathogens in the airways (especially Pseudomonas aeruginosa and Burkholderia cepacia complex) is associated with accelerated decline in lung function and poor prognosis. Effective anti-infective strategies are essential for slowing disease progression.
7. Complications: Severe complications, such as CF-related diabetes, cirrhosis, hemoptysis, pneumothorax, etc., also affect the patient's prognosis.
8. Accessibility of Medical Care: Access to specialized, multidisciplinary cystic fibrosis care center services is crucial for patients' long-term management and prognosis.
9. Patient Adherence: Patient adherence to treatment plans (e.g., airway clearance, medication intake, nutritional supplementation) directly affects treatment efficacy and disease progression.

Long-term Challenges: Despite significant improvements in prognosis, cystic fibrosis remains a chronic, progressive disease. Patients still face:

• Progressive Decline in Lung Function: Even with CFTR modulators, lung function may still slowly decline.
• Chronic Complications: Such as CF-related diabetes, liver disease, bone disease, etc., may appear or worsen in adulthood.
• Psychosocial Burden: Chronic illness has a continuous impact on the psychological and socioeconomic aspects of patients and their families.
• Treatment Resistance: Bacteria may develop resistance to antibiotics, and CFTR modulators may also have long-term efficacy and safety issues.

In the future, with the continuous development of new drug research (such as therapies for rare mutations, gene therapy) and individualized treatment strategies, the prognosis for cystic fibrosis patients is expected to improve further.

Prevention

Cystic fibrosis is a genetic disease, so its prevention strategies primarily focus on genetic counseling, early diagnosis, and preventing disease complications and progression through effective management.

1. Primary Prevention

Since cystic fibrosis is caused by gene mutations, it is currently not possible to completely prevent the disease through primary prevention measures.

2. Secondary Prevention

Secondary prevention aims to detect the disease or high-risk individuals early for timely intervention and improved prognosis.

• Newborn Screening (NBS):
  • Purpose: To identify infants with cystic fibrosis in the asymptomatic neonatal period.
  • Importance: Early diagnosis allows children to start comprehensive treatment and management as early as possible, including nutritional support, airway clearance, and anti-infective therapy. Studies show that early intervention can significantly improve children's nutritional status, lung function, and reduce the incidence of complications, thereby improving long-term prognosis.
  • Method: Typically involves measuring immunoreactive trypsinogen (IRT) levels in blood spots, combined with CFTR gene mutation analysis or sweat chloride test for confirmation.
• Genetic Counseling and Carrier Screening:
  • Purpose: To identify cystic fibrosis gene carriers, assess disease risk, and provide reproductive options.
  • Target Population:
    • Individuals with a family history of cystic fibrosis.
    • Relatives of cystic fibrosis patients.
    • Couples planning to have children, especially Caucasian populations.
    • Males with congenital bilateral absence of the vas deferens (CBAVD), as this may be a manifestation of atypical cystic fibrosis.
  • Method: CFTR gene mutation analysis is performed on blood samples to detect common CFTR mutations.
  • Counseling Content: Genetic counselors explain the inheritance pattern of cystic fibrosis, the significance of carrier status, the risk of disease, and available reproductive options, including:
    • Prenatal Diagnosis: For couples with known CFTR mutations, fetal CFTR gene testing can be performed during pregnancy via amniocentesis or chorionic villus sampling to determine if the fetus has cystic fibrosis.
    • Preimplantation Genetic Diagnosis (PGD): For couples conceiving through in vitro fertilization (IVF), CFTR gene testing can be performed on embryos before implantation into the uterus, selecting unaffected embryos for implantation.
• Pre-marital and Pre-conception Screening:
  • In some high-risk populations, incorporating CFTR gene carrier screening into pre-marital or pre-conception examinations can help couples understand their risk of having a child with cystic fibrosis and make informed reproductive decisions.

3. Tertiary Prevention

Tertiary prevention aims to prevent the occurrence of complications, slow disease progression, and improve patients' quality of life and survival through effective disease management. For patients already diagnosed with cystic fibrosis, all treatment and management measures fall under the scope of tertiary prevention.

• Early and Continuous Comprehensive Treatment:
  • Lung Management: Adherence to airway clearance techniques, regular use of mucolytics and bronchodilators, timely and effective antibiotic therapy, and the application of CFTR modulators to prevent and control lung infections and inflammation, and slow lung function decline.
  • Nutritional Management: Pancreatic enzyme replacement therapy, high-calorie high-fat diet, fat-soluble vitamin supplementation to prevent malnutrition and growth retardation.
  • Complication Monitoring and Management: Regular monitoring and management of complications such as CF-related diabetes, liver disease, and bone disease.
• Infection Control:
  • Strict hand hygiene, avoiding cross-infection with other cystic fibrosis patients, and timely vaccination to prevent respiratory infections.
• Patient Education and Self-Management:
  • Educate patients and families on disease knowledge, treatment plans, symptom recognition, and self-monitoring skills to improve treatment adherence and empower patients for effective self-management.
• Psychosocial Support:
  • Provide psychological counseling and support to help patients and families cope with the psychological stress caused by chronic illness.

Through these prevention strategies, particularly newborn screening and genetic counseling, the early diagnosis rate and long-term prognosis of cystic fibrosis patients can be significantly improved, and reproductive options can be provided to high-risk families.