[Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)]

Cystic fibrosis (CF) is one of the most common autosomal recessive genetic diseases in Caucasians, but CF patients in China are rare, and it was listed as the first batch of rare diseases in China in 2018. In recent years, CF has been gradually recognized in China, and the number of CF patients reported in China in the past 10 years is more than 2.5 times the total number in the previous 30 years, and the total number of CF patients is estimated to be more than 20 000. The research progress of CF gene modification has led to the innovation of CF treatment. However, the sweat test as an important test for the diagnosis of CF has not been widely implemented in China. At present, the diagnosis and treatment of CF in China still lacks standardized recommendations. In view of these updates, the Chinese Experts Cystic Fibrosis Consensus Committee has formed "the Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis" based on extensive opinion gathering, literatures review, multiple meetings and discussions. This consensus collects 38 core issues related to CF, including pathogenesis, epidemiology, clinical characteristics, diagnosis, treatment, rehabilitation, and patient management. Finally, 32 recommendations were formulated. The consensus used the modified GRADE methodology to grade the evidence evaluation and recommendations. This is the current state of CF consensus in China, and we hope to improve the diagnosis and treatment of CF in China in the future.Summary of recommendationsQuestion 1: How can CF be identified?CF should be suspected if there is: (1) a family history of CF; (2) delayed meconium expulsion or meconium ileus; (3) pancreatic exocrine insufficiency, mainly characterized by long-standing steatorrhea and malnutrition; (4) recurrent lower respiratory tract infections of infantile onset, especially Pseudomonas aeruginosa (PA), Staphylococcus aureus infections of respiratory aetiology; (5) chronic sinusitis, especially when combined with juvenile presentation of nasal polyps; (6) chest CT abnormalities such as the presence of air trapping, bronchiectasis (upper lobe predominant); (7) pseudo-Bartter syndrome; (8) absence of vas deferens in males; (9) clubbing in young bronchiectasis patients(1C).Question 2: What are the diagnostic criteria for CF?1.1 Presence of one or more of the characteristic clinical manifestations or family history consistent with CF, and meeting at least one of the following definite diagnostic criteria in 1.2 or 1.3.1.2 Sweat chloride testing:(1) Concentrations of more than 60 mmol/L are diagnostic; (2) concentrations between 30-59 mmol/L are intermediate, and genetic variation must be considered to confirm the diagnosis; (3) concentrations less than 30 mmol/L are considered normal.1.3 Genetic testing:(1) Detection of two disease-causing CFTR(cystic fibrosis transmembrane conductance regulator) mutations on biallelic alleles; (2) The CFTR variants are of undetermined significance, but tests such as sweat chloride concentration, intestinal current measurement, or nasal mucosal potential difference suggest abnormal CFTR function, then CF is diagnostic(1C).Question 3: What is the diagnostic process for CF arranged?Sweat chloride testing and CFTR gene analysis are recommended in all patients suspected of CF(1D).Question 4: What is the value of sweat chloride testing in the diagnosis of CF?Sweat chloride testing is the gold standard for the clinical diagnosis of CF(1C).Question 5: What is the value of CFTR genetic testing in Chinese CF diagnosis?Biallelic pathogenic variants of CFTR are a definitive diagnosis of CF(1D).Question 6: What is the diagnostic value of imaging for CF?Chest CT is a sensitive test for early stages of lung disease in patients with CF and is appropriate in younger patients and to assess disease progression. The imaging findings of abdominal visceral involvement in CF lack specificity(2C).Question 7: How to evaluate the pancreatic function of CF patients?Fecal elastase may be used as the first indicator to assess pancreatic exocrine function in patients with CF (2C).Question 8: How to diagnose hepatic abnormality of CF?CF related liver disease was diagnosed when CF was confirmed and 2 of the following 4 criteria were met: (1) hepatomegaly and/or splenomegaly confirmed by ultrasound; (2) ALT, AST, and GGT on three consecutive occasions above the upper limit of normal on three consecutive occasions for more than 12 months and excluding other causes; (3) had evidence of liver involvement, portal hypertension, or bile duct dilatation by ultrasound; (4) liver biopsy confirmation (focal biliary cirrhosis or multilobular cirrhosis) may be indicated if the diagnosis is suspected(2D).Question 9: How to identify pulmonary exacerbations in patients with CF?Pulmonary exacerbations are indicated when any 4 of the following 12 signs or symptoms are met: increased sputum; new onset haemoptysis or increased haemoptysis; exacerbation of cough; increased dyspnea; malaise, fatigue, or somnolence; body temperature above 38 ℃; anorexia or weight loss; sinus pain or tenderness; increased sinus secretions; new chest signs; FEV₁≥10% decline from previous; imaging changes suggestive of pulmonary infection(2D).Question 10: How to diagnose CF related diabetes?Diagnostic criteria for CF related diabetes are the same as those for diabetes in the population(1D).Question 11: How to evaluate the nutritional status of CF patients?Anthropometric parameters reflecting nutritional status should be assessed regularly. And the goal of nutritional assessment is to evaluate and monitor whether pediatric patients are achieving normal standards of growth and development or whether adult patients are maintaining adequate nutritional status(1C).Question 12: Does CF require pathological examination as a diagnostic basis?Pathohistological biopsy is not recommended as a first-line diagnostic method in patients with a suspected diagnosis of CF(1D).Question 13: Do CF patients need long-term macrolides?At least 6 months of azithromycin treatment is recommended for CF patients with chronic PA infection(2A).Question 14: Do CF patients need long-term inhalation of hypertonic saline?Long term treatment with hypertonic saline is recommended for patients with CF(1A).Question 15: Do CF patients need long-term inhalation of Dornase alfa(DNase)?Long term use of DNase is recommended in patients with CF aged 6 years and older(1A).Question 16: Do CF patients need inhalation of mannitol?Inhaled mannitol therapy is recommended for more than 6 months in patients with CF aged 18 years and older when other inhaled treatments are unavailable or intolerable(2A).Question 17: How to deal with PA found in the sputum culture of CF patients?When sputum cultures from patients with CF are positive for PA, it needs to determine the characteristics of the infection first. The purpose for acute infection is to eradicate PA. Chronic colonization does not need to be eradicated, and the main purpose is to reduce the bacterial load and improve symptoms(1A).Question 18: Do CF patients need inhalation of antibiotics?Inhaled antibiotic therapy is recommended for CF patients with PA infection(1A).Question 19: Do CF patients need inhaled or systemic corticosteroids?In patients with CF without asthma or ABPA, routine inhaled or systemic glucocorticoids are not recommended (2A).Question 20: Do CF patients need to inhale bronchodilators?Bronchodilators can be used in the short term to improve symptoms in patients with CF in the presence of airway obstruction, but the long-term benefit is insufficient (2B).Question 21: Do CF patients need expectorant medicine?Patients with CF can take acetylcysteine orally or aerosolized(2A).Question 22: How to deal with acute pulmonary exacerbation in CF patients?Intensive implementation of non-antimicrobial therapy is recommended during pulmonary exacerbations in patients with CF. Antimicrobials with activity against PA were selected for empirical treatment, and the treatment was adjusted according to the results of bacterial culture and drug susceptibility testing. A 21-day long course of anti-infective therapy is not recommended(1B).Question 23: How to treat CF patients with ABPA?Medical therapy is recommended for CF patients with ABPA who meet any of the following criteria: patients with elevated immunoglobulin E levels and concomitant worsening of pulmonary function and/or pulmonary symptoms, or imaging suggesting new infiltrative foci in the chest(1D).Glucocorticoids are recommended for ABPA exacerbations in CF patients without contraindications(2D).Itraconazole should be added if the patient presents with poor response to corticosteroids, recurrence of ABPA, corticosteroid dependence, or corticosteroid toxicity(2D).Question 24: Is lung transplantation recommended for patients with CF? When is it recommended?Patients with CF may be evaluated for lung transplantation when they meet the following criteria after optimal medical therapy: (1) FEV₁<30% predicted; (2) FEV₁<40% predicted (<50% predicted in children) with the following: 6-minute walk distance<400 meters; PaCO₂>50 mmHg(1 mmHg=0.133 kPa); hypoxia at rest or after activity; pulmonary artery pressure measured by cardiotocography>50 mmHg or right heart dysfunction; continued deterioration despite aggressive supplementation of nutritional support; two exacerbations requiring intravenous antibiotic therapy per year; massive hemoptysis (>240 ml) requiring pulmonary artery embolization; presented with pneumothorax; (3) FEV₁<50% predicted and rapid decline in lung function or rapid worsening of symptoms; (4) Presented with an acute exacerbation requiring positive pressure mechanical ventilation(2C).Question 25: How to deal with pancreatic disease in CF patients?Pancreatic enzyme replacement therapy is recommended in patients with CF pancreatic disease(1A).Question 26: How to deal with hepatobiliary disease in CF patients?Ursodeoxycholic acid is not recommended in asymptomatic patients with CF hepatobiliary disease(2B).Question 27: How to deal with gastrointestinal problems such as acid regurgitation in CF patients?Acid suppression is recommended for CF patients with gastrointestinal symptoms such as acid regurgitation (2B).Question 28: How to deal with CF related diabetes?Insulin therapy is recommended in CF related diabetes(1B).Question 29: How should nutritional support be given to patients with CF?Energy intake in patients with CF is recommended to be 110%-200% of the energy requirement of a healthy person under equivalent physiological conditions. And maintaining adequate protein, appropriate intake of fats, electrolytes, and fat-soluble vitamins are recommanded(1A).Question 30: How should respiratory rehabilitation be performed in patients with CF?Airway clearance therapy and appropriate exercise are recommended for patients with CF(1A).Question 31: What is included in the follow-up of CF patient?Patients with CF should have regular follow-up. Adult patients are recommended to be followed every 3-6 months, and children should be followed more frequently(2A).Question 32: How should CF patients avoid infections?Inpatients and outpatients are recommended to be separated according to microbiota carriage status(1D).Good hand hygiene is recommended for the patients with CF and their contacts(1D).It is recommended that CF patients wear masks in healthcare settings. This may reduce the release of potentially infectious aerosols during coughing (1D).Annual influenza vaccination is recommended for patients with CF>6 months of age and for all family members of patients with CF and all healthcare workers caring for these patients(2D).Palivizumab may be considered for the prevention of respiratory syncytial virus infection in patients with CF under two years of age(2A).