Incidence and Prevalence

Global Incidence and Prevalence of Cystic Fibrosis

Cystic fibrosis (CF) is the most common lethal genetic disease in the white population, affecting approximately 80,000 people worldwide according to the most recent data from 2023. As the most frequent autosomal recessive hereditary disease among Caucasians, CF has an incidence of approximately 1 in 2,000 to 3,500 newborns in these populations.

The global distribution of CF shows significant geographic and ethnic variations. In Western Europe, there is a gradient in both the incidence of CF and the frequency of the ΔF508 mutation, with the highest values found in western regions. The overall frequency of delta F508 in the present mutant CF gene pool is about 70%, but there is marked variation among different geographic populations.

In Italy, the prevalence of CF was 8.6/100,000 residents in 2015 and 8.8/100,000 in 2016, with an estimated patient population of 5,204 in 2015 and 5,362 in 2016. The estimated incidence was 1/4,176 living births in 2015 and 1/5,510 in 2016.

The United Kingdom reported 5,274 CF patients in 2003, with 96.3% being Caucasian. The UK CF population showed a male preponderance that significantly increased with age.

In Brazil, the incidence varies significantly by region: 1:10,000 in Minas Gerais, 1:9,500 in Paraná, 1:8,700 in Santa Catarina, and 1:1,600 in Rio Grande do Sul. Similarly, the prevalence of the ΔF508 mutation varies: 33% in Sao Paulo, 49% in Rio Grande do Sul, 27% in Santa Catarina, and 52% in Minas Gerais.

Historically, the incidence of CF in non-Caucasian populations was thought to be low. However, growing epidemiological evidence shows CF is more common in Indian, African, Hispanic, Asian, and other ethnic groups than previously thought. A 2019 study noted that CF incidence in Asian and African countries is underestimated, with few patients reported having rare or unique CFTR pathogenic variants.

The genetic landscape of CF varies significantly by ethnicity. Only 14 CF-causing variants were found in the East-Asian population, while South-Asian and African populations had 43 and 52 variants respectively. In patients of African descent, molecular diagnosis is often confounded because most investigations to identify causative mutations have been conducted on European populations.

In the United States, Hispanic patients comprise an appreciable and increasing proportion of CF patients, with known increased morbidity and mortality compared to non-Hispanic white patients. The most common CFTR variant, p.Phe508del, is proportionally underrepresented in Hispanic patients.

The ethnic heterogeneity of populations like Brazil poses challenges for neonatal screening and accurate prevalence estimation. As a consequence of racially inequitable CF testing frameworks, non-Caucasians with CF encounter greater delays in diagnosis and associated harms than Caucasians.

Study Design Parameters

Study Design Parameters and Endpoints in Key Cystic Fibrosis Trials

Study Designs

• The Cystic Fibrosis Foundation established a committee to examine clinical evidence for therapies
• Evidence was addressed through systematic reviews and summaries of Cochrane reviews
• MRI studies utilized rapid Look-Locker acquisition to detect regional lung disease
• Functional pulmonary MRI protocols used very short echo-time sequences
• Observational studies evaluated ivacaftor efficacy in CF-related sinus disease
• Patients were monitored for at least one year before and after starting therapy
• Phase 3 trials like TRAFFIC and TRANSPORT were 24-week randomized controlled trials
• PROGRESS was a 96-week extension study conducted in 191 sites across 15 countries

Patient Populations

• Adult CF patients with normal spirometry compared to healthy controls
• Patients with G551D-CFTR mutation (median age 17 years)
• Patients homozygous for the F508del-CFTR mutation (aged 12+ years)
• Primary CF human bronchial epithelial cells in laboratory studies
• Inclusion criteria typically specified age requirements (often 12+ years), specific mutations, and completion of previous trial phases
• Exclusion criteria included comorbidities, laboratory abnormalities, drug intolerance, and poor compliance

Primary Endpoints

• Normalized T1 values in upper lung regions
• Sinus disease progression monitored by CT scans
• Weight, BMI, FEV1 and sweat chloride levels in ivacaftor studies
• Trans-epithelial electrical resistance in cell culture studies
• CFTR-mediated short-circuit currents with corrector drugs
• Signal intensity and lung volumes during functional MRI
• Long-term safety of combined therapy in extension studies
• Pulmonary exacerbation rates in self-management interventions

Secondary Assessments

• Hospital admissions and pulmonary exacerbations
• Psychological functioning using standardized scales
• Quality of life measures using CF-12 and CFQ-R respiratory domain score
• Lung function tests including FEV1, Lung Clearance Index (LCI), and Forced Vital Capacity (FVC)
• Growth parameters including BMI
• Sweat chloride concentration
• Imaging assessments including Modified Bhalla score and Reiff score
• Percentage of lung tissue within normal density range

Emerging Technologies and Future Directions

• Normalized T1 MRI relaxometry for detecting early-stage lung disease
• Functional pulmonary MRI as a radiation-free assessment tool
• Patient-Reported Experience Measures questionnaires for different age groups
• 3D epithelial cultures expressing functional CFTR ion channels
• Comprehensive scores incorporating clinical, lung function, imaging, and laboratory data for predicting disease progression
• FEV1 and rate of FEV1 decline remain the most significant predictors of mortality
• CT scores and airway secretion biomarkers are main predictors of early CF lung disease