[Italian Cystic Fibrosis Registry (ICFR). Report 2019-2020]. / Registro italiano Fibrosi Cistica (RIFC). Rapporto 2019-2020.

INTRODUCTION: Italian cystic fibrosis registry (ICFR) collects data from cystic fibrosis (CF) patients through the collaboration with Italian CF referral and support Centres (Italian law 548/93). ICFR contributes: • to the analysis of medium and long term clinical and epidemiological trends of the disease; • to the identification of the main health care needs at regional and national level to contribute to the Health Care programmes and to the distribution of resources; • to the comparison of the Italian data with international ones. This latter is based on the collaboration with the European CF registry and, due the COVID-19 pandemic emergency, with important global projects. OBJECTIVES: The purpose of this Report is to update the demographic and clinical data of the Italian FC population in the years 2019 and 2020, contributing to the information necessary to implement projects to improve the management of patients affected by this disease. DESIGN: Analyses and results described in the present Report are referred to patients currently followed at the Italian National Referral and Support Centres for Cystic Fibrosis in the 2019-2020 period. Data were sent by clinical Centres through a dedicated web-based software. Data undergo a double quality control (QC): the first is automatically performed by the software (quantitative QC), the second is performed at a European level (before the inclusion of the Italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and the accuracy of data as well as their longitudinal consistency with the European core data. SETTING AND PARTICIPANTS: A total of 29 CF Centres (referral and support centres and 'Bambino Gesù' Children's Hospital CF centre) sent to ICFR their data referred referred to years 2019-2020. CF Centres of Verona, Messina, and Palermo (this latter only for 2019) do not use the ICFR software; however, their data are firstly collected in a centralized manner, then sent to the European Registry. Data from support centres of Treviso and Rovereto are sent through the Verona CF Center. Finally, data from Sardinia Centre are still missing. RESULTS: The present Report has been organized into 10 sections. 1. Demography: in 2019, 5,585 CF patients were registered in the ICFR and 5,801 in 2020; median age was 21.6 years in 2019 and 22.4 years in 2020. Prevalence was 9.36/100,000 and 9.79/100,000 residents in Italy in 2019 and in 2020, respectively. Male percentage was 51.5% in 2019 and 2020 and CF distribution by age range showed higher frequency in patients aged 7 to 35 years. Adult patients (aged more than 18 years) were 59.5% on average in both years. 2. Diagnoses: most of the CF patients were diagnosed before two years of age (median value 68.5%); a significant percentage of patients (12.9% in 2019 and 13.4% in 2020) was diagnosed in adult age. 3. New diagnoses: new diagnoses were 136 in 2019 and 96 in 2020. Estimated incidence was 1/5.568 living births in 2019 and 1/7.369 in 2020. 4. Genetics: 99.9% of patients underwent genetic analyses and in 98.2% of these patients a mutation in Cystic Fibrosis Transmembrane Regulator (CFTR) gene was identified. The F508del mutation was the most frequent (identified in 44.7% allele; 2019 data). Furthermore, on average 17.3% of patients had at least one 'residual function' mutation. At least one gating mutation is present in 3.3% of Italian patients. Finally, 20.5% of patients had at least one stop codon mutation (class 1). 5. Lung function: percent predicted FEV1 (Forced Expiratory Volume in the first second) progressively declined before adult age, in accordance with the natural history of the disease. The majority of paediatric patients (6-17 years of age), i.e., 86.7% in 2019 and 90.5% in 2020, had percent predicted FEV1 >=70%; whereas paediatric patients with a FEV1% >=40% are less than 2% in the study period. 6. Nutrition: the two most critical periods are the first 6 months of life and adolescence. Prevalence of malnourished adolescent males (12-17 years of age) is higher than the prevalence observed in females. Increasing percentages of female patients with a suboptimal BMI value (33.5% and 31.4%, respectively, in 2019 and 2020) are observed in adult age. 7. Complications: in 2019, CF-related liver disease without cirrhosis was the main complication both in patients aged less than 18 years (20.3% on average) and in adults (37.5%). CF-related diabetes was also frequent in CF adults (23.4%). 8. Transplantation: in 2019-2020, 64 patients received a double-lung transplantation. Median and range of age were 33 years (12.29-57.46) in 2017 and 32.9 (16.5-53.6) years in 2020. Median waiting times for lung transplantation in the two-year period ranged from 6 to 8 months. 9. Microbiology: percentage of adult patients with chronic Pseudomonas aeruginosa infection was 41.6% in 2019 and 38.8% in 2020 vs 14.3% in 2019 and 7.6% in 2020 in paediatric age. Staphylococcus aureus infection is present in 31.1% and 35.9% of adult patients in 2019 and in 33.5% and 34.7% of paediatric patients in 2020. 10. Mortality: a total of 51 patients died in the 2019-2020 period (28 females and 23 males); median age at death was 35.7 years in 2019 and 39 years in 2020 (transplanted patients are not included). CONCLUSIONS: The present report shows that the Italian CF population is growing (4,159 in 2010 vs 5,801 in 2020). Median age of patients increased in the 2010-2020 period (17 years in 2010 vs 22.4 years in 2020). Prevalence of adult patients is increasing (in 2020, 60.5% of patients is more than 18 years old). About 68.5% of new patients is diagnosed within the second year of life and median age at death (transplanted patients not included) increased in 2020 up to 39 years (in 2018 this value was 35.8). Some statistical differences between 2019 and 2020 are mainly due to the absence of about 200 patients not included in 2019 data by a participating centre for a technical problem.

Risk factors for severe COVID-19 in people with cystic fibrosis: A systematic review

Background People with cystic fibrosis (CF) are considered a clinically fragile population with an intrinsic higher risk of developing severe COVID-19, though a certain variability in terms of outcomes and hospitalization has been noticed. Aim To highlight the main risk factors for severe COVID-19 in patients with CF. Methods A systematic review of the current literature was conducted through PubMed and EMBASE databases. English-written articles reporting clinical data on CF subjects with SARS-CoV2 infection were included and analyzed. Selected reports were evaluated for adherence to STROBE recommendations. Results After the selection phase, 9 observational studies were included, 5 of which reported data from CF Registry Global Harmonization Group. The hospitalization rate ranged from 18.2 to 58.1%. The main risk factors for severe outcome were as follows: FEV1 < 70%p, CF-related diabetes, age > 40 years, pancreatic insufficiency, underweight, previous transplant, azithromycin use. Use of dornase alfa was associated with decreased risk for severe disease, while there was insufficient evidence to establish the role of inhaled steroids or CFTR modulators. No solid data regarding specific SARS-CoV-2 therapies in patients with CF emerged. Conclusion Most people with CF experience a mild course of SARS-CoV-2 infection, nevertheless subgroups with higher risk of severe outcome emerged. Maintenance therapies for CF overall did not show a clear preventive effect against severe outcomes, although dornase alfa seems to give some protection. Due to the current lack of data on specific COVID-19 therapies and immunization in patients with CF, further studies are needed to establish their impact in this population.

Factors associated with clinical progression to severe COVID-19 in people with cystic fibrosis: A global observational study.

BACKGROUND: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen. RESULTS: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007). CONCLUSIONS: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2.

Factors for severe outcomes following SARS-CoV-2 infection in people with cystic fibrosis in Europe.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. METHODS: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. RESULTS: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). CONCLUSION: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes.

Case Report: Analysis of Inflammatory Cytokines IL-6, CCL2/MCP1, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP10 in a Cystic Fibrosis Patient Cohort During the First Wave of the COVID-19 Pandemic.

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, data registered in the European countries revealed increasing cases of infection in cystic fibrosis (CF) patients. In the course of this pandemic, we enrolled 17 CF patients for a study evaluating inflammatory markers. One of them developed COVID-19, giving us the possibility to analyze inflammatory markers in the acute phase as compared to levels detected before and after the infectious episode and to levels measured in the other CF patients enrolled to the study who did not experience COVID-19 and 23 patients referred to our center for SARS-CoV-2 infection.

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.

BACKGROUND: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams. METHODS: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020. RESULTS: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease. CONCLUSIONS: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease.

The global impact of SARS-CoV-2 in 181 people with cystic fibrosis.

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group.