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310 Prevalence of CF and spectrum of CFTR mutations in the Portuguese population
S138
12. Epidemiology/Registry
Posters
310 Prevalence of CF and spectrum of CFTR mutations in the Portuguese population
312 Outcomes and factors associated with poor outcome of children with cystic fibrosis admitted to the intensive care unit
A. Grangeia1 , S. Alves1 , L. Gon¸calves1 , A. Santos2 , A. Barros1 , C. Moura1 , F. Carvalho1 . 1 Faculty of Medicine of University of Porto, Genetics, Porto, Portugal; 2 Faculty of Medicine of University of Porto, Epidemiology, Porto, Portugal
J. Bucher1 , M. Oualha2 , L. Dupic2 , M. Lebourgeois1 , F. Lesage2 , S. Renolleau2 , V. Boussaud3 , F. Le Pimpec3 , P. Hubert2 , I. Sermet-Gaudelus1 , L. de Saint Blanquat2 . 1 Hˆopital Necker Enfants Malades, Service de Pneumologie et Allergologie P´ediatrique, CRCM, Paris, France; 2 Hˆopital Necker Enfants Malades, Service de R´eanimation P´ediatrique Polyvalente, Paris, France; 3 HEGP APHP, Service Chirurgie Thoracique, Paris, France
In the Portuguese population the prevalence of CF is unknown, as well as, the spectrum of CFTR gene mutations. Objectives: The main objective of this work was to evaluate the prevalence of CF and to establish the type and frequency of CFTR mutations in the Portuguese population. Methods: DNA was extracted from buccal mucosa cells of 512 Portuguese children, using a commercial kit. CFTR gene analysis was performed by Sanger Sequencing in 206 samples and by Next Generation Sequencing in 306 samples. Results: A total of 124 CF- and CFTR-related disorders (RD) mutations were identified. From de 512 samples analyzed, 90 had one mutation (17.6%) and 10 had two (1.9%). Taking into account only mutations included in the CFTR2 mutation database classified as CF-mutations or with varying consequences, the carrier frequency rate was 2.3%, being the most frequent mutation the p.Phe508del (0.98%). From the mutations detected, only the p.Phe508del is included in the screening commercial kits. The majority of mutations detected have been associated to CFTR-RD. The 5T allele (c.1210−12[5T]) was detected with an allelic frequency of 3.4%, followed by the complex allele p.Gly576Ala-p.Arg668Cys with 1.1%. Conclusion: A wide spectrum of CFTR mutations was identified, confirming the highest CFTR allelic heterogeneity previously reported in Mediterranean countries. These results highlight the low power detection of the commercial kits for CFTR gene screening in our population. Additionally, this emphasizes the importance of the implemented Neonatal Screening Program last year in Portugal, as it facilitates the early diagnosis of symptom-free newborns carrying mutations.
Prognosis of adult patients with cystic fibrosis (CF), admitted to intensive care unit (ICU), has improved. Few data are available for children. The aim is to describe clinical course and outcomes of CF children hospitalized in ICU. Baseline characteristics of children, reasons for admission in ICU, ventilatory support and outcomes at discharge from ICU were retrospectively analyzed. Non parametric statistical test compared data of survivors at ICU to those with poor outcome (death or lung transplantation in super emergency). From 2000 to 2013, 26 children, median age 13.4 years (1.9–17.6), were admitted to ICU (NeckerEnfants Malades, Paris). Before admission, 15 children (58%) had a non-invasive ventilation (NIV) and 23 (88%) were colonized with Pseudomonas aeruginosa. The median forced expiratory volume (FEV1 ) was 32% (13–101). Eighteen children (69%) were admitted for respiratory exacerbation, NIV was initiated for 18 (69%) and 9 (35%) were intubated. Half of the 26 children had a poor outcome, 5 (19%) died and 8 (31%) needed urgent lung transplantation. Poor outcome-associated factors were female sex (p = 0.015), history of hemoptysis (p = 0.03), ventilation (p = 0.001) or nutritional (p = 0.017) support before ICU, chronic intravenous antibiotics use (p = 0.001), lower FEV1 before ICU (27% (13−49) for poor outcome group and 40% (17–101) for survival group, p = 0.036), admission for respiratory exacerbation (p = 0.030), hypercapnia (p = 0.010), metabolic acidosis (p = 0.007) and hypochloremia (p = 0.013). Our study highlights poor outcomes in children hospitalized in ICU and points factors associated with poor outcomes. This will help to improve indications of pediatric lung transplant.
311 Treatment and demographic factors affecting time to next pulmonary exacerbation in cystic fibrosis
313 An international study of survival of children with cystic fibrosis after the first episode of invasive mechanical ventilation
D.R. VanDevanter1 , D.J. Pasta2 , M. Konstan1 . 1 Case Western Reserve University School of Medicine, Cleveland, United States; 2 ICON Clinical Research, San Francisco, United States
A. Prayle1 , R. Parslow2 , S. Erikson3,4 , J. Alexander5 , H. Vyas6 , A. Fogarty1 , A.R. Smyth1 , ANZICS Paediatric Study Group. 1 University of Nottingham, Nottingham, United Kingdom; 2 University of Leeds, Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, United Kingdom; 3 Princess Margaret Hospital for Children, Intensive Care Unit, Western Australia, Australia; 4 Paediatric Study Group of ANZICS, Victoria, Australia; 5 ANZPIC Registry, Victoria, Australia; 6 Nottingham University Hospitals NHS Trust, Paediatric Intensive Care Unit, Nottingham, United Kingdom
Objectives: Pulmonary exacerbations (PEx) are important clinical events and reduction of PEx risk is a useful clinical trial efficacy endpoint in CF. Methods: We studied time to next intravenous (IV) antibiotic-treated PEx following IV treatment of PEx among Cleveland Ohio CF Care Center patients from 2010 to 2014. Using Cox proportional hazards regression, we evaluated 63 demographic, clinical, and treatment covariates to identify those associated with time to next PEx. Results: 193 patients were treated for PEx between Jan 2010 and Sept 2014; 155 (80.3%) had a subsequent IV-treated PEx. Median follow-up for the remaining 38 patients was 705 days (range 48–1487). Median age at PEx treatment was 23.0 years. IV antibiotics were given an average of 19.7 days (median 17 days), with an average of 12.2 treatment days in hospital (median 12 days). Median time to next PEx was 311 days [95% CI 242, 389] among the 193 patients studied. Six covariates were associated with future PEx hazard: number of PEx in the prior year (hazard ratio 25.1 for 3 and 4.4 for 1−2 prior-year PEx versus none; P < 0.0001), IV treatment duration in weeks (1.2; P = 0.0004), percent hospital treatment (1.1; P = 0.0018), and chronic inhaled aminoglycosides (2.5; P < 0.0001), leukotriene modifiers (1.8; P = 0.0031), and high dose ibuprofen (0.52; P = 0.0006). Conclusion: The dramatic differences in future PEx hazard rates (more than 25fold) associated with prior-year PEx suggest fundamentally different phenotypes among persons with CF. Given the substantial community interest in improving PEx management and outcomes, high-risk PEx phenotypes warrant recognition and further study.
The outcome of cystic fibrosis (CF) patients who require invasive mechanical ventilation (IMV) is generally considered to be poor, although limited data are available. Objectives: To determine a current estimate of survival in the UK, Ireland, Australia and New Zealand amongst children with CF requiring IMV, in a setting where both CF services and intensive care are well resourced. Methods: Analysis of data from two clinical databases collected on Paediatric Intensive Care Unit (PICU) admissions in the UK and Ireland (PICANet database) and Australia and New Zealand (ANZPIC database). The primary outcome was survival at discharge from PICU of patients after their first episode of IMV. Results: There were 139 CF admissions to intensive care in the PICANet study population. The survival to discharge for these patients was 121/139 (87.1%; 95% Confidence Interval: 80.5 to 91.7%). There were 84 CF admissions to intensive care in the ANZPIC study population. The survival to discharge for these patients was 79/84 (94.0%; 95% CI 86.8 to 97.4%). Survival was better for younger age groups (log-rank test p < 0.001). Conclusion: The survival at discharge from paediatric intensive care for nontransplant admissions that required mechanical ventilation in patients with CF is better than previously reported. IMV should not be withheld solely due to a diagnosis of CF.
12. Epidemiology/Registry
Posters
310 Prevalence of CF and spectrum of CFTR mutations in the Portuguese population
312 Outcomes and factors associated with poor outcome of children with cystic fibrosis admitted to the intensive care unit
A. Grangeia1 , S. Alves1 , L. Gon¸calves1 , A. Santos2 , A. Barros1 , C. Moura1 , F. Carvalho1 . 1 Faculty of Medicine of University of Porto, Genetics, Porto, Portugal; 2 Faculty of Medicine of University of Porto, Epidemiology, Porto, Portugal
J. Bucher1 , M. Oualha2 , L. Dupic2 , M. Lebourgeois1 , F. Lesage2 , S. Renolleau2 , V. Boussaud3 , F. Le Pimpec3 , P. Hubert2 , I. Sermet-Gaudelus1 , L. de Saint Blanquat2 . 1 Hˆopital Necker Enfants Malades, Service de Pneumologie et Allergologie P´ediatrique, CRCM, Paris, France; 2 Hˆopital Necker Enfants Malades, Service de R´eanimation P´ediatrique Polyvalente, Paris, France; 3 HEGP APHP, Service Chirurgie Thoracique, Paris, France
In the Portuguese population the prevalence of CF is unknown, as well as, the spectrum of CFTR gene mutations. Objectives: The main objective of this work was to evaluate the prevalence of CF and to establish the type and frequency of CFTR mutations in the Portuguese population. Methods: DNA was extracted from buccal mucosa cells of 512 Portuguese children, using a commercial kit. CFTR gene analysis was performed by Sanger Sequencing in 206 samples and by Next Generation Sequencing in 306 samples. Results: A total of 124 CF- and CFTR-related disorders (RD) mutations were identified. From de 512 samples analyzed, 90 had one mutation (17.6%) and 10 had two (1.9%). Taking into account only mutations included in the CFTR2 mutation database classified as CF-mutations or with varying consequences, the carrier frequency rate was 2.3%, being the most frequent mutation the p.Phe508del (0.98%). From the mutations detected, only the p.Phe508del is included in the screening commercial kits. The majority of mutations detected have been associated to CFTR-RD. The 5T allele (c.1210−12[5T]) was detected with an allelic frequency of 3.4%, followed by the complex allele p.Gly576Ala-p.Arg668Cys with 1.1%. Conclusion: A wide spectrum of CFTR mutations was identified, confirming the highest CFTR allelic heterogeneity previously reported in Mediterranean countries. These results highlight the low power detection of the commercial kits for CFTR gene screening in our population. Additionally, this emphasizes the importance of the implemented Neonatal Screening Program last year in Portugal, as it facilitates the early diagnosis of symptom-free newborns carrying mutations.
Prognosis of adult patients with cystic fibrosis (CF), admitted to intensive care unit (ICU), has improved. Few data are available for children. The aim is to describe clinical course and outcomes of CF children hospitalized in ICU. Baseline characteristics of children, reasons for admission in ICU, ventilatory support and outcomes at discharge from ICU were retrospectively analyzed. Non parametric statistical test compared data of survivors at ICU to those with poor outcome (death or lung transplantation in super emergency). From 2000 to 2013, 26 children, median age 13.4 years (1.9–17.6), were admitted to ICU (NeckerEnfants Malades, Paris). Before admission, 15 children (58%) had a non-invasive ventilation (NIV) and 23 (88%) were colonized with Pseudomonas aeruginosa. The median forced expiratory volume (FEV1 ) was 32% (13–101). Eighteen children (69%) were admitted for respiratory exacerbation, NIV was initiated for 18 (69%) and 9 (35%) were intubated. Half of the 26 children had a poor outcome, 5 (19%) died and 8 (31%) needed urgent lung transplantation. Poor outcome-associated factors were female sex (p = 0.015), history of hemoptysis (p = 0.03), ventilation (p = 0.001) or nutritional (p = 0.017) support before ICU, chronic intravenous antibiotics use (p = 0.001), lower FEV1 before ICU (27% (13−49) for poor outcome group and 40% (17–101) for survival group, p = 0.036), admission for respiratory exacerbation (p = 0.030), hypercapnia (p = 0.010), metabolic acidosis (p = 0.007) and hypochloremia (p = 0.013). Our study highlights poor outcomes in children hospitalized in ICU and points factors associated with poor outcomes. This will help to improve indications of pediatric lung transplant.
311 Treatment and demographic factors affecting time to next pulmonary exacerbation in cystic fibrosis
313 An international study of survival of children with cystic fibrosis after the first episode of invasive mechanical ventilation
D.R. VanDevanter1 , D.J. Pasta2 , M. Konstan1 . 1 Case Western Reserve University School of Medicine, Cleveland, United States; 2 ICON Clinical Research, San Francisco, United States
A. Prayle1 , R. Parslow2 , S. Erikson3,4 , J. Alexander5 , H. Vyas6 , A. Fogarty1 , A.R. Smyth1 , ANZICS Paediatric Study Group. 1 University of Nottingham, Nottingham, United Kingdom; 2 University of Leeds, Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, United Kingdom; 3 Princess Margaret Hospital for Children, Intensive Care Unit, Western Australia, Australia; 4 Paediatric Study Group of ANZICS, Victoria, Australia; 5 ANZPIC Registry, Victoria, Australia; 6 Nottingham University Hospitals NHS Trust, Paediatric Intensive Care Unit, Nottingham, United Kingdom
Objectives: Pulmonary exacerbations (PEx) are important clinical events and reduction of PEx risk is a useful clinical trial efficacy endpoint in CF. Methods: We studied time to next intravenous (IV) antibiotic-treated PEx following IV treatment of PEx among Cleveland Ohio CF Care Center patients from 2010 to 2014. Using Cox proportional hazards regression, we evaluated 63 demographic, clinical, and treatment covariates to identify those associated with time to next PEx. Results: 193 patients were treated for PEx between Jan 2010 and Sept 2014; 155 (80.3%) had a subsequent IV-treated PEx. Median follow-up for the remaining 38 patients was 705 days (range 48–1487). Median age at PEx treatment was 23.0 years. IV antibiotics were given an average of 19.7 days (median 17 days), with an average of 12.2 treatment days in hospital (median 12 days). Median time to next PEx was 311 days [95% CI 242, 389] among the 193 patients studied. Six covariates were associated with future PEx hazard: number of PEx in the prior year (hazard ratio 25.1 for 3 and 4.4 for 1−2 prior-year PEx versus none; P < 0.0001), IV treatment duration in weeks (1.2; P = 0.0004), percent hospital treatment (1.1; P = 0.0018), and chronic inhaled aminoglycosides (2.5; P < 0.0001), leukotriene modifiers (1.8; P = 0.0031), and high dose ibuprofen (0.52; P = 0.0006). Conclusion: The dramatic differences in future PEx hazard rates (more than 25fold) associated with prior-year PEx suggest fundamentally different phenotypes among persons with CF. Given the substantial community interest in improving PEx management and outcomes, high-risk PEx phenotypes warrant recognition and further study.
The outcome of cystic fibrosis (CF) patients who require invasive mechanical ventilation (IMV) is generally considered to be poor, although limited data are available. Objectives: To determine a current estimate of survival in the UK, Ireland, Australia and New Zealand amongst children with CF requiring IMV, in a setting where both CF services and intensive care are well resourced. Methods: Analysis of data from two clinical databases collected on Paediatric Intensive Care Unit (PICU) admissions in the UK and Ireland (PICANet database) and Australia and New Zealand (ANZPIC database). The primary outcome was survival at discharge from PICU of patients after their first episode of IMV. Results: There were 139 CF admissions to intensive care in the PICANet study population. The survival to discharge for these patients was 121/139 (87.1%; 95% Confidence Interval: 80.5 to 91.7%). There were 84 CF admissions to intensive care in the ANZPIC study population. The survival to discharge for these patients was 79/84 (94.0%; 95% CI 86.8 to 97.4%). Survival was better for younger age groups (log-rank test p < 0.001). Conclusion: The survival at discharge from paediatric intensive care for nontransplant admissions that required mechanical ventilation in patients with CF is better than previously reported. IMV should not be withheld solely due to a diagnosis of CF.