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Cystic fibrosis is a rare life-long genetic disease that affects approximately 4,000 people in Canada and about 70,000 worldwide regardless of race or ethnicity but is more common in Caucasians 1,2 CF generally manifests in infancy or early childhood and leads to a shortened lifespan. Availability of multiple treatments and an improved understanding of the course of the disease has led to increased life expectancy; however, the median predicted age of survival was reported to be 52.1 years in Canada in 2015 1 Clinical manifestations of CF occur throughout the body and affect many key organs and systems, including lungs, sinuses, pancreas, digestive and reproductive tracts, sweat glands and others 3 References 1. Canadian Cystic Fibrosis Registry, 2013 Annual Report. 2. Cystic Fibrosis Foundation (CFF) Patient Registry. 2015 Annual Data Report. Bethesda, MD CFF, 2016 3. O Sullivan BP, Freedman SD. Lancet. 2009;373:1891-1904. 4
Key Points: 1. CF is present before birth and manifests early in life. Some signs such as meconium ileus and abnormal pancreas function appear in a proportion of CF patients even before birth. 2 2. Throughout infancy and early childhood, CF children are more susceptible to bouts of lung infection, leading to increasing proportions of patients with chronic lung infection by adulthood. 3,4 3. The progressive nature of CF means that widespread manifestations of the disease often appear and accumulate throughout the lifespan. 2-6 References: 1. Zielenski J. Respiration. 2000;67:117 133 2. Wilschanski M, Durie PR. Gut. 2007;56(8):1153 1163 3. Cystic Fibrosis Foundation (CFF) Patient Registry. 2013 Annual Data Report. Bethesda, MD: CFF, 2014 4. Yankaskas JR et al. Chest. 2004;125(1 suppl):1s 39S 5. Davis PB et al. Am J Resp Crit Care Med. 1996;154(5):1229 1256 6. O Sullivan BP, Freedman SD. Lancet. 2009;373(9678):1891 1904 Canadian data from the Canadian Cystic Fibrosis Registry 2015 Annual Report Respiratory status: From the Canadian Registry, the majority (53.1%) of children, ages 6 to 17 years, have normal lung 5
function while the majority (37.3%) of adults have moderate lung function. Approx 30% of children have mild lung disease (FEV 1 70-89%), approx. 13% have moderate lung disease (FEV 1 40-69%), and approx. 2% have severe lung disease (FEV 1 <40%). (ref page 16, Figure 15) Approx 28% of adults have mild lung disease (FEV 1 70-89%), approx. 37% have moderate lung disease (FEV 1 40-69%), and approx. 16% have severe lung disease (FEV 1 <40%). (ref page 16, Figure 15) Microbiology: Overall, Pseudomonas aeruginosa (36.0%) and Staphylococcus aureus (51.1%) are the most common pulmonary pathogens in Canadians with CF (Ref page 26, Figure 31). Staphyloccocus aureus is more common in children with CF and Pseudomonas aeruginosa is more common in the adult CF population (Figure 33). CFRD: There is an increasing prevalence of CFRD with age (Page 29, Figure 36). CFRD was reported in 992 (23.7%) individuals with CF in 2015 and of those, 22.0% have had a transplant, 49.3% were female and 42.6% were 35 years of age or older. 5
Canadian data from the Canadian Cystic Fibrosis Registry 2015 Annual Report Survival: There were 47 deaths recorded in the CCFR in 2015. The cumulative number of deaths reported in 2010 to 2015 are included in Figure 41. The median age at death in 2015 was 29.7 years of age (Figure 42) indicating that half of those who died were younger than the median age at death and the other half who died were older. The most common cause of death was related to pulmonary complications and 16 of the 47 (34.0%) individuals with CF who passed away in 2015 were posttransplant. (ref page 32) 6
While this increase in median predicted survival is encouraging, mean predicted survival is increased to an extent by new-born screening and other early detection of disease, which have allowed diagnosis of cystic fibrosis in children with CFTR mutations that result in less rapidly progressive disease. Median age at death has remained lower, with a median age at death in 2015 of 29 years (Cystic Fibrosis Foundation (CFF) Registry. 2015 Annual Data Report Bethesda, MD: CFF 2016.) Canadian data from the Canadian Cystic Fibrosis Registry 2015 Annual Report Survival: In 2015, the median age of survival is currently estimated to be 52.1 years of age (Figure 43). The median age of survival is the estimated age to which 50% of the CF population would be expected to survive assuming that current treatments, therapies and mortality rates remain constant. Since transplant is considered a form of therapy for end-stage CF, transplanted individuals are included in the analysis because excluding deaths post-transplant would bias the survival estimates resulting in an overestimation of survival. 7
Key Points: 1. Of note, early recognition of CF resulted in survival benefits in patients even before major therapeutic advances had been made 1 2. Predicted survival rates in CF patients have continued to improve over time, increasing from only a few months in 1968 before the first pathologic description of CF was made, to a current median survival of 41.7 years 2 in the US and 52.1 years in Canada 3 References: 1. Shwachman H and Kulczycki LL. Am J Dis Child 1958;96:7 15 2. Cystic Fibrosis Foundation (CFF) Patient Registry, Annual Data Report. Bethesda, MD: CFF, 2016 3. Canadian Cystic Fibrosis Registry, 2015 Annual Report 8
This study compared ppfev 1 in patients with CF with a genotype that confers residual CFTR activity (e.g., CFTR-R117H) vs CFTR-F508del, a genotype associated with classical CF disease. A retrospective cohort of patients in the US CFF Patient Registry from 2006 to 2014 was used to compare patients with a residual function (RF) mutation heterozygous for F508del with patients homozygous for the F508del mutation In total, 1242 RF patients (353 with the R117H mutation) and 11,916 homozygous F508del patients met the selection criteria and were included in the analysis The ppfev 1 rate of change (slope) was estimated for the R117H and F508del cohorts, adjusted for age group (6-12, 13-17, 18-24, and 25 years) While the rate of decline in patients with an RF mutation was slower compared with patients homozygous for F508del, both cohorts of patients experienced annual decline in ppfev 1 across all age groups and the decline was most severe in adolescent and young adults. Limitations: The study only included RF patients heterozygous for F508del and thus may not be generalizable to patients with other RF genotypes (e.g., R117H/R117H). Phenotypic variability in patients with the R117H mutation is also influenced by the poly-t tract status of intron 8, which was not examined in this study. Reference Sawicki GS et al. ATS. 2017. Poster A4847. 9
Key Points: 1. FEV 1 effectively measures disease progression in later stage lung disease, but is not sensitive enough to detect early localized or small airway obstructions 2-5 2. CF patients have evidence of structural lung abnormalities prior to decline or changes in FEV 1 6-10 3. CT scans of both children and adults reveal that FEV 1 does not capture certain structural lung changes. The top figure is an example of extensive localized bronchiectasis and mucus plugging in a 13-year old boy with cystic fibrosis who presented with ppfev 1 of 99. The bottom figure is an example of a 30-year old CF patient with clear signs of lung damage and severe progression detected by CT with a ppfev 1 value of 94% 13. 4. It is important to note, these structural abnormalities are likely irreversible. 9 References 1. Aurora P et al. Thorax. 2004; 59(12):1068-1073 2. Yankaskas JR, et al. Chest. 2004;125:1-39; 3. Corey M. Proc Am Thorac Soc. 2007;4:334-337; 4. Macklem P. Am J Respir Crit Care Med. 1998;157:S181-S183; 5. Tiddens HA. Pediatr Pulmonal. 2002;34:228-231; 6. Owens CM. Thorax. 2011;66(6):481-488; 10
7. Ellemunter H. Respir Med. 2010;104:1834-1842; 8. Gustafsson PM. Thorax. 2008;63(2):129-134; 9. de Jong PA, et al. Radiology. 2004;231(2):434-439; 10. Brody AS, et al. Am J Respir Crit Care Med. 2005;172(10):1246-1252; 11. Aurora P et al. Am J Respir Crit Care Med. 2011;183(6):752-758 12. Judge EP et al. Chest. 2006;130(5):1424-32 10
We now know that lung damage can occur even when lung function may appear normal with spirometry and that use of spirometry measures can impact treatment decisions. Next we will focus on evidence and techniques that demonstrate that CF disease begins early. 11
Key messages: - Most CF-related morbidities can be seen at very young age in the first year of life - Both in the lung and outside the lung pancreatic insufficiency, nutritional deficiencies Fig. 1. Percentage of study samples with morbidity - The shaded portion of each pie chart corresponds to the percentage of the study sample with CF that was reported to have specific morbidities or abnormalities. - The sizes of the study samples with CF ranged from 11 to 9895. - Numbers next to each pie chart are the study citation can be ignored on the slide. - Mid-range age was calculated by subtracting the youngest age from the oldest age, dividing by two, and adding the result to the youngest age. 12
Each circle represents 1 study. The shaded proportion of the circle represents the percentage of patients in that study who had that abnormality at that timepoint Key messages: - Most CF-related morbidities can be seen at very young age in the first year of life - Both in the lung and outside the lung pancreatic insufficiency, nutritional deficiencies Fig. 1. Percentage of study samples with morbidity - The shaded portion of each pie chart corresponds to the percentage of the study sample with CF that was reported to have specific morbidities or abnormalities. - The sizes of the study samples with CF ranged from 11 to 9895. - Numbers next to each pie chart are the study citation can be ignored on the slide. - Mid-range age was calculated by subtracting the youngest age from the oldest age, dividing by two, and adding the result to the youngest age. 13
Similar information as previous 2 slides (slides 12 and 13) but depicted in a different way. Key points: 1. This figure shows us studies included in a review of early disease manifestations in CF. Age in years is represented along the horizontal axis, and disease features are shown on the vertical axis. 2. Click animation. Even within the first year of life, there is evidence of a wide range of CF-related morbidities including pancreatic insufficiency, nutritional and growth deficiencies, and liver dysfunction. 3. In addition to ex-pulmonary findings, patients show multiple abnormalities of the lung, many of them being detected within the first year of life. Notes: - The sizes of the study samples represented ranged from 11 to 9895. Reference: 1. VanDevanter DR et al. J Cyst Fibros. 2016;15(2):147-57. 14
Key Points: 1. Infants with CF may already have structural lung damage, as revealed by a prospective study of all infants with CF through newborn screening in Western Australia and Victoria. The majority of infants (80.7%) already had abnormal CT scans at the time of assessment. The figure on the left show differences between CF lungs compared with healthy lungs in infants at an average of 28 days old. The CT scans reveal bronchial dilatation (or bronchiectasis), bronchial wall thickening, and gas trapping. 1 2. Other abnormalities detected by CT scans include mucus plugging and mosaic perfusion 2,3 Notes: Infants in the study underwent a CT scan that collected 3 discrete slices, a method that may underestimate the detection of all lung abnormalities 4 84.2% of infants in the study presented with no respiratory symptoms but 21.1% tested positive for bacterial infection and 29.8% had detectable neutrophil elastase activity, considered one of the most destructive pro-inflammatory enzymes in the body 5 References 1. Sly PD et al. Am J Respir Crit Care Med. 2009;180(2):146-152. 2. Brody AS, et al. Am J Respir Crit Care Med. 2005;172(10):1246-1252 3. Judge EP et al. Chest. 2006;130(5):1424-32 4. Sitck SM et al. J Pediatr. 2009;155(5):623-8 5. Kawabata et al. Eur J Pharmacol. 2002;451(1):1-10 15
Key Points: Another study of 71 infants (mean age 39 weeks) with positive CF screening demonstrated that LCI was significantly higher than that of healthy infants (mean age 40 weeks), while forced expiratory volume (FEV), forced vital capacity (FVC), forced expiratory flow (FEF), and functional residual capacity (FRC) all of which were tested using the raised volume technique during quiet sleep were significantly lower. In addition, the CF infants exhibited hyperinflation and gas trapping. 2 References 1. Hoo AF, Thia LP, Nguyen TT, et al. Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax. 2012;67(10):874-881. 16
Key Points: LCI, a tool that can be used to detect early lung disease 3, detects abnormal lung function in infants with CF (LCI score of 8.4) compared with healthy infants (LCI score of 7.2) 56.4% of infants (median age of 41.4 weeks) with CF were over the LCI ULN (7.8), in contrast, no healthy subjects (median age of 37 weeks) were over the ULN. Furthermore, LCI, a measure of lung function, significantly correlates with findings from CT scans 2. Notes (Left Figure): Measurements were performed during quiet sleep, with tidal breathing MBW technique being performed before the forced expiratory maneuvers MBW testing was done with SF 6 and measured using mass spectrometry Notes (Right Figure): N=34 patients (6-26 years of age) with CF, all with normal FEV 1 (defined as >80% predicted) LCI was increased in 26/34 (76.5%) CT was abnormal (Bhalla score) in 26/34 (76.5%) References: 1. Lum S et al. Thorax. 2007;62(4):341-347 2. Ellemunter H et al. Respir Med. 2010;104(12):1834-1842 3. Gustafsson PM et al. Thorax. 2008;63:129 34 17
Study of preschool children with CF and age-matched controls (n=156) Aged 2.5 6 years 800 LCI measurements 18
Association between pulmonary symptoms and lung clearance index (LCI) in health (solid line) and cystic fibrosis (CF) (dashed line). Neither upper airway symptoms nor cough were associated with higher LCI values in healthy participants, whereas both cough and pulmonary exacerbation were associated with significantly higher LCI values in CF. Upper airways symptoms were not associated with higher LCI values in CF. Additional notes: Study of preschool children with CF and age-matched controls (n=156) Aged 2.5 6 years 800 LCI measurements 19
Key Points 1. Acute pulmonary exacerbations are a common consequence of CF 2. These are acute episodes of worsening lung disease and often require hospitalisation and/or treatment with IV antibiotics 3. The number of exacerbations a person with CF experiences per year increases with age 4. The major clinical consequences of pulmonary exacerbations include irreversible and progressive loss of lung function, increased risk for future exacerbations, reduced health-related quality of life, and increased risk of death. 5. Preventing pulmonary exacerbations is an important goal in the care of CF patients Additional Information Patients who experience pulmonary exacerbations on a frequent basis are at greater risk of worsened lung function, in turn putting them at greater risk of lung transplant or death. Patients who have more than 2 exacerbations in a year have reduced lung function at baseline, which continues to decline progressively over time. Patients who have 1 to 2 exacerbations a year have not been shown to experience a significantly accelerated risk of lung transplant or death compared with those who have less than 1 exacerbation. Patients with CF who regularly experience more than 2 exacerbations a year should be monitored closely, and lung transplants should be considered in a timely fashion for these patients. 20
References 1. Goss CH, Burns JL. Thorax. 2007;62(4):360-367. 2. CFF Patient Registry. Annual Report to the Center Directors, 2015. 3. Sanders DB et al. Am J Resp Crit Care Med. 2010;182(5):627-632. 4. Sanders DB et al. Pediatr Pulmonol. 2011;46(4):393-400. 5. Waters V et al. J Cyst Fibros. 2012;11(1):8-13. 6. Collaco JM et al. Am J Respir Crit Care Med. 2010;182(9):1137-1143. 7. VanDevanter et al. J Cyst Fibros. 2015 :14(6):763-9. 8. Britto et al. Chest. 2002;121:64 72. 9. de Boer K et al. Thorax. 2011;66(8):680-685. 10. Liou TG et al. Am J Epidemiol. 2001;153(4):345-352. 11. Stephenson AL et al. Eur Resp J. 2015;45(3):670-679. 12. Buzzetti R. J Cyst Fibros. 2012;11(1):24-29. 20
Key Points: In addition to structural changes, inflammatory events in the airways of children with CF are thought to start early in life. Pro-inflammatory markers are elevated in the lungs of CF patients, even at an early age, compared with healthy control patients. Lungs with substantial damage (i.e. bronchiectasis) display significantly elevated levels of inflammatory markers compared with healthy controls Elevated inflammatory activity, likely a result of the increased susceptibility of CF patients to infection at an early age 2, and subsequent lung damage can result in pulmonary exacerbation induced lung function decline that may not recover 3 Reference: 1. Tan H et al. Am J Respir Crit Care Med. 2011;184(2):252-8 2. Lyczak et al. Clin Microbiol Rev. 2002;15(2):194-222 3. Sanders et al. Am J Respir Crit Care Med. 2010;182(5):627-32 21
Key Points: This study examined early radiologic and infection abnormalities in CF patients with genotypes considered to have residual function (i.e. R117H and 3849+10kb C->10) compared with patient characteristics who are homozygous for F508del. - Although there was a numerical trend for residual function patients having higher FEV 1 compared with the F508del patients (86.5% vs. 76%, n.s.), all 11 patients in the residual function cohort demonstrated some radiologic evidence of lung disease, including signs of bronchial wall thickening, hyperinflation, as well as the majority demonstrating positive sputum cultures associated with lung infection (e.g., P. aeruginosa). Notes: - The age range of patients was 1-11 for both the residual function cohort and F508del cohort - Patients had been under care between 1 and 7 years with a mean follow-up of 5.2 years Reference: 1. Lording A et al. J Cyst Fibros. 2006;5(2):101-4 22
Key Points: This study focused on survival of patients with CF in the US CFF database based on the severity of their genotypes 1 Of note, patients lung function between severe and residual function phenotypes, as assessed by FEV 1, was similar at the time they entered the cohort Median survival and median age of death for both severe and residual function phenotypes indicate early mortality compared with normal life expectancy, regardless of genotype Notes: Analysis was limited to CFTR genotypes that were recorded in the database, had a known functional class, and whose allele frequency was >0.1% 1 Genotypes were classified as severe if the mutations on both alleles fell into class I, II, or III, and classified as mild if at least one mutation on one allele fell into class IV or V 1 Patients were followed between 1993 and 2002 1 Median follow-up was 8.6 years for patients with a high-risk CFTR genotype vs 5.1 years for patients with a low-risk CFTR genotype 1 There were a total of 1672 deaths during the 10-year follow-up period 1 Reference 1. McKone EF et al. Chest. 2006;130(5):1441-1447. 23
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The objectives shown on this slide were suggested by an expert panel of cystic fibrosis specialists. 25
Key Points: - Observations as early as the 1950s suggested that early recognition of even mild CF disease resulted in better health outcomes in patients 1 - Studies from one of the earliest NBS programs demonstrated improved health outcomes, including pulmonary, in patients screened by the program compared with those that were clinically diagnosed (unscreened) 2 1. Shwachman H and Kulczycki LL. Am J Dis Child 1958;96:7 15 2. Dankert-Roelse JE and Meerman GJ. Thorax. 1995;50(7):712-718 26
Key Points: - The example demonstrates positive outcomes of early diagnosis via NBS with a relatively large gap in age for clinically diagnosed patients. This study shows that early diagnosis can lead to positive health outcomes when there is a difference in age at diagnosis 1 - Considering structural abnormalities and lung damage may already be evident by the first year of life 2,3, early diagnosis and access to expert care may be necessary to better preserve lung function and promote overall health compared with intervention due to clinical diagnoses and standard measures of respiratory decline (i.e. FEV 1 ) References: 1. Coffey M et al. J Pediatr. 2017;181:137-145 2. Sly PD et al. Am J Respir Crit Care Med. 2009;180(2):146 152 3. Hoo A-F et al. Thorax. 2012;67(10):874 881 27
Key Points: - Strong evidence of the benefit of early diagnosis and expert care comes from a study examining 57 patients diagnosed clinically before an NBS program was in place and 60 patients diagnosed after an NBS program was put in place in the same center (New South Wales, Australia) 1 - Patients who were identified at 1.6 months of age on average had better health outcomes than those who were diagnosed on the basis of symptoms at an average of 7.1 months, highlighting the positive outcomes that can arise from early diagnosis with even relatively small differences in age - Significantly improved health outcomes in infection, growth and nutrition status, as well as spirometry (FEV 1, FVC, FEF 25 ) were observed 1 Reference: 1. Dijk NF, et al. Arch Dis Child. 2011;96(2):1118-23 28
Key Points: Overall, achievements have been made in standard of care that have led to a quantifiable increase in FEV 1 in more recent birth cohorts However, a similar decline in lung function across birth cohorts suggests that the problem of preventing or slowing irreversible lung disease remains a major hurdle A paradigm shift in recognizing that CF starts early and that early intervention in preschool years or earlier can improve health outcomes later in life is warranted 2 1. Cystic Fibrosis Foundation (CFF) Patient Registry, 2015 2. Ranganathan SC, et al. AmJ Respir Crit Care Med. 2017; 195(12):1567-75 29
Arrows indicate the ages in each study at which the children diagnosed earlier weighed significantly more than the children diagnosed later. Circles denote the age at which weights between the two groups were no longer significantly different, due to catch-up growth of the late-diagnosis group of children. For 3 studies, weight was still significantly different between the two groups at the end of the study (black ). Note: these comparisons were between groups of children with CF, and while these data represent improved weight, weight was not always improved to population norms with early diagnosis and treatment initiation 30
FIGURE 2. Forced expiratory volume in 1 s (FEV 1 ) and number of patients by age. Data are presented as mean (95% CI) unless otherwise stated. % pred: % predicted. FEV 1 % pred was negatively associated with age (fig 2): mean FEV 1 % pred decreased from 91.2% (95% CI 90.4 91.9) in the 6 9-year-olds to 55.5% (95% CI 53.4 57.6) in the 40 44-year-olds (table 1 in the publication). As shown in figure 2, the decline starts slowly, becomes sharper at age 12 years, continues until the age of 20 years and then stays fairly stable. In contrast, the number of patients (fig. 2) is quite uniform up to age 18 years, when it steadily decreases across the remaining years, although with a less steep decrease from the age of 30 years. Thus, we noticed a gap of roughly 6 years between the sharper decline in FEV 1 and the subsequent decline in the number of patients. Reference: Eur Respir J. 2014 Jan;43(1):125-33. Factors associated with FEV 1 decline in cystic fibrosis: analysis of the ECFS patient registry. Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, Drevinek P, Gulmans V, Krivec U, Olesen H; ECFS Patient Registry Steering Group. Abstract: Pulmonary insufficiency is the main cause of death in cystic fibrosis (CF). We analyzed forced expiratory volume in 1 s (FEV 1 ) data of 14,732 patients registered in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database in 2007. We used linear and logistic regressions to investigate associations between FEV 1 % predicted and clinical outcomes. Body mass index (BMI), chronic infection by Pseudomonas aeruginosa, pancreatic status and CF-related diabetes (CFRD) showed a statistically significant (all p<0.0001) and clinically relevant effect on FEV 1 % pred after adjusting for age. Patients with a lower BMI experience a six-fold 31
increased odds ratio (95% CI 5.0-7.3) of having severe lung disease (FEV 1 <40% pred) compared to patients with normal BMI. Being chronically infected with P. aeruginosa increases the odds ratio of severe lung disease by 2.4 (95% CI 2.0-2.7), and patients with pancreatic insufficiency experience a 2.0-fold increased odds ratio (95% CI 1.6-2.5) of severe lung disease compared to pancreatic sufficient patients. Patients with CFRD have a 1.8-fold increased odds ratio (95% CI 1.6-2.2) compared to patients not affected. These potential risk factors for pulmonary disease in patients with CF are to some degree preventable or treatable. We emphasize the importance of their early identification through frequent routine tests, the implementation of infection control measures, and a timely initiation of relevant therapies. 31
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