Across the European Union , about 1 in 2, to 3, babies are diagnosed with CF at birth, slightly higher than the U. In many countries, infants are not tested for CF at birth and national registries if they exist are lacking in data. In countries without a national CF registry, most studies are conducted by individuals rather than national organizations, making it difficult to establish a reliable prevalence of the disease.
A trend toward increasing lifespan for CF patients is also present in the global population. However, patients in developing countries generally have a much lower life expectancy , with many dying in their teens. Cystic Fibrosis News Today is strictly a news and information website about the disease.
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This population, which includes patients carrying mild genotypes but also patients diagnosed in adulthood, is particularly interesting for identifying the predictors of better survival [ 58 ]. Many factors are responsible for these major advances such as standardization of care, with management of patients in specialized centers by multidisciplinary teams, better control of pulmonary infection with the development of new inhaled therapies, better control of Pseudomonas aeruginosa colonization, aggressive nutritional supplementation with pancreatic enzymes, early diagnosis through newborn screening, and lung transplantation [ 5 ].
Providing up-to-date estimates of survival is crucial for advising patients and their families on life expectancy, planning health care needs and guiding the development of new therapies. For many years, changes in prognosis of CF were described by monitoring the proportion of adult patients, the death rates or the median age at death.
This last metric, which informs on the distribution of the age of patients at time of their death, is not a survival metric as it does not consider the patients who survived. Nowadays, time trends in survival can be monitored by additional metrics such as survival probabilities by birth cohort, the estimated median age of survival also called the predicted median survival age and the estimated median age of survival conditional on living to a given age see below.
It should be noted that life expectancy, which is often misused in CF, is almost never estimated. There are several ways to estimate survival in CF and the terminology used in that field is complex and often confusing for patients and their families, but also for the medical community. It is, however, crucial for clinicians to understand the difference between the various metrics, so that they can provide appropriate information to patients.
A very comprehensive guide has recently been published by Keogh and Stanojevic [ 59 ] in order to facilitate the interpretation of the estimated median age of survival in CF and to standardize the presentation of survival data in CF patient registry reports.
One other paper by Sykes et al. Briefly, these methods are:. The birth cohort approach, which is a longitudinal method that consists of following one or several birth cohorts and registering all the deaths that occur in those cohorts over time. This method, which requires time, draws for each birth cohort a Kaplan—Meier survival curve, which looks like a staircase curve that goes down at each death.
The period approach, which is a cross-sectional method that is commonly used by registries. It analyzes the structure of the CF population present in a registry on a specified period usually a 5 year window; for example, the period — and estimates a survival curve by applying the age-specific mortality rates observed among those prevalent cases to a fictive cohort.
This method estimates the median age of survival from birth, which corresponds to the age beyond which half of the babies born today with CF are expected to live. This approach assumes that death rates remain unchanged over time which is not true and requires large samples. The conditional survival approach, which was applied recently in CF [ 61 ]. As the estimated median age of survival only applies to babies born today and as some patients have already surpassed the estimated age, another metric has been proposed recently: the estimated median age of survival conditional to surviving to a given age for example, age of 30 or It is more relevant for CF patients and is higher than the estimate from birth.
Keogh et al. Phedel homozygous patients, the estimated median age of survival from birth was 46 years in males and 41 years in females, whereas the estimated median age of survival conditional on surviving to 30 was 6 and 8 years higher, respectively [ 61 ].
The prerequisite for a quality survival analysis is to have a well-defined study population with complete registration of CF cases and deaths. Comparisons of survival data between countries require standardization in data processing and analysis.
National CF registries are valuable tools for performing quality survival analyzes and have been instrumental in demonstrating improved survival.
Examination of the annual CF registry reports shows, however, that the presentation of survival data is not homogeneous [ 10 , 11 , 12 , 47 , 48 , 49 , 50 , 51 ].
To date, all CF registries show the median age at death, which may be supplemented by a graph representing the distribution of ages at death or the time trends in this median age at death. Four registries the Canadian, Irish, UK and US ones determine the estimated median age of survival based on the period approach. The French and Canadian registries show survival probabilities by birth cohort, while the US registry also presents two other metrics: a graph representing the estimates of conditional survival at specific ages up to 40 years and another one illustrating time trends in annual mortality rates.
Longitudinal monitoring of registry data shows that the median age at death and the estimated median age of survival continue to increase gradually, while mortality rates decrease. When CF was described for the first time in [ 9 ], patients with CF usually died in their first year of life.
In the s, they rarely survived beyond the age of five. The most recent CF registry data or annual reports show that the median age at death ranges from The estimated median age of survival, which is determined by four registries, is currently This metrics has increased by more than 15 years in 30 years in the USA [ 12 ].
Regarding conditional survival analysis, the US registry report shows that the estimated median age of survival is close to 55 years for patients who reach the age of 30, and exceeds 60 years for patients who reach the age of 40 [ 12 ]. Although survival estimate has greatly improved globally, it continues to be impacted by various individual factors. Prognostic scores based on various variables have thus been developed to predict the risk of death or the risk of lung transplantation [ 63 , 64 , 65 , 66 ].
Two other factors should have a major impact on the survival of CF, which will have to be measured precisely in the coming years: the expanding implementation of NBS for CF and the emergence of targeted therapies.
A survey that was recently carried out to decipher how CF patients access and use information on life expectancy shows that most respondents wanted more personalized survival data [ 67 ]. Mathematical developments are therefore underway in order to further improve the modeling of survival by providing personalized estimates. One of the challenges is to develop models based on longitudinal data that are able to consider the current health status of the patients and not only their baseline characteristics.
A dynamic predictive model providing personalized estimates of survival was recently developed using data from the UK CF Registry [ 68 ]. This model, which integrates 16 predictors, is able to predict survival up to 10 years for patients up to 50 years of age. The estimated median age of survival of CF patients, which is close to 50 years today, is expected to continue to improve in the future, with the rapid expanding of NBS for CF worldwide over the past decade and with the recent advent of CFTR modulator therapies.
Further work is needed to assess the effect of these factors on the survival of CF. Some studies have suggested that NBS for CF results in a prolonged survival, but few are yet able to assess its long-term effects. The studies performed in that field are presented in the next section. The discovery of the CFTR gene in marked an important milestone in the history of CF and raised tremendous hope in the medical and scientific community.
An exemplary collaboration involving more than laboratories worldwide and carried out through an international consortium for the study of the gene mutations Cystic Fibrosis Genetic Analysis Consortium has led to the identification of more than different CFTR mutations to date [ 69 ].
In a very comprehensive article published in this special issue of Genes , Farrell et al. Quickly after the gene discovery, the CFTR mutations could be classified into six classes according to their impact on the level of protein function [ 72 ]. Schematically, mutations in classes I, II, and III are usually associated with a classical form of CF severe mutations , while those in classes IV, V, and VI are related to a milder phenotype mild mutations characterized by pancreatic sufficiency and later bacterial colonization.
The estimated median age of survival of patients carrying at least one mild mutation is generally ten years higher than that of patients with severe mutations. Despite these tools, it often remains difficult to predict with certainty the phenotype of a given genotype, and it quickly became obvious that the CFTR genotype could not explain all the phenotypic variability observed in CF, in particular in lung damage.
Further research has been undertaken to identify other factors that influence the severity of the disease, including gene modifiers such as genes involved in the immune response or in inflammation [ 73 , 74 ], epigenetic factors and environmental factors such as tobacco, pollution, socio-economic status, and adherence to therapies [ 75 ]. Those disorders, called CFTR -related disorders CFTR -RDs [ 76 ], include congenital bilateral absence of vas deferens, acute recurrent or chronic pancreatitis and disseminated bronchiectasis.
Inclusion of patients with such conditions in epidemiological studies dealing with incidence or survival of CF can bias the estimates and the time trends. In-depth knowledge of the molecular abnormalities of the CFTR gene [ 77 ] has enabled genetic screening policies to be implemented, allowing prevention within families such as prenatal diagnosis for one-in-four at-risk couples or carrier testing in families or in the general population in some areas such as population carrier screening.
As mentioned above, these health policies have contributed to reducing—in most countries and with varying degrees of importance—the incidence of CF through the identification of cases before birth [ 23 , 39 , 40 , 41 , 42 , 43 , 46 ]. The coupling of the immunereactive trypsinogen assay to the search for CFTR mutations has eliminated the need for a second blood sample. This has reduced the anxiety generated in families, leading to an earlier diagnosis and early access to specialized care centers, which prevents malnutrition and lung damage [ 80 ].
The positive effects of NBS for CF on short-term and long-term clinical outcomes are widely recognized [ 80 , 81 , 82 , 83 ] and include better nutritional status, lower pancreatic insufficiency, better lung function, lower infection rates, fewer and shorter hospitalizations.
Some studies have shown that NBS for CF results in prolonged survival [ 84 , 85 , 86 ], but it is still too early for most countries to assess its long-term impact on survival. Tridello et al. The expanding of NBS worldwide in the past decade will inevitably continue to impact survival in the future.
Deciphering of the molecular bases of CF has also led to the development of novel therapeutic approaches and the search for pharmaceutical treatments aiming at correcting the defective CFTR protein. These drugs, called CFTR modulators, search to improve the production, processing or expression of the protein and include correctors, potentiators, stabilizers, amplifiers and read through agents [ 88 , 89 ].
Many studies have been carried out in that field over the past decade and have led to major clinical advances in treatment, with significant improvements in biological and clinical endpoints of CF as sweat chloride concentration orFEV 1 [ 90 ].
This treatment was associated with significant improvements at day 28 in sweat chloride level, nasal potential difference and lung function median increase of 8. Phedel homozygous [ 92 ]. This combination significantly increased the percentage of predicted FEV 1 from 2.
Phedel mutation [ 94 ]. This very promising therapy resulted in an increase up to 14 points in the percentage of predicted FEV 1 but also in significant improvements in sweat chloride concentration, pulmonary exacerbations and quality of life. While there is variability in response, the targeted therapies are transforming the life of CF patients and their advent is expected to further improve patient survival in the coming years.
As these molecules have only been marketed since , it is too early to assess their impact on patient survival. This treatment is predicted to increase the estimated median age of survival of p.
Phedel homozygous patients by 6. The increment in survival is further improved by the initiation of treatment at an early age and the persistence of treatment an increment of Over the past decade, the treatment of CF has therefore shifted from a therapy treating the symptoms to a therapy that also restores the function of the CFTR protein.
These targeted therapies have expanded the field of personalized or precision medicine [ 89 ]. The epidemiological profile of CF has changed considerably in recent decades. This disease is no longer the most common serious illness in children but is now also a serious genetic disease among adults. Today, more than half of the patients are adults and patient survival has substantially increased with an estimated median age of survival close to 50 years today.
The incidence of CF appears to be declining in most regions. The discovery of the CFTR gene in upset our knowledge of the pathophysiology of the disease. It also paved the way for pharmacology work and CFTR modulator therapies have been marketed for 10 years. Such treatments are revolutionizing the treatment of CF and transforming the life of CF patients.
All these phenomena have contributed to changing the epidemiology of CF. The advent of targeted therapies is expected to further improve patient survival in the future.
Efforts must nevertheless continue to find other efficient drugs, optimize treatment adherence and promote equitable access to these therapies. The authors are grateful to the national cystic fibrosis registries, data from which were very useful for carrying out this review.
Writing—original draft preparation, V. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Journal List Genes Basel v. Genes Basel. Published online May Find articles by Virginie Scotet. Author information Article notes Copyright and License information Disclaimer.
Received Apr 25; Accepted May This article has been cited by other articles in PMC. Abstract Significant advances in the management of cystic fibrosis CF in recent decades have dramatically changed the epidemiology and prognosis of this serious disease, which is no longer an exclusively pediatric disease.
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