Predictive factors of survival in people with cystic fibrosis from a Spanish rare disease registry.

doi:10.21203/rs.3.rs-2842798/v1

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Predictive factors of survival in people with cystic fibrosis from a Spanish rare disease registry.

https://doi.org/10.21203/rs.3.rs-2842798/v1

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Background:Cystic fibrosis (CF) is the most common multisystem, chronic, and life-threatening rare disease in the Caucasian population. Progressive loss of lung function remains the leading cause of death. However, improvementsin prognosis and survival have caused CF to go from being a lethal disease in childhood to becoming an increasingly frequent pathology in adults. In Spain, the factors that influence survival have not been determined. The objective of the study is to analyse survival and determine the factors associated with it in people with CF from a region in southeastern Spain based on information from a rare disease registry.

Methods: A cross-sectional study was carried out in people with a confirmed diagnosis of CF up to December 31 2018, who were registered in the Rare Disease Information System of the Region of Murcia (SIERrm). The Kaplan‒Meier method and the log-rank test were used to estimate and compare survival curves. Predictors of survival were calculated using the Cox proportional hazards model.

Results:Of the 192 patients registered in SIERrm with a confirmed diagnosis of CF, 39 patients died with a median age of 22 years (IQR: 15.0 - 33.0), of which 77% were classified within high-risk genotypes. The median survival age was 26.0 years (95% CI: 22.0 - 30.0),and the 10-year survival from diagnosis was 87.6%. In addition, high-risk genotype [HR: 5.8 (95% CI: 1.97 - 16.94)], pancreatic insufficiency [HR: 5.4 (95% CI: 1.24 - 23.48)], chronic colonization by Pseudomonas aeruginosa [HR: 6.8 (95% CI: 1.21 - 38.54)], the development of CF-related liver disease [HR: 5.0 (95% CI: 1.61 - 15.61)] and bone anomalies [HR: 6.4 (95% CI: 1.91 - 21.61)] were associated with decreased survival (p<0.05).

Conclusions: In the Regionof Murcia, people with a high-risk genotype, pancreatic insufficiency, chronic colonization by Pseudomonas aeruginosa, and the development of CF-related bone and liver complications predict a higher risk of dying or being transplanted and therefore a decrease in survival. The use of population registries is useful for estimating survival and showing the factors associated with it, which is important for planning care needs and implementing personalized medicine that influences these factors.

Cystic fibrosis

Rare Disease

Survival

Epidemiology

Rare Disease Registry

Cystic fibrosis (CF) (ORPHA: 586; OMIM: 219700) is the most common rare and life-threatening genetic disease among the Caucasian population¹. It is an autosomal recessive disorder produced by different alterations in the CF transmembrane conductance regulator gene sequence (CFTR), of which p. Phe508del is the most frequent worldwide².

The CFTR gene encodes a protein located in the apical membrane of different organs that regulates the transport of chloride and bicarbonate. The alteration in ionic transport leads to the appearance of a series of multisystemic clinical manifestations responsible for the chronic and progressive deterioration of patients with CF that has been associated with a high impact on their life expectancy³.

The major affectation occurs at the respiratory and digestive level, with respiratory failure secondary to chronic colonization of the airways and progressive loss of lung function being the main cause of death⁴. Furthermore, numerous studies have analysed other factors that could be related to reduced survival, and it has been observed that certain genotypes, nutritional status or poor lung function are the predominant factors ^5–7. Other authors have also discussed gender and socioeconomic factors as possible causes, obtaining inconclusive results^8–10.

Currently, diagnostic advances, the expansion of neonatal screening¹¹, new targeted therapies, improvements in transplants^12,13 and multidisciplinary care have led to a progressive increase in median survival, exceeding 40 years in many countries¹⁴. In this way, CF has gone from being a lethal disease in children to becoming an increasingly frequent pathology in adults, reaching the number of adults to exceed the number of children in some countries of Europe and North America¹⁵.

This increase in longevity has led to a higher frequency of CF complications, such as CF-related diabetes (CFRD) and CF-related liver, bone or kidney disease, of which the true impact is still unknown and which may contribute to greater morbidity and mortality in these patients^16–18.

In Spain, most of the studies that have been carried out in people with CF have addressed changes in mortality trends over the years^19,20. However, there are few studies that analyse the survival of these patients²¹, without actually evaluating in none of them the factors that determine a decrease of the same. Therefore, the objective of the study is to analyse survival and determine the factors associated with it in people with CF from a region of southeastern Spain based on information from the rare disease registry.

Study population

A cross-sectional study of people registered in the Rare Disease Information System of the Region of Murcia (SIERrm)²² with a confirmed diagnosis of cystic fibrosis was carried out through 31 December 2018. Healthy carriers and those with entities that did not correspond to confirmed CF, such as CFTR-related disorders (CFTR-RDs) or CF- screen positive inconclusive diagnosis (CF-SPID), were excluded from the study.

The SIERrm is a population-based registry that has existed since 2010 and in which people with a rare disease (RD) are registered in the Region of Murcia, a Spanish autonomous community whose population on 1 January 2019 was 1,493,898 people.

Individual informed consent was not required since the SIERrm is included among the exceptions incorporated in the personal data protection regulations on public health actions related to RDs of the Public Health Law and is authorized to this by its own regulatory standards²³. Even so, the study was presented to the Clinical Research Ethics Committee of the International Doctoral School of the University of Murcia (no. 3376/2021), and it was approved on 6 May 2021.

Data collection

The demographic, clinical and genotypic information registered in SIERrm was gathered for each patient individually. In a previous paper, the sources that provide information to the SIERrm are described, as well as the process of incorporating and validating these data into the registry²⁴.

Obtaining demographic variables

The collected variables were sex, age on 31 December 2018, age at diagnosis of the disease, diagnosis by neonatal screening and country of origin of the parents. The variable “age at diagnosis of the disease” was dichotomized into < 18 years and ≥ 18 years to determine the proportion of adult and child/young patients in the study. In addition, the deceased and transplanted patients were obtained, as well as the type of transplant (lung, liver or kidney), the date of the transplant and the date of death, in each case. Those cases in which their vital status (alive/deceased) or their date of death was doubtful or unknown were consulted in the Spanish National Death Index (S-NDI)²⁵.

Collection and classification of genetic information

Information was obtained on the CFTR sequence variants that made up each of the alleles of people with CF. Based on this, patients were classified into 2 risk genotypes. Those people in whom both alleles carried "minimal function variants" (class I, II, III and VII) were classified as “high-risk genotype”. On the other hand, those in which at least one allele carried a “residual function variant” (class IV, V, and VI) were classified as a “low-risk genotype”, with some previously described exceptions²⁴.

Achievement of clinical variables

Respiratory, digestive, metabolic and bone alterations were collected from each patient, which the literature considers relevant for the study of the disease.

At the respiratory level, lung function was evaluated using the Global Lung Function Initiative (GLI) tool to calculate the percentage of the best Forced Expiratory Volume in the first second (%FEV₁) in 2018, normalized with respect to the values predicted by sex, age, height and ethnicity. Chronic colonization by Staphylococcus aureus, Burkholderia cepacia, or Pseudomonas aeruginosa and at least one documented acute episode of allergic bronchopulmonary aspergillosis (ABPA), methicillin-resistant Staphylococcus aureus (MRSA), Achromobacter xylosoxidans, and nontuberculous mycobacteria were also measured. Additionally, the presence of sinonasal polyposis and one or more clinically relevant episodes of hemoptysis (> 200 mL) were recorded.

Likewise, information was collected on the following digestive symptoms: meconium ileus at birth, rectal prolapse, intussusception, distal intestinal obstruction syndrome (DIOS), pancreatic insufficiency, recurrent acute or chronic pancreatitis and liver disease related to CF (liver disease with or without cirrhosis, including fatty liver).

Low bone density, osteoporosis and digital arthropathy were the bone disorders that were selected as variables of interest.

Finally, people with CF-related diabetes (CFRD) who required insulin treatment and those who had at least one episode of dehydration requiring clinical care were considered to have metabolic alterations.

Statistical analysis

Demographic, genetic and clinical characteristics of people with CF were summarized using descriptive statistics (absolute frequencies, percentages, median, interquartile range (IQR), mean, and standard deviation (SD)).

Survival was calculated from age at CF diagnosis to age at death or transplant (end event) or through 31 December 2018 (censoring). The time scale to the event was measured in years. The transplant variable was analysed as a whole, including all types of transplants. Patients with missing or unknown data regarding the age at diagnosis or age at which the transplant was performed were not included in the analyses. The Kaplan‒Meier method and the log-rank test were used to estimate and compare survival curves.

Predictors of death or transplantation were calculated using the Cox proportional hazards model, in which crude and adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. The multivariate model included those variables with a value ≤ 0.05 in the log-rank test and other relevant variables according to the literature (e.g., %FEV₁ or CFRD). Each of the variables included was adjusted for sex, age at diagnosis, and parental origin. Finally, a new multivariate model was carried out, also adding the genotype as an adjustment variable to differentiate the effects due to the high-risk genotype from the independent effects of the rest of the variables.

Proportional hazards assumptions were tested using the log survival plot and Schoenfield residuals depending on the type of variable being analysed. Furthermore, a sensitivity analysis was carried out to verify that the patients diagnosed by neonatal screening did not imply an interaction or modification of the effects.

The level of statistical significance was set at ≤ 0.05. Statistical analyses were performed with the statistical package IBM SPSS 25.0 (IBM Corporation, Armonk, New York, USA).

Of the patients registered in SIERrm up to the date of the study, 192 were cases with a confirmed diagnosis of CF. Table 1 shows their demographic, clinical, and genotypic characteristics.

The population with CF in the Region of Murcia at the time of the study was mainly composed of children and adolescents. However, the percentage of adults (≥ 18 years) was 41.7%. In 84.9% of the patients, the country of origin of their parents was Spain. Of the total number of people studied, 103 were males whose mean age and standard deviation (SD) was 20.0 ± 15.2 years [median: 15.0, interquartile range (IQR): 7.0–31.0], and 89 were females (mean and SD: 24.5 ± 16.2, median: 23.0, IQR: 10.0–35.0). The mean age at diagnosis ± SD was 7.8 ± 14.4 years, and the median was 0.0 years (IQR: 0.0–7.5), which was higher in females (8.8 ± 16.0 years) than in males (6.9 ± 12.8 years), without statistically significant differences. Sixteen point one percent of the people (n = 31) were diagnosed after testing positive in the heel prick test through the neonatal screening program that began in the Region of Murcia in March 2007.

The genetic information was known in 94.8% of the people (n = 182). Of these, 67% (n = 122) were classified as “high-risk genotype”.

Observing the clinical manifestations, 63% of the patients manifested some respiratory affection, and 53.6% presented colonization by Pseudomonas aeruginosa, Staphylococcus aureus or Burkholderia cepacia. In order of frequency, gastrointestinal manifestations follow, among which pancreatic insufficiency stands out.

Of the total study population, 39 patients died, with 53.8% of deaths occurring in females. The median age of death in this group was 20 years (IQR: 7–24) versus 24 years (IQR: 17.3–36.5) in males. Despite this, the differences were not significant (p = 0.234). In addition, 23 patients received a transplant and in 16 of them it was after the age of 18. The median age at transplant was 24 years (IQR: 16.8–28.0). Twenty patients received a lung transplant, another received a liver transplant, and the remaining two were recipients of a double transplant, in one case liver and lung and in another kidney and lung.

To analyse survival, 8 patients with missing or unknown data relative to age at diagnosis or age at transplant were excluded. The median years of survival from diagnosis to the composite outcome of death or transplantation was 26.0 years (95% CI: 22.0–30.0). Survival from diagnosis was 97.6% at 1 year, 93.7% at 5 years and 87.6% at 10 years.

Kaplan‒Meier curves comparing the influence of different characteristics of people with CF on survival are shown in Fig. 1. Median survival age was lower in subjects with high-risk genotype (23.8 vs 34.9; p = 0.001), presence of pancreatic insufficiency (28.3 vs 33.9; p = 0.022), chronic colonization by Pseudomonas aeruginosa (28.0 vs 32.0; p = 0.001) and the appearance of CF complications such as bone disorders (25.2 vs 35.7; p = 0.001) or CF-related liver disease (25.6 vs 34.4, p = 0.005). In supplement S1, the Kaplan‒Meier curves of the rest of the variables can be consulted, in which no statistically significant differences were observed.

In the multivariate model adjusted for the variables sex, country of origin of the parents, and age at diagnosis (Table 2), the high-risk genotype was associated with a 6-fold increased risk of death or transplantation compared with the low-risk genotype [HR: 5.8 (95% CI: 1.97–16.94)]. Additionally, an increased risk was also found in patients who had pancreatic insufficiency [HR: 5.4 (95% CI: 1.24–23.48)], Pseudomonas aeruginosa colonization [HR: 6.8 (95% CI: 1.21–38.54)], CF-related liver disease [HR: 5.0 (95% CI: 1.61–15.61)], or CF-related bone abnormalities [HR: 6.4 (95% CI: 1.91–21.61)], (p < 0.05).

A higher associated risk was obtained in women and in those with CFRD; however, the differences were not statistically significant. Similarly, it was observed that for each unit increase in %FEV₁, there was a 50% decrease in the risk of death or transplantation, although these differences did not reach statistical significance.

When the genotype variable was incorporated into the model fit, an increased risk of dying or receiving a transplant continued to be observed in all the variables included in the model, but the association was no longer significant for all except the high-risk genotype [HR: 5.3 (95% CI: 1.87–15.26)] (p = 0.002), development of CF-related liver disease [HR: 3.3 (95% CI: 1.10–10.00)] (p = 0.035) and bone changes [HR: 3.6 (95% CI: 1.05–11.99)] (p = 0.041). After checking the proportional hazards assumptions, no significant deviations were observed for the variables included in the models, and similar associations were found in the group of screened patients after sensitivity analysis.

This is the first Spanish study to report on the influence of demographic, clinical, and genetic characteristics on the survival of people with CF.

Through 31 December 2018 in the Region of Murcia, patients are mostly children and young adults. However, the percentage of adults is close to 42%, a figure similar to that reported by other authors²⁶, which offers an idea of the change that is taking place in the population affected by this disease. In fact, researchers such as Simmons et al.²⁷ and Stephenson AL et al.²⁸ have spent years studying adult patients with CF to determine the characteristics that have influenced this increase in longevity. One of these factors is the age at diagnosis, which can influence the development of more severe symptoms and a worse evolution of the disease²⁹. In our study, 84% of the patients were diagnosed before the age of 18, with a mean age at diagnosis of 7.8 years; however, we did not observe an association between age at diagnosis and survival. In addition, some publications highlight the existence of a gender gap during childhood diagnosis, with women being older and less likely to reach 40 years of age³⁰. Nevertheless, in our study, no significant difference was observed in this regard.

Likewise, research has been carried out to determine the influence of screening in these patients, concluding that those patients diagnosed by neonatal screening have better nutritional and respiratory values, which demonstrates a benefit of this program in survival³¹. In the Region of Murcia, neonatal screening was implemented in 2007, so it is difficult to visualize its effects, since only 16.1% of our patients were diagnosed through screening, and at the date of the study, their maximum age was 11 years. However, the benefit of the screening program on these patients is an aspect of great interest to be evaluated in future studies.

Furthermore, the genotype has been reported as one of the most determining factors both in the phenotype and in the survival of people with CF³². The Region of Murcia is one of the regions that has described a lower allelic frequency of the p. Phe508del variant both at the national and European level and with a high percentage of heterozygous forms^24,33. This fact may explain to a large extent because 33% of patients for whom genetic information was available have low-risk genotypes that have been associated with higher survival.

On the other hand, our data reflect a median age at death of 25.7 years, in line with the increase reported by Ramalle-Gomara et al.¹⁹ Likewise, higher mortality was observed in females (53.8%) and a lower age at death compared to males. This has also been described in other publications^7,28; however, the differences found in our results were not statistically significant.

In this study, taking death or receiving a transplant as the final event and considering that mortality remains constant over time, the median survival age of CF patients is 26 years from diagnosis of the disease. The data are far from those reported by the rest of the European and North American countries, with Canadian patients being those with the highest median survival age of 52.1 years^9,34. This is largely due to the patient selection criteria and the age distribution of the sample, for example, the inclusion of transplantation as the final event, since the median age at transplantation is 24 years. Furthermore, the impact of the screening is not yet visible, and the regional population is mainly composed of children and young people. Nevertheless, life expectancy at 10 years is similar to that reported by the European CF registry⁹ and by Sameer et al.²⁹ analysing patients from the Canadian CF Patient Registry. These figures give us a more objective idea of the survival of people with CF in the Region of Murcia.

According to our results, both the high-risk genotype, pancreatic insufficiency, colonization of the airways by Pseudomonas aeruginosa, and the development of CF complications have been associated with a higher risk of dying or being transplanted and therefore with a survival disadvantage. This fact reinforces previous research that indicates that patients with a high-risk genotype have lower survival than low-risk ones^21,26,35, as well as the development of respiratory and digestive disorders^6,36,37 or diseases related to FQ^38,39. However, in the genotype-adjusted model, only this and the development of CF-related liver disease and bone abnormalities were independent predictors of mortality and transplantation. These data are consistent with a previous study in which an association was found between the high-risk genotype and the most severe symptoms²⁴.

On the other hand, and unlike other publications, our study did not find differences in terms of sex or the development of CF-related diabetes^10,40.

Regarding the limitations of our work, the main limitation could be the sample size. Despite this, the effect size was large, and significant associations were obtained. Even so, there were variables in which no statistical significance was found. This may be because the effect size was not large enough or there was excessive variability in the data.

Despite missing information, information bias is unlikely, as there were no significant differences between the participants with or without information on mortality and transplantation. In addition to the clinical characteristics and related diseases addressed in the present work, variables such as nutritional status or socioeconomic factors could be included in future studies. It would also be interesting to investigate the effect that recently introduced CFTR-modulating drugs might have on the survival of these patients.

To exclude neonatal screening as an association modifier, we carried out a sensitivity test. Associations were similar when analysing both groups separately, ruling out the modification effect of the screening.

The main strength of our results is the use of a population-based registry, which offers up-to-date and extensive information on these patients and allows us to know the frequency, distribution, evolution and needs of patients affected by CF or other RD. Additionally, the SIERrm offers representative data of those affected by the disease, constituting the reference registry for the region. This not only makes it possible to estimate survival but also to show the characteristics that predict a higher risk of death or transplantation, which is important for planning healthcare needs and implementing personalized medicine that influences these factors. Despite this, it would be of great interest to carry out future studies that address the aspects discussed here and use the same methodology in a larger population to support the results obtained.

This is the first regional and national study that analyses the factors that influence survival and those that could predict a decrease in survival in people with CF.

In the Region of Murcia, due to the existing genetic heterogeneity, a higher proportion of people with low-risk genotypes and mild phenotypes have been described. A survival advantage is observed in these patients compared to those with severe genotype and phenotype.

In fact, people with a high-risk genotype, the presence of pancreatic insufficiency, chronic colonization by Pseudomonas aeruginosa, and the development of bone and liver complications predict a higher risk of dying or being transplanted and therefore a decrease in survival.

Our results are important to select patients with certain genetic and clinical characteristics who may be beneficiaries of specific treatments and particular health resources that affect these factors to increase their survival.

CF: cystic fibrosis.

CFRD: CF-related diabetes mellitus.

CF-SPID: cystic fibrosis screen positive inconclusive diagnosis.

CFTR: cystic fibrosis transmembrane conductance regulator.

CFTR-RDs: cystic fibrosis transmembrane conductance regulator-related disorders.

CI: confidence interval.

FEV₁: forced expiratory volume in the first second.

HR: hazard ratio

IQR: interquartile range.

MRSA: methicillin-resistant Staphylococcus aureus.

RD: rare disease.

SD: standard deviation

SIERrm: rare diseases information system of the Region of Murcia.

Ethics approval and consent to participate: Individual informed consent was not required since the SIERrm is included among the exceptions incorporated in the personal data protection regulations on public health actions related to rare diseases of the Public Health Law and is authorized to this by its own regulatory standards²³. The study received ethical approval from the Clinical Research Ethics Committee of the International Doctoral School of the University of Murcia. Ref. no 3376/2021, 6 May 2021.

Consent for publication: Not applicable.

Availability of data and materials

The pseudoanonymized data set used to carry out this study and that support its findings are restricted following Regulation (EU) 2016/679, Law 3/2018 on the Protection of Personal Data, Law 14/2007 on Biomedical Research and Law 37/2007. and Law 18/2015 on the Reuse of Public Sector Information. By virtue of the foregoing, it is only possible to access the aggregated data with a reasonable request at the following address: [email protected]

Competing interests: The authors declare no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: This article has not received funding from any organization or entity.

Contributions: SRN and MPME designed and initiated the current study. PML was responsible for collecting clinical and genetic manifestation data and follow-up of patients. MPME and JAPR coordinated the purification of the information and managed the SIERrm. LAMR clarified the genetic concepts and helped in their correct writing. SRN, MPME, ACT and JJAG were responsible for analysing the data. MPME and SRN wrote the draft version of the manuscript. All authors commented on and approved the final manuscript.

Acknowledgement

We appreciate the collaboration of all the sources that make up the SIERrm and the work carried out by the staff of the Planning and Health Financing Department in charge of its maintenance: Pilar Ciller Montoya, Fernando Cano Candela, Antonio Serrano Pinto, Antonia Sánchez Escámez, Juana María Cayuela Fuentes.

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Table 1\| Demographic, genetic and clinical characteristics in people with cystic fibrosis (n=192).
	N° patients/N° studied (%)*
Demographic characteristics
Male sex	103/192 (53.6)
Age (years)^a. Median (25 - 75)^b	19.0 (8.0 - 33.0)
Age at diagnosis <18 years	155/185 (83.8)

Clinical characteristics
Respiratory manifestation
FEV₁ as % predicted^c. Mean ± SD^d	90.0 ± 21.4
Nasal polyposis	32/139 (23.0)
Haemoptysis	30/139 (21.6)
ABPA^e	15/139 (10.8)
Infection by^f
Staphylococcus aureus	79/138 (57.2)
MRSA	10/138 (7.2)
Pseudomonas aeruginosa	44/140 (31.4)
Achromobacter xylosoxidans	16/138 (11.6)
Burkholderia cepacia	2/138 (1.4)
Non-tuberculous mycobacteria	9/138 (6.5)

Gastrointestinal manifestations
Meconium ileus	17/162 (10.5)
Pancreatic insufficiency	109/162 (67.3)
Pancreatitis^g	8/139 (5.8)
CF-Liver disease^h	16/142 (11.3)
Rectal prolapse	4/139 (2.9)
Intussusception	3/140 (2.1)
DIOSⁱ	10/139 (7.2)

Metabolic disturbances
CF-Related diabetes	15/141 (10.6)
Clinically significant dehydration	23/139 (16.5)

Bone alterations^j	15/140 (10.7)






Table 1\| Continued.
	N° patients/N° studied (%)
Genotypes^k
High-risk	122/182 (67.0)
Low-risk	60/182 (33.0)
Unknown	10/192 (5.2)

Death	39/192 (20.3)
Lung or liver transplant	23/192 (12.0)
Values are presented as N° patients/N° studied (%) unless otherwise specified. Manifestations that have been present at some point in the patient's life through 31 December 2018. a. Age through 31 December 2018. b. 25-75= 25th – 75th percentile. c. Forced expiratory volume in the first second. The best value of the year 2018 was measured. d. SD= Standard deviation. e. ABPA= Allergic bronchopulmonary aspergillosis. f. It was included chronic colonization by Staphylococcus aureus, Pseudomonas aeruginosa* and Burkholderia cepacia and some acute infection by methicillin-resistant Staphylococcus aureus (MRSA), Achromobacter xylosoxidans and non-tuberculous mycobacteria. g. Recurrent acute or chronic pancreatitis. h. Cirrhosis or liver disease without cirrhosis related with cystic fibrosis, including fatty liver. i. DIOS= Distal intestinal obstruction syndrome. j. It was included low bone density, osteoporosis and digital arthropathy k. High-risk genotype consisted of 2 CFTR minimal function variants or class I, II, III, and VII mutations and the low-risk genotype consisted of at least one residual function variant or class IV, V, and VI.

Table 2\|Cox proportional hazard models for survival.
Variable	Unadjusted HR^a (95%CI)^d	p-Value	Adjusted HR^a,b (95%CI)^d	p-Value	Adjusted HR^a,c (95%CI)^d	p-Value
Sex
Male	Ref.	-	Ref.	-	Ref.	-
Female	1.4 (0.78 - 2.48)	0.268	1.3 (0.72 - 2.34)	0.381	1.5 (0.82 - 2.90)	0.176
Age at diagnosis^e	1.0 (1.01 - 1.05)	0.001	1.0 (1.01 - 1.05)	0.001	1.0 (0.99 - 1.08)	0.093
Genotype
Low-risk	Ref.	-	Ref.	-	Ref.	-
High-risk	4.1 (1.60 - 10.47)	0.003	5.8 (1.97 - 16.94)	0.001	5.3 (1.87 -15.26)	0.002
%FEV₁^f	0.8 (0.52 - 1.16)	0.219	0.5 (0.12 - 2.51)	0.438	0.7 (0.25 - 1.77)	0.412
Infection by Pseudomonas aeruginosa
Yes	6.5 (1.16 - 36.02)	0.033	6.8 (1.21 - 38.54)	0.030	4.2 (0.74 - 24.21)	0.106
No	Ref.	-	Ref.	-	Ref.	-
Pancreatic Status
Pancreatic sufficiency	Ref.	-	Ref.	-	Ref.	-
Pancreatic insufficiency	4.5 (1.07 - 19.26)	0.040	5.4 (1.24 - 23.48)	0.025	2.8 (0.51 - 15.38)	0.235
Bone alterations
Yes	5.7 (1.81 - 17.75)	0.003	6.4 (1.91 - 21.61)	0.003	3.6 (1.05 - 11.99)	0.041
No	Ref.	-	Ref.	-	Ref.	-
CF-Liver disease
Yes	4.1 (1.40 - 11.97)	0.010	5.0 (1.61 - 15.61)	0.005	3.3 (1.10 - 10.00)	0.035
No	Ref.	-	Ref.	-	Ref.	-
CFRD^g
Yes	2.1 (0.68 - 6.48)	0.198	2.2 (0.66 - 7.59)	0.199	1.6 (0.47 - 5.62)	0.440
No	Ref.	-	Ref.	-	Ref.	-
a. HR= Hazard Ratio.
b. Hazard Ratio adjusted for age at diagnosis, sex and country of origin of the parents. c. Hazard Ratio adjusted for age at diagnosis, sex, country of origin of the parents and genotype.
d. CI= Confidence Interval.
e. Hazard Ratio for age at diagnosis was that observed for a change of 1 year. f. %FEV1= Forced Expiratory Volume in the first second (Percentage of predicted). Hazard Ratio for %FEV₁was that observed for a change of 1 unit.
g. CFRD= Cystic fibrosis related diabetes.

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Predictive factors of survival in people with cystic fibrosis from a Spanish rare disease registry.

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