Abstract
Background
Elexacaftor/tezacaftor/ivacaftor (ETI) has improved outcomes for people with cystic fibrosis (pwCF). This study evaluated changes in airway microbiological infection status after initiating ETI.
Methods
Using the European Cystic Fibrosis Society registry, pwCF who started ETI between 2019 and 2021 were identified. The changes in microbiological status from 1 year before to 1 year after ETI initiation, were compared with the changes seen from 3 to 1 years before starting ETI. Mixed-effect regression models were used to analyse changes. Data from 2 years after initiation were examined for those starting ETI in 2019–2020.
Results
Included were 15 739 pwCF from 30 countries. In the year before ETI, 38.4% were positive for Pseudomonas aeruginosa (PsA) and 36.4% for methicillin-sensitive Staphylococcus aureus (MSSA). After ETI, 38.7% of PsA-positive and 47.2% of MSSA-positive patients transitioned to negative status, compared with 14.8% and 29.1%, respectively, in the previous years. The adjusted difference in transitioning to negative was 14.6% (PsA) and 17.1% (MSSA), both p<0.001. Similar improvements were seen for Burkholderia cepacia complex and Stenotrophomonas maltophilia. For those starting ETI in 2019–2020, PsA positivity remained low over 2 years, decreasing from 46.8% pre-ETI to 30.4% and 27.7% at 1 and 2 years after ETI treatment.
Conclusion
One year after starting ETI, many pwCF who were initially positive for various CF-related pathogens, shifted to a negative status, a change less common before ETI. These findings suggest that ETI reduces airway infections, with benefits extending into the second year of treatment, although some pwCF continue to carry these pathogens despite treatment.
Shareable abstract
Many pwCF with initial positivity for CF-related pathogens shifted to a negative status after starting ETI, a shift less common pre-ETI. These findings suggest ETI reduces airway infections, with sustained benefits observed into the second treatment year. https://bit.ly/4gxC3KU
Background
Elexacaftor/tezacaftor/ivacaftor (ETI) has revolutionised the management of cystic fibrosis (CF), significantly enhancing the lives of those affected by the condition. ETI, as a highly effective triple-combination therapy, has dramatically improved lung function, reduced the frequency of respiratory infections and enhanced overall quality of life for people with CF (pwCF) [1–6]. By targeting the underlying cause of the disease, by improving the CF transmembrane conductance regulator (CFTR) protein function, ETI has not only led to substantial clinical improvements but also offered hope for a better and more stable life, marking a major advancement in CF care and transforming patient outcomes. However, it is important to note that it does not cure the disease. CF remains a chronic and progressive condition. Patients may still experience some disease-related complications and require ongoing treatment and monitoring to manage their overall health [7–9].
Prior to the introduction of CFTR modulators, bacterial lung infections were known to cause a decline in lung function and shorten survival rates in pwCF [10, 11]. However, the impact of these infections once CFTR function is partially restored remains unclear. Gaining a better understanding of infection rates in this new context could inform clinical decisions, such as the necessity of eradicating specific pathogens. This knowledge is particularly crucial given the ongoing efforts to reduce treatment burdens in the era of highly effective modulator therapy (HEMT) [12, 13]. In this study, we use data of the European Cystic Fibrosis Society Patient Registry (ECFSPR) to assess changes in microbiological status of pwCF following ETI treatment.
Methods
The European Cystic Fibrosis Society Patient Registry
The ECFSPR annually collects data on pwCF from CF centres and national CF registries across the World Health Organization's defined region of Europe. The registry contains data spanning from 2008 to 2022. In 2022, data collection included over 50 000 pwCF from 40 countries [14], providing a comprehensive reflection of the CF landscape across the continent. Data are provided to ECFSPR under existing ethical approvals and data-governance structures, and all participants or guardians signed an informed consent prior to data collection. The study was approved by the ECFSPR Scientific Committee and Steering Committee on 6 September 2023, and data used in this analysis were extracted from ECFSPR on 28 November 2023. A detailed description of the ECFSPR can be found online at www.ecfs.eu/ecfspr.
Study population
The study population included all pwCF with a confirmed diagnosis of CF, who began ETI treatment between 2019 and 2021. Exceptions were made for certain countries: in Belgium, Greece and the Russian Federation, only pwCF starting ETI in 2019 or 2020 were included, as 2022 data had not been validated by the time of data request approval. For Switzerland, only those who initiated ETI in 2019 were included, due to changes in microbiological data collection methods after 2020, which differed from previous years. The pwCF who died during the study period were included until the year of death. ETI was prescribed at the discretion of the treating physician and based on regulatory eligible criteria, local and national reimbursement approvals and compassionate programs.
Study design
Changes in the microbiological status of CF pathogens in pwCF were analysed as outlined in figure 1. Microbiological data of pwCF from the year following ETI initiation (+1) were compared with the year prior to ETI initiation (−1). While all pwCF with available data 1 year after ETI initiation were included in the main analysis, many of those who began ETI in 2020 or earlier also had microbiological data available for 2 years post-ETI. For this subset, microbiological status was assessed up to 2 years following ETI initiation. Additionally, we compared the microbiological status of the same individuals in the year prior to initiation (−1) with their status 2 years earlier (−3).
FIGURE 1.
Study timeline. The considered time points for the analysis are shown. “Pre to post” defines the time comprising 1 year before (−1) and after (+1) elexacaftor/tezacaftor/ivacaftor (ETI) initiation (0). “Pre to pre” defines the years before treatment: 3 (−3) and 1 (−1) year before ETI initiation. For those starting ETI in 2019 and 2020 (n=7973) data from the second year after ETI were included.
Microbiological definition
Data on the following pathogens is included in the ECFSPR: Methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa (PsA), Stenotrophomonas maltophilia (SM), Burkholderia cepacia complex (BCC) and Achromobacter spp. (AS). Chronic status is defined by ECFSPR when 50% of respiratory samples collected during the last 12 months are positive with at least four samples collected during that period, and/or significantly raised bacteria-specific antibodies according to local laboratories are present [15]. The ECFSPR also labels pwCF microbiological status as chronic when the specified criteria were met in recent years, and there is no indication from the physician that the status has changed. Prior to 2021, PsA, MSSA and BCC were reported annually as chronic/not chronic and SM, MRSA and AS were reported as no/at least once during the year of follow-up. Since 2021, cultures are reported similarly for all pathogens: no/intermittent (defined as at least once but not chronic)/chronic infection. For the present study, the classifications of infections were harmonised along the follow-up years, so that for PsA, MSSA and BCC chronicity was considered, thus chronic status was classified as positive, while intermittent or negative status were classified as negative. On the other hand, for SM, MRSA and AS infection at least one during the year was considered, thus intermittent or chronic status were classified both as positive.
Statistical analysis
Categorical variables were summarised as number and percentage and by means of graph bars and alluvial plots; numerical variables are shown as mean±sd. Missing data were accounted for and then were excluded when computing descriptive statistics. Linear mixed-effects models were used to evaluate the proportion of pwCF with negative status after ETI among those who were positive before ETI, taking into consideration repeated microbiological status on same pwCF along time points; furthermore, these models were used to test whether the proportion between pwCF who turned negative after ETI was statistically different from any change in proportions observed in the years before ETI; in particular, the analysis looked at the difference in the proportion of pwCF who were negative, among those who were positive between selected time points. Biological sex (female/male), genotype (F508del heterozygote/F508del homozygote/not F508del), percentage of predicted forced expiratory volume in 1 s (FEV1 % pred), age at follow-up (years), administration of any CFTR modulator before ETI (yes/no) and gross national income (GNI) per capita in 2022, extracted from the World Bank database (https://databank.worldbank.org/home), were used as adjusting factors. Model estimates are presented as marginal crude and adjusted proportions, with 95% confidence interval (CI). p-values <0.05 were considered statistically significant. Comparison of proportions were assessed using Pearson's chi-squared test. Analyses were conducted with the open-source software R Core Team 2024, v.4.4.0. with the nlme, emmeans and ggalluvial packages added.
Results
Population description
A total of 15 739 pwCF aged 26.9±11.6 years (53.1% males) met the inclusion criteria and were included in the analysis (supplementary table S1). Of these, 7973 had 2 years of data available after ETI initiation and were included in the 2-year follow-up analysis. According to the World Bank classification, 4 of the 30 countries included were upper-middle income and the rest were high-income countries. Most patients started ETI in 2020 (48.3%) and 2021 (49.3%). The majority carried at least one F508del mutated allele (43.5% heterozygotes and 54.9% homozygotes), whereas only 241 pwCF (1.5%) were non-F508del. In the year prior to ETI initiation, the mean FEV1 % pred was 70.0±24.2%. Treatment with at least one CFTR modulator (i.e. ivacaftor, lumacaftor/ivacaftor or tezacaftor/ivacaftor) was reported by 39.1% before starting ETI. Additional demographic and clinical characteristics are shown in table 1.
TABLE 1.
Characteristics of people with cystic fibrosis (pwCF) at ETI initiation.
| n=15 739 | |
|---|---|
| Age, years | 26.9±11.6 (1.5–86.4) |
| Sex, female | 7384 (46.9) |
| Genotype | |
| F508del heterozygote | 6853 (43.5) |
| F508del homozygote | 8645 (54.9) |
| Not F508del | 241 (1.5) |
| BMI, kg·m−2 | |
| z-score of children (<18 years) | −0.3±0.98 (−6.16–2.7) |
| Adults (≥18 years) | 22.4±3.4 (12.45–48.6) |
| FEV1 % pred | 74.0±24.5 (11.9–161.0) |
| Missing | 620 |
| Pancreatic enzymes | 14 397 (92.7) |
| Missing | 204 |
| Previous use of CFTR modulators | |
| Ivacaftor | 609 (4.0) |
| Missing | 390 |
| Lumacaftor/ivacaftor | 2955 (19.2) |
| Missing | 362 |
| Tezacaftor/ivacaftor | 4209 (27.4) |
| Missing | 367 |
| Start year of ETI | |
| 2019 | 372 (2.3) |
| 2020 | 7601 (48.3) |
| 2021 | 7766 (49.3) |
| Pseudomonas aeruginosa | |
| Positive | 5956 (38.6) |
| Missing | 295 |
| Methicillin-sensitive Staphylococcus aureus | |
| Positive | 5461 (35.5) |
| Missing | 358 |
| Burholderia cepacia complex | |
| Positive | 587 (3.8) |
| Missing | 300 |
| Methicillin-resistant Staphylococcus aureus | |
| Positive | 934 (6.0) |
| Missing | 291 |
| Achromobacter spp. | |
| Positive | 1197 (7.7) |
| Missing | 285 |
| Stenotrophomonas maltophilia | |
| Positive | 1659 (10.7) |
| Missing | 283 |
Data are presented as mean±sd (range) or n (%). ETI: elexacaftor/tezacaftor/ivacaftor; BMI: body mass index; FEV1 % pred: percentage predicted forced expiratory volume in 1 s; CFTR: CF transmembrane conductance regulator. Age is calculated on 1 January of the follow-up year. BMI is provided as z-scores for children ≥2 and <18 years, otherwise is reported as kg·m−2 for pwCF aged ≥18 years. FEV1 % pred is reported for pwCF aged ≥6 years.
Positive microbiological status
Overall, 11 245 out of 15 082 pwCF (74.6%) were positive for at least one pathogen in the year prior to ETI. This proportion decreased to 8148 out of 15 158 pwCF (53.8%), 1 year after ETI initiation (p<0.001). In contrast, there was only a minimal change in the number of individuals with at least one positive pathogen 3 years prior to ETI initiation (4552 of 6388, 71.3%) compared with the year before ETI initiation (74.6%) (p<0.001). The proportions of pwCF who were found positive for the specific pathogens at 3 years and 1 year before ETI and 1 year after ETI are shown in figure 2 and supplementary table S2. Overall, the microbiological status of pwCF improved, demonstrating a reduction in positivity rates in the year following ETI initiation. Subsequently, the results of the adjusted model are presented individually for each pathogen, with the magnitude of the coefficients detailed in supplementary table S3.
FIGURE 2.
Proportion of positive microbiological status at considered time points. Bars denote the proportion of people with cystic fibrosis with positive microbiological status at considered time points. Specific numbers and percentages for the different time points can be seen in supplementary table S2. ETI: elexacaftor/tezacaftor/ivacaftor.
Pseudomonas aeruginosa
The distribution and transitions of pwCF across PsA positivity at 3 years before ETI, 1 year before ETI initiation and at 1 year after ETI, are represented in figure 3a. The majority (51.3%) remained negative across years, while 21.8% remained positive. Of those who were PsA positive 3 and 1 year before ETI, 11.6% transitioned to a negative status following ETI. In comparison, 2.3% became positive after starting ETI despite being negative at 3 and 1 years before ETI.
FIGURE 3.
Alluvial plots: Pseudomonas aeruginosa status at all time points . Stacked bars denote the percentage of people with cystic fibrosis (pwCF) with a) positive/negative P. aeruginosa and b) methicillin-sensitive Staphylococcus aureus (MSSA) at different time points. Colours identify pwCF with positive/negative bacterial detection 3 years before elexacaftor/tezacaftor/ivacaftor (ETI). The flow streams show how their frequency changed from 3 years before ETI through 1 year after exposure to ETI.
When examining the ETI and pre-ETI periods separately, among those who were PsA positive 3 years before ETI, 14.8% (840 of 5663) changed to negative 1 year before ETI. This corresponds to an estimate of 24.6% (95% CI 19.0–30.3; p<0.001) based on the adjusted model. In contrast, 38.7% (2340 of 6048) of those who were positive at 1 year before ETI became negative 1 year after ETI initiation. This corresponds to an estimate of 39.3% (95% CI 37.5–41.0; p<0.001) from the adjusted model. Overall, the adjusted difference between the two periods (−3 → −1 versus −1 → +1) was 14.6% (95% CI 7.3–21.9; p<0.001).
To further examine whether this reduction was sustained for a longer period, we assessed PsA positivity in the second year after ETI initiation for those starting ETI in 2019–2020 (figure 4 and supplementary table S4). While 46.8% (3280 of 7016) were PsA positive 1 year before ETI initiation, this proportion decreased to 30.4% (2097 of 6904) 1 year after ETI and further to 27.7% (1901 of 6861) 2 years after ETI.
FIGURE 4.
Proportion of positive microbiological status for those starting elexacaftor/tezacaftor/ivacaftor (ETI) in 2019/2020 and with 2 years of follow-up. Bars denote proportion of positive microbiological status for those starting ETI in 2019/2020 with continuous follow-up from −1 to +2 years after ETI. Specific numbers and percentages for the different time points can be seen in supplementary table S4.
Methicillin-sensitive Staphylococcus aureus
The proportions of pwCF who were MSSA positive at various time points are shown in figure 3b. The largest proportion (45.7%) remained negative across years, compared with 16.4% who remained positive at all study points.
Of those who were MSSA positive 3 and 1 year before ETI, 12.0% transitioned to negative status following ETI. In comparison, 4.0% became MSSA positive after starting ETI despite being negative 3 and 1 year before ETI
When examining the two periods separately, among those who were MSSA positive 3 years before ETI, 29.1% (1634 of 5611) were negative 1 year before ETI. This corresponds to an estimate of 31.5% (95% CI 27.5–35.6; p<0.001) based on the adjusted model. In contrast, 47.2% (2706 of 5737) of those who were positive before ETI, became negative after ETI initiation, reflected in an estimate of 48.6% (95% CI 46.6–50.5; p<0.001) from the adjusted model. Overall, the adjusted difference between the two periods was 17.1% (95% CI 12–22.1; p<0.001).
For those who started ETI in 2019–2020, 32.8% were MSSA positive 1 year pre-ETI. This proportion decreased to 21.5% 1 year after ETI, and further to 19.6% 2 years after ETI (figure 4 and supplementary table S4).
Burkholderia cepacia complex
An estimated 60.1% (95% CI 59.1–61.1; p<0.001) of those who were BCC positive 1 year before ETI, transitioned to a negative status in the year following ETI initiation. In the years prior to ETI, 17.9% (95% CI 12.6–23.2; p<0.001) transitioned from positive to negative, reflecting a difference of 42.2% (95% CI 35.2–49.2; p<0.001) between the pre-to-post-ETI years. For those who started ETI in 2019–2020, 5% were BCC positive 1 year before ETI. This proportion decreased to 1.6% 1 year after ETI and 1.4% 2 years after ETI initiation (figure 4 and supplementary table S4).
Methicillin-resistant Staphylococcus aureus, Stenotrophomonas maltophilia and Achromobacter spp.
Since MRSA and AS were reliably documented in the registry only after 2018, there was insufficient data from the pre-ETI period to present valid estimates. However, the frequency of pwCF who were MRSA-positive decreased from 5.4% prior to ETI initiation to 3.7% 1 year after initiation. The proportion of those who were AS positive decreased from 7.8% to 5.6% in the same period.
Among pwCF who were SM positive 3 years before ETI, 802 (50.9%) were negative 1 year before ETI. This corresponds to an estimate 56.6% (95% CI 52.5–60.6; p<0.001) based on the adjusted model. A larger proportion of pwCF who were positive before ETI transitioned to a negative status after ETI (1372, 78.1%), reflected in an estimate of 77.9% (95% CI 76.5–79.4; p<0.001) from the adjusted model. The adjusted difference between the two periods was 21.4% (95% CI 16.0–26.7; p<0.001).
For those starting ETI in 2019–2020, MRSA, SM and AS positivity was reduced 1 year after ETI, with these reductions being sustained at 2 years after ETI (figure 4 and supplementary table S4).
Pattern of pathogen detection
The pattern of detection of considered pathogens in those who started ETI in 2020, were examined 1 year before, and 1 and 2 years after ETI. Overall, 23.5% were negative for all pathogens at 1 year before ETI, and this proportion was more than doubled in the years after ETI (48.4% and 53.7 at 1 and 2 years after ETI, respectively). A pattern towards lower occurrence of co-infection after ETI can be seen in table 2.
TABLE 2.
Pattern of the most frequent microbiological combinations in people with cystic fibrosis (pwCF) starting ETI in 2019–2020
| Co-detection | 1 year pre-ETI (n=7232) | 1 year post-ETI (n=7191) | 2 years post-ETI (n=7154) |
|---|---|---|---|
| No detection | 1702 (23.5) | 3477 (48.4) | 3845 (53.7) |
| PsA+MSSA | 768 (10.6) | 548 (7.6) | 467 (6.5) |
| MSSA+SM | 203 (2.8) | 75 (1) | 57 (0.8) |
| PsA+SM | 201 (2.8) | 72 (1) | 67 (0.9) |
| MSSA+AS | 110 (1.5) | 72 (1) | 62 (0.9) |
| PsA+AS | 109 (1.5) | 67 (0.9) | 65 (0.9) |
Data are presented as n (%). ETI: elexacaftor/tezacaftor/ivacaftor; PsA: Pseudomonas aeruginosa; MSSA: methicillin-sensitive Staphylococcus aureus; SM: Stenotrophomonas maltophilia; AS: Achromobacter species. The most frequent positive microbiological combinations in pwCF 1 year before ETI and 1 and 2 years after ETI are presented.
Discussion
This study, using ECFSPR data, shows a significant reduction in PsA, MSSA, BCC, MRSA, AS and SM positivity following ETI initiation. To our knowledge, this is the first study to show real-world microbiological data following ETI in a large international cohort, including a diverse population.
It has been previously shown that HEMT influences lung infection in pwCF: ivacaftor, the first approved modulator was linked to a reduced occurrence of sputum cultures testing positive for PsA [16–18]. Regarding ETI, one study showed sputum densities of common CF pathogens significantly decreased 1 month after initiation, but in most cases the pathogens were not totally eradicated 6 months after ETI initiation [19]. Another, relatively small, single-centre study showed a significant reduction in PsA colonisation after 2 years of ETI use [20]. Recently, a local German CF registry-based study showed a reduction in MSSA-positive cultures from 54.3% to 44.3% and 40.2% and in PsA from 39.9% to 31.9% and 22.6% at 3 and 21 months, respectively. This reduction was associated with age, previous lung function and pre-ETI colonisation status [21]. In this current study, we detected a significant reduction in the positivity of all assessed pathogens up to 2 years after ETI initiation.
Along with the significant reduction in detection of specific pathogens, we also found that the proportion of pwCF with negative status for all assessed pathogens, more than doubled over 2 years following ETI initiation. It is well recognised that pwCF using HEMT expectorate significantly less sputum, which may reduce the amount of collected samples. Using the current methodology, the extent of this reduction could not be estimated, as ECFSPR reports only annual positive culture results without specifying the number of cultures obtained. However, monitoring airway pathogens and antibiotic treatments has been, and still is an important practice in pwCF [22]. Current guidelines continue to advocate for routine sputum collection, among other ways, by encouraging induced sputum techniques. It is reasonable to assume that most centres adhere to these guidelines, but sputum collection rates are not documented by ECFSPR and therefore this could not be confirmed. Additionally, the ECFSPR states that a subject previously chronically infected should be reported as non-chronic only if there is clinical evidence supporting this change. Therefore, in cases where no sputum was collected over the year, patients can still be reported as chronically infected. The ECFSPR guidelines of reporting positive airway infection, based on previous years, even when there are no cultures available, might overestimate the rate of bacterial infection in the HEMT era when obtaining cultures is more difficult.
So far, practices for PsA eradication or maintenance antibiotic therapy for PsA have remained unchanged [23]. In the ETI era, efforts are made to reduce the burden of CF care in a safe way [12, 13]. While this study did not focus on the clinical benefits for those that reduced the detection of CF-related pathogens, the fact that much less patients are reported as chronically infected with PsA after ETI, can encourage clinicians to insist on proper culture sampling, and when appropriate, to carefully explore options for reduction in antibiotic treatments.
Despite the overall significant reduction in pathogen detection following ETI initiation, a small proportion of pwCF experienced the opposite trend. Specifically, 2.3% and 4% of individuals who were PsA or MSSA negative, respectively, shifted to positive status for these pathogens after starting ETI. This was significantly less than the numbers seen in the years prior to ETI (11.9% and 17.2% for PsA and MSSA, respectively). These encouraging results suggest that ETI not only reduced pathogen detection in individuals who had already acquired them but also slowed the natural progression of acquiring new airway pathogens over time. Despite that, the proportion of pathogens acquired after starting ETI is not negligible. Especially for individuals who began ETI after significant and irreversible lung damage had already occurred, managing lung infections is likely to remain a lifelong challenge.
The main strength of this study is the large and diverse population included in the study. Data included in the ECFSPR are collected and reported annually, therefore reducing biases that are often subject in retrospective analyses studies and presenting real-world data. However, the present study has some limitations that should be considered. The microbiological definitions used by the ECFSPR have evolved over the years and were slightly different for different pathogens. We therefore had to harmonise definitions to have comparable data. Also, in middle- and high-income countries, most pwCF who qualify for ETI therapy started treatment between 2019 and 2021. Therefore, a comparator group with similar characteristics, in terms of socioeconomic levels and CFTR mutations but without ETI treatment, was not available. Since pwCF with stop mutations [24] and those from lower GNI countries [25] typically have a poorer prognosis, they are less suitable for use as comparator groups. Instead, to isolate the effect of ETI on pathogen detection, we used data from the same patients, over 2 years prior to ETI as a proper comparison. Hence, other factors that change over time could potentially confound our results. For example, the prevalence of airway pathogens in pwCF often changes with age [26]. Notably, PsA infections usually increase with time, so the observed reduction in PsA after ETI, despite the passage of time, underscores the significance of our results.
Another potential confounding to our results could be the impact of the COVID-19 pandemic, which led to fewer in-person visits and possibly fewer cultures being obtained. Additionally, isolation practices and mask-wearing may have influenced infection rates. While it is difficult to quantify the exact effect of the pandemic, the limited reduction in positivity during the pandemic years before ETI initiation, coupled with the sustained reduction observed after ETI initiation, even after the peak of the pandemic had passed, suggests that the pandemic's impact on our findings was limited.
In conclusion, 1 year after ETI initiation, a significant proportion of pwCF with a positive microbiological status transitioned to negative. This proportion was notably lower before ETI initiation, suggesting that this change is likely attributable to ETI therapy. Additionally, the reduction seems to be sustained into the second year after ETI initiation. The clinical significance of these findings warrants further investigation in future studies.
Acknowledgements
We thank the pwCF and their families for consenting to their data being included in the ECFSPR. We thank the centres and individual country representatives for allowing the use of the data, and the ECFSPR for providing access to anonymised patient data.
Footnotes
List of contributors: We would like to thank the people representing the countries that provided the data and the members of the ECFSPR Scientific Committee: Egil Anita C.S. Bakkeheim Wathne (National Resource Centre for Cystic Fibrosis, Oslo University Hospital, Oslo, Norway); Antoine Bessou (Vaincre la Mucoviscidose, Paris, France); Pierre-Régis Burgel (ECFSPR Scientific Committee) (National Reference CF Center and Respiratory Medicine, Cochin Hospital APHP and Université Paris Cité, Institut Cochin (InsermU1016), Paris, France); Siobhán B. Carr (ECFSPR Scientific Committee) (Department of Respiratory Paediatrics, Royal Brompton Hospital; NHLI, Imperial College, London, United Kingdom); Anna-Maria Charatsi (Centre Hospitalier de Luxembourg, Luxembourg); Sarah Clarke (UK Cystic Fibrosis Registry, Cystic Fibrosis Trust, London, United Kingdom); Géraldine Daneau (Sciensano, Epidemiology and public health, Health services research, Brussels, Belgium); Deniz Dogru (Cystic Fibrosis Registry of Turkey, Ankara, Turkey); Pavel Drevinek (Department of Medical Microbiology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic); Helga Elídóttir (Children's Medical Center Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland); Godfrey Fletcher (The Cystic Fibrosis Registry of Ireland, Dublin, Ireland); Elpis Hatziagorou (Paediatric Pulmonology and Cystic Fibrosis Unit, 3rd Paediatric Department, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece); Andreas Jung (Department of Paediatric Pulmonology, University Children's Hospital Zurich, Zurich, Switzerland); Hana Kayserová (Cystic Fibrosis Centre, University Hospital of Bratislava, Bratislava, Slovakia); Elena Kondratyeva (Clinical research Department of cystic fibrosis and Department of Hereditary Lung Diseases, Research Centre for Medical Genetics, Moscow, Russian Federation); Christina Krantz (Uppsala CF Centre, Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden); Uroš Krivec (Department of Paediatric Pulmonology, University Children's Hospital, Ljubljana University Medical Centre, Ljubljana, Slovenia); Elise Lammertyn (ECFSPR Scientific Committee) (Cystic Fibrosis Europe, Brussels; Association Muco A.S.B.L. – Mucovereniging V.Z.W. Brussels, Belgium); Anders Lindblad (ECFSPR Scientific Committee) (Gothenburg CF Centre, Queen Silvia Children's Hospital, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden); Milan Macek Jr (ECFSPR Scientific Committee) (Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic); Lutz Naehrlich (Universities of Giessen and Marburg Lung Center, German Center of Lung Research, Justus-Liebig-University Giessen, Giessen, Germany); Hanne V. Olesen (Department of Pediatrics and Adolescent Medicine, Cystic Fibrosis Center, Aarhus University Hospital, Aarhus, Denmark); Rita Padoan (Scientific Board of Italian CF Registry, Lega Italiana Fibrosi Cistica, Rome, Italy); Andrea Párniczky (Heim Pál National Paediatric Institute, Budapest, Hungary; Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary); M. Dolores Pastor-Vivero (Cystic Fibrosis Group, Biobizkaia Health Research Institute, Paediatric Pulmonology and Cystic Fibrosis Unit, Cruces University Hospital, Barakaldo, Spain); Luísa Pereira (Centre for Cystic Fibrosis, Hospital de Santa Maria, Lisbon, Portugal); Guergana Petrova (Alexandrovska University Hospital, Paediatric Clinic, Sofia, Bulgaria); Andreas Pfleger (Department of Paediatrics and Adolescent Medicine, Division of Paediatric Pulmonology and Allergology, Medical University of Graz, Graz, Austria); Liviu Pop (Victor Babes University of Medicine and Pharmacy Timisoara, National Cystic Fibrosis Centre, Timisoara, Romania); Milan Rodić (National Centre for Cystic Fibrosis, Mother and Child Health Institute of Serbia “Dr Vukan Čupić”, Belgrade, Serbia); Duska Tješić-Drinković and Andrea Vukić Dugac (University Hospital Centre Zagreb, Cystic Fibrosis Centre – Paediatrics and Adults, Zagreb, Croatia); Łukasz Woźniacki (Dziekanow Paediatric Hospital, Cystic Fibrosis Centre, Institute of Mother and Child, Warsaw, Poland); Panayiotis Yiallouros (Medical School, University of Cyprus, Nicosia, Cyprus); Anna Zolin (ECFSPR Scientific Committee) (Department of Clinical Sciences and Community Health, Laboratory of Medical Statistics, Biometry and Epidemiology “G.A. Maccaccaro”, University of Milan, Milan, Italy); and Domenique Zomer (Dutch Cystic Fibrosis Foundation (NCFS), Baarn, The Netherlands).
Provenance: Submitted article, peer reviewed.
Ethics statement: Data are provided to ECFSPR under existing ethical approvals and data-governance structures, and all participants or guardians signed an informed consent prior to data collection (details are at www.ecfs.eu/ecfspr).
This article has an editorial commentary: https://doi.org/10.1183/23120541.00211-2025
Conflict of interest: The authors report no conflicts of interest related to this work.
Supplementary material
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Supplementary material
01248-2024.SUPPLEMENT
References
- 1.Barry PJ, Mall MA, Álvarez A, et al. Triple therapy for cystic fibrosis phe508del-gating and -residual function genotypes. N Engl J Med 2021; 385: 815–825. doi: 10.1056/NEJMoa2100665 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Nichols DP, Paynter AC, Heltshe SL, et al. Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a clinical trial. Am J Respir Crit Care Med 2022; 205: 529–539. doi: 10.1164/rccm.202108-1986OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019; 394: 1940–1948. doi: 10.1016/S0140-6736(19)32597-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381: 1809–1819. doi: 10.1056/NEJMoa1908639 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175–184. doi: 10.1164/rccm.201404-0703OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–1672. doi: 10.1056/NEJMoa1105185 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zaher A, ElSaygh J, Elsori D, et al. A review of Trikafta: triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Cureus 2021; 13: e16144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Schaupp L, Addante A, Völler M, et al. Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis. Eur Respir J 2023; 62: 2202153. doi: 10.1183/13993003.02153-2022 [DOI] [PubMed] [Google Scholar]
- 9.Sergeev V, Chou FY, Lam GY, et al. The extrapulmonary effects of cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Ann Am Thorac Soc 2020; 17: 147–154. doi: 10.1513/AnnalsATS.201909-671CME [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Harun SN, Wainwright C, Klein K, et al. A systematic review of studies examining the rate of lung function decline in patients with cystic fibrosis. Paediatr Respir Rev 2016; 20: 55–66. [DOI] [PubMed] [Google Scholar]
- 11.Kerem E, Viviani L, Zolin A, et al. Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur Resp J 2014; 43: 125–133. doi: 10.1183/09031936.00166412 [DOI] [PubMed] [Google Scholar]
- 12.Mayer-Hamblett N, Ratjen F, Russell R, Donaldson SH, Riekert KA, Sawicki GS, et al. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respir Med 2023; 11: 329–340. doi: 10.1016/S2213-2600(22)00434-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Mayer-Hamblett N, Gifford AH, Kloster M, et al. Impact of discontinuing both hypertonic saline and dornase alfa after elexacaftor/tezacaftor/ivacaftor in cystic fibrosis. Ann Am Thorac Soc 2024; 21: 1507–1515. doi: 10.1513/AnnalsATS.202404-366OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Zolin A, Adamoli A, Bakkeheim E, et al. ECFSPR Annual Report 2022 , 2024. https://www.ecfs.eu/sites/default/files/Annual%20Report_2022_ECFSPR_20240603.pdf.
- 15.Lee TWR, Brownlee KG, Conway SP, et al. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros 2003; 2: 29–34. doi: 10.1016/S1569-1993(02)00141-8 [DOI] [PubMed] [Google Scholar]
- 16.Heltshe SL, Mayer-Hamblett N, Burns JL, et al. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60: 703–712. doi: 10.1093/cid/ciu944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kawala CR, Ma X, Sykes J, et al. Real-world use of ivacaftor in Canada: a retrospective analysis using the Canadian cystic fibrosis registry. J Cyst Fibros 2021; 20: 1040–1045. doi: 10.1016/j.jcf.2021.03.008 [DOI] [PubMed] [Google Scholar]
- 18.Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: data from national US and UK registries. J Cyst Fibros 2020; 19: 68–79. doi: 10.1016/j.jcf.2019.05.015 [DOI] [PubMed] [Google Scholar]
- 19.Nichols DP, Morgan SJ, Skalland M, et al. Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist. J Clin Invest 2023; 133: e167957. doi: 10.1172/JCI167957 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Szabo MM, Foushee SE, McPheeters CM, et al. Impact of elexacaftor/tezacaftor/ivacaftor on respiratory colonization in an adult cystic fibrosis clinic. Am J Med Sci 2024; 367: 337–342. doi: 10.1016/j.amjms.2024.02.001 [DOI] [PubMed] [Google Scholar]
- 21.Dittrich AM, Sieber S, Naehrlich L, et al. Use of elexacaftor/tezacaftor/ivacaftor leads to changes in detection frequencies of Staphylococcus aureus and Pseudomonas aeruginosa dependent on age and lung function in people with cystic fibrosis. Int J Infect Dis 2024; 139: 124–131. doi: 10.1016/j.ijid.2023.11.013 [DOI] [PubMed] [Google Scholar]
- 22.Grasemann H, Ratjen F. Cystic fibrosis. N Engl J Med 2023; 389: 1693–1707. doi: 10.1056/NEJMra2216474 [DOI] [PubMed] [Google Scholar]
- 23.Elborn JS, Blasi F, Burgel PR, et al. Role of inhaled antibiotics in the era of highly effective CFTR modulators. Eur Respir Rev 2023; 32: 220154. doi: 10.1183/16000617.0154-2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Orenti A, Pranke I, Faucon C, et al. Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children. J Cyst Fibros 2023; 22: 1070–1079. doi: 10.1016/j.jcf.2023.06.005 [DOI] [PubMed] [Google Scholar]
- 25.Kerem E, Orenti A, Adamoli A, et al. Cystic fibrosis in Europe: improved lung function and longevity - reasons for cautious optimism, but challenges remain. Eur Respir J 2024; 63: 2301241. doi: 10.1183/13993003.01241-2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Cystic Fibrosis Foundation Patient Registry 2022 Annual Data Report. Bethesda, Cystic Fibrosis Foundation, 2023.
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