Assessment of efficacy and tolerability of elexacaftor-tezacaftor-ivacaftor in an observational cohort study of “aged” people with cystic fibrosis

Abstract

Background:

Therapeutic advancements utilizing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) have revolutionized the treatment of people with cystic fibrosis (pwCF). Elexacaftor-Tezacaftor-Ivacaftor (ETI) is a highly effective modulator therapy and has been shown to improve health outcomes in people with CF (PwCF). Due to these therapeutic advancements, many pwCF are getting older, but little is known regarding the safety and efficacy of ETI in pwCF at a more advanced age.

Objectives:

We aimed to determine the effect of ETI on clinical outcomes in older pwCF.

Design:

This study was a single-center, retrospective analysis of pwCF who received open-label ETI following FDA approval and were over the age of 40 at the time of ETI initiation.

Methods:

Data were obtained from the electronic medical record from a large CF center in the United States of America between November 2019 and January 2021, including body mass index (BMI), lung function as % predicted FEV₁ before ETI initiation, and approximately 3 months and one a follow-up visit within 9–15 months post-ETI initiation. The exacerbation frequency over 12 months was recorded before and after ETI initiation.

Results:

Forty-two patients met the inclusion criteria. Mean age at time of ETI initiation was 47.9, 23 patients (54.8%) were male, and 11 (26.2%) were homozygous for the F508del mutation. Linear mixed effects models suggest a monthly increase of 0.24 (95% CI 0.08–0.41, p = 0.003) for ppFEV1 and 0.03 (95% CI 0.002–0.06, p = 0.036) for BMI post-ETI, resulting in a 2.96 (95% CI 0.98–4.95) increase in ppFEV1 and 0.39 (95% CI 0.03–0.76) increase in BMI approximately 1-year post-ETI. In addition, a significant decline in pulmonary exacerbations was seen in the year following ETI initiation (1.5 ± 1.3 exacerbations/year prior vs 0.5 ± 0.7 exacerbations/year post; p < 0.0001).

Conclusion:

Treatment with ETI in this unique cohort of pwCF was safe. Whereas ETI affected BMI in a subtle way, initiation of ETI was associated with stabilization of lung disease with a significant but moderate increase in lung function and a decline in the number of exacerbations in the follow-up period. Longer and larger studies will be needed to analyze the effect of ETI on an aging CF population.

Plain language summary

Modulator therapy in an aged cystic fibrosis cohort

Cystic fibrosis is a genetic disease, which affects multiple organ systems often from birth on leading to a markedly decreased life expectancy. Over the last decades, optimization of care and more treatment options especially medication that restores the defective chloride channel ultimately responsible for the disease manifestations changed this poor prognosis and people with cystic fibrosis can live into their 60s. While most clinical trials focused on a “younger” representative patient population studying the effects of the first triple combination of these chloride channel correctors (Elexacaftor, Tezacaftor, Ivacaftor – ETI), our study focused on assessing the effect of ETI on an older population showing that they also tolerated ETI well and experienced improvement in their lung function and a decrease in hospitalizations due to cystic fibrosis flare ups, which were both statistically significant and comparable to ETI effects seen in different CF populations.

Introduction

Cystic fibrosis (CF) is a multiorgan disease that leads to increased morbidity and mortality, caused by an autosomal recessive genetic disorder resulting in dysfunction of the CF transmembrane conductance regulator (CFTR). CFTR is an ion channel expressed on the apical surface of epithelial cells, and a dysfunctional CFTR leads to impaired water-electrolyte balance, causing increased mucus viscosity and mucociliary dysfunction.^1,20 Primary organ systems affected include airways, the gastrointestinal system, the reproductive system, and sweat glands.^2,3 CF affects more than 70,000 people worldwide. ⁴ Since the discovery of CFTR in the 1980s, correction of the CFTR has been a prioritized therapeutic target. The first Food and Drug Administration (FDA) approved medication designed to target CFTR function emerged in 2012 and quickly became the cornerstone of treatment over the past decade for those genetically eligible.^5,6 CFTR modulators are divided into two groups: potentiators (Ivacaftor), which enhance CFTR function at the cell membrane, and correctors (Lumacaftor, Tezacaftor, Elexacaftor), which increase the quantity of CFTR channels at the apical surface of the cell.^6–8 The most advanced therapy combines these modalities, leading to the development of Elexacaftor-Tezacaftor-Ivacaftor (ETI), a next-generation triple therapy. In 2019, ETI was approved to treat individuals with one or two F508del alleles, which is the most common mutation in people with CF (pwCF) worldwide. ⁹ ETI proved to be clinically efficacious with significant improvements in respiratory symptoms and function, a decreased risk of acute pulmonary exacerbations, and weight gain in several clinical trials.^10–12 The mean age (standard deviation; SD) of participants who received ETI in the landmark trials that led to FDA approval was 27.9 (10.8) and 25.6 (9.7). ¹⁰ Since the widespread use of ETI and additional therapeutic advancements in CF treatment and care, life expectancy and longevity have significantly increased for pwCF. ¹³ Although ETI has been shown to be well tolerated in the majority of pwCF, there is limited knowledge regarding the efficacy and safety of ETI in pwCF at a more advanced age with potential polypharmacy and whether ETIs affect aging-related diseases and comorbidities. Here we present results from a single-center, retrospective analysis of pwCF who received open-label ETI following FDA approval and were over the age of 40 at the time of ETI initiation, to better understand the efficacy of ETI in an “older” CF population.

Methods

Study population

This retrospective cross-sectional study was conducted at the Adult Cystic Fibrosis Clinic of the University of Alabama at Birmingham in the United States. Medical records of subjects of this clinic, who were all older than 40 years, were collected from 10/2019 to 07/2021. Data collection included the documentation of demographic features, age, race, sex, and genotype. In addition, lung function (FEV1%), body mass index (BMI), sputum/swap microbiology (colonization with methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, atypical mycobacteria) and exacerbation frequency within 12 months were collected before the initiation of ETI and the same outcome from clinic visits approximately 3 months and 9–15 months after ETI initiation, while subjects were taking ETI. Almost all patients were able to expectorate sputum, whereas one patient underwent a pharyngeal swab to obtain a specimen for microbiological analysis. For sputum processing, the most-purulent portion is used to prepare a thin smear for Gram stain, and a sterile swab, will be used to inoculate in an appropriate medium and streak appropriate plates for isolation. Throat swabs will be used directly to streak plates for isolation.

Exacerbations were defined as the sudden onset of respiratory symptoms, including congestion and productive cough with or without a decrease in lung function, requiring oral or intravenous antibiotics in- or outpatient.^14,15 Our study protocol was authorized by the Human Studies Subcommittee of the Institutional Review Board of the University of Alabama at Birmingham on 11 May 2016 (ID: 01265). The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Material). ¹⁶

Eligibility criteria

Criteria for subjects to be included were to have a diagnosis of CF confirmed by genotype and symptoms consistent with CF and ⩾40 years of age. In addition, subjects needed to be started on ETI and tolerating ETI for the length of the study. Exclusion criteria included subjects who discontinued ETI or underwent lung transplantation prior.

Statistical analysis

Study size was limited by the number of clinic patients that fit the inclusion criteria and had data points acquired. All observations are included in the analysis. Sample size varies by the availability of data per variable, which is due to data missing completely at random. As such, the sample size changes according to how many participants had information for a given characteristic. Since this was a pilot study with a small sample size to begin with, no imputation strategies were considered. We examined descriptive statistics for the entire sample and by CFRD status. Statistical significance by CFRD status is determined using the generalized Fisher’s exact test for categorical variables and Student’s t-test for continuous variables. Continuous measures showed approximately a normal distribution and were expressed as mean ± SD. BMI and ppFEV1 are observed at three time points (pre-Trikafta, ~3 months post-Trikafta, and ~9–15 months post-Trikafta). Changes in ppFEV1 and BMI are explored using linear mixed models (LMM) with a random intercept, which corrects for the interdependency created by using multiple observations from the same person. ¹⁷ We did not include a random slope for BMI, as there was very little level 1 variation in the slope (e.g., time), and model fit statistics (AIC and BIC) suggest that including time as a random effect does not improve the model fit. For ppFEV1, we did include a random slope as the likelihood ratio test indicates that the model that included time as a random effect is a better fit (LR χ²(2) = 6.46, p = 0.039) though AIC and BIC were similar between the two models. Time is measured as the number of exact days since the first observation and is presented as a monthly change. Additional analyses examined whether there were significant differences in ppFEV1 by CFRD. We did not include covariates in our model, given our limited sample size, though additional analyses indicate that including covariates for the baseline characteristics of sex at birth, age at first encounter, and F508del homozygous (adjusted in separate models) did not substantially influence the relationship between time and the outcomes. We used paired t-tests to examine changes in pulmonary exacerbations 12 months post-Trikafta. In addition, we used McNemar’s test to examine changes in no exacerbations compared to any exacerbations, given the relatively few number of exacerbations, especially post-Trikafta. We used PRISM (version 8.4.3) and Stata (version 17.0) for all statistical analyses. Statistical significance was set at p-value < 0.05 for a two-sided test.

Results

Cohort characteristics

41 participants were enrolled in the study. Participants were 47.9 years old on average, with a mean ppFEV₁ of 56.3 ± 19.8%. Baseline characteristics of the study population are shown in Table 1, which is representative of the CF population in our area. 44% of patients were female, and the majority were white (98%). Eleven patients were homozygous for the F508del mutation, one participant had a G551D genotype and switched from Ivacaftor to ETI, 26 were heterozygous for F508del, and 4 patients had non-F508del mutations. 23/42 participants had a ppFEV₁ lower than 65% (data not shown), and the BMI average was 25.9, making this cohort unique compared to many study cohorts with generally lower BMI and higher lung function as seen in the PROMISE study. ¹⁰

Table 1.

Patient characteristics of the “aged” CF cohort.

Patient baseline characteristics (n = 42)	Mean/number
Age (mean)	47.9
Sex at birth, female (n)	19
Ethnicity
White (n)	41
Black, or African American (n)	1
Hispanic or Latino (n)	1
Spirometry
ppFEV1 < 65 (n)	23
ppFEV1 65–90 (n)	17
ppFEV1 >90 (n)	2
Body Mass Index (BMI), mean	25.9
Exocrine Pancreatic Insufficiency (EPI) (n)	28
CFRD (n)	21
Number of exacerbations (mean)	1.5
Genotype
F508del homozygous (n)	11
G551D (n)	1
F508del heterozygous (other) (n)	26
Non-F508 mutation (n)	4

BMI, body mass index; CFRD, CF-related diabetes; EPI, exocrine pancreatic insufficiency; ppFEV₁, percent predicted Forced Expiratory Volume in 1 second.

The effect of ETI on lung function in pwCF > 40 years of age

Full spirometric data sets for all three time points were available for 34 patients, and an additional 5 patients had 2 of the three measurements. LMM indicates that pre-Trikafta individuals had an average baseline ppFEV1 of 58.37 and a monthly increase of 0.24 (p = 0.003, 95% CI 0.08–0.41), which was statistically significant. This results in an annual increase of 2.96 (95% CI 0.98–4.95) in ppFEV1 post-Trikafta (Table 2).

Table 2.

Linear mixed models for body mass index (BMI) and ppFEV1.

Parameter	BMI (n = 106)				ppFEV1 (n = 111)
	Estimate	p-Value	95% CI		Estimate	p-Value	95% CI
Monthly change	0.03	0.036	0.00	0.06	0.24	0.003	0.08	0.41
Baseline	25.81	<0.001	24.00	27.63	59.37	<0.001	53.79	64.95

Since it has been shown that CFRD can negatively affect lung function, ¹⁸ we had a specific interest in whether pwCF with CFRD see a similar beneficial effect with Trikafta. LMM indicate that those with CFRD do start off with lower baseline ppFEV1 (−9.0, p = 0.105) and have greater monthly gains in ppFEV1 (0.42 vs 0.35, p = 0.729), but these differences were not significant (Table 3).

Table 3.

Descriptive statistics of study variables.

Parameter	CFRD-no (n = 21, 51.2%)	CFRD-yes (n = 20, 48.8%)	Total (n = 41)	p-Value
Clinical characteristics, mean (std)
ppFEV1 pre-Trikafta a	64.05 (18.05)	52.63 (21.75)	58.49 (20.50)	0.082
BMI pre-Trikafta b	26.87 (6.97)	24.54 (3.14)	25.71 (5.46)	0.193
ppFEV1 3 mos post-Trikafta c	57.47 (17.82)	57.47 (17.82)	59.74 (16.41)	0.434
BMI 3 mos post-Trikafta	24.96 (3.33)	24.96 (3.33)	26.02 (5.88)	0.273
ppFEV1 9-15 mos post-Trikafta b	58.95 (17.89)	58.95 (17.89)	63.03 (16.76)	0.135
BMI 9-15 mos post-Trikafta b	25.56 (3.61)	25.56 (3.61)	26.12 (5.36)	0.528
Number of PEx pre-Trikafta	1.29 (1.15)	1.95 (1.32)	1.61 (1.26)	0.003
Number of PEx 12 mos post-Trikafta	0.67 (0.80)	0.40 (0.50)	0.54 (0.67)	0.026
Demographics
Age, mean (std) b	47.28 (15.06)	45.12 (5.45)	46.25 (11.46)	0.359
Race/Ethnicity, % (n)
Black/AA	-	5.00 (1)	2.44 (1)	0.284
Hispanic	4.76 (1)	5.00 (2)	4.88 (2)
White	95.24 (2)	90.00 (18)	92.68 (38)
Gender, % (n)
Female	47.62 (10)	40.00 (8)	43.90 (18)	0.252
Male	52.38 (11)	60.00 (12)	56.10 (23)
Genotype, % (n)
Non-F508 mutation	19.05 (4)	–	9.76 (4)	<0.001
F508del heterozygous	66.67 (14)	55.00 (4)	60.98 (25)
F508del homozygous	9.52 (2)	45.00 (9)	26.83 (11)
G155D	4.76 (1)	–	2.44 (1)
Pancreatic insufficiency, % (n)
No	52.38 (11)	10.00 (4)	31.71 (13)	<0.001
Yes	47.62 (10)	90.00 (18)	68.29 (28)

p-Values for differences by CFRD status were calculated using the generalized Fisher’s exact test for categorical variables and Student’s t-test for continuous variables.

^an = 39.

^bn = 38.

^cn = 35.

The effect of ETI on BMI in pwCF > 40 years of age

Thirty-eight subjects had their weight recorded at all three time points and were included in the analysis. The cohort’s mean BMI pre-Trikafta was 25.7 ± 5.5 kg/m², which was well within CFF guidelines. ¹⁹ Ten participants of our cohort were underweight, with three of those meeting CFF weight guidelines after 9–15 months (BMI > 22 and 23 for adult women and men, data not shown). ¹⁹ LMM in Table 2 indicates that there is a significant, but modest average monthly increase in BMI post-Trikafta (0.03, p = 0.036, 95% CI: 0.002–0.06). In addition, 16 subjects had a BMI at ETI initiation above 25 kg/m² and 3 additional subjects had a BMI above 30 kg/m², which will lead to counseling in a clinic appointment about weight loss and maintaining a healthy weight.

Effect of ETI on exacerbation frequency

For the analysis of exacerbation frequency, consisting either of initiation of antibiotics (oral or intravenous) or hospitalization, all 42 subjects were included in the analysis. We compared the exacerbation frequency during the 12-month period before ETI initiation with a 12-month period after starting ETI. Our results showed that the mean baseline exacerbation frequency in this cohort was 1.5 ± 1.3 exacerbations/year, which was reduced to 0.5 ± 0.7 after 9–15 months on ETI. Additional analyses examined whether there were changes in any exacerbations compared to no exacerbation after ETI initiation, given the relatively few numbers of exacerbations post-ETI, and found a significant difference (McNemar’s χ² = 7.54, p < 0.001, Figure 1).

Figure 1.

Violin plot showing number of exacerbations in CF cohort 9–15 months before and 12 months after ETI initiation.

Effect of ETI on sputum microbiology

Thirty-five subjects had airway microbiologic data available at baseline before ETI start and 9–15 months after ETI initiation. The majority of patients (except one throat swab culture) were all sputum cultures. Six Participants had culture negativity before ETI initiation and five were culture positive after ETI start, but only two subjects did not have any culture growth at both measured timepoints. The majority of patients were colonized with Pseudomonas aeruginosa (Psa), Methicillin-resistant Staphylococcus aureus (MRSA), or multiple bacterial species, with most of those being positive for both Psa and MRSA. After initiation of ETI, culture negativity remained in four patients, but there were increases in positivity for Psa and MRSA cultures, mainly due to a decrease in culture positivity with both organisms before (Figure 2).

Figure 2.

Pie charts showing different microbiology sputum cultures from the same CF cohort before and 9–15 months after initiation of ETI.

Discussion

This retrospective single-center study assessed the tolerance and effects on initiation of ETI over 9-15 months in a cohort of “aged” CF patients older than 40 years of age. All 42 included subjects tolerated ETI and continued it for the study period. Whereas there were no significant changes in BMI over the study period, FEV₁ increased significantly, accompanied by a significant reduction in exacerbation frequency over a year. Patients also showed a change in sputum microbiology with a reduction in colonization with multiple organisms (mainly Psa in combination with MRSA). Comparing these results to the PROMISE study, which was a prospective observational multicenter study that included 478 pwCF ages 12 years or older, the PROMISE study’s mean average age was 25.1 years compared to a mean age of 48 years in our small CF patient cohort. ¹⁰ After 6 months of ETI therapy, the PROMISE cohort showed a significant increase in ppFEV₁ of 9.8% in comparison to 3.4% and 5.4% at 3- and 9–15-month post-ETI initiation. These discrepancies compared to our study could be due to age itself, but also a lower baseline ppFEV₁ in our cohort, which was a mean 56.3% compared to an average of approximately 80% in the PROMISE study, with less than 30% of participants showing a ppFEV₁ <65%. The observational period was shorter and only 6 months, though other reports, including a Danish study of 229 participants, assessed exercise capacity 1 year after initiation of ETI, showing that ppFEV₁ also increased significantly by 11.9%. Of note, this patient population also had a median age of 27. ²⁰ Our cohort’s mean BMI was 25.9 kg/m², which was higher than the mean BMI of the PROMISE cohort (23.1). Our study showed an increase of 0.3 compared to 0.85 kg/m² in the PROMISE study after 3 months of initiation, with a further increase of 0.4 versus 1.2 kg/m² after 9–15- or 6-month post-ETI in both studies. The reason for these differences could be attributed to a higher baseline BMI, the age itself, or the small cohort of our study, which is a limitation of this study. As mentioned in the results, some of our patients were considered overweight and obese, and those patients were actively working with the CF dietician to either keep their weight stable or lose weight. Therefore, their diet was already modified from the high-calorie diet many pwCF are consuming without significant changes when they started ETI, leading to a more significant increase in body weight. Chronic inflammation is a characteristic shared by cystic fibrosis and the obese state, with higher circulating pro-inflammatory markers in obesity and infiltrating macrophages, which are also significantly contributing to CF pathology, especially in the airways.^21,22 Furthermore, our study reflects current trends in CF, with the prevalence of obesity having markedly increased due to multiple factors, including the general population trend, but also reduced exercise tolerance in combination with therapeutic advances. An increase in weight within a BMI target of 22 kg/m², a “healthy weight,” correlates with improved lung function in CF, but those benefits diminish with a BMI greater than 30 kg/m². ²³ Therefore, not only has modulator therapy contributed to increased weight in CF, but it has also been shown over the last decade that obese and overweight patients are generally older than those who are underweight, ²⁴ which is consistent with our characteristics, and for the future, interdisciplinary teams are working on caloric goals, diet quality and the implementation of exercise.

The PROMISE study did not assess exacerbation frequency, which was probably due to the limited follow-up time of 6 months. Sutharsan et al. conducted an observational cohort study using the German CF Registry, which included 67 centers in Germany, an average patient age of 28 years, and followed lung function, BMI, and exacerbation frequency over the first year, among other outcomes. ¹² Patients included in this study had a mean age of 28 years, a mean ppFEV₁ of 64.7%, which was lower than the PROMISE study, and a mean BMI of 21.3 kg/m². After 1 year, there was a significant 11.3% change in ppFEV₁ and a significant increase of 1.4 kg/m² in BMI, which was higher compared to both our study and the shorter PROMISE study, indicating that there can be increased benefit over time in a young cohort, which had a mean BMI consistent with being underweight. Furthermore, the German study also found a significant reduction in exacerbations and exacerbation frequency. All studies were conducted during the COVID-19 pandemic, and therefore, limitations to outside contacts could have also contributed to these changes in both our and the German study.

In a more recent study from Cohen et al., analyzing the long-term efficacy of ETI in CF patients with advanced lung disease over 24 months in a retrospective multicenter study of 64 patients with ppFEV₁ < 40%. ²⁵ These patients were younger than our study cohort with a mean age of 31.6, a mean ppFEV₁ of 34.0, and a BMI of 21.5 kg/m². Lung function and BMI both increased significantly by 3 months and remained increased over 12–24 months to a higher extent, almost to a similar extent as in our study (ppFEV1 change 6%–8% and BMI change 0.4–1.4). The exacerbation frequency went down from 3.1 to 1.2 as well, which was overall higher compared to our patient cohort, but the ETI-attributed change was similar.

Assessment of CFTR modulator-induced changes to the airway microbiota has been studied before, but shows conflicting results so far. Several studies show reductions in bacterial load and pathogen abundance in the CF lung after modulator initiation, but lung infections generally persisted.^26,27

It has also been shown that CF pathogens, specifically MRSA, continue to persist in the upper airway after ETI initiation, but there is a reduction in Psa.^28,29 In our small cohort, we did not see changes in colonization with Psa or MRSA exclusively, but a reduction in colonization with multiple organisms, which was mainly a combination of Psa and MRSA, and then reduced to just one organism. Previous studies have shown controversial results when assessing microbial burden and CFTR modulator therapy. In a Swedish cohort, Al Shakirchi et al. could show that treatment with lumacaftor/ivacaftor led to a reduction of microbial burden after 1 year, but no marked changes were seen for Staphylococcus aureus and Psa. ³⁰ Similar results have been seen by others with ivacaftor treatment alone,^31,32 whereas several studies investigating the effects of ETI have shown a reduction in bacterial load accompanied by a diversification of the microbiome with a reduction in Psa and S. aureus, though lung infections generally persist,^33–35 even with an initial improvement in lung function but persistence of infection with CF pathogens. ³⁶

Sosinski et al. also showed that the sputum diversity was increased after ETI treatment, including a decrease in the log-ratio of classic CF pathogens to anaerobes. ³⁵

In contrast to our study, most of those studies included pwCF at a younger age, with mean ages of 28–33 years, and with some studies having participants with higher lung function than in our study. The combination of increased lung disease damage and aging itself might have influenced bacterial burden, which has been shown partially in non-CF bronchiectasis, which is an aging-associated disease, that bacterial colonization is associated with low lung function. ³⁷ The underlying factors by which ETI could alter bacterial colonization could be due to improving mucus viscosity and mucociliary clearance, thereby perturbing biofilm formation as well as improving immune function to help with bacterial clearance. ³⁸ Our results are encouraging, since chronic coinfections, especially with MRSA and Psa, are correlated with significantly more rapid lung decline and higher frequency of IV antibiotic use. ³⁹ We will need dedicated studies with more patients to assess whether ETI affects coinfections in a multicenter trial and longitudinally.

Overall, our study is unique in its way that we focus on “aged” pwCF showing still benefit from ETI but to a lower degree compared to younger patients in previous studies. Limitations of our study include the small sample size, which makes it difficult to control for potential confounding variables such as baseline severity of lung disease, comorbidities, and gender differences, but our populations resembled several other studied CF populations that had similar baseline characteristics. Further limitations included missing values for some measured outcomes, the retrospective nature, and that we only included one center, and that it was challenging to control for bias. We still think that our results are of value due to pwCF achieving higher ages with preexisting lung damage when they started CFTR modulator therapy. Clinical trials will be needed in the future to assess the specific needs and concerns “aged” pwCF will be facing, especially taking into consideration CF- and aging- related complications, which might occur earlier in life in a patient population in a persistent pro-inflammatory state. Polypharmacy, defined as the use of four or more medications, has been associated with potential negative outcomes in older patients, such as drug interactions and adverse drug effects. ⁴⁰ pwCF even at young ages can take between 8 and 10 medications each day, and even with the initiation of CFTR modulator therapy, this number remains high. Most geriatric meta-analysis are revealing conflicting results what interventions will improve appropriate use of medications in the elderly and this will be even more important to assess in an aging CF population with both CF-related complications and aging-related comorbidities; not only medications can cause adverse reactions due to interactions, but also the comorbidities themselves might affect each other leading to unique presentations, for example, CFRD in an obese patient or CFRD and cardiovascular disease. As discussed above, there is an association between CFRD and lung function decline, with translational studies pointing to airway hyperglycemia affecting both epithelial barrier function and mucociliary clearance.^41,42

Although our small cohort tolerated ETI well, the tolerability of medication can be affected by age. Using established tools in CF research such as ALI cultures of nasal or bronchial epithelial cells from “aged” patients and assessing not only responsiveness to different generations of CFTR modulator combinations but also including a multi-omic approach to analyze the effect of CFTR modulation on proteomic, metabolomic and even microbiomics changes studying host pathogen responses can help not only elucidate novel underlying signaling pathways, but also identify potential novel age specific therapeutic targets. Patients with rare CFTR variants can also be studied using high-throughput sequencing and in silico analysis, as it has been done by Villa-Nova Pereira et al. for assessing the association of age with severity of disease. ⁴³

Conclusion

Despite some limitations of our study as discussed above, we can conclude that ETI was safe for the pwCFs we studied at an advanced age and with generally lower lung function, and they still received the benefits like other previously studied cohorts. This is consistent with previous studies. It will be important to continue extending those studies to other centers for more patients and even older ages to draw comprehensive conclusions about the risk and benefit of highly effective modulator therapies in general in an aging CF population.