Modulator-refractory cystic fibrosis: Defining the scope and challenges of an emerging at-risk population

Abstract

Cystic fibrosis (CF) causes life-shortening respiratory and systemic disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Highly effective modulator therapies (HEMT) improve the lives of many people with cystic fibrosis (PwCF) by correcting the structure and function of the defective CFTR channel at the molecular level. Despite these advancements, a subset of patients—termed modulator-refractory CF—continues to experience two or more pulmonary exacerbations per year requiring hospitalization or intravenous antibiotics, regardless of other modulator benefits. This underrecognized group represents an emerging challenge within the CF community. We discuss the benefits and limitations of current CFTR modulator therapies and the urgent need to investigate this emerging at-risk population. While HEMT improves lung function, decreases exacerbations, reduces the need for lung transplantation, and lowers mortality, increasing evidence shows that not all patients benefit equally. At the University of Virginia, nearly 6% of adults with CF exhibit the modulator-refractory phenotype. The driving factors of modulator-refractory CF are likely multifactorial, including genetic variations, variable immune responses, preexisting bronchiectasis, microbiological colonization, preexisting comorbid conditions, and environmental and socioeconomic factors. This perspective review recognizes and defines modulator-refractory CF as a distinct emerging clinical phenotype in the post-modulator era. Understanding this phenotype is crucial for reducing morbidity and mortality, and for improving the quality of life for PwCF. Raising awareness of modulator-refractory CF will help the community address this population and perform further research to identify causes. The emergence of modulator-refractory CF highlights a significant gap in our current treatment landscape and provides an opportunity to develop innovative therapeutic strategies that may benefit the entire CF community, ensuring that no person with CF is left behind.

Plain language summary

Modulator-refractory cystic fibrosis: defining and understanding an emerging at-risk population

Background: Cystic fibrosis (CF) is a genetic disease that primarily affects the lungs and other organs, significantly shortening life expectancy. Recent advances have led to the development of CFTR modulators, which correct the defective protein responsible for CF, resulting in improved lung health, reduced need for lung transplant, and longer life expectancy for many with CF.The Problem: Despite the success of modulators, about 6% of adults with CF do not respond well to these treatments. These individuals continue to experience severe lung problems, frequent hospitalizations, and a need for antibiotics. This group is identified as having modulator-refractory CF, meaning that their disease does not adequately respond to current modulator therapies.Possible Reasons for Modulator-Refractory Response: Several factors may contribute to modulator-refractory exacerbations, including:

Medication utilization

Genetic variations that may influence drug efficacy

Variations in immune response

Existing lung damage that has already occurred

Persistent bacterial infections

Co-existing health conditions that may interfere with modulators

Living conditions and lifestyle choices

Importance of Research: Understanding why some people with CF do not respond to modulator therapies is crucial for developing new strategies to help this at-risk population. By studying modulator-refractory CF, researchers hope to discover new treatments that can improve the lives of all people with CF, ensuring that no one is left behind as new therapies are developed.Conclusion: This article emphasizes the importance of focusing research and clinical efforts on understanding and addressing modulator-refractory CF. Increased awareness and targeted research are needed to find better treatments and support for this emerging population within the CF community.

The impact of CFTR modulator therapies

Cystic fibrosis (CF) remains one of the most challenging genetic diseases, affecting at least 105,000 individuals worldwide. ¹ Characterized by the production of thick, sticky mucus that blocks airways, obstructs exocrine pancreatic function, and disrupts other organs, CF leads to life-shortening respiratory and systemic disease.^2,3 An estimated 88% of people with CF (PwCF) in the United States carry at least one copy of the class II mutation F508del, qualifying them for highly effective modulator therapies (HEMT). ⁴ These novel therapeutics improve the lives of many PwCF by addressing the dysfunctional CFTR protein at the molecular level.^5,6 Correctors such as elexacaftor, lumacaftor, and tezacaftor assist in refolding and transporting the CFTR protein to the cell surface, ensuring it reaches its functional destination. Once at the cell surface, the CFTR protein facilitates the flow of chloride and bicarbonate ions through the channel. Potentiators like ivacaftor enhance this activity, thereby improving the protein’s overall function.^{7 –11}

CFTR modulator therapies have ushered in a new era of hope for many people living with CF. For the majority of PwCF, HEMTs mean the opportunity for a greater quality of life, fewer symptoms, fewer pulmonary exacerbations, stabilization of lung function, improved nutritional status, and many more years ahead. Many in the CF community learned of the highly-anticipated FDA approval of elexacaftor/tezacaftor/ivacaftor (ETI) during the 2019 North American Cystic Fibrosis Conference. This “triple therapy,” combines the potentiator ivacaftor with correctors tezacaftor and the novel and highly effective elexacaftor. Considered potentially the most effective treatment for those with at least one F508del mutation, ETI inspired a wave of optimism. CF blogs and forums exploded with personal experiences and attestations to the new treatment, while evening news segments and print articles ran pieces about the “miracle treatment,” and “the closest thing to a cure.”^{10 –12}

However, not all outcomes have met these high expectations. Surprisingly, from 2021 to 2022, the proportion of modulator-eligible individuals not taking HEMT rose from 12.8% to 18.0%. ¹³ Adequate access to and optimal utilization of modulator therapy also remain a significant challenge. ¹⁴ As we approach the 5-year anniversary of ETI’s release, the CF community reflects on its profound impact and the emerging challenges faced by those whose experiences have not matched the initial optimism.

The benefits and limitations of highly effective modulator therapy

For eligible individuals, the triple combination therapy of elexacaftor, tezacaftor, and ivacaftor has been a game changer in the management of CF across the lifespan. These therapies have not only improved clinical outcomes but have also significantly enhanced quality of life for PwCF. By targeting the underlying defective CFTR protein, highly effective modulators mitigate the multisystemic effects of CF, leading to sustained improvements in lung function, nutritional status, and overall health. However, the impact of modulator therapy can vary by age, with distinct benefits observed in children compared to adolescents and adults.

Adolescents and adults: Adolescents (age 12 years and older) and adults experience substantial clinical benefits when treated with highly effective CFTR modulator therapy. In clinical trials, parameters of CFTR function, including sweat chloride concentration (SCC) improved by a range of 37.5–45.1 mmol/L, with real-world studies showing a 48% to 59% reduction in SCC in F508del heterozygous and homozygous respectively.^{5,15 –18} More importantly, in clinical trials and real-world studies, PwCF experienced significant improvements in lung function, with the percent predicted forced expiratory volume in one second (ppFEV1) increasing by 9.5% to 14.3% over periods ranging from 4 weeks to 24 months.^{5,15 –17,19,20} Moreover, longitudinal studies sustained the benefits of HEMT, especially triple combination therapy. In a pivotal single-center study, PwCF undergoing ETI treatment maintained stable pulmonary function over a two-year period, showing a marked contrast to untreated individuals who saw a decline in ppFEV1 by nearly 2% annually. ²¹

In addition to lung function and CFTR channel function, pulmonary exacerbation rates declined dramatically, by 63%–79% across many clinical studies^6,16,17,19 These reductions in exacerbation rates are complemented by a significant decrease in hospitalizations, with a reported 68% decline in hospitalization over 12 months, which was sustained over longer observational periods.^17,19 Across all investigated age groups, PwCF who have at least one copy of G551D or F508del mutation have shown improvements in body mass index (BMI) and growth curves, with gains in BMI of 1.5–1.8 kg/m² observed over 12–24 months, in addition to improved levels of fat-soluble vitamins A and E.^{6,17,19,20,22} Furthermore, ETI therapy has led to meaningful improvements in quality of life, with Cystic Fibrosis Questionnaire-Revised Respiratory Domain (CFQ-R RD) scores increasing by 17.4–20.2 points.^{5,15 –17} Perhaps most critically, the introduction of ETI has significantly reduced mortality and lung transplantation rates, with observed reductions of 72% and 85%, respectively, highlighting the profound impact of next-generation modulator therapy on long-term survival. ⁶

Children (under age 12 years): For children with CF, particularly those aged 6 through 11 years, the introduction of ETI has brought about transformative changes in disease management and outcomes, similar to those observed in older populations. Clinical trials have shown that children in this age group experience marked improvements in lung function, with ppFEV1 increasing by an average of 11%. ²³ Additionally, there is a substantial reduction in SCC by approximately 51.2 mmol/L, underscoring the effective restoration of CFTR function. ²³ These improvements are mirrored by the positive changes in quality of life, with CFQ-R RD scores increasing by 5.5 points, which, although smaller than those observed in older populations, still indicate a meaningful improvement in respiratory symptoms and overall well-being. ²³ Despite the high baseline lung function often observed in younger patients, real-world studies and clinical trials suggest that early and sustained intervention with ETI can significantly alter the trajectory of CF, potentially preventing the progression of lung damage and improving long-term outcomes. Moreover, children treated with ETI have demonstrated improvements in lung clearance index, further supporting ETI efficacy in ameliorating early lung disease in young people. ²³

Despite these significant advancements, the benefits of CFTR modulators are not uniformly experienced across the CF population and a subset of people continue to experience two or more CF pulmonary exacerbations, requiring intravenous antibiotics or hospitalization per year in spite of modulator use, independent of other modulator benefits such as improved nutritional status and ppFEV1. ²⁴ Understanding the unique factors that contribute to modulator-refractory CF is crucial to reduce morbidity and mortality and improve quality of life for PwCF. By increasing awareness and understanding of the modulator-refractory phenotype, the community can better target and expand research efforts to uncover underlying causes.

Challenges in modulator accessibility, tolerance, and efficacy

While CFTR modulator therapies offer significant improvements in quality of life and disease management in CF, they are not a one-size-fits-all solution. These therapies, despite their overall efficacy, present challenges that can limit their use among some individuals within the CF community. Here, we explore the reasons why HEMT may not be as effective for all modulator-eligible people.

Access to medication and regular use

Consistent access and regular use of CFTR modulator therapy is a significant factor contributing to recurrent exacerbations. Recent studies indicate that regular daily use of CFTR modulators is suboptimal, with self-reported utilization rates ranging from 50%–99%. ¹⁴ The complexities of managing CF, including financial, emotional, and lifestyle factors, can create understandable barriers to achieving “perfect utilization.” ²⁵ Many PwCF skip doses, reduce the dose without medical supervision (e.g., take only half of the recommended amount), and are inconsistent timing of medication (e.g., “drug holidays” during leisure days). ¹⁴ There is significant variability in treatment utilization complementary to modulators, including airway clearance, pancreatic enzyme usage, vitamin intake, and others.^26,27 A specific challenge related to CFTR modulators includes drug administration without the recommended intake of dietary fat. CFTR modulators like elexacaftor are hydrophobic and require fatty intake for optimal absorption. Insufficient fat intake, which is particularly common among individuals following a vegan or low-fat lifestyle, can lead to reduced bioavailability and subtherapeutic drug levels. ²⁸ This issue is further complicated by the presence of restrictive or avoidant eating disorders, which have been reported in up to 13.5% of adolescents and young adults with CF. ²⁹ These practices can lead to fluctuations in drug levels, reducing the overall efficacy of therapy.

Genetic and regional disparities in access to CFTR modulators

Modulator availability and efficacy are not universally experienced across all regions. Differences in genetic profiles of PwCF between countries play a significant role in modulator eligibility, while variations in healthcare systems further impact access to treatment. In the United States, Northwestern Europe, and Australia, a majority of PwCF carry the F508del mutation, making them eligible for ETI. However, the genetic landscape worldwide includes a broader variety of CFTR mutations. For example, Italy has a more diverse CFTR mutation spectrum compared to the United States. ³⁰ Many of these mutations are not yet targeted by available modulator therapies, leaving some PwCF without viable CFTR modulator options. In addition to genetic factors, disparities in healthcare systems may also contribute to uneven access to modulators. Regulatory approval processes, the availability of national healthcare coverage, and high out-of-pocket costs associated with these treatments can severely limit access. ³¹ In countries like Italy, where regulatory delays and cost constraints are significant, access to modulator therapies may be restricted even for those who are otherwise eligible. This contrast between countries underscores the need for coordinated international efforts to address both genetic and healthcare system-related barriers, ensuring equitable access to CFTR modulators for all PwCF, regardless of where they live.

Intolerance

While HEMT is generally well-tolerated, some individuals report significant—and sometimes debilitating—increase in cough, sputum production, congestion, and headaches, especially in the initial phase of treatment. This is commonly referred to in the CF community as “the purge.” ³² Many individuals experience headaches (up to 17%) and sinus pressure (9%). These side effects are often transient and typically subside after the first 2 weeks of treatment.^10,17 This adjustment period is well-documented in clinical practice, with most individuals reporting significant relief once the initial phase of therapy has passed. However, for those who find it challenging to consistently take ETI, the recurrence of these symptoms can be a deterrent to continuing treatment. Modulators may also negatively affect liver function and the digestive tract (11%–14%), requiring careful monitoring during the first year of treatment.^17,33 ETI-associated biliary dysfunction can often be mitigated by dose adjustment; however, in rare cases, severe dysfunction has resulted in cholecystectomy. ³⁴ Skin reactions are also reported, ranging from acne (2%–5%) to rash (10%) sometimes requiring drug desensitization, to severe rare cases of urticaria multiforme.^15,35,36 In addition to these physical side effects, there is increasing recognition of the potential mental health impacts associated with ETI. Although the relationship between ETI and mental health is complex and the subject of ongoing investigations, these effects—whether directly related to the medication or as a part of the broader experience of living with CF—may contribute to treatment intolerance for some PwCF (see Mental Health Effects). ³⁷

Drug-drug interactions and modulator efficacy

Drug-drug interactions (DDIs) present a significant challenge in optimizing the efficacy of CFTR modulator therapy, particularly for PwCF who rely on combination therapies like ETI. Ivacaftor, a critical component of triple therapy, is primarily metabolized via the cytochrome P450 3A (CYP3A) pathway, making it susceptible to interactions with other drugs that inhibit or induce CYP3A activity. Co-administration of ivacaftor with potent CYP3A inhibitors such as the ritonavir combination used to treat COVID-19 or antifungals (“-azoles”) used to treat concomitant pulmonary fungal infections can lead to substantial increases in ivacaftor plasma levels, necessitating significant dose adjustments to avoid potential toxicity.^38,39 Conversely, inducers of CYP3A can lower the efficacy of ivacaftor by accelerating its metabolism. Additionally, CFTR modulators themselves can affect the metabolism of other medications; for example, lumacaftor has been shown to alter concentrations of CYP3A and P-glycoprotein (P-gp) substrates. ⁴⁰ Further compounding these challenges, DDIs may contribute to lower-than-expected clinical efficacy of triple therapy in certain patient populations. Notably, ivacaftor has been shown to paradoxically increase SCCs in some individuals with specific residual-function CFTR mutations like A455E, potentially indicating a destabilizing effect on the CFTR protein at the plasma membrane. This destabilization could undermine the clinical benefits of the therapy, particularly in people with class II mutations like F508del, where ivacaftor is expected to potentiate the function of CFTR proteins that have been rescued by correctors such as tezacaftor and elexacaftor.^41,42 Additionally, ivacaftor may diminish the efficacy of correctors by reducing the folding efficacy and metabolic stability of F508del-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, leading to decreased cell surface density and function of the F508del-CFTR protein. ⁴³ These findings underscore the complexity of CFTR modulators and the importance of optimizing drug combinations to ensure that PwCF achieves the maximum potential benefits.

Off-target effects

Emerging evidence suggests that ETI may have off-target, potentially harmful, effects that warrant further investigation. Recent investigations demonstrate that prolonged exposure to tezacaftor—a key component in ETI—acts as a direct inhibitor of the sphingolipid delta-4 desaturase enzyme (DEGS). This inhibition leads to the accumulation of dihydroceramides (dHCer) in human bronchial epithelial cells and hepatocytes in vitro. Notably, dHCer accumulation is observed in brain tissue of non-CF mice following repeated administration of ETI, raising concerns about the potential impact on nervous system development, particularly during pregnancy, breastfeeding, and early childhood. ⁴⁴ Given the critical role of sphingolipids in myelin formation and maintenance, these findings suggest a need for further research into the long-terms safety of tezacaftor, especially in vulnerable populations. These findings have already garnered attention in the CF community through lay press publications highlighting concerns about the safety of tezacaftor during early development. ⁴⁵ Such reports can understandably influence patient perception and utilization. Understanding and mitigating these off-target effects, while addressing valid patient concerns, is essential to ensure the safe and effective use of CFTR modulators across diverse patient populations.

Ability to assess CFTR function

The effectiveness of CFTR modulators is commonly evaluated using SCC as a primary biomarker. However, SCC alone may not fully capture the complexity of CFTR function, particularly in cases where modulator therapy yields variable clinical outcomes. Other biomarkers such as nasal potential difference (NPD), intestinal current measurement (ICM), and rectal organoid morphology analysis (ROMA) are being increasingly utilized.^{46 –48} NPD and ICM are electrophysiological techniques that measure CFTR function in respiratory and intestinal epithelia, respectively. These measures are particularly valuable in diagnosing CFTR-related disorders in individuals with inconclusive sweat tests or unidentifiable CFTR genotypes. NPD and ICM may reveal CFTR dysfunction in individuals with suggestive clinical symptoms, even when SCC and genetic testing are inconclusive. ⁴⁶ Meanwhile, ROMA is an emerging tool that offers insights into CFTR function by analyzing morphological changes in rectal organoids. ROMA may effectively discriminate between CF and non-CF individuals, making it a promising diagnostic tool complementing SCC and other traditional biomarkers. ROMA’s utility in standardizing CFTR function across different age groups adds another layer of precision in evaluating the effects of modulator therapies. ⁴⁸ By incorporating these additional functional biomarkers into the assessment of CFTR function, clinicians may be able to achieve a more nuanced understanding of how modulator therapies actually impact CFTR activity across different tissues and in different people. This approach may become increasingly important in understanding modulator-refractory CF, where traditional biomarkers such as SCC may not fully reflect clinical outcomes.

Lack of perceived benefit

In the CF Foundation’s 2022 Annual CF Registry Report, respondents indicated many reasons for choosing not to start HEMT or electing to discontinue therapy. Common reasons include satisfaction with their current health status without HEMT, fear of potential side effects, and a perceived lack of benefit. ¹³ Personal experiences, often shared in patient communities online and not always with the CF care team, reflect personal experiences that may not align with broader clinical outcomes. It is important to acknowledge these feelings, as they can significantly impact treatment utilization and overall satisfaction. Robust clinical studies consistently demonstrate the benefits of ETI, though the discrepancy between individual patient perceptions and clinical data reinforces the need for open communication, patient education, support, and individualized care strategies. Atul Gawande’s analysis in The Bell Curve highlights how variability in patient outcomes often stems from differences in care strategies and patient engagement. ⁴⁹ By better understanding and addressing these perceptions, and by managing patient expectations through tailored care, we can help ensure that more individuals fully benefit from ETI therapy.

The importance of a patient-centered approach

In addition to quantitative outcomes, there is a growing recognition of the importance of patient-centered research in CF. Qualitative studies and interviews with patients and caregivers can provide deeper insights into the barriers faced in accessing and adhering to CFTR modulator therapies.^50,51 These insights are critical for developing supportive strategies that address the unique needs of this vulnerable group and improve overall treatment outcomes.

Disparities in treatment outcomes for modulator-refractory CF

In recent years, efforts have intensified within the CF community to ensure that modulator-ineligible and modulator-intolerant individuals achieve health outcomes equitable to those who are benefiting from modulators.^52,53 At the same time, investigations into the reasons why a growing number of people are discontinuing HEMT are gaining traction. However, people with modulator-refractory CF are emerging as an at-risk and underrecognized group who are failing to achieve equitable clinical outcomes and deserve our attention. Recognizing and defining modulator-refractory CF is a step in addressing health disparities within the CF community.

At the University of Virginia, nearly 6% of adults with CF live with the modulator-refractory phenotype, characterized by two or more severe pulmonary exacerbations per year requiring intravenous antibiotic interventions or hospitalizations. Additionally, when considering mild exacerbations, defined as those necessitating oral antibiotics in an outpatient setting, the percentage of adults experiencing frequent exacerbations rises dramatically to 35%. This highlights a broader impact of the disease that includes less severe, but significant and potentially underrecognized events. These exacerbations occur despite appropriate modulator use and are independent of other extra-pulmonary modulator benefits including quality of life, digestive function, or even the relative decrease in exacerbation rates. These individuals continue to live with the direct life-limiting implications of recurrent exacerbations, including the potential for decreased lung function, progression toward lung transplant, increased mental health burden, and significant healthcare expenses. ⁵⁴ By understanding what drives frequent pulmonary exacerbations in the context of modulator use, we may not only improve outcomes for people with modulator-refractory CF but also extend mutation-agnostic therapeutic benefits to people with all forms of CF.

Genetic, immunological, and environmental insights into modulator-refractory CF

Defining modulator-refractory CF as a distinct phenotype requires a comprehensive approach, taking into account genetic variations and their interactions with CFTR modulators, variable immune responses, the impacts of preexisting structural lung disease, microbiological colonization, existing comorbid conditions, and environmental and socioeconomic factors. Preliminary findings suggest a convergence of host and environmental factors that contribute to an incomplete response to CFTR modulators. These complex interactions, including individual health status, consistent medication utilization, and the timing of HEMT initiation, may be key predictors of the effectiveness of CFTR modulator therapies. Comprehensive studies are critical to fully understand these gaps in knowledge and to identify potential targets for more effective interventions.

Genetic variations and gene interactions (Tables 1 and 2): The efficacy of modulator therapy in PwCF depends not just on the specific CFTR mutation, but also on variations within the CFTR locus, its regulatory elements, and the influence of external or non-CFTR genes. ⁵⁵ While the impact of genetic modifications on CFTR function accounts for only a small percentage of variance, there remains a subset of patients who do not respond as expected.

Table 1.

Non-CF modifier genes of interest in cystic fibrosis.

Gene	Key variant	Function and clinical impact
SLC26A9	rs7512462	Chloride and bicarbonate ion channel. Interacts with CFTR chloride homeostasis. Linked to CF-RD and MI. Possible association with altered responses to ivacaftor.40 –42
SLC6A14	rs3788766	L-arginine channel regulated by sodium and chloride. Diminished epithelial repair. Increased risk of MI, early PA colonization, reduced lung function. Implicated in impaired response to ivacaftor and lumacaftor.43 –45
SLC11A1	rs17235416	Bivalent iron and manganese transporter. Regulation of iron protects macrophages against reactive species, and sequesters nutrients from certain pathogens. Increased susceptibility to mycobacteria, Leishmania, and Salmonella. Increased association with inflammatory bowel diseases.41,46
SLC9A3	rs17563161	Sodium and hydrogen carrier proteins involved in pH regulation. Associated with earlier PA colonization, pancreatic insufficiency, and accelerated decline in lung function.41,47,48

CF-RD, cystic fibrosis-related diabetes; MI, meconium ileus; PA, pseudomonas aeruginosa.

Table 2.

Genetic regions of interest in cystic fibrosis.

Locus	Function and clinical impact
11p13	SNPs between EHF and APIP genes on 11p13 modulate highly interactive enhancer elements, which alters EHF expression, significantly impacting lung disease severity in cystic fibrosis by affecting epithelial responses to inflammation and injury. 49
20q13.2	Linkage analyses the locus at 20q13.2 as significantly associated with lung disease severity among people with cystic fibrosis. This region may harbor genes or regulatory elements that contribute to increased pulmonary manifestations in CF. 50

APIP, Apaf-1 interacting protein; EHF, Ets homologous factor.

CFTR mutations: F508del is commonly viewed as the benchmark mutation in CFTR modulator testing. However, over 2000 CFTR mutations have been identified, each affecting the disease phenotype and response to treatment differently. Real-world studies indicate that modulators like ETI are also effective in PwCF with select non-F508del mutations, broadening the potential application of these treatments. ⁵⁶ In real-world studies, including the French compassionate use programme, dramatic improvements in lung function have been observed even among those with advanced lung disease with no F508del mutation. ²⁰

Non-CF modifier genes and genetic regions of interest: Beyond mutations in the CFTR gene, genetic variations in non-CFTR genes significantly influence the clinical manifestations of CF and responses to modulator therapies. Particularly, genes within the solute carrier (SLC) family play critical roles by affecting ion channels and transporter functions, which impact everything from lung function and nutritional status to susceptibility to infections (Table 1). Additionally, linkage analyses have identified at least two key regions that may influence clinical outcomes in CF (Table 2).

Sex differences: In addition to genetic and environmental factors, sex may also influence the response to CFTR modulators. A recent study by Holtrop et al. ⁵⁷ found that sex disparities persist in patients treated with ivacaftor, particularly in pulmonary exacerbation rates, with male patients showing greater improvement compared to female patients. ⁵⁷ These findings suggest that factors beyond CFTR dysfunction, potentially including hormonal differences or differential immune responses, may contribute to the variability in treatment outcomes and warrant further investigation.

Susceptibility to Pseudomonas aeruginosa (PA) infection: Genetic factors may contribute to as much as 55% of the variation in infection susceptibility, with specific genes such as Caveolin 2 (CAV2), Dynactin subunit 4 (DCTN4) and Transmembrane channel like 6 (TMC6) as modifiers on the age at chronic colonization by PA. Additionally, the Tumor Necrosis Factor (TNF) gene has been associated with both the initial acquisition and chronic colonization stages of the infection. ⁵⁸

Implications for Treatment: Variants in these genes can decrease responsiveness to treatments such as ivacaftor, compounding susceptibility to bacterial pathogens, impairing nutrition, and worsening lung function, which may disadvantageously position PwCF at the onset of HEMT.^58,59

Variable immune responses: The immune response plays a pivotal role in CF disease progression, with both the innate and adaptive immune systems significantly impacted by CFTR dysfunction. While ETI therapy provides some improvements, it does not fully resolve the immune dysfunctions that contribute to chronic inflammation and infection in CF.

Innate immunity in CF: The innate immune system in CF is significantly compromised due to defective CFTR protein function. This impairment affects multiple aspects of the immune response:

Mucociliary dysfunction: Defective CFTR leads to poor mucociliary clearance and abnormal mucosal barriers, creating an environment prone to infections and chronic inflammation. ETI therapy helps restore CFTR function, leading to improved mucociliary clearance and a healthier airway surface liquid environment, which improves innate immune functions by restoring the homeostatic barrier against pathogens. ⁶⁰

Neutrophil Activation: Neutrophils, the first responders in the innate immune system, are paradoxically hyperactive and ineffective in CF. CFTR dysfunction leads to a cascade of cytokines including elevated levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, IL-8, IL-17, and GM-CSF. ⁶¹ These cytokines lead to a prematurely primed basal state of neutrophils, resulting in exaggerated activation, chemotaxis, pattern recognition and immune signaling.^62,63 Thick, viscous mucous in CF airways impedes neutrophil chemotaxis and cell-signaling, which impairs their ability to effectively combat pathogens and contributes to tissue damage through excessive release of neutrophil extracellular traps (NETs) and reactive oxygen species (ROS). CFTR modulators reduce the presence of pro-inflammatory cytokine IL-6, but not the neutrophil-recruiting IL-8, leading to ongoing exaggerated ROS generation, chemotaxis, and phagocytic activities, perhaps priming some individuals for increased exacerbations more akin to those seen in non-CF bronchiectasis.^63,64

Macrophage Dysfunction: Macrophages in CF show dysfunctional behavior, characterized by altered phagocytosis and cytokine production. ⁶⁵ CF macrophages produce excessive inflammatory mediators, which, like neutrophils, can lead to excessive inflammation and lung tissue damage. ⁶⁶ Production of anti-inflammatory mediators like IL-10, nitric oxide, and lipoxin-A4, are diminished in CF, failing to resolve the inflammatory state. ⁶³ CFTR modulators restore some normal macrophage function—specifically phagocytosis and regulation of inflammation via cytokine regulation, but does not completely mitigate the abnormal cytokine production by macrophages. ⁶⁷

Therapeutic Interventions: Recent research into targeted therapies like mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitors has shown promise in modulating the immune response by reducing proinflammatory cytokine production without dampening the appropriate neutrophil or macrophage responses. ⁶⁵

Adaptive immunity in CF: Adaptive immunity involves a highly specific response mediated by T and B lymphocytes. In CF, the defective CFTR protein impacts T- and B-cell functionality, resulting in altered cytokine production and impaired immune memory. Recent evidence suggests that these alterations in cytokine production may skew toward a type 2 (T2) inflammatory profile in the presence of chronic lung infections:

B Lymphocytes: In CF, heightened expression of mucosal cytokines B-cell activating factor (BAFF), IL-12p40, IL-32, IL-8, IL-22, and soluble tumor necrosis factor-1 (sTNFR1), lead to the development of lung lymphoid follicles and increased B-cell survival and maturation.^68,69 CFTR dysfunction further leads to increased Nuclear Factor of Activated T-cells (NFAT) activity in T-cells, which enhances expression of IL-4 and IL-13. ⁷⁰ These type 2 inflammatory cytokines promote B-cell class switching, favoring B-cell secretion of IgE. ⁷¹ Heightened activation of B cells is protective against chronic infections but also perpetuates inflammation. Treatment with ETI has been shown to reduce levels of these BAFF and other cytokines, potentially normalizing B-cell responses. ⁶⁹

T Cell Dysfunction and Type 2 Inflammation: CD4+ T helper cells differentiate into Th1, Th2, and Th17 cells. Th1 cells produce Interferon-gamma (IFN-γ) which activates macrophages, and are critical for fighting intracellular bacteria and viruses. Th2 cells are associated with humoral immunity, are important for fighting extracellular parasites, and contribute to the production of antibodies by B cells, particularly IgE. ⁷² Th17 cells produce Interleukin-17 (IL-17) and are involved in the response to fungal and bacterial infections at mucosal surfaces. CD8+ T cytotoxic T cells (Tc cells) primarily attack and kill virus-infected cells, tumor cells, and other pathogen-infected cells. Regulatory T cells (Tregs) modulate tolerance to self-antigens, preventing autoimmune disease. In CF, dysregulation of pro-inflammatory cytokines in CF—particularly IL-8, TNF-α, and IL-6—alters the balance and function of normal T cells.^67,73 After initiation of ETI, the relative percentage of Tregs increases, suggesting that CFTR modulators may restore balance to an abnormally-inflammatory immune T-helper response in CF. ⁷³

Increasing evidence suggests that type 2 inflammation characterized by elevated levels of IL-4, IL-5, and IL-13, IL-33, Th2 cellular response, B-cell production of IgE, and eosinophilia, may be a key driver in the modulator-refractory CF phenotype.^{8,74 –77} Real-world studies show that elevated peripheral eosinophils and serum IgE levels are linked to worse outcomes in CF.^74,78 T2 cytokines promote allergic inflammation and are associated with elevated IgE levels and eosinophilia, contributing to the persistent pulmonary complications in CF. The underlying mechanism appears to be related to CFTR dysfunction that leads to aberrant calcium signaling pathways in T cells, which enhances the nuclear translocation of the transcription factor NFAT. ⁷⁰ Increased NFAT activity in CFTR-deficient T cells subsequently promotes overproduction of IL-4 and IL-13. ⁷⁰ CFTR deficiency is also associated with increased basal levels of the T2 cytokine IL-33. ⁷⁹ Treatment with ETI reduces IgE levels, suggesting modulation of the T2 response. Modulator-refractory CF may be influenced by epigenetic modifications induced by chronic inflammation and infection which can sustain gene expression patterns favoring T2 differentiation, even after the triggering antigenic stimulation is reduced by CFTR modulator therapy. ⁸ Observational case studies suggest that T2 biologics like anti-IL-5 mepolizumab may improve outcomes for PwCF who have frequent exacerbations in spite of modulator therapy. ⁷⁷

Microbiological colonization: CFTR dysfunction in CF leads to viscous mucus accumulation that fosters microbial growth. ⁶³ Inefficiencies in the innate immune response fail to eradicate pathogens, leading to chronic colonization, while the cycle of exacerbations coupled with antibiotic usage leads to a progressively more drug-resistant microbiome. ⁸⁰

Persistent Infections Despite Modulator Therapy: Chronic infections in CF are often sustained by the ability of bacteria like Pseudomonas aeruginosa to form sticky, skyscraper-like biofilms, which evade normal host defenses and antibiotic treatment. Biofilms contribute to the difficulty in eradicating bacteria once they are established in the CF lungs.^80,81 Modulators significantly reduce the bacterial burden of Staphylococcus aureus (SA) and PA from 54.3% to 40.2% (p < 0.001) and from 39.9% to 22.6% (p < 0.001), respectively. ⁸² Nonetheless, colonization by PA remains a significant challenge. Recent evidence demonstrates that, while the total bacterial load and density of PA in the lungs with ETI, it is not eradicated and continues to evolve.^83,84 These findings indicate that traditional clinical detection methods, such as sputum and throat swabs, may be less effective in identifying potentially resistant organisms in the post-modulator era.

Impact of Viral Infections: Acute viral upper respiratory infections are implicated in nearly half of all CF exacerbations in adults, disrupting airway homeostasis and fostering bacterial overgrowth and inflammation.^{85 –88} In bronchoalveolar lavage samples obtained during viral-induced CF exacerbations, typical upper airway CF pathogens such as PA and SA are frequently recovered, but other pathogens more typically associated with lower respiratory including Haemophilus spp., Moraxella spp., and Streptococcus pneumoniae are also frequently identified. ⁸⁹ These findings suggest that viral infections may exacerbate lower airway inflammation and contribute to increased susceptibility to non-CF typical respiratory infections. Rhinovirus (RV) particularly affects the expression and function of CFTR in nasal mucosa. Acute and chronic RV infection increases the expression of CFTR, which could potentially exacerbate mucus accumulation and impair mucociliary clearance in CF. ⁹⁰ While modulators improve barrier function, they do not decrease the incidence or severity of viral infections in CF.^88,91

Role of Aspergillus and other Fungi: Aspergillus fumigatus, a prevalent fungal colonizer in CF, remains a persistent challenge even in the post-modulator era. T2 inflammation and the use of inhaled antibiotics may predispose to higher fungal colonization rates.^74,92 CFTR dysfunction allows fungi such as A. fumigatus to invade the airway epithelium, particularly affecting the tight junctions and disrupting transepithelial resistance, leading to increased permeability and vulnerability to infection. CFTR modulators appear to decrease the exaggerated inflammatory response typically seen in aspergillus colonization in PwCF.^9,93,94

Role of nontuberculous mycobacterium infection (NTM): NTM infection in CF is associated with worsened lung function and increased exacerbation rates. ⁹⁵ Infection with mycobacterium abscessus is particularly challenging due to its resistance to conventional antibiotics and association with more severe disease manifestations. ⁹⁶ Recent studies have shown that ETI may contribute to improved outcomes in patients with NTM infections by restoring innate immune function. Recent case reports have documented significant clinical and radiological improvements in NTM lung disease following ETI initiation, even in patients for whom traditional antimycobacterial treatments were not feasible. ⁹⁷ The direct effect of CFTR modulators on NTM infections remains unclear, though incidence rates of NTM declined dramatically from 52.5% to 34.3% after the introduction of ETI. ¹ Nonetheless, after the initial improvement in NTM incidence after the introduction of ETI, incidence rates have plateaued, indicating ongoing issues with NTM management in CF. ¹³

While CFTR modulators significantly improve mucociliary clearance and overall lung function, they have not fully eradicated pathogens such as PA or SA, nor have they substantially impacted the persistence and evolution of fungal and NTM infections. Additionally, the unchanged impact of viral infections underscores the complex relationship between CFTR function and the microbiome in CF airways.

Preexisting structural lung disease: In CF, primed but ineffective neutrophils are recruited to the lungs in response to infections but often fail to clear the bacteria effectively.^63,98,99 The products of these overactive neutrophils, including proteases and oxidative substances, damage delicate lung tissue, leading to inflammation, scarring, and traction bronchiectasis. ⁶¹ The cycle of infection and inflammation, combined with the inability to signal the end of inflammation, and increasingly resistant bacterial strains, leads to the progression of structural lung disease. Even after ETI has effectively restored the function of the CFTR protein, existing bronchiectasis may serve as a reservoir for chronic infection and inflammation, driving further airway damage and exacerbations, mirroring the clinical course observed in non-CF bronchiectasis.^98,100 In addition, the development—and persistence—of abnormal airway inflammatory pathways caused by alterations in DNA methylation and histone modifications may contribute to persistent gene expression that sustains inflammation and mucous production. ⁹⁸

Other preexisting comorbid conditions: In addition to structural lung disease, other comorbid conditions may complicate actual and perceived pulmonary responses to CFTR modulator therapy.

Comorbid Lung Diseases: Between 25% and 30% of PwCF carry a comorbid diagnosis of asthma. ¹³ Yet, diagnosis of asthma in CF is itself a challenge due to the fact that methacholine challenges are frequently positive in PwCF, independent of pulmonary symptoms or severity of illness. ¹⁰¹ Heterozygous carriers of CFTR mutations have a significantly greater incidence of asthma, chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis (ABPA) and bronchial hyperresponsiveness, suggesting a common pathway of inflammation—possibly due to the same cascade of cytokine dysfunction or impaired mucociliary clearance mechanisms described above. ¹⁰² Furthermore, how does one differentiate an asthma exacerbation in a PwCF from a CF pulmonary exacerbation? Understanding the role of T2 inflammation in CF may provide some of these answers.

The Role of Mental Health: Mental health plays a significant role in the overall treatment and clinical outcomes for people living with CF. PwCF experiences depression and anxiety at rates nearly fivefold greater than those of the general population. ¹³ Nearly a quarter of PwCF experience some form of depression or anxiety, conditions which can significantly impact treatment utilization and disease progression. Self-reported symptoms of depression have been linked to reduced utilization of treatments, as well as accelerated decline in lung function.^103,104

In the context of ETI therapy, the relationship between mental health and treatment outcomes is complex and variable. A single-center retrospective study initially observed that while 22% of patients either started or changed their psychiatric medication regimens after ETI initiation, there was no significant change in depression or anxiety scores. ¹⁰⁵ The stability in mental health scores may have indicated that medication adjustments were made as a precautionary or proactive measure rather than a response to worsening symptoms. Nonetheless, this initial observation led to more comprehensive investigations. A recent, multicenter review of placebo-controlled clinical trials and postmarketing data involving over 60,000 patients found that the incidence of depression-related events in those treated with ETI appears to be consistent with the background epidemiology in the CF population, suggesting no causal relationship between the therapy and the occurrence of these mental health issues. ¹⁰⁶ Moreover, several recent real-world studies have indicated depression scores, particularly in those with higher baseline symptoms, significantly improved after ETI initiation.^107,108 These findings suggest that ETI may have an overall positive impact on mental health for many PwCF, especially for those with moderate to severe depression.

Despite the generally positive or stable mental health outcomes, anecdotal reports suggest a minority of individuals discontinue ETI due to severe mental health effects.^37,109 These reports, though not widely supported by largescale data, underscore the variability in patient experiences and highlight the need for careful monitoring and individualized care.

Environmental and socioeconomic influences: Environmental factors directly and indirectly influence the exacerbation cycle and progression of disease. Air quality and socioeconomic status are significant contributors to the exacerbation cycle, with poorer outcomes often observed in populations facing socioeconomic disadvantage, possibly due to disparities in access to care, adherence to treatment plans, and exposure to environmental pollutants.^{52,110 –112} The role of climate change is of increasing interest due to the impact of worsening air quality, air pollution, and increased prevalence of allergens associated with rising temperatures. ¹¹³ For PwCF environmental changes may exacerbate respiratory symptoms by increasing the burden of airway inflammation and infection susceptibility due to more prevalent allergens and pollutants. This may become especially challenging in PwCF who experience T2 inflammation, as rising temperatures contribute to an increase in pollen. More frequent heatwaves and changes in air quality may also significantly impact people with chronic respiratory conditions. ¹¹⁴ These factors may contribute to more frequent pulmonary exacerbations and changes in microbial colonization patterns in the lungs. ¹¹⁵ In addition, increased levels of carbon dioxide and other greenhouse gases contribute to increased aeroallergens, which can further aggravate respiratory conditions especially asthma, CF, and ABPA. ¹¹⁵

While CFTR modulators represent a significant advancement in treating cystic fibrosis by targeting the underlying defect, they do not directly address the structural airway changes or epigenetic modifications that have occurred as a result of prolonged disease processes, nor can they address the socioeconomic and environmental factors that perpetuate the cycle. Significant research gaps exist in identifying the underlying mechanisms that drive frequent exacerbations in modulator-refractory CF.

Future directions

A significant portion of PwCF who experience frequent exacerbations already face barriers to healthcare access or come from historically marginalized communities. ¹¹⁰ The effects of frequent pulmonary exacerbations compound the negative impact on quality of life, lung function, nutritional status, and mental health. Efforts to broaden the genetic inclusivity of clinical trials and enhance global access to CF therapies are critical to address the gaps in care. However, substantial disparities persist, particularly in access to these life-saving treatments. Innovative therapeutic and research strategies must ensure that advancements in CF care benefit all segments of the CF community, including those who face barriers to accessing these therapies due to socioeconomic or geographic factors.

Future research and therapeutic strategies must prioritize developing targeted interventions through advanced genetic, proteomic, and metabolomic analyses to better understand and treat the complex phenotypes of modulator-refractory CF. Additionally, there is a critical need to explore and develop treatments that address underlying inflammatory processes, particularly type 2 inflammation, which current modulators may not fully address. Finally, it is critical to address the socioeconomic and environmental factors impacting CF care to ensure that all patients, regardless of their economic status, have access to the latest treatments and care innovations.

Addressing the complexities of modulator-refractory CF may shed light on universal pathophysiological pathways applicable to mutations not yet targeted by current therapies, bridging the treatment gap for all. This is not just a scientific challenge; it is a moral imperative to ensure equity in healthcare outcomes and quality of life for all individuals with CF, by embracing more personalized therapeutic approaches that consider the unique genetic, environmental, and socioeconomic factors influencing each patient’s experience.

Conclusion

Modulator-refractory CF is a distinct clinical phenotype, characterized by frequent and recurrent pulmonary exacerbations despite the use of highly effective CFTR modulators. A multitude of factors may contribute to modulator-refractory recurrent exacerbations, including inconsistent medication utilization, genetic predispositions, the development of type 2 inflammation, variable immune responses, and socioeconomic factors. This at-risk population not only reveals a critical gap in our current treatment landscape, but also highlights the urgent need for targeted research, advocacy, and clinical innovation. Understanding modulator-refractory CF may shed light on universal pathologies that lead to frequent exacerbations. Addressing this group goes beyond improving outcomes for this specific cohort; it is a crucial step toward making treatment outcomes fairer for everyone with CF. The pathophysiology of modulator-refractory CF may be the key to innovative therapeutic strategies that improve outcomes for the entire CF community, including those who are ineligible or intolerant of current modulator therapies.

Researchers and providers in the CF community are encouraged to adopt a comprehensive and inclusive approach to tackling this issue. Defining, recognizing, and addressing this unique population represents a commitment to healthcare justice, ensuring equitable advancements in CF care for all, regardless of genetic background or socioeconomic status. ³¹ Recognizing and understanding the unique pathophysiology behind modulator-refractory CF will uncover new therapeutic targets and strategies that benefit all individuals with CF, including historically marginalized communities, and those who are currently face barriers to accessing modulator therapies. Ensuring equitable advancements in CF care is not only a scientific challenge but a moral imperative.