Cystic fibrosis transmembrane conductance regulator therapy with elexacaftor/tezacaftor/ivacaftor reduces detection of hallmark cystic fibrosis pathogens in Europe: progress made but no time to slow down

Extract

The introduction of triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has improved the lives of many people with cystic fibrosis (pwCF) to an unprecedented degree. Yet, 5 years after the introduction of this therapy, studies show that pwCF on ETI will continue to experience residual infection [1–3] and inflammation [4, 5], which are known to be central drivers of disease course. Furthermore, mathematical models of disease trajectories after the introduction of triple CFTR modulator therapy ascertain that age at introduction and thereby severity of lung disease are central determinants of disease trajectories for pwCF on ETI, suggesting that not all pwCF will benefit similarly from these therapies [6].

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ETI reduces pathogen detection rates in respiratory samples, yet a significant proportion of pwCF continue to harbour hallmark pathogens putting them at risk of more rapid decline in lung function https://bit.ly/3DAcKKH

The introduction of triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has improved the lives of many people with cystic fibrosis (pwCF) to an unprecedented degree. Yet, 5 years after the introduction of this therapy, studies show that pwCF on ETI will continue to experience residual infection [1–3] and inflammation [4, 5], which are known to be central drivers of disease course. Furthermore, mathematical models of disease trajectories after the introduction of triple CFTR modulator therapy ascertain that age at introduction and thereby severity of lung disease are central determinants of disease trajectories for pwCF on ETI, suggesting that not all pwCF will benefit similarly from these therapies [6].

Data from the European cystic fibrosis registry, which covers over 55 000 pwCF from 42 countries [7], shows, that even in the era of highly effective CFTR modulator therapies, socioeconomic status continues to contribute significantly to disease course [8]. The European cystic fibrosis registry thus provides the unique opportunity to query the impact of CFTR modulator therapy in detail, considering heterogeneous genetic backgrounds, treatment practices and clinical trajectories of pwCF, as well as permitting to assess the impact of socioeconomic factors.

It is therefore commendable that Pollak et al. [9] turned to data from the European cystic fibrosis registry to address the impact of ETI on microbial infections, including >15 000 pwCF from 30 countries, by far the largest number of pwCF in a real-world study addressing this aspect of the impact of ETI. Their study extends analyses from the national registries, which showed early and significant decline of hallmark cystic fibrosis pathogen detections in sputa and throat swabs, such as Pseudomonas aeruginosa and Staphylococcus aureus, which were sustained up to 3.5 years. These previous studies already cautioned that culture negativity is not achieved in all pwCF and does not correspond to lack of detection via molecular methods, suggesting residual infection remains [1–3].

Pollak et al. [9] confirm that ETI significantly impacts P. aeruginosa and S. aureus as well as Stenotrophomonas maltophilia and Burkholderia cepacia complex detections. Their data are encouraging in that a significantly higher proportion of pwCF classified as P. aeruginosa- or S. aureus-positive transitioned to negative status within the first year of treatment compared to pre-ETI, effects that were sustained into a second year of observation. For both pathogens, >30% of pwCF positive in the year prior to initiation of ETI converted to negative status (38.7% and 47.2% for P. aeruginosa and S. aureus, respectively). Data for S. maltophilia and B. cepacia complex showed similar results, as did analyses of co-infections with different pathogens. Yet, like other studies, the small numbers of pwCF acquiring positive status after the initiation of ETI and the fact that 20–30% of all pwCF examined remain P. aeruginosa- or S. aureus-positive after introduction of ETI also caution that in some pwCF, airway infections will remain a challenge and risk factor for further lung function decline. Inferring from the known correlation of sweat chloride with survival [10] and the fact that ETI improves CFTR function to 40–50% of wildtype [11], the study by Pollak et al. [9] joins the ranks of previous publications, which ascertain that this degree of improvement of CFTR function will most likely not be sufficient to prevent long-term lung disease progression over a whole lifetime. Their data direct the physicians involved in current and future care of pwCF towards particular attention to those 20–30% of pwCF who do not achieve conversion to culture negativity, and to consider them as a population at risk for more rapid decline.

The changes observed by Pollak et al. [9] certainly need to be seen in light of the fact that many patients do not produce sputum anymore, thus rendering culture-dependent methods to detect hallmark cystic fibrosis pathogens less reliable. Yet, longstanding as well as more recent epidemiological analyses on the biological effects of these hallmark pathogens of cystic fibrosis, which identified the critical contribution of these pathogens to less favourable disease trajectories from the past, all relied on culture-dependent sputum or swab positivity [12, 13]. Molecular methods, such as those used elegantly by Nichols et al. [2] and Loske et al. [3], have demonstrated for some time that culture negativity does not necessarily translate to “molecular” negativity. Furthermore, metagenomic data also suggest that 1 year after the initiation of ETI, the airway microbiome as a whole does not achieve increased stability compared to pre-ETI (figure 1). However, the biological effects of molecular positivity in combination with culture negativity or an unstable microbiome are much less understood than epidemiological data on culture positivity from the past. These historic studies unequivocally point towards a negative impact of those pathogens examined in detail by Pollak et al. [9]. Considering the epidemiological data, the results of the study by Pollak et al. [9] on the effects of ETI might suggest that pwCF who turn culture negative can hope for improved outcomes regarding the progression of lung disease.

FIGURE 1.

Airway species co-occurrence network a) prior to (13 cough swabs) and b) 12 months after (24 cough swabs) initiation of elexacaftor/tezacaftor/ivacaftor. The observed modularity classes are depicted based on decreasing network contribution. Reproduced and modified from [14] with permission.

The data of Pollak et al. [9] derive strength from their use of linear mixed-models to test for differences between proportions of culture-positive versus -negative samples from pwCF prior to and after initiation of ETI. Their stringent use of statistics included several adjusting factors (biological sex, genotype, lung function, age, prior CFTR modulator use and gross national income). These analyses confirm previous findings regarding the dependency of the effects of ETI on age and lung function. They also uncover determinants not identified previously, such as sex, genotype and gross national income, which affect some but not all pathogens uniformly. Along that line, the influence of gross national income on both methicillin-sensitive and -resistant S. aureus detections but not P. aeruginosa detections merit special interest. The data of Pollak et al. [9] might suggest that S. aureus detections need to be addressed more stringently to ensure equal benefit of ETI, regardless of gross national income. As S. aureus is the first hallmark pathogen in childhood to colonise the lower airways, such an approach promises a particular long-lasting impact for pwCF. In summary, the study by Pollak et al. [9] invites confirmational analyses of other cohorts and suggests directions for future research to provide more granular, ideally even mechanistic, insight into some of the dependencies they found.

Importantly, the data of Pollak et al. [9] call urgently for broader access of ETI in countries where access is prevented by socioeconomic status. Considering the discrepancies in improvements of lung function and life expectancy between low and middle- and high-income countries [8], the data of Pollak et al. [9] suggest that broader access to ETI in low-income countries will critically benefit those patients that carry the mutations necessary to respond. This also reminds us that in these same countries, larger patient groups also need to be addressed by therapies other than CFTR modulators as they are home to larger proportions of pwCF carrying mutations that are not amenable to CFTR modulation. In that, the findings of Pollak et al. [9] recall that a cure is still far away and research in cystic fibrosis for pwCF benefitting from CFTR modulator therapies as well as those that cannot needs to maintain the impressive pace, which made it into a showcase of modern medicine, to finally achieve a cure.