LAUSR

elexacaftor–tezacaftor–ivacaftor (1). We congratulate the authors on capturing real-world population data in this key group of patients with FEV1,40% who have significant potential to benefit from these treatmentsbutwereexcludedfromthepivotalphase3trials.Theauthors demonstrated significant and rapid improvements in lung function, nutritional parameters, and treatment burden in line with previous studies (2–4). Importantly, they are the first to describe a significant reduction in the need for lung transplantation, with 11 of 16 patients removed from the lung transplantwaiting list and a remarkable 36 of 37 removed from consideration of transplant within the next 3 months. Therefore, at a population level, there are many reasons to be optimistic, but clinicians must remain cautious in their expectations andnotprematurely alter theirpractice,which is amessage thatwasnot highlighted in the manuscript. Our own experience and that of others (2–4) suggests that not every patient will experience such a dramatic improvement in lung function, because of either lack of response or medication intolerance. For example, in one phase 3 trial of triple therapy, 1% of subjects had to cease the medication because of adverse events, 11.6% developed elevated liver enzymes, and 10.9%developed a rash (3). In addition, nonresponding cases may not be reported as frequently because of publication bias. Enthusiasm for this class of medications may also be heightened because of the widespread involvement of CF care teams (including the authors of this letter) in the clinical trials and the frequent conflict of interests that have developed consequently through associations with manufacturers. As clinicianswemust remainalert to all possibleoutcomesandcontinue to follow existing standards of care, which currently include early referral for consideration of lung transplantation. The importance of continuing to consider lung transplantation is a key aspect ofmanagement, as early engagement with transplant services leads to better outcomes (5). In addition, early involvement with palliative care services can benefit patients with severe, end-stage lung disease considerably. The Cystic Fibrosis Foundation recommends that discussions about lung transplantation should occur when FEV1 declines below 50%, and lung transplant referral should occur for those with advanced but not end-stage lung disease (5). Lung transplantation is a major undertaking, and consideration includes significant education, support, and joint decision-making over time. Although CFTR modulator therapies such as elexacaftor–tezacaftor–ivacaftor now play an important role in discussions about disease trajectory and treatment options, we suggest that the practice of early transplant discussion and referral should continue. Despite the remarkable outcomes described in this paper and the optimisticpromiseoffutureCFTRmodulatortherapies,wemustremain cautious about changing our practice and continue to prepare and offer options for those who do not tolerate or respond to triple therapy.