The introduction of cystic fibrosis transmembrane conductance regulator (CTFR) modulators, which target the basic genetic defect in cystic fibrosis (CF), has revolutionized the treatment of the disease over the past five years. With a new, triple CTFR modulator expected to be approved by the end of 2019, in the next year, 90% of those with CF may benefit from these new drugs. However, studies of currently available modulator therapies find that between 20% to 25% of patients who should respond based on their disease’s genetic fingerprint don’t.[1][2]
Researchers from the University of Alabama at Birmingham (UAB) think they may know why: patients’ exposure to secondhand smoke. Now they have embarked upon a study to test this hypothesis.
While it might seem counterintuitive that families with a child with CF would expose them to secondhand smoke, approximately one-third of pediatric CF patients are exposed to tobacco smoke, half of whom have been around a smoker in the past 3 months.[3] And yet, said Gabriela Oates, Ph.D., assistant professor in the UAB Division of Pediatric Pulmonary and Sleep Medicine at Children’s of Alabama and an associate scientist in the UAB Cystic Fibrosis Research Center, “many think their child isn’t exposed to the smoke if the family member is smoking outside.”
But that’s simply not true.
“We’re not just talking about secondhand smoke but also about thirdhand smoke exposure,” Oates said. Tobacco particulates remain on the hair, skin and clothes of the smoker, even if he or she smokes outside, and are also found on household surfaces. “You can find relatively high level of nicotine metabolites in the urine of kids whose parents smoke out of doors,” she said. In fact, children demonstrate exposure even if their household members do not smoke but they live in multifamily housing that shares a wall with a smoking household.
This all ties into the new CFTR modulators because in-vitro, animal and non-CF studies indicate that “even indirect exposure to tobacco smoke actually blunts the effect of the drug,” she said. So while the CFTR modulators are designed to correct the underlying genetic mutation that causes the disease, “the smoke exposure undermines that.”
Her project will define the consequences of secondhand smoke on CF respiratory decline and CFTR modulator response using both self-reported and objective measures of exposure such as urine biomarkers. Results will underscore the necessity of clinically driven smoking cessation programs for CF families and will inform recommendations for smoke exposure screening and control.
Given that most children exposed to smoke are clustered in the low-income segment of the CF population, this becomes a health equity issue, Oates said. “It’s particularly concerning because the smoke exposure may be outside of the household and there’s nothing the family can do about it,” she said. “I worry that in the era of CFTR modulators we may see an increased gap in CF outcomes between kids living in poorer environments and their advantaged counterparts. This issue needs to be watched carefully.”
Oates also fears that if her hypothesis is supported, payers may institute smoke exposure screening programs and base drug coverage on the results. This creates quite the conundrum for researchers like herself. “As scientists, we have a responsibility to determine why drugs work or don’t work,” she said, “yet we have little control over how the results of our science are used.” If her study does show that smoke exposure limits the benefits of CFTR modulators, she said, “the very first step is major education on several levels, including CF families, clinicians and insurance providers.”
Her team is being proactive in this regard, already holding interviews with current and former smokers who have a family member with CF, as well as with CF clinicians and other stakeholders. The goal is to develop materials to better inform caregivers and clinical providers about the impact of second-hand smoke and to test a smoking cessation intervention tailored to CF families. “You would be amazed that there is not a single U.S. study evaluating smoking cessation programs in the CF community,” Oates said.
[1] Hebestreit H, Sauer-Heilborn A, Fischer R, Kading M, Mainz JG. Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. J Cyst Fibros. 2013;12(6):599-603.
[2] Taylor-Cousar J, Niknian M, Gilmartin G, Pilewski JM, investigators VX. Effect of ivacaftor in patients with advanced cystic fibrosis and a G551D-CFTR mutation: Safety and efficacy in an expanded access program in the United States. J Cyst Fibros. 2016;15(1):116-122.
[3] Ong T, Schechter M, Yang J, et al. Socioeconomic Status, Smoke Exposure, and Health Outcomes in Young Children With Cystic Fibrosis. Pediatrics. 2017;139(2).
Breathe Easier
Learn more about the Cystic Fibrosis Center at Children’s of Alabama.