Abstract
The combination of medication containing elexacaftor, ivacaftor, and tezacaftor (EIT) has dramatically impacted the treatment and prognosis for patients with cystic fibrosis (CF). Lung function, weight, and self-reported quality of life have improved for many of these patients, but little is known about whether this treatment will have a beneficial effect in preventing morbidity and/or mortality from respiratory infections such as COVID-19. EIT received Food and Drug Administration (FDA) approval shortly before the first cases of COVID-19 appeared in the United States. We performed an analysis using the TriNetX (Cambridge, MA, USA) research database to determine if patients being treated with EIT who became infected with COVID-19 experienced significantly different outcomes compared to patients who were not receiving it.
Introduction
The COVID-19 pandemic resulted in approximately 20 million documented cases of infection in the United States by the end of 2020 [1]. Patients with comorbidities were quickly found to have inferior outcomes [2]. The combination medication containing elexacaftor, ivacaftor, and tezacaftor (EIT) received Food and Drug Administration (FDA) approval in October 2019 for the treatment of cystic fibrosis (CF) in patients aged 12 and older who have at least one F508del mutation [3]. This mutation is highly prevalent in cystic fibrosis patients, enabling 90% of those patients to potentially qualify for this combination therapy [4]. Elexacaftor and tezacaftor enhance the processing and transport of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) protein, thereby increasing the number of transporters on the cell surface [5]. Ivacaftor is a potentiator, which binds to the CFTR protein in the plasma membrane and increases the channel’s opening frequency and ion conductance [5]. In CF patients, this combination of medications results in significant improvement in FEV1, sweat chloride concentration, and cystic fibrosis questionnaire-revised (CFQ-R) scores in comparison to patients treated with only tezacaftor and ivacaftor [6].
We designed this study to evaluate whether CF patients who contracted COVID-19 while on treatment with EIT had superior outcomes with regard to acute respiratory failure and dependence on a mechanical ventilator. Overall survival at three months was also evaluated.
Materials & Methods
Study design
This is a retrospective cohort study performed by query of the TriNetX (Cambridge, MA, USA) research database. The TriNetX platform provides anonymized medical record information of more than 90 million patients in 65 large healthcare organizations. Two patient cohorts were created, both with cystic fibrosis and COVID-19 infection. One cohort was receiving treatment with EIT, while the other was not.
Inclusion criteria
The inclusion criteria for both cohorts consisted of a diagnosis of cystic fibrosis, identified by the International Classification of Disease-10 (ICD-10) code E84. Both were also required to have a diagnosis of COVID-19 infection, identified in the TriNetX system by laboratory code 9088, signifying “presence of SARS coronavirus 2 and related RNA.” The inclusion criteria for the EIT-treated cohort also included medication code 2256951, indicating treatment with elexacaftor. At the time of this study, elexacaftor was not available as either a single agent or in combination with any other medications other than ivacaftor and tezacaftor. Its presence, therefore, indicated treatment with the EIT combination.
The time frame for patient inclusion was specified as the first 12 months of the COVID-19 pandemic in the United States, January through December of 2020, for several reasons. These included the recent FDA approval of the EIT combination for the treatment of cystic fibrosis, the uniformity of COVID-19 infection due to the absence of multiple variants at that time, and the unavailability of any vaccines until mid-December of 2020 [7]. This time frame specification was designed to reduce or eliminate potential confounding variables.
Exclusion criteria
Medication code 2256951 (mentioned above) was used as an exclusion criterion for the cohort not treated with EIT.
Data collection
Cohort creation was performed according to the ICD-10 code criteria mentioned previously. Balancing of the cohorts was performed for the factors of age, race, gender, and ethnicity via the greedy nearest neighbor algorithm and resulted in 1,030 patients in each arm. The cohorts were then compared for the outcomes of acute respiratory failure (ICD-10 J96.0) and dependence on a respirator (ICD-10 Z99.11) within three months of developing COVID-19 infection to establish a high likelihood of a causal relationship.
Source: https://www.cureus.com/articles/105229-the-impact-of-elexacaftorivacaftortezacaftor-on-cystic-fibrosis-patients-who-acquire-covid-19-infection