INITIATION OF ELEXACAFTOR-TEZACAFTOR-IVACAFTOR LEADING TO LUNG TRANSPLANTATION

Abstract

SESSION TITLE: Medical Student/Resident Genetic and Developmental Disorders Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in impaired chloride conductance, a dehydrated airway surface liquid, and multi-organ dysfunction (1). The highly effective CFTR modulator elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) has shown efficacy in people with the ∆F508 mutation (2). We report a case of a patient who developed acute respiratory failure with hypoxia and hypercapnia requiring lung transplantation after starting ELX/TEZ/IVA. CASE PRESENTATION: A 23-year-old male with CF (∆F508/621+1G–>T) complicated by very severe obstructive lung disease with a ppFEV1 of 32% presented with hypoxemia and productive cough three days after starting treatment with ELX/TEZ/IVA. Physical exam revealed bilateral crackles and bilateral lower extremity pitting edema. Labs showed WBC 20.8 and IgE 563. Sputum culture was positive for Pseudomonas aeruginosa. CT chest revealed extensive upper lobe cystic bronchiectasis with mucus plugging and consolidation. Patient was started on culture-directed antimicrobials and ELX/TEZ/IVA was held. Patient improved clinically, and on day 5 of hospitalization, he was restarted on ELX/TEZ/IVA at a reduced dose. Within 13 hours, he developed worsening hypoxemia and hypercapnia requiring high flow oxygen and intermittent noninvasive positive pressure ventilation and was transferred to a lung transplant center, where he was listed for lung transplantation and eventually transplanted. DISCUSSION: ELX/TEZ/IVA is usually well tolerated; adverse events leading to discontinuation of the drug only occurred in 1% of study participants (2). The most commonly reported adverse event was an infective pulmonary exacerbation, likely because pulmonary exacerbations are frequently observed in CF (2). The temporal relationship between starting ELX/TEZ/IVA to onset of symptoms, both initially and after restarting the drug despite being on appropriate antimicrobial therapy, suggests an adverse effect directly related to the drug rather than a classic pulmonary exacerbation. This observation may be the result of significant CFTR upregulation in a patient with very severe obstructive lung disease. Since individuals with a ppFEV1 < 40% were not studied, more data is needed to determine if closer monitoring is warranted around the time of initiation with ELX/TEZ/IVA in this more severe cohort. CONCLUSIONS: ELX/TEZ/IVA is an extremely effective and overall safe drug for around 90% of individuals with CF (1). Our case necessitates asking if individuals with more severe CF should undergo closer monitoring with hospitalization when initiating treatment. Reference #1: Ratjen F, Döring G. Cystic fibrosis. Lancet. 2003;361(9358):681-9. Reference #2: Middleton PG et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809-1819. DISCLOSURES: No relevant relationships by Christopher Barrios, source=Web Response No relevant relationships by Travis Homan, source=Web Response No relevant relationships by Stephanie Link, source=Web Response