Current drug hypersensitivity challenges facing patients with cystic fibrosis

This review explores the changing landscape of drug safety in patients with cystic fibrosis (CF) prescribed Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy. While serious adverse reactions are infrequent, they can necessitate treatment withdrawal and thereby negatively impact clinical outcomes. The CFTR correctors (vanzacaftor, elexacaftor, tezacaftor, lumacaftor) and potentiators (ivacaftor, deuterated ivacaftor) target the underlying CFTR defect to improve protein function. The CF patient population encounter a high prevalence of non-immediate adverse drug reactions and T-cell mediated hypersensitivity to β-lactam antibiotics are among the most well characterised. Piperacillin has been defined as a leading drug culprit within non-immediate drug allergy in patients with CF, with a growing body of evidence alluding to the central role of T-lymphocytes. The prevalence of reactions in CF is likely due to factors including exaggerated inflammation, overactive immune states and cumulative drug exposure. While the introduction of the CFTR modulators has led to improvements in patients inflammatory and immune states, some patients have been reported to develop drug-related allergies. Uniquely, patients presenting with drug hypersensitivity have been found to later tolerate CFTR modulators, often without the need for desensitisation protocols. This phenomenon has led us to hypothesise that increased levels of inflammation and dysregulation of regulatory T-cells in CF patients could propagate adverse reactions to CFTR modulators that resolve alongside underlying infection. The introduction of CFTR modulator therapies has been highly transformative for patients with CF, therefore, adverse reactions to these compounds that lead to cessation of treatment are serious and important to understand.