D2.416 - Skin reaction to Kaftrio/Kalydeco (CFTR) in cystic fibrosis: safe reintroduction using an outpatient desensitization protocol

Skin reactions to cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor/tezacaftor/ivacaftor (Kaftrio) and ivacaftor (Kalydeco), are rare but clinically relevant, with an incidence of skin rashes ranging from 4% to 12%. They usually present as late-onset generalized maculopapular rashes and may be associated with eosinophilia, usually without severe systemic involvement.

Although the clinical phenotype is usually delayed, immediate reactions may occur during drug challenge or re-exposure, underscoring the importance of careful allergy evaluation. Identification of the responsible drug and its temporary withdrawal are essential for patient safety. Reintroduction using structured desensitization protocols has been shown to be safe and effective, allowing treatment with CFTR modulators in cystic fibrosis (CF) to continue.

We present the case of a 38-year-old woman with CF admitted for severe hemoptysis in the context of a Mycobacterium abscessus infection. She received meropenem and linezolid (37 days), amikacin and clofazimine (14 days), and the CFTR modulators Kaftrio and Kalydeco (12 days).

During hospitalization, she developed a generalized pruritic maculopapular rash with eosinophilia (peak of 2700/µL), without renal or hepatic involvement. All treatments were discontinued, and symptomatic therapy led to complete resolution within five days.

Allergy testing included skin tests and intradermal tests, delayed-reading patch tests (PPL, MDM, meropenem, linezolid, amikacin, Kaftrio, and Kalydeco; clofazimine not available), and lymphocyte activation testing (LAT) with antibiotics.

- Skin and intradermal tests were negative.

- Delayed-reading patch tests were negative. 

- LAT results were negative. 

Sequential reintroduction at five-day intervals showed good tolerance to linezolid, amikacin, and meropenem. Following reintroduction of Kaftrio, immediate skin rash developed, confirming its involvement.

A slow outpatient desensitization protocol for Kaftrio/Kalydeco, based on Balijepally et al. (2022), was successfully completed without immediate or delayed adverse reactions.

CFTR modulators are essential in CF management and should not be permanently discontinued without adequate allergological assessment. Although reactions are usually delayed, immediate responses may occur during re-exposure. A structured outpatient desensitization protocol is a safe and effective strategy to preserve treatment, respiratory function, and quality of life under specialized supervision.