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Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from melanoma or metastatic cutaneous squamous cell carcinoma profit from immune checkpoint blockade as a therapy. Pneumonitis is a rare but potentially fatal immune-related adverse event, and even more subclinical damage is most likely to occur. The sensitive marker lung clearance index, integrated into pulmonary function testing, was used to detect possible early pulmonary impairment. As slightly impaired lung function could be observed, we recommend the sensitive marker lung clearance index as a diagnostic method that should be implemented into the clinical routine follow-ups during immune checkpoint therapy in order to enable possible further recommendations. Background: Immune checkpoint blockade (ICB) has presented a breakthrough in the treatment of malignant tumors and increased the overall survival of patients with various tumor entities. ICB may also cause immune-related adverse events, such as pneumonitis or interstitial lung disease. The lung clearance index (LCI) is a multiple-breath washout technique offering information on lung pathology in addition to conventional spirometry. It measures the degree of pulmonary ventilation inhomogeneity and allows early detection of pulmonary damage, especially that to peripheral airways. Methods: This cross-sectional study compared the lung function of patients with melanoma or metastatic cutaneous squamous cell carcinoma who received programmed cell death 1 (PD-1) and cytotoxic T-Lymphocyte-associated Protein 4 (CTLA-4) antibodies, alone or in combination, to age- and sex-matched controls. Lung function was assessed using spirometry, according to American Thoracic Society and European Respiratory Society standards, the LCI, and a diffusion capacity of carbon monoxide (DLCO) measurement. Results: Sixty-one screened patients and thirty-eight screened controls led to nineteen successfully included pairs. The LCI in the ICB-treated patients was 8.41 ± 1.15 (mean ± SD), which was 0.32 higher compared to 8.07 ± 1.17 in the control group, but the difference was not significant (p = 0.452). The patients receiving their ICB therapy for under five months showed a significantly lower LCI (7.98 ± 0.77) compared to the ICB patients undergoing therapy for over five months (9.63 ± 1.22) at the point of testing (p = 0.014). Spirometric analysis revealed that the forced expiratory volume between 25 and 75% of the forced vital capacity (FEF25–75%) in the ICB-treated patients was significantly reduced (p = 0.047) compared to the control group. DLCO (%predicted and adjusted for hemoglobin) was 94.4 ± 19.7 in the ICB patients and 93.4 ± 21.7 in the control group (p = 0.734). Conclusions: The patients undergoing ICB therapy showed slightly impaired lung function compared to the controls. Longer periods of ICB treatment led to deterioration of the LCI, which may be a sign of a subclinical inflammatory process. The LCI is feasible and may be easily integrated into the clinical daily routine and could contribute to early detection of pulmonary (auto-)inflammation. [ABSTRACT FROM AUTHOR]

The major cause of mortality in people with cystic fibrosis (pwCF) is progressive lung disease characterised by acute and chronic infections, the accumulation of mucus, airway inflammation, structural damage and pulmonary exacerbations. The prevalence of Pseudomonas aeruginosa rises rapidly in the teenage years, and this organism is the most common cause of chronic lung infection in adults with cystic fibrosis (CF). It is associated with an accelerated decline in lung function and premature death. New P. aeruginosa infections are treated with antibiotics to eradicate the organism, while chronic infections require long-term inhaled antibiotic therapy. The prevalence of P. aeruginosa infections has decreased in CF registries since the introduction of CF transmembrane conductance regulator modulators (CFTRm), but clinical observations suggest that chronic P. aeruginosa infections usually persist in patients receiving CFTRm. This indicates that pwCF may still need inhaled antibiotics in the CFTRm era to maintain long-term control of P. aeruginosa infections. Here, we provide an overview of the changing perceptions of P. aeruginosa infection management, including considerations on detection and treatment, the therapy burden associated with inhaled antibiotics and the potential effects of CFTRm on the lung microbiome. We conclude that updated guidance is required on the diagnosis and management of P. aeruginosa infection. In particular, we highlight a need for prospective studies to evaluate the consequences of stopping inhaled antibiotic therapy in pwCF who have chronic P. aeruginosa infection and are receiving CFTRm. This will help inform new guidelines on the use of antibiotics alongside CFTRm., Competing Interests: Competing interests: P-RB has received advisory board fees from Viatris; research grants (paid to the institution) from GSK and Vertex Pharmaceuticals; consulting fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Vertex Pharmaceuticals, Viatris and Zambon and support for attending meetings from AstraZeneca and Chiesi. MB has received consultancy fees from Vertex Pharmaceuticals and Viatris; honoraria for presentations from ALK and Vertex Pharmaceuticals and advisory board honoraria from Viatris. PD has received honoraria for lectures from Chiesi and Vertex Pharmaceuticals; participated in advisory boards for Vertex Pharmaceuticals and Viatris and is President of the Czech Society for Medical Microbiology. HH has received consultancy fees from Vertex Pharmaceuticals and Viatris; honoraria for educational activities and advisory boards from Vertex Pharmaceuticals; honoraria for educational activities from AstraZeneca and advisory board honoraria from Viatris. AJ has received consultancy fees from EffRx Pharmaceuticals and Vertex Pharmaceuticals; honoraria for presentations from OM Pharma and Vertex Pharmaceuticals and participated in advisory boards for OM Pharma, Sanofi Aventis and Viatris. JGM has received consultancy fees from Chiesi, Pari, Vertex Pharmaceuticals and Viatris; honoraria for presentations from Chiesi and Vertex Pharmaceuticals; support for attending meetings from Chiesi and participated in advisory boards for Viatris. DP has received an educational grant from Gilead; honoraria for educational lectures; participated in past advisory boards for AbbVie, Chiesi, Gilead, Sanofi, Vertex Pharmaceuticals and Viatris and support for attending an advisory board meeting from Viatris. BP has received consultancy fees from Chiesi and Vertex Pharmaceuticals; honoraria for lectures from AstraZeneca, Chiesi, GSK, Insmed, Vertex Pharmaceuticals and Viatris; and advisory board fees from Viatris. CS has received honoraria as a speaker from AbbVie, Chiesi, Horizon Therapeutics, TFF Pharmaceuticals, Vertex Pharmaceuticals and Viatris and support for attending conferences from the European Cystic Fibrosis Society. GT has received consultancy fees from Pfizer, Shionogi, Vertex Pharmaceuticals and Viatris and honoraria from Chiesi and DMF Pharma FoodAR. AS has received research grants (paid to the institution) from Vertex Pharmaceuticals (outside of the current work) and payment for an advisory board (paid to the institution) from Viatris for participation in a workshop to discuss inhaled antibiotics in CF. He has patents issued (Camara M, Williams P, Barrett D, Halliday N, Knox A, Smyth A, Fogarty A, Barr H, Forrester D. Alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof. US-2016131648-A1. https://pubchem.ncbi.nlm.nih.gov/patent/US-2016131648-A1 (outside of the current work)) and reports participation on a Data Safety Monitoring Board for the North American Cystic Fibrosis Foundation Therapeutics Development Network., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)