Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least One F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Gallbladder sludge and microlithiasis disappearance in a cystic fibrosis patient 1 year after triple combination therapy initiation.

Gallstones, microlithiasis, gallbladder sludge, and micro-gallbladder are frequently reported in cystic fibrosis patients, and modulators could modify gallbladder disease, probably reducing biliary secretions viscosity.

Maternal, newborn and breast milk concentrations of elexacaftor/tezacaftor/ivacaftor in a F508del heterozygous woman with cystic fibrosis following successful pregnancy.

With the introduction of elexacaftor/tezacaftor/ivacaftor (ETI), more women with cystic fibrosis (CF) are likely to grow families. Hence, an understanding long-term safety and effects of CFTR modulators on fertile women and children while monitoring their concentrations is crucial. Here, we report on the development of an improved LC-MS/MS methodology to measure ETI concentrations in maternal and child blood and breastmilk, applied in one case of successful pregnancy of a 30-year-old woman with CF (F508del/R334W). We observed that ETI remains stable in breastmilk, is absorbed by the infant and can be detected in child plasma. Our results confirm accumulating evidence of a successful pregnancy in women treated with CFTR modulators without significant side effects on the child and provide valuable analytical procedures suitable for the post-marketing evaluation of CFTR modulators in pregnant and lactating women, as well as in their infants.

Sinus Disease Grading on Computed Tomography Before and After Modulating Therapy in Adult Patients with Cystic Fibrosis.

Objectives: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy effects on respiratory function, pulmonary exacerbations and quality of life have been well documented. However, CFTR modulator therapy effects on sinus disease have not been so well reported. A previous study reported that ivacaftor improves appearance of sinus disease on Computed Tomography (CT) in cystic fibrosis (CF) patients with G551D mutation. The aim of this study was to evaluate the effect of CFTR modulator therapy in sinus disease using CT scores in a wider CF patient population. Materials and Methods: Forty-eight adult patients with CF underwent at least one CT sinus examination before CFTR modulator therapy (ivacaftor, lumacaftor, ivacaftor/lumacaftor or elexcaftor/tezacaftor/ivacaftor) and one CT sinus examination one year after CFTR modulator therapy initiation. Two radiologists assessed the images in consensus. The Lund-Mackay score (LM score) and the Sheikh-Lind CT sinus disease severity scoring system (SL score) were used. The 22-item SinoNasal Outcome Test (SNOT-22) questionnaire was evaluated before CFTR modulator therapy and one year after CFTR modulator therapy initiation. Results: CT sinus examination after CFTR modulator therapy showed statistically significant lower mean LM, SL and SNOT-22 scores than CT sinus examination before CFTR modulator therapy (p < 0.001). Conclusion: Evolution of imaging findings on CT during follow-up closely correlate with improved SNOT-22 score one year after CFTR modulator therapy initiation, indicating that CT may be a useful adjunct during follow-up of CF patients under this treatment as an objective measure of sinonasal disease improvement.

Adverse reaction to benzathine benzylpenicillin due to soy allergy: a case report.

INTRODUCTION: Soybean allergy is one of the most common food allergies especially among children. The Food Allergen Labeling and Consumer Protection Act (FALCPA) in the US requires the labeling of soy lecithin because it is derived from soybeans and may contain a number of IgE-binding proteins, possibly representing a source of hidden allergens. Here we describe a pediatric case of soy allergy misunderstood as drug allergy. CASE PRESENTATION: An 11-year-old Caucasian girl was referred to our Allergy Unit because of the delayed appearance of an itching papular rash at the site of an injection of benzathine benzylpenicillin delivered by prefilled syringe. A skin test with benzathine benzylpenicillin and detection of serum-specific IgE to penicilloyl V, penicilloyl G, ampicillin and amoxicillin were negative. From her past medical history we know that, at the age of three years, she presented with edema of the lips and difficulty in breathing after eating a soy ice-cream. For that reason, she underwent a skin prick test with soybean that was negative and a serum-specific IgE to soybean test that was weakly positive (0.21KU/L). She underwent an oral provocation test with soy milk that yielded a positive result. CONCLUSIONS: We describe a case of a patient with a delayed reaction to soy as a hidden allergen in a benzathine benzylpenicillin prefilled syringe. This case shows that lecithin contaminated by soy proteins and used as an excipient in drugs can cause reactions in patients with soy allergy. For that reason, the source of lecithin should always be specified among the constituents of drugs to avoid a source of hidden allergens and difficulties in the allergy work-up.

Increased incidence of thyroid dysfunction and autoimmunity in patients with vernal keratoconjunctivitis.

Hormones may play a role in the pathophysiology of vernal keratoconjunctivitis (VKC). An increased incidence of thyroid autoantibodies was recently observed in VKC, although there were no data on thyroid function. Two hundred and eighty-eight patients (202 males, 86 females; range 5.5 to 16.9 years) with VKC were evaluated and compared with 188 normal age- and sex-matched subjects. In all subjects, serum concentrations of free T4, TSH, thyroperoxidase, thyroglobulin, and TSHr autoantibodies were evaluated. In VKC, the family history of thyroid diseases showed no significant differences compared to the controls (9.4 versus 8.6%), whereas the family history of autoimmune diseases was significantly higher (13.2% versus 6.3%; P<0.05). Subclinical hypothyroidism was diagnosed in 6.6% (versus 1.6% of the controls; P<0.05) and overt hypothyroidism in 0.7% (versus 0.0% of the controls; P = NS). Finally, 5.2% of patients were positive for thyroid autoantibodies, which were significantly higher with respect to the controls (0.5%, P<0.05). In the patients positive for thyroid autoantibodies, 80% showed a sonography pattern that suggested autoimmune thyroiditis. Thyroid function and autoimmunity abnormalities are frequently present in children with VKC. Children with VKC should be screened for thyroid function and evaluated for thyroid autoimmunity.

Increased prevalence of growth hormone deficiency in patients with vernal keratoconjuntivitis; an interesting new association.

INTRODUCTION: Vernal keratoconjunctivitis (VKC) is a chronic conjunctivitis that mainly affects children living in temperate areas. The notable difference between genders and VKC's resolution with puberty have persistently suggested a role of hormonal factors in VKC development. OBJECTIVE: To describe six cases of males with VKC and growth hormone deficiency (GHD) reported as a long-term follow-up during rhGH treatment. METHODS: Six consecutive male patients (median age at GHD diagnosis 9.7, range 7.9 to 13.1 years) with VKC, were recruited from July 2005 to July 2013 at the Paediatric Endocrinology Unit of Anna Meyer Children's Hospital in Florence, Italy. In these patients, anthropometric data were collected periodically. In three of these patients, data were collected to near-adult or adult height. RESULTS: Familial history was uneventful for all patients. The target height was normal, ranging from 0.65 standard deviation scores (SDS) to 2.01 SDS. The patients showed a normal birth-weight (from -1.21 to 1.35 SDS) and birth-length (from -0.93 to 1.21 SDS). At GHD diagnosis, all of the patients exhibited demonstrated important growth retardation (from -2.05 to -2.78 SDS). Plasmatic concentrations of IGF-1 and IGFBP-3 were low (from -1.85 to -3 SDS and from -1.81 to -2.76 SDS, respectively). GH stimulation tests showed classic GHD symptoms in all of the patients. Pubertal onset was normal. All of the patients treated with rhGH responded well to rhGH treatment. Adult height, evaluated in three patients, was in accordance with their target height. CONCLUSIONS: To our current knowledge, we have described for the first time six patients affected by VKC with GH deficiency, in some of whom we performed a long-term follow-up to adult height. Further studies will be needed to establish whether GHD may be a common feature of VKC patients. Nevertheless, it appears to be useful to carefully follow statural growth of VKC patients, while the possibility of a GH deficiency must to be taken into account in the presence of growth failure.