Resolution of recurrent pancreatitis and nutritional recovery with CFTR modulator therapy in CFTR-related disorder: a case report

[Bronchiectasis with elevated liver enzymes and pancreatic exocrine insufficiency].

Recurrent Severe Infections and Bronchiectasis in a Heterozygous CFTR Mutation Carrier: A Case Report

Cystic fibrosis (CF) is associated with impaired innate immune function, including dysfunction of circulating monocytes and macrophages, and is currently classified within group V inborn errors of immunity. Emerging evidence suggests that heterozygous CFTR variants may also contribute to immune dysregulation and increase susceptibility to recurrent respiratory infections and bronchiectasis. A previously healthy 5-year-old girl was admitted to the pediatric intensive care unit with bilateral pleuropneumonia complicated by distributive shock and multiorgan dysfunction syndrome. Streptococcal toxic shock syndrome associated with influenza A infection was diagnosed. Treatment included hemodynamic support, targeted antimicrobial therapy, invasive mechanical ventilation, renal replacement therapy, pleural drainage, and intravenous immunoglobulin (IVIG). After 39 days, she was discharged in good clinical condition. Subsequently, she developed protracted bacterial bronchitis requiring antibiotic therapy and, one year later, was readmitted with influenza B infection complicated by severe left-sided pleuropneumonia. Given her history of recurrent life-threatening respiratory infections, a comprehensive immunological and pulmonary evaluation was undertaken. Serum immunoglobulin levels, IgG subclasses, complement concentrations, and complement functional assays were within reference ranges. Lymphocyte immunophenotyping revealed a transient reduction in natural killer cell counts. Chest computed tomography demonstrated bronchiectasis of the right middle lobe. Whole-exome sequencing identified a heterozygous pathogenic CFTR variant, c.1521_1523del (p.Phe508del), while sweat chloride concentrations were within the normal range. Seasonal IVIG prophylaxis and annual influenza vaccination were initiated. No further severe infections were observed during follow-up. This case adds to the emerging evidence that clinically relevant CFTR heterozygosity may contribute to susceptibility to recurrent severe respiratory infections and bronchiectasis. Evaluation of CFTR variants should be considered in patients with primary immunodeficiency-like respiratory phenotypes, particularly when standard immunological investigations are unrevealing. Further studies are needed to elucidate the underlying immunological mechanisms and establish evidence-based preventive strategies for this population.

Clinical benefit without sweat chloride response after ETI therapy in an adult with cystic fibrosis bearing the L467F;F508del complex CFTR allele: a case report and the role of AI-assisted chest CT in longitudinal monitoring

Elexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. However, predicting responses to CFTR modulators in rare or complex CFTR genotypes is challenging. Sweat chloride concentration (SCC) and patient-derived functional assays assessing CFTR-mediated chloride transport are commonly used to classify modulator responsiveness. Carriers of the p.Leu467Phe;p.Phe508del (henceforward legacy nomenclature: L467F;F508del) complex CFTR allele have been considered unlikely to respond to ETI, based on short-term clinical, biomarker and ex vivo evidence. We report a discordant long-term response in an adult carrying this complex allele, with clinically meaningful benefit despite persistently negative CFTR chloride transport biomarkers. We describe an 8-year longitudinal pre- and post-treatment assessment of an adult woman with CF, adherent to therapy, with the L467F;F508del complex allele compounded with the non-responsive c.489 + 1G > T (621 + 1G > T) variant in trans . She has pancreatic insufficiency, progressive lung disease, and recurrent pulmonary exacerbations. After ETI commencement (at 40.5 years; July 2021) SCC remained unchanged at ∼100 mmol/L. Intestinal organoid and primary nasal epithelial cell assays showed no measurable ETI-related CFTR-mediated chloride transport rescue. Nevertheless, BMI increased from 22.0 to 26.8 kg/m 2 , annual exacerbations decreased from 5 to 3, and ppFEV₁ improved from 51% to 55–59%. Serial chest CT showed a shift from pre-ETI progression to post-ETI stabilisation, with reductions in air trapping and the extent of bronchiectasis on manual Brody II scoring and LungQ/PRAGMA-AI quantification. Exploratory in vitro exposure of nasal epithelial cells to vanzacaftor/tezacaftor/ivacaftor yielded ∼5% CFTR-mediated rescue, contrasting with the negative ETI response. Persistent CFTR biomarker negativity may not fully exclude clinically meaningful ETI-associated benefit in rare or complex CFTR genotypes. The pulmonary and extrapulmonary improvements observed in this case support multidimensional response assessment beyond single-biomarker endpoints. These hypothesis-generating observations support individualised long-term monitoring and comprehensive interpretation of CFTR biomarkers in the clinical context. AI-assisted chest CT may provide complementary real-world evidence. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles.

Pediatric cystic fibrosis is associated with type 3 immune response

Unusual Association of Cystic Fibrosis and Coeliac Disease: A Rare Case Report

Chronic malabsorption in early childhood is commonly associated with gastrointestinal disorders such as coeliac disease, but overlapping clinical features may delay recognition of other systemic causes, including cystic fibrosis. This case report describes a 2½-year-old boy who presented with chronic loose, bulky, oily, offensive stools, abdominal distension, irritability, recurrent abdominal pain, recurrent infections, and failure to thrive. His clinical examination showed pallor, sparse scalp hair, undernutrition, abdominal distension, hepatomegaly, and muscle wasting. Initial evaluation revealed microcytic hypochromic anaemia, stool fat globules, positive Sudan IV staining, reduced stool elastase, mildly elevated transaminases, and positive coeliac serology with elevated tissue transglutaminase IgA. Although the child was managed for coeliac disease, persistent steatorrhoea and poor growth prompted further evaluation. Sweat chloride testing showed a chloride concentration of 81.57 mmol/L, and CFTR testing identified a homozygous F508del mutation, supporting the diagnosis of cystic fibrosis coexisting with coeliac disease. The child was managed with a high-calorie gluten-free diet, fat-soluble vitamins, iron supplementation, pancreatic enzyme replacement therapy, and supportive care. During four months of follow-up, stool consistency, appetite, abdominal distension, general appearance, and weight improved. This case highlights the need to consider concurrent cystic fibrosis in children with confirmed or suspected coeliac disease who continue to have malabsorption and poor growth despite appropriate dietary management.

Long-term clinical outcomes of neonatal cystic fibrosis presentation: a single-center retrospective study