Characterizing individuals with elevated sweat chloride results in the absence of CFTR variants

Abstract Background Cystic fibrosis (CF) is a multi-system disease caused by CFTR dysfunction. Genetic defects in the CFTR protein cause impaired chloride and bicarbonate secretion on the apical surface of epithelial cells throughout the body. Classically, the diagnosis of CF is established based on a clinical presentation suggestive of CF along with two elevated sweat chloride test results (≥ 60 mmol/L) or the presence of two pathogenic disease-causing CFTR variants. This study aimed to characterize and compare a subset of patients who present with a CF-like phenotype and elevated sweat chlorides with (‘CF control’) vs. without (‘cases’) disease-causing CFTR variants. Results Cases were found to have more upper respiratory tract symptoms (sinusitis, nasal polyps, and recurrent sinus infections) compared to CF controls. Furthermore, cases experienced fewer pulmonary exacerbations per year, had less evidence of bronchiectasis, peribronchial thickening, and mucus plugging on CT scan imaging, and fewer organisms identified on sputum microbiology. Compared to CF controls, cases were also noted to have fewer gastrointestinal and genitourinary manifestations of CF. Conclusion The clinical features of patients with elevated sweat chlorides in the absence of CFTR variants are distinct from patients with CFTR variants and comparable sweat chlorides. Further investigation into this subset of patients may elucidate alternative causes for this CF-like phenotype.