ABCA3-related interstitial lung disease beyond infancy

Abstract

BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year.MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly.ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8–11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss −1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, theABCA3sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

Variants in FGF10 cause early onset of severe childhood interstitial lung disease: A detailed description of four affected children

“…Thus, in addition to the type of genetic variant, other cofactors appear to have a relevant influence on the extent of lung disease and thus on the overall prognosis also in children with pathogenic FGF10 variants associated chILD. This phenomenon has already been described in other hereditary chILD forms such as surfactant deficiencies, hereditary alveolar proteinosis, or FLNA associated diffuse lung disease 31–33 . It is important, however, to identify these modifying factors because they may allow the development of preventive or more efficient therapeutic strategies in the future.…”

“…This phenomenon has already been described in other hereditary chILD forms such as surfactant deficiencies, hereditary alveolar proteinosis, or FLNA associated diffuse lung disease. [31][32][33] It is important, however, to identify these modifying factors because they may allow the development of preventive or more efficient therapeutic strategies in the future.…”

Lung biopsies in infants and children in critical care situation

“…For example, ABCA3 bi-allelic mutations' pathogenicity can range from fatal (null/null mutations) to less severe forms of the disease (null/ hypo; hypo/hypo) with variations in individual expression of the diseases within a single family. 11,12 For other than null/null mutations, early therapeutic intervention with corticosteroids, azithromycin and hydroxychloroquine may hold the potential to improve the prognosis.…”

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“…Ground-glass opacities that are prominent early in the course of the disease decrease with time and reticular opacities become more prominent as the disease progresses. 22,69 Recently, Li et al 21 FVC % predicted of 0.8% per year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Increased awareness of pulmonary fibrosis in children will improve our understanding of both the natural course of these disorders and eventually the impact of treatment for fibrosis in children.…”