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Published on: June 16, 2020
ABCA3-related interstitial lung disease beyond infancy
Yang Li1,2,3, Elias Seidl1,2, Katrin Knoflach1,2
1Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University, Munich, Germany.
Insights
Children with ABCA3 lung disease often face severe respiratory issues. This study shows their interstitial lung disease progresses through childhood, highlighting the need for new treatments.
Area of Science:
- Pediatric Pulmonology
- Genetic Respiratory Diseases
- Interstitial Lung Disease
Background:
- Childhood interstitial lung disease (chILD) from ATP binding cassette subfamily A member 3 (ABCA3) variants typically leads to severe respiratory insufficiency and high mortality in the first year of life.
- Lung transplantation is often the only option for survival in severe ABCA3-related chILD.
- This study focuses on the long-term outcomes of patients with ABCA3 lung disease who survive beyond infancy.
Purpose of the Study:
- To review the long-term clinical course, oxygen requirements, and pulmonary function in children with ABCA3 deficiency who survived past one year of age.
- To understand the natural history and progression of ABCA3-related interstitial lung disease in a pediatric cohort.
- To identify factors influencing survival and disease progression in this patient group.
Main Methods:
- A register-based cohort study utilizing the Kids Lung Register database over a 21-year period.
- Identification and review of 44 patients diagnosed with chILD due to ABCA3 deficiency who survived beyond their first year.
- Assessment of long-term clinical course, oxygen supplementation, pulmonary function, chest CT scans, and histopathology, with blind scoring.
Main Results:
- Of 44 patients, 82% (36/44) were alive without transplantation at a median age of 6.3 years.
- Survival was significantly longer for patients never requiring oxygen supplementation compared to those requiring persistent oxygen (9.7 years vs. 3.0 years).
- Evidence of progressive interstitial lung disease was observed through declining lung function (-1.1% FVC/year) and increasing cystic lesions on CT scans.
Conclusions:
- ABCA3-related interstitial lung disease follows a progressive natural history throughout childhood and adolescence.
- The findings underscore the urgent need for disease-modifying therapies to slow the progression of ABCA3-related lung disease.
- Residual ABCA3 transporter function may be present in some patients with missense variants or small indels.
Background:
The 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.
Method:
Over 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.
Results:
At 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, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.
Conclusion:
The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.
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