Analyses of 1,236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: 1236 individuals carried 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%; 47-100%) and laterality defects (mean 42%; 28-69%) varied widely among the countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). In the group of individuals with CCNO (-3.26), CCDC39 (-2.49), and CCDC40 (-2.96) variants, FEV1 z-scores were significantly lower, while the group of DNAH11 (-0.83) and ODAD1 (-0.85) variant individuals had significantly milder FEV1 z-score reductions compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function.

Inherited pulmonary surfactant metabolism disorders in Argentina: Differences between patients with SFTPC and ABCA3 variants.

BACKGROUND: Patients with inherited pulmonary surfactant metabolism disorders have a wide range of clinical outcomes and imaging findings. Response to current anti-inflammatory therapies has been variable and efficacy is unclear. OBJECTIVE: To describe and compare genetic, clinical, histological, and computed tomography (CT) outcomes in a cohort of patients with variants in the genes encoding surfactant protein C (SP-C) or adenosine triphosphate-binding cassette transporter A3 (ABCA3) in Argentina. METHODS: Observational cohort retrospective study. Patients carrying variants in genes encoding SP-C and ABCA3 proteins were included. RESULTS: Fourteen patients met the inclusion criteria: SFTPC n = 6, ABCA3 n = 8 (seven were heterozygous and one compound heterozygous). Neonatal respiratory distress was more frequent and severe in neonates with variants in the ABCA3 gene. The onset of the disease occurred in infancy before the age of 20 months in all cases. Patients with ABCA3 pathogenic variants had a severe clinical course, while long-term outcomes were more favorable in individuals with SFTPC variants. Initial CT findings were ground glass opacities and intraparenchymal cysts in both groups. Over time, signs of lung fibrosis were present in 57% of patients with ABCA3 variants and in 33% of the SFTPC group. The efficacy of anti-inflammatory interventions appears to be poor, especially for patients with ABCA3 pathogenic variants. CONCLUSIONS: Clinical, histological, and radiological features are similar in patients with SFTPC and ABCA3 variants; however, the latter have more severe clinical course. Current anti-inflammatory regimens do not appear to stop the progression of the disease.

Clinical, functional, and computed tomography findings in a cohort of patients with neuroendocrine cell hyperplasia of infancy.

INTRODUCTION: Neuroendocrine cell hyperplasia of infancy (NEHI) is one of the most common interstitial lung diseases in children. Both the etiology and pathophysiological mechanisms of the disease are still unknown. Prognosis is usually favorable; however, there are significant morbidities during the early years of life. OBJECTIVE: To describe the clinical course, infant pulmonary function tests and computed tomography (CT) findings in a cohort of patients with NEHI in Argentina. METHODS: This is a observational multicenter cohort study of children diagnosed with NEHI between 2011 and 2020. RESULTS: Twenty patients participated in this study. The median age of onset of symptoms was 3 months and the median age at diagnosis was 6 months. The most common clinical presentation was tachypnea, retractions and hypoxemia. The chest CT findings showed central ground glass opacities and air trapping. Infant pulmonary function tests revealed an obstructive pattern in 75% of the cases (10/12). Most patients (75%) required home oxygen therapy for 17 months (interquartile range 12-25). In 85% of them, tachypnea and hypoxemia spontaneously resolved between the second and third years of life. CONCLUSION: In this cohort, the first symptoms appeared during the early months of life. The typical clinical, CT, and functional findings allowed the diagnosis without the need of a lung biopsy. Although most patients required home oxygen therapy, they showed a favorable evolution.

Evolución de la función pulmonar en niños con fibrosis quística durante los primeros 3 años de vida / Course of lung function in children with cystic fibrosis in their first 3 years of life

Introducción. La prevención temprana de las complicaciones respiratorias en niños con fibrosis quística determina una mayor sobrevida. La aplicación de pruebas de función pulmonar desde los primeros meses de vida permite detectar el compromiso respiratorio, inclusive en niños asintomáticos. Objetivo. Evaluar la evolución de la función pulmonar en niños con fibrosis quística durante los primeros 3 años de vida e identificar aquellos factores que la comprometen. Población y métodos. Estudio analítico, observacional, retrospectivo. Se incluyeron menores de 36 meses con, al menos, dos estudios funcionales respiratorios. Resultados. Entre 2008 y 2016, se incluyeron 48 pacientes, de los cuales el 85 % fue diagnosticado por pesquisa neonatal. La primera evaluación funcional respiratoria fue a los 5 meses. La mediana de puntaje Z de flujo máximo a nivel de la capacidad residual funcional fue de -0,05 (intervalo intercuartil: de -1,09 a 1,08). La mediana de cambio del puntaje Z del flujo máximo entre las evaluaciones fue de -0,32 (intervalo intercuartil: de -1,11 a 0,25), p = 0,045. Los pacientes con infecciones respiratorias por Staphylococcus aureus, especialmente los resistentes a meticilina, evidenciaron una mayor declinación de la función pulmonar comparados con los no infectados. Ni el sexo ni el tipo de mutación genética se asociaron a la evolución respiratoria. Se evidenció una muy buena recuperación nutricional a lo largo del estudio. Conclusión. Los niños con fibrosis quística presentan una función pulmonar que, progresivamente, desmejora durante los primeros 3 años de vida. Estos hallazgos se asocian a las infecciones respiratorias por Staphylococcus aureus.

Introduction. The early prevention of respiratory complications in children with cystic fibrosis is determining for a longer survival. The implementation of lung function tests in the first months of life allows to detect respiratory involvement, even in asymptomatic children. Objective. To assess the course of lung function in children with cystic fibrosis in their first 3 years of life and identify the factors affecting it. Population and methods. Observational, retrospective, analytical study. Children younger than 36 months with at least 2 lung function tests were included. Results. Between 2008 and 2016, 48 patients were included; 85 % of them had been diagnosed by newborn screening. The first lung function test was done at 5 months old. The median Z-score of maximal flow at functional residual capacity was -0.05 (interquartile range: -1.09 to 1.08). The median change in the maximal flow Z-score between tests was -0.32 (interquartile range: -1.11 to 0.25), p = 0.045. Patients with Staphylococcus aureus respiratory infections, especially methicillin-resistant SA, evidenced a greater deterioration of lung function compared to those without infection. Neither sex nor the type of genetic mutation were associated with the course of lung function. Nutritional recovery throughout the study was really good. Conclusion. Lung function in children with cystic fibrosis worsens progressively during their first 3 years of life. These findings are associated with Staphylococcus aureus respiratory infections.

Course of lung function in children with cystic fibrosis in their first 3 years of life. / Evolución de la función pulmonar en niños con fibrosis quística durante los primeros 3 años de vida.

INTRODUCTION: The early prevention of respiratory complications in children with cystic fibrosis is determining for a longer survival. The implementation of lung function tests in the first months of life allows to detect respiratory involvement, even in asymptomatic children. OBJECTIVE: To assess the course of lung function in children with cystic fibrosis in their first 3 years of life and identify the factors affecting it. POPULATION AND METHODS: Observational, retrospective, analytical study. Children younger than 36 months with at least 2 lung function tests were included. RESULTS: Between 2008 and 2016, 48 patients were included; 85 % of them had been diagnosed by newborn screening. The first lung function test was done at 5 months old. The median Z-score of maximal flow at functional residual capacity was -0.05 (interquartile range: -1.09 to 1.08). The median change in the maximal flow Z-score between tests was -0.32 (interquartile range: -1.11 to 0.25), p = 0.045. Patients with Staphylococcus aureus respiratory infections, especially methicillin-resistant SA, evidenced a greater deterioration of lung function compared to those without infection. Neither sex nor the type of genetic mutation were associated with the course of lung function. Nutritional recovery throughout the study was really good. CONCLUSION: Lung function in children with cystic fibrosis worsens progressively during their first 3 years of life. These findings are associated with Staphylococcus aureus respiratory infections.

Introducción. La prevención temprana de las complicaciones respiratorias en niños con fibrosis quística determina una mayor sobrevida. La aplicación de pruebas de función pulmonar desde los primeros meses de vida permite detectar el compromiso respiratorio, inclusive en niños asintomáticos. Objetivo. Evaluar la evolución de la función pulmonar en niños con fibrosis quística durante los primeros 3 años de vida e identificar aquellos factores que la comprometen. Población y métodos. Estudio analítico, observacional, retrospectivo. Se incluyeron menores de 36 meses con, al menos, dos estudios funcionales respiratorios. Resultados. Entre 2008 y 2016, se incluyeron 48 pacientes, de los cuales el 85 % fue diagnosticado por pesquisa neonatal. La primera evaluación funcional respiratoria fue a los 5 meses. La mediana de puntaje Z de flujo máximo a nivel de la capacidad residual funcional fue de ­0,05 (intervalo intercuartil: de -1,09 a 1,08). La mediana de cambio del puntaje Z del flujo máximo entre las evaluaciones fue de -0,32 (intervalo intercuartil: de -1,11 a 0,25), p = 0,045. Los pacientes con infecciones respiratorias por Staphylococcus aureus, especialmente los resistentes a meticilina, evidenciaron una mayor declinación de la función pulmonar comparados con los no infectados. Ni el sexo ni el tipo de mutación genética se asociaron a la evolución respiratoria. Se evidenció una muy buena recuperación nutricional a lo largo del estudio. Conclusión. Los niños con fibrosis quística presentan una función pulmonar que, progresivamente, desmejora durante los primeros 3 años de vida. Estos hallazgos se asocian a las infecciones respiratorias por Staphylococcus aureus.

Growth of lung parenchyma in infants and toddlers with chronic lung disease of infancy.

RATIONALE: The clinical pathology describing infants with chronic lung disease of infancy (CLDI) has been limited and obtained primarily from infants with severe lung disease, who either died or required lung biopsy. As lung tissue from clinically stable outpatients is not available, physiological measurements offer the potential to increase our understanding of the pulmonary pathophysiology of this disease. OBJECTIVES: We hypothesized that if premature birth and the development of CLDI result in disruption of alveolar development, then infants and toddlers with CLDI would have a lower pulmonary diffusing capacity relative to their alveolar volume compared with full-term control subjects. METHODS: We measured pulmonary diffusing capacity and alveolar volume, using a single breath-hold maneuver at elevated lung volume. Subjects with chronic lung disease of infancy (23-29 wk of gestation; n = 39) were compared with full-term control subjects (n = 61) at corrected ages of 11.6 (4.8-17.0) and 13.6 (3.2-33) months, respectively. MEASUREMENTS AND MAIN RESULTS: Alveolar volume and pulmonary diffusing capacity increased with increasing body length for both groups. After adjusting for body length, subjects with CLDI had significantly lower pulmonary diffusing capacity (2.88 vs. 3.23 ml/min/mm Hg; P = 0.0004), but no difference in volume (545 vs. 555 ml; P = 0.58). CONCLUSIONS: Infants and toddlers with CLDI have decreased pulmonary diffusing capacity, but normal alveolar volume. These physiological findings are consistent with the morphometric data obtained from subjects with severe lung disease, which suggests an impairment of alveolar development after very premature birth.

Growth of the lung parenchyma early in life.

RATIONALE: Early in life, lung growth can occur by alveolarization, an increase in the number of alveoli, as well as expansion. We hypothesized that if lung growth early in life occurred primarily by alveolarization, then the ratio of pulmonary diffusion capacity of carbon monoxide (Dl(CO)) to alveolar volume (V(A)) would remain constant; however, if lung growth occurred primarily by alveolar expansion, then Dl(CO)/V(A) would decline with increasing age, as observed in older children and adolescents. OBJECTIVES: To evaluate the relationship between alveolar volume and pulmonary diffusion capacity early in life. METHODS: In 50 sleeping infants and toddlers, with equal number of males and females between the ages of 3 and 23 months, we measured Dl(CO) and V(A) using single breath-hold maneuvers at elevated lung volumes. MEASUREMENTS AND MAIN RESULTS: Dl(CO) and V(A) increased with increasing age and body length. Males had higher Dl(CO) and V(A) when adjusted for age, but not when adjusted for length. Dl(CO) increased with V(A); there was no gender difference when Dl(CO) was adjusted for V(A). The ratio of Dl(CO)/V(A) remained constant with age and body length. CONCLUSIONS: Our results suggest that surface area for diffusion increases proportionally with alveolar volume in the first 2 years of life. Larger Dl(CO) and V(A) for males than females when adjusted for age, but not when adjusted for length, is primarily related to greater body length in boys. The constant ratio for Dl(CO)/V(A) in infants and toddlers is consistent with lung growth in this age occurring primarily by the addition of alveoli rather than the expansion of alveoli.