Diagnostic workup of childhood interstitial lung disease

Interstitial and orphan lung diseaseEnfermedad pulmonar intersticial y huérfanaMalaltia pulmonar intersticial i orfeChildhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of “undefined chILD” is stressed

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry

Genetics; Heritable pulmonary arterial hypertension; Pediatric pulmonary hypertensionGenética; Hipertensión arterial pulmonar hereditaria; Hipertensión pulmonar pediátricaGenètica; Hipertensió arterial pulmonar hereditària; Hipertensió pulmonar pediàtricaBackground: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.This project was funded by project “Bases Genético-Moleculares de la Medicina de Precisión en la Hipertensión Arterial Pulmonar”. Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Gobierno de España. Co-funded by “Fondo Europeo de Desarrollo Regional, Programa Operativo Crecimiento Inteligente 2014–2020” (Award number: PI 18/01233). A.C.-U. holds a research-training contract “Rio Hortega” (CM20/00164) from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). REHIPED is supported by unrestricted grants of Janssen and Ferrer

Caracterización epidemiológica, clínica y genética de las enfermedades difusas del parénquima pulmonar en la edad pediátrica

Introducció: Les malalties difuses del parènquima pulmonar pediàtriques, també conegudes com chILD (de l'anglès Children Interstitial Lung Diseases), són un grup heterogeni de malalties rares amb una morbiditat i mortalitat rellevants, i de diagnòstic i classificació complexos. Dins d'aquest grup es troba la Glucogenosi intersticial pulmonar, que es diagnostica en els primers mesos de vida. Aquesta, es caracteritza per l'augment de cèl·lules mesenquimals intersticials amb augment del glucogen citoplasmàtic, i es considera que representa un trastorn del desenvolupament pulmonar. Es disposa d'escasses dades epidemiològiques i hi ha poques sèries publicades sobre el seguiment de pacients afectats de Glucogenosi intersticial pulmonar. Per aquest motiu, l'objectiu d'aquesta tesi és analitzar la incidència i prevalença de les chILD en una àmplia mostra de població espanyola, i descriure les característiques clíniques, radiològiques i genètiques de la Glucogenosi intersticial pulmonar al diagnòstic i a llarg termini. Mètodes: Estudi prospectiu observacional multicèntric en pacients de 0 a 18 anys afectes de chILD a partir de les dades comunicades al 2018 i 2019. La investigació realitzada en una cohort de pacients afectats de Glucogenosi intersticial pulmonar (GIP) és un estudi multicèntric que descriu les característiques clíniques, radiològiques i funcionals i el resultat a llarg termini de nou lactants amb GIP associada a simplificació alveolar en absència d'altres malalties. Resultats: En relació amb l'estudi epidemiològic es van notificar 381 casos afectes de chILD procedents de 51 unitats de pneumologia pediàtrica de tot Espanya, cobrint el 91,7% de la població pediàtrica. La incidència mitjana va ser de 8,18 (IC 95% 6,28-10,48) casos nous / milió de nens a l'any. La prevalença mitjana va ser de 46,53 (IC 95% 41,81-51,62) casos / milió de nens. El grup d'edat amb major prevalença va ser el dels nens menors d'1 any. Es van observar diferents tipus de trastorns en els nens de 2 a 18 anys en relació amb els nens de 0 a 2 anys. Els casos més freqüents van ser: glucogenosi intersticial pulmonar primària en nounats (17/65), hiperplàsia de cèl·lules neuroendocrines de la infància en nens d'1 a 12 mesos (44/144), hemosiderosis pulmonar idiopàtica en nens d'1 a 5 anys (13 / 74), pneumonitis per hipersensibilitat a nens de 5 a 10 anys (9/51) i esclerodèrmia en majors de 10 anys (8/47). En relació amb l'estudi de la GIP es va evidenciar que tots els pacients van presentar taquipnea inicialment, i set pacients van tenir dificultat respiratòria i hipoxèmia. Es van observar anomalies en el TAC d'alta resolució pulmonar consistents en patró d'opacitat en vidre esmerilat, engroiximent septal i atrapament d'aire en tots els individus, amb imatges que suggerien un creixement alveolar anormal. Totes les biòpsies pulmonars van mostrar una simplificació alveolar associada a un major nombre de cèl·lules intersticials amb augment de glucogen citoplasmàtic. El període de seguiment mitjà va ser de 12 anys. Durant aquest temps tots els pacients van quedar asimptomàtics. El TAC d'alta resolució realitzat després d'una mitjana de 6,5 anys des de la investigació inicial, va revelar una millora parcial de el patró d'opacitat en vidre desllustrat, però, van persistir alteracions rellevants. Conclusions: Vam trobar una major incidència i prevalença de les malalties difuses del parènquima pulmonar pediàtriques que la descrita prèviament, probablement a causa d'un major coneixement i millors estratègies diagnòstiques d'aquestes malalties rares. Els pacients de la cohort de GIP van tenir una bona evolució clínica, tot i que es van seguir observant alteracions radiogràfiques significatives i seqüeles en la funció pulmonar, el que suggereix que la glucogenosi intersticial pulmonar és un marcador d'una anomalia persistent de el desenvolupament pulmonar que té efectes més enllà de el període simptomàtic.Introducción: Las enfermedades difusas del parénquima pulmonar pediátricas, también conocidas como chILD (del inglés Children Interstitial Lung Diseases), son un grupo heterogéneo de enfermedades raras con una morbilidad y mortalidad relevantes, cuyo diagnóstico y clasificación son complejos. Dentro de este grupo se encuentra la glucogenosis intersticial pulmonar, que se diagnostica en los primeros meses de vida. Se caracteriza por el aumento de células mesenquimales intersticiales con aumento del glucógeno citoplasmático, y se considera que representa un trastorno del desarrollo pulmonar. Se dispone de escasos datos epidemiológicos y hay pocas series publicadas sobre el seguimiento de pacientes afectos de glucogenosis intersticial pulmonar. Por este motivo, el objetivo de esta tesis es analizar la incidencia y prevalencia de las chILD en una amplia muestra de población española, y describir las características clínicas, radiológicas y genéticas de la glucogenosis intersticial pulmonar al diagnóstico y a largo plazo. Métodos: Estudio prospectivo observacional multicéntrico en pacientes de 0 a 18 años afectos de chILD a partir de los datos comunicados en 2018 y 2019. La investigación realizada en una cohorte de pacientes afectos de glucogenosis intersticial pulmonar es un estudio multicéntrico que describe las características clínicas, radiológicas y funcionales y el resultado a largo plazo de nueve lactantes con GIP asociada a simplificación alveolar en ausencia de otras enfermedades. Resultados: En relación con el estudio epidemiológico se notificaron 381 casos afectos de chILD procedentes de 51 unidades de neumología pediátrica de toda España, cubriendo el 91,7% de la población pediátrica. La incidencia media fue de 8,18 (IC 95% 6,28-10,48) casos nuevos/millón de niños al año. La prevalencia media fue de 46,53 (IC 95% 41,81-51,62) casos/millón de niños. El grupo de edad con mayor prevalencia fue el de los niños menores de 1 año. Se observaron diferentes tipos de trastornos en los niños de 2 a 18 años en relación con los niños de 0 a 2 años. Los casos más frecuentes fueron: glucogenosis intersticial pulmonar primaria en neonatos (17/65), hiperplasia de células neuroendocrinas de la infancia en niños de 1 a 12 meses (44/144), hemosiderosis pulmonar idiopática en niños de 1 a 5 años (13/74), neumonitis por hipersensibilidad en niños de 5 a 10 años (9/51) y esclerodermia en mayores de 10 años (8/47). En relación con el estudio de la GIP se evidenció que todos los pacientes presentaron taquipnea inicialmente, y siete pacientes tuvieron dificultad respiratoria e hipoxemia. Se observaron anomalías en el TAC de alta resolución pulmonar consistentes en patrón de opacidad en vidrio esmerilado, engrosamiento septal y atrapamiento de aire en todos los individuos, con imágenes que sugerían un crecimiento alveolar anormal. Todas las biopsias pulmonares mostraron una simplificación alveolar asociada a un mayor número de células intersticiales con aumento de glucógeno citoplasmático. El periodo de seguimiento medio fue de 12 años. Durante este tiempo todos los pacientes quedaron asintomáticos. El TAC de alta resolución realizado después de una media de 6,5 años desde la investigación inicial, reveló una mejora parcial del patrón de opacidad en vidrio deslustrado, sin embargo, persistieron alteraciones relevantes. Conclusiones: Encontramos una mayor incidencia y prevalencia de las enfermedades difusas del parénquima pulmonar pediátricas que la descrita previamente, probablemente debido a un mayor conocimiento y mejores estrategias diagnósticas de estas enfermedades raras. Los pacientes de la cohorte de GIP tuvieron una buena evolución clínica, aunque se siguieron observando alteraciones radiográficas significativas y secuelas en la función pulmonar, lo que sugiere que la GIP es un marcador de una anomalía persistente del desarrollo pulmonar que tiene efectos más allá del periodo sintomático.Introduction: Paediatric diffuse parenchymal lung diseases, also known as chILD (Children Interstitial Lung Diseases), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are complex. Within this group there is pulmonary interstitial glycogenosis, which is diagnosed in the first months of life. It is characterized by increased interstitial mesenchymal cells with increased cytoplasmic glycogen, and is considered to represent a disorder of lung development. Scarce epidemiological data are available and there are few published series on the follow-up of patients with pulmonary interstitial glycogenosis. For this reason, the aim of this thesis was to analyse the incidence and prevalence of chILD in a large Spanish population sample, and to describe the clinical, radiological and genetic characteristics of pulmonary interstitial glycogenosis at the diagnosis and in the long term. Methods: multicentre prospective observational study in patients aged 0-18 years affected by chILD from data reported in 2018 and 2019. The investigation conducted in a cohort of patients affected by pulmonary interstitial glycogenosis (PIG) is a multicentre study describing the clinical, radiological and functional characteristics and long-term outcome of nine infants with GIP associated with alveolar simplification in the absence of other diseases. Results: In relation to the epidemiological study, 381 cases with chILD were reported from 51 paediatric pulmonology units throughout Spain, covering 91.7% of the paediatric population. The mean incidence was 8.18 (95% CI 6.28-10.48) new cases/million children per year. The mean prevalence was 46.53 (95% CI 41.81-51.62) cases/million children. The age group with the highest prevalence was children under 1 year of age. Different types of disorders were observed in children aged 2 to 18 years in relation to children aged 0 to 2 years. The most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in children aged 1 to 12 months (44/144), idiopathic pulmonary hemosiderosis in children aged 1 to 5 years (13/74), hypersensitivity pneumonitis in children aged 5 to 10 years (9/51) and scleroderma in children older than 10 years (8/47). In relation to the PIG study it was evidenced that all patients presented tachypnea initially, and seven patients had respiratory distress and hypoxemia. Abnormalities on high-resolution CT scan of the lung consisting of ground-glass opacity pattern, septal thickening and air trapping were observed in all individuals, with images suggestive of abnormal alveolar growth. All lung biopsies showed alveolar simplification associated with an increased number of interstitial cells with increased cytoplasmic glycogen. The mean follow-up period was 12 years. During this time all patients remained asymptomatic. High-resolution CT performed after a mean of 6.5 years from the initial investigation revealed a partial improvement of the ground-glass opacity pattern, however, relevant alterations persisted. Conclusions: We found a higher incidence and prevalence of paediatric diffuse lung parenchymal lung diseases than previously described, probably due to increased awareness and improved diagnostic strategies for these rare diseases. Patients in the GIP cohort had a good clinical course, although significant radiographic alterations and sequelae in pulmonary function were still observed, suggesting that GIP is a marker of a persistent anomaly of lung development that has effects beyond the symptomatic perio

Diagnostic workup of childhood interstitial lung disease

Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of “undefined chILD” is stressed

Diagnostic workup of childhood interstitial lung disease

Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of "undefined chILD" is stressed. Childhood interstitial lung diseases are rare and severe diseases. A stepwise approach to an aetiological diagnosis includes specific investigations performed in expert centres. The term "undefined chILD" must be regularly reassesse

Pulmonary arterial hypertension in children after neonatal arterial switch operation

OBJECTIVES: Paediatric pulmonary arterial hypertension (PAH) after neonatal arterial switch operation (ASO) for transposition of the great arteries (TGA) is a clinically recognised entity with an estimated incidence of 0.6%-1.0%. Nevertheless, a clinical characterisation is lacking. We present an international cohort of children with PAH after neonatal ASO for TGA and describe epidemiology and clinical course. METHODS: Data were collected of children with PAH after neonatal ASO (≤6 weeks after birth) for simple TGA without residual shunt defects, identified in four national paediatric PAH networks in Europe and one US referral centre. RESULTS: Twenty-five children were identified between 1989 and 2014. In 17 children (68%), PAH was detected <1 year after ASO. In the remaining children, PAH was detected after median 64 months (IQR 19.5, 94.5). Nineteen children (96%) received PAH-targeted therapies. During follow-up after ASO (median 5.2 years), eight children died, four underwent lung transplantation and two received a Potts shunt. 1-year and 5-year Potts shunt- and transplantation-free survival after ASO was 100% and 73%. From first PAH detection, this was 100% and 58%, respectively, which did not differ between children with early (<1 year after ASO) or late PAH detection. CONCLUSIONS: The occurrence of PAH after ASO for TGA represents a specific association. PAH onset may be early or late after ASO, with similar fatal course from first PAH detection. Mechanisms leading to PAH in this association are unknown, but may include abnormal prenatal pulmonary haemodynamics and/or genetic susceptibility. Routine, lifelong follow-up for children who undergo ASO for TGA should include screening for PAH

FARS1

Aminoacyl‐tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non‐canonical) functions outside of translation. Bi‐allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi‐allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl‐tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient‐derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non‐canonical function in FARS1‐associated recessive disease

FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs!

Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non-canonical) functions outside of translation. Bi-allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi-allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl-tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient-derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non-canonical function in FARS1-associated recessive disease

FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!

Aminoacyl‐tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non‐canonical) functions outside of translation. Bi‐allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi‐allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl‐tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient‐derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non‐canonical function in FARS1‐associated recessive disease