Primary Ciliary Dyskinesia and Retinitis Pigmentosa: Novel RPGR Variant and Possible Modifier Gene.

We report a novel RPGR missense variant co-segregated with a familial X-linked retinitis pigmentosa (XLRP) case. The brothers were hemizygous for this variant, but only the proband presented with primary ciliary dyskinesia (PCD). Thus, we aimed to elucidate the role of the RPGR variant and other modifier genes in the phenotypic variability observed in the family and its impact on motile cilia. The pathogenicity of the variant on the RPGR protein was evaluated by in vitro studies transiently transfecting the mutated RPGR gene, and immunofluorescence analysis on nasal brushing samples. Whole-exome sequencing was conducted to identify potential modifier variants. In vitro studies showed that the mutated RPGR protein could not localise to the cilium and impaired cilium formation. Accordingly, RPGR was abnormally distributed in the siblings' nasal brushing samples. In addition, a missense variant in CEP290 was identified. The concurrent RPGR variant influenced ciliary mislocalisation of the protein. We provide a comprehensive characterisation of motile cilia in this XLRP family, with only the proband presenting PCD symptoms. The variant's pathogenicity was confirmed, although it alone does not explain the respiratory symptoms. Finally, the CEP290 gene may be a potential modifier for respiratory symptoms in patients with RPGR mutations.

Implementación de programas de transición de la adolescencia a la edad adulta / Implementation of programmes for the transition of adolescents to adult care

Hasta un 15-20% de adolescentes tienen algún problema de salud crónico. La adolescencia representa un periodo de riesgo especial para la evolución de las enfermedades crónicas, tanto en aquellos con padecimientos con mayor prevalencia como en los afectados por enfermedades raras. La transición de la asistencia pediátrica a la adulta empieza con la preparación y capacitación del paciente pediátrico, acostumbrado a los cuidados tutelados, para que asuma la responsabilidad de su autocuidado en una unidad de adultos. La transferencia es el momento en el que la persona joven pasa a los servicios de adultos y es dada de alta de los servicios pediátricos. La transición sólo se completa cuando los jóvenes están integrados y funcionan con total competencia dentro del servicio de adultos. Los profesionales de adultos tienen un rol crucial al momento de recibir e integrar a los adultos jóvenes. Un programa de transición puede incluir transiciones de diferente complejidad, desde enfermedades frecuentes y conocidas como el asma, que requieren un proceso más sencillo, hasta enfermedades raras complejas con necesidad de participación de personal muy especializado. La transición requiere un trabajo en equipo con participación de numerosos profesionales: pediatras y médicos de adultos, enfermeras, psicólogos clínicos, trabajadores sociales sanitarios, equipo de Farmacia, y personal administrativo. Es importante implicar a los adolescentes en la toma de decisiones y que los padres los dejen ir progresivamente. Un programa de transición bien estructurado puede mejorar los resultados en salud, la experiencia del paciente y la utilización y coste de los cuidados sanitarios.(AU)

Up to 15%–20% of adolescents have a chronic health problem. Adolescence is a period of particular risk for the development or progression of chronic diseases for both individuals with more prevalent conditions and those affected by rare diseases. The transition from paediatric to adult care begins with preparing and training the paediatric patient, accustomed to supervised care, to assume responsibility for their self-care in an adult care setting. The transition takes place when the young person is transferred to adult care and discharged from paediatric care services. It is only complete when the youth is integrated and functioning competently within the adult care system. Adult care providers play a crucial role in welcoming and integrating young adults. A care transition programme can involve transitions of varying complexity, ranging from those required for common and known diseases such as asthma, whose management is more straightforward, to rare complex disorders requiring highly specialized personnel.(AU)

Arrangement of residence before hospital discharge for children on home-invasive mechanical ventilation.

Children on long-term home mechanical ventilation are a growing population due to clinical and technological advances and the benefit for the child's quality of life. Invasive home ventilation is one of the most complex therapies offered in the home setting, requiring adequate home environment and appropriate equipment and supplies before discharge. The transition from hospital to home represents a vulnerable period that can be facilitated with an established transition plan with multidisciplinary team involvement. Readiness for home care is achieved when the patient is stable and has been transitioned from a critical care ventilator to a home mechanical ventilator. In parallel, comprehensive competency-based training regarding the knowledge and skills needed to help families use the equipment confidently and safely. Before discharge, families should be counseled on an adequate home environment to ensure a safe transition. The residence arrangement may include physical space modifications, verifying electrical installation, or moving to another home. Durable medical equipment and supplies must be ordered, and community healthcare support arranged. Parents should receive practical advice on setting up the equipment at home and on preventive measures to minimize complications related to tracheostomy and ventilator dependence, including regular maintenance and replacement of necessary equipment. Given the overall impact of invasive ventilation on home life, a structured home care action package is essential to alleviate the burdens involved.

Implementation of programmes for the transition of adolescents to adult care.

Up to 15-20% of adolescents have a chronic health problem. Adolescence is a period of particular risk for the development or progression of chronic diseases for both individuals with more prevalent conditions and those affected by rare diseases. The transition from paediatric to adult care begins with preparing and training the paediatric patient, accustomed to supervised care, to assume responsibility for their self-care in an adult care setting. The transition takes place when the young person is transferred to adult care and discharged from paediatric care services. It is only complete when the youth is integrated and functioning competently within the adult care system. Adult care providers play a crucial role in welcoming and integrating young adults. A care transition programme can involve transitions of varying complexity, ranging from those required for common and known diseases such as asthma, whose management is more straightforward, to rare complex disorders requiring highly specialized personnel. The transition requires teamwork with the participation of numerous professionals: paediatricians and adult care physicians, nurses, clinical psychologists, health social workers, the pharmacy team and administrative staff. It is essential to involve adolescents in decision-making and for parents to let them take over gradually. A well-structured transition programme can improve health outcomes, patient experience, the use of health care resources and health care costs.

ABCA3-related interstitial lung disease beyond infancy.

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.

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

BACKGROUND: 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.

Development of Lung Function in Preterm Infants During the First Two Years of Life.

INTRODUCTION: It remains unclear if prematurity itself can influence post delivery lung development and particularly, the bronchial size. AIM: To assess lung function during the first two years of life in healthy preterm infants and compare the measurements to those obtained in healthy term infants during the same time period. METHODS: This observational longitudinal study assessed lung function in 74 preterm (30+0 to 35+6 weeks' gestational age) and 76 healthy term control infants who were recruited between 2011 and 2013. Measurements of tidal breathing, passive respiratory mechanics, tidal and raised volume forced expirations (V'maxFRC and FEF25-75, respectively) were undertaken following administration of oral chloral hydrate sedation according to ATS/ERS recommendations at 6- and 18-months corrected age. RESULTS: Lung function measurements were obtained from the preterm infants and full term controls initially at 6 months of age. Preterm infants had lower absolute and adjusted values (for gestational age, postnatal age, sex, body size, and confounding factors) for respiratory compliance and V'maxFRC. At 18 months corrected postnatal age, similar measurements were repeated in 57 preterm infants and 61 term controls. A catch-up in tidal volume, respiratory mechanics parameters, FEV0.5 and forced expiratory flows was seen in preterm infants. CONCLUSION: When compared with term controls, the lower forced expiratory flows observed in the healthy preterm group at 6 months was no longer evident at 18 months corrected age, suggesting a catch-up growth of airway function.

Incidence and Prevalence of Children's Diffuse Lung Disease in Spain.

BACKGROUND: Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain. METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019. RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47). CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

Epigenetic regulation of inflammation by microRNAs in post-infectious bronchiolitis obliterans.

OBJECTIVES: Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic disease initiated by severe infection and followed by perpetuating inflammation and obliteration of the small airways. MicroRNAs (miRNAs) have been proposed to play a central role as epigenetic regulators, which control resolution and prevent the uncontrolled progress of inflammation. The aim of this study was to define biomarkers on the level of post-transcriptional gene regulation in order to characterise PiBO. METHODS: A total of 39 patients with well-defined PiBO and 31 controls from two centres, Barcelona, Spain, and Frankfurt, Germany, were analysed by next-generation sequencing (NGS). The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein-protein interaction network analysis respectively. RESULTS: Patients with PiBO had significantly lower lung function values and increased airway inflammation in induced sputum as indicated by total cell counts, neutrophils, IL-1ß, IL-6, IL-8 and TGF-ß compared to controls.Next-generation sequencing analysis revealed a total of 22 dysregulated miRNAs, which passed significance threshold for Padj ≤ 0.001 with 17 being upregulated and 5 being downregulated. Of these dysregulated miRNAs, miR-335-5p, miR-186-5p, miR-30b-5p and miR-30c-5p were further validated using qRT-PCR. Interestingly, these miRNAs are functionally implicated in cytokine-cytokine receptor interaction, TGF-ß signalling and FoxO signalling pathway and significantly correlated with lung function values (FEV1). CONCLUSION: Our results demonstrate an aberrant miRNA expression profile in PiBO, which impacts pathways responsible for the regulation of inflammation and fibrosis. The defined miRNAs are useful biomarkers and should be assessed as potential target in the field of miRNA therapeutics.

Development of Lung Function in Preterm Infants During the First Two Years of Life / Desarrollo de la función pulmonar en lactantes pretérmino durante los 2 primeros años de vida

Introduction: It remains unclear if prematurity itself can influence post delivery lung development and particularly, the bronchial size.AimTo assess lung function during the first two years of life in healthy preterm infants and compare the measurements to those obtained in healthy term infants during the same time period.MethodsThis observational longitudinal study assessed lung function in 74 preterm (30+0 to 35+6 weeks’ gestational age) and 76 healthy term control infants who were recruited between 2011 and 2013. Measurements of tidal breathing, passive respiratory mechanics, tidal and raised volume forced expirations (V’maxFRC and FEF25–75, respectively) were undertaken following administration of oral chloral hydrate sedation according to ATS/ERS recommendations at 6- and 18-months corrected age.ResultsLung function measurements were obtained from the preterm infants and full term controls initially at 6 months of age. Preterm infants had lower absolute and adjusted values (for gestational age, postnatal age, sex, body size, and confounding factors) for respiratory compliance and V’maxFRC. At 18 months corrected postnatal age, similar measurements were repeated in 57 preterm infants and 61 term controls. A catch-up in tidal volume, respiratory mechanics parameters, FEV0.5 and forced expiratory flows was seen in preterm infants.ConclusionWhen compared with term controls, the lower forced expiratory flows observed in the healthy preterm group at 6 months was no longer evident at 18 months corrected age, suggesting a catch-up growth of airway function. (AU)

Introducción: Todavía no está claro si la prematuridad por sí sola puede tener influencia en el desarrollo pulmonar tras el parto y, en particular, en el tamaño bronquial.ObjetivoValorar la función pulmonar durante los 2 primeros años de vida en lactantes pretérmino sanos y comparar las medidas con las obtenidas en lactantes nacidos a término sanos durante el mismo periodo de tiempo.MétodosEste ensayo longitudinal observacional valoró la función pulmonar en 74 lactantes pretérmino (30+0 a 35+6 semanas de edad gestacional) y 76 lactantes nacidos a término sanos como controles, que se seleccionaron entre 2011 y 2013. Se llevaron a cabo las mediciones de la respiración corriente, la mecánica respiratoria pasiva, los flujos espiratorios forzados a volumen corriente y con insuflación previa (V’maxFRC y FEF25-75, respectivamente) tras la sedación con hidrato de cloral siguiendo las recomendaciones de las ATS/ERS a la edad corregida de 6 y 18 meses.ResultadosInicialmente se obtuvieron las medidas de función pulmonar de los lactantes pretérmino y los controles a término a los 6 meses de edad. Los lactantes pretérmino presentaron unos valores absolutos y ajustados (a la edad gestacional, la edad posnatal, el sexo, el tamaño corporal y los factores de confusión) menores para la distensibilidad pulmonar y la V’maxFRC. A los 18 meses de edad posnatal corregida, se repitieron las mismas mediciones en 57 lactantes pretérmino y 61 controles a término. Se observó una recuperación del volumen corriente, los parámetros de mecánica respiratoria, el FEV0,5 y los flujos espiratorios forzados en los lactantes pretérmino.ConclusiónEn comparación con los controles a término, los flujos espiratorios forzados más bajos observados en el grupo de pretérminos sanos a los 6 meses no se observaron a los 18 meses de edad corregida, lo que evidencia un crecimiento de recuperación de la función de la vía respiratoria. (AU)

Genetic diagnosis of basal ganglia disease in childhood.

AIM: To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition. METHOD: Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis. RESULTS: We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutières syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutières syndrome. INTERPRETATION: Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.

Incidence and Prevalence of Children's Diffuse Lung Disease in Spain / Incidencia y prevalencia de las neumopatías intersticiales pediátricas en España

Background Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain. Methods Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019. Results A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28–10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81–51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2–18 years of age compared with children 0–2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47). Conclusions We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

Antecedentes Las neumopatías intersticiales pediátricas, también conocidas con el acrónimo chILD (del inglés children's Interstitial Lung Diseases), es un grupo heterogéneo de enfermedades raras con morbimortalidad relevante, cuyo diagnóstico y clasificación son complejos. Los estudios epidemiológicos son escasos. El objetivo de este trabajo fue analizar la incidencia y la prevalencia de chILD en España. Métodos Estudio prospectivo observacional multicéntrico en pacientes de 0 a 18 años afectos de chILD para analizar la incidencia y la prevalencia en España, a partir de datos recogidos en 2018 y 2019. Resultados Se recogieron 381 casos de chILD entre 51 unidades de neumología pediátrica de toda España, que cubrían el 91,7% de la población pediátrica. La incidencia promedio fue 8,18 (IC 95%: 6,28-10,48) casos nuevos/millón de niños por año. La prevalencia promedio fue de 46,53 (IC 95%: 41,81-51,62) casos/millón de niños. El grupo de edad con mayor prevalencia fue el de niños menores de un año. Se observaron diferentes entidades en niños de 2 a 18 años en comparación con niños de 0 a 2 años. Los diagnósticos más frecuentes fueron: glucogenosis intersticial pulmonar primaria en neonatos (17/65), hiperplasia de células neuroendocrinas en lactantes de uno a 12 meses (44/144), hemosiderosis pulmonar idiopática en niños de uno a 5 años (13/74), neumonía por hipersensibilidad en niños de 5 a 10 años (9/51) y esclerodermia en mayores de 10 años (8/47). Conclusiones Encontramos una mayor incidencia y prevalencia de chILD que las descritas previamente, probablemente debido a un mayor conocimiento y detección de estas enfermedades raras.

International BEAT-PCD consensus statement for infection prevention and control for primary ciliary dyskinesia in collaboration with ERN-LUNG PCD Core Network and patient representatives.

INTRODUCTION: In primary ciliary dyskinesia (PCD) impaired mucociliary clearance leads to recurrent airway infections and progressive lung destruction, and concern over chronic airway infection and patient-to-patient transmission is considerable. So far, there has been no defined consensus on how to control infection across centres caring for patients with PCD. Within the BEAT-PCD network, COST Action and ERS CRC together with the ERN-Lung PCD core a first initiative has now been taken towards creating such a consensus statement. METHODS: A multidisciplinary international PCD expert panel was set up to create a consensus statement for infection prevention and control (IP&C) for PCD, covering diagnostic microbiology, infection prevention for specific pathogens considered indicated for treatment and segregation aspects. Using a modified Delphi process, consensus to a statement demanded at least 80% agreement within the PCD expert panel group. Patient organisation representatives were involved throughout the process. RESULTS: We present a consensus statement on 20 IP&C statements for PCD including suggested actions for microbiological identification, indications for treatment of Pseudomonas aeruginosa, Burkholderia cepacia and nontuberculous mycobacteria and suggested segregation aspects aimed to minimise patient-to-patient transmission of infections whether in-hospital, in PCD clinics or wards, or out of hospital at meetings between people with PCD. The statement also includes segregation aspects adapted to the current coronavirus disease 2019 (COVID-19) pandemic. CONCLUSION: The first ever international consensus statement on IP&C intended specifically for PCD is presented and is targeted at clinicians managing paediatric and adult patients with PCD, microbiologists, patient organisations and not least the patients and their families.

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.

Implementation of a Gene Panel for Genetic Diagnosis of Primary Ciliary Dyskinesia. / Implementación de un panel de genes para el diagnóstico genético de la discinesia ciliar primaria.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is characterized by an alteration in the ciliary structure causing difficulty in the clearance of respiratory secretions. Diagnosis is complex and based on a combination of techniques. The objective of this study was to design a gene panel including all known causative genes, and to corroborate their diagnostic utility in a cohort of Spanish patients. METHODS: This was a multicenter cross-sectional study of patients with a high suspicion of PCD, according to European Respiratory Society criteria, designed around a gene panel for massive sequencing using SeqCap EZ capture technology that included 44 genes associated with PCD. RESULTS: We included 79 patients, 53 of whom had a diagnosis of confirmed or highly probable PCD. The sensitivity of the gene panel was 81.1%, with a specificity of 100%. Candidate variants were found in some of the genes of the panel in 43 patients with PCD, 51.2% (22/43) of whom were homozygotes and 48.8% (21/43) compound heterozygotes. The most common causative genes were DNAH5 and CCDC39. We found 52 different variants, 36 of which were not previously described in the literature. CONCLUSIONS: The design and implementation of a tailored gene panel produces a high yield in the genetic diagnosis of PCD. This panel provides a better understanding of the causative factors involved in these patients and lays down the groundwork for future therapeutic approaches.

Respuesta a «Pautas cortas de antibioterapia en neumonías adquiridas en la comunidad en niños» / Reply to "Short-term antibiotic regimens in community-acquired pneumonia in children"

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Immunofluorescence Analysis as a Diagnostic Tool in a Spanish Cohort of Patients with Suspected Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is an autosomal recessive rare disease caused by an alteration of ciliary structure. Immunofluorescence, consisting in the detection of the presence and distribution of cilia proteins in human respiratory cells by fluorescence, has been recently proposed as a technique to improve understanding of disease-causing genes and diagnosis rate in PCD. The objective of this study is to determine the accuracy of a panel of four fluorescently labeled antibodies (DNAH5, DNALI1, GAS8 and RSPH4A or RSPH9) as a PCD diagnostic tool in the absence of transmission electron microscopy analysis. The panel was tested in nasal brushing samples of 74 patients with clinical suspicion of PCD. Sixty-eight (91.9%) patients were evaluable for all tested antibodies. Thirty-three cases (44.6%) presented an absence or mislocation of protein in the ciliary axoneme (15 absent and 3 proximal distribution of DNAH5 in the ciliary axoneme, 3 absent DNAH5 and DNALI1, 7 absent DNALI1 and cytoplasmatic localization of GAS8, 1 absent GAS8, 3 absent RSPH9 and 1 absent RSPH4A). Fifteen patients had confirmed or highly likely PCD but normal immunofluorescence results (68.8% sensitivity and 100% specificity). In conclusion, immunofluorescence analysis is a quick, available, low-cost and reliable diagnostic test for PCD, although it cannot be used as a standalone test.

Documento de consenso sobre la neumonía adquirida en la comunidad en los niños. SENP-SEPAR-SEIP / Consensus Document on Community-Acquired Pneumonia in Children. SENP-SEPAR-SEIP

La neumonía adquirida en la comunidad (NAC) es una enfermedad prevalente en la edad pediátrica y que ofrece frecuentemente dudas tanto diagnósticas como terapéuticas. Se ha realizado un consenso entre SEPAR, SENP y SEIP, con las siguientes conclusiones: 1. La etiología depende fundamentalmente de la edad y de otros factores, como estado inmunitario, presencia de enfermedad de base o estado vacunal y no existe un marcador analítico único con una absoluta fiabilidad diagnóstica. 2. Ante la sospecha clínica de neumonía, no es imprescindible la realización de una radiografía de tórax en los niños sanos. La ecografía torácica se va imponiendo como método de seguimiento, e incluso de diagnóstico. 3. El tratamiento antibiótico empírico de elección en las formas típicas es la amoxicilina oral a una dosis de 80mg/kg/ día generalmente durante 7 días, mientras que en las atípicas en mayores de 5 años son los macrólidos. En las formas típicas graves se recomienda la combinación de cefalosporina de 3.a generación y cloxacilina (o clindamicina o vancomicina) por vía intravenosa. 4. En caso de requerir drenaje pleural, se recomienda la inserción ecoguiada de un catéter de pequeño tamaño. La administración intrapleural de fibrinolíticos (urocinasa) reduce la estancia hospitalaria en comparación con el drenaje pleural simple. 5. En el derrame pleural paraneumónico el tratamiento con antibioticoterapia junto con drenaje pleural y fibrinolíticos se asocia con una estancia hospitalaria y una tasa de complicaciones similar al tratamiento antibiótico más videotoracoscopia asistida. 6. Se recomienda la vacunación antineumocócica conjugada sistemática en menores de 5 años, ya que reduce la incidencia de NAC y de hospitalización por esta causa

Community-acquired pneumonia (CAP) is a prevalent disease among children and is frequently associated with both diagnostic and therapeutic uncertainties. Consensus has been reached between SEPAR, SENP and SEIP, and their conclusions are as follows: 1. Etiology depends mainly on age and other factors and no single analytical marker offers absolute diagnostic reliability. 2. In the event of clinical suspicion of pneumonia in a healthy child, chest X-ray is not necessary. Chest ultrasound is increasingly implemented as a follow-up method, and even as a diagnostic method. 3. The empirical antibiotic treatment of choice In typical forms of the disease is oral amoxicillin at a dose of 80mg/kg/day for 7 days, while in atypical presentations in children older than 5 years, macrolides should be selected. In severe typical forms, the combination of 3rd generation cephalosporins and cloxacillin (or clindamycin or vancomycin) administered intravenously is recommended. 4. If pleural drainage is required, ultrasound-guided insertion of a small catheter is recommended. Intrapleural administration of fibrinolytics (urokinase) reduces hospital stay compared to simple pleural drainage. 5. In parapneumonic pleural effusion, antibiotic treatment combined with pleural drainage and fibrinolytics is associated with a similar hospital stay and complication rate as antibiotic treatment plus video-assisted thoracoscopy. 6. Systematic pneumococcal conjugate vaccination is recommended in children under 5 years of age, as it reduces the incidence of CAP and hospitalization for this disease