Cystic fibrosis: when neonatal screening is unsatisfactory for early diagnosis / Fibrose cística: quando a triagem neonatal é insatisfatória para o diagnóstico precoce

Abstract Introduction: cystic fibrosis newborn screening must enable its earlier diagnosis, which may enhance outcomes. This study was a series case of delayed-diagnosis children submitted to cystic fibrosis newborn screening. Description: fourteen children were included; eight (57.1%) were due to false-negative screening, while six (42.9%) were due to processing errors. Two samples collected after 30 days of life were incorrectly classified as negative, and four infants with a positive test could not be located due to screening processing errors. Cystic fibrosis diagnosis was confirmed at a median (IQR) age of 5.3 (4.2-7.4) months. Poor nutritional status was the most prevalent clinical sign at diagnosis, being present in 78.6% of infants. The mean (SD) weight-for-length and length-for-age Z-scores were -3.46 (0.84) and -3.99 (1.16), respectively. Half of the children had Pseudo-Bartter syndrome, and 42.9% had breathing difficulties. Twelve children (85.7%) required hospitalization, with a median (IQR) length of stay of 17.0 (11.5-26.5) days. Discussion: newborn screening had some faults, from incorrect collections to inefficient active search. Early identification of these children in which screening was unsatisfactory is essential, emphasizing the importance and efforts to not miss them. In the case of a failed test, healthcare professionals must be prepared to recognize the main symptoms and signs of the disease.

Resumo Introdução: a triagem neonatal para fibrose cística deve contribuir para diagnóstico precoce e melhor prognóstico da doença. O estudo é uma série de casos com lactentes submetidos à triagem, porém com diagnóstico tardio da doença. Descrição: quatorze crianças foram incluídas; oito (57,1%) com triagem falso-negativo e seis (42,9%) com erros processuais na triagem neonatal. Duas amostras foram coletadas tardiamente, sendo incorretamente classificadas como negativas e quatro lactentes com triagem positiva não foram localizados, por erros na busca ativa. Confirmou-se o diagnóstico da fibrose cística com idade mediana (IIQ) de 5,3 (4,2-7,4) meses. O Comprometimento nutricional precoce foi o sinal clínico mais prevalente ao diagnóstico, presente em 78,6% das crianças. Os Z escores médios (SD) do peso para altura e altura para idade foram -3,46 (0,84) e -3,99 (1,16), respectivamente. Metade das crianças teve síndrome de Pseudo-Bartter e 42,9% dificuldade respiratória. Doze crianças (85,7%) precisaram hospitalização com tempo mediano de permanência de 17 dias. Discussão: a triagem neonatal para fibrose cística apresentou falhas, desde testes falso-negativos, coletas incorretas, até problemas com a busca ativa. Entretanto, o diagnóstico ágil é essencial e os profissionais de saúde devem reconhecer os sintomas e sinais precoces da doença, mesmo quando a triagem neonatal não for satisfatória.

Alternativa terapéutica para mejorar la calidad de vida en pacientes con fibrosis quística y discinesia ciliar primaria / Therapeutic alternative to improve quality of life in patients with cystic fibrosis and primary ciliary dyskinesia

Objective: To evaluate the clinical response of patients with cystic fibrosis and primary ciliary dyskinesia after endoscopic sinus surgery at the Dr. Robert Reid Cabral Children's Hospital from September 2021 to February 2022. Methods: An ambispective, cross-sectional, observational case series study was conducted, where the study population was made up of patients with cystic fibrosis and primary ciliary dyskinesia at the Dr. Robert Reid Cabral children's hospital during the study period. Inclusion criteria: Patients older than 6 years with a confirmed diagnosis of cystic fibrosis and primary ciliary dyskinesia (Genetic test with 2 homozygous mutations, positives electrolytes in sweat), severe respiratory symptoms of CRS that did not improve with conventional treatment and underwent endoscopic surgery for sinuses. Results: Of a total of 41 patients, only 10 met the inclusion criteria, the most prevalent age range was 14 to 18 years. Both CF and PCD patients decreased the frequency of CRS symptoms. After ENC, there were discrete changes in lung function, and only patients with severe to moderate disease increased % of FEV1. Most of the patients did not require admission after surgery. The most common germ found in nasopharyngeal and sputum cultures in preoperative patients was Pseudomonas aeruginosa in 86%; after ESS there was a significant increase in MRSA colonization in both CF and PCD patients. More than 50% of postoperative patients improved their quality of life, so endoscopic sinus surgery is effective in this population in the treatment of chronic rhinosinusitis.

Objetivo: Evaluar la respuesta clínica de los pacientes con fibrosis quística y discinesia ciliar primaria posterior a la cirugía endoscópica de senos paranasales en el Hospital Infantil Dr. Robert Reid Cabral en el período septiembre 2021 a febrero 2022. Métodos: Se realizó un estudio observacional tipo serie de casos, de corte transversal y ambispectivo, donde la población estudiada estuvo conformada por los pacientes con fibrosis quística y discinesia ciliar primaria del hospital infantil Dr. Robert Reid Cabral en el período de estudio. Criterios de inclusión: Pacientes mayores de 6 años con diagnóstico confirmado de fibrosis quística y discinesia ciliar primaria (Prueba genética con 2 mutaciones homocigotas, electrolitos en sudor positivos), síntomas respiratorios severos de RSC que no mejoraron con tratamiento convencional y sometidos a la cirugía endoscópica de senos paranasales. Resultados: De un total de 41 pacientes, sólo 10 cumplieron con los criterios de inclusión, el rango de edad más prevalente fue de 14 a 18 años. Tanto los pacientes con FQ como los de DCP disminuyeron la frecuencia de los síntomas de RSC. Posterior a la CEN hubo cambios discretos en la función pulmonar, y sólo los pacientes con enfermedad grave a moderada aumentaron el % de FEV1. La mayoría de los pacientes no ameritaron ingresos posterior a la cirugía. El germen más común encontrado en los cultivos nasofaríngeo y esputo en los pacientes preoperatorios fue la Pseudomonas aeruginosa en el 86%, luego de la CEN hubo un aumento significativo de la colonización por MRSA tanto en los pacientes con FQ como en los de DCP. Más del 50% de los pacientes postquirúrgicos mejoraron su calidad de vida, por lo que la cirugía endoscópica de senos paranasales es efectiva en dicha población en el tratamiento de la rinosinusitis crónica.

Íleo meconial y falsos negativos del resultado de tripsina inmunorreactiva en una niña portadora de fibrosis quística

Introducción: la fibrosis quística (FQ) es una enfermedad genética, multisistémica, caracterizada por la disfunción de las glándulas de secreción exocrina secundaria a la mutación de una proteína transmembrana que actúa como canal de cloro. La inclusión de su búsqueda en el Sistema Nacional de Pesquisa Neonatal (SNPN) determinó un gran impacto sobre la morbimortalidad de esta enfermedad, permitiendo un diagnóstico y tratamiento precoz. El íleo meconial (IM) es la manifestación más precoz de la enfermedad, ocurriendo en un 10% a 18% de los pacientes. Objetivo: describir una forma de presentación precoz de FQ con resultado de pesquisa neonatal normal. Caso clínico: 18 meses. Sexo femenino; 33 semanas de edad gestacional. Retraso en la expulsión del meconio. Al tercer día de vida íleo meconial con oclusión intestinal, vólvulo de intestino medio y necrosis intestinal. Se realiza resección quirúrgica. Tripsina inmunorreactiva (TIR) normal a los 7 y 23 días de vida. No se solicita proteína asociada a la pancreatitis (PAP). Desnutrición crónica, bronquiolitis grave a los 3 meses, neumonías virales a los 7 y 11 meses. Ingreso con diagnóstico de neumonía aguda comunitaria con insuficiencia respiratoria. Test del sudor alterado en dos oportunidades. Elastasa pancreática insuficiente. Se aísla Staphylococcus aureus y Pseudomonas aeruginosa en exudado nasal y de secreciones respiratorias. Estudio genético: mutación Delta F508. Con diagnóstico de FQ se inició abordaje multidisciplinario, tratamiento y derivación al centro especializado. Conclusiones: la existencia de IM puede dar falsos negativos en el valor de la TIR, siendo necesaria la dosificación de la PAP. El pronóstico de estos pacientes va a depender de un diagnóstico precoz y el manejo terapéutico oportuno en centros especializados.

Summary: Introduction: cystic fibrosis (CF) is a genetic, multisystemic disease, characterized by dysfunction of the exocrine secretion glands secondary to the mutation of a transmembrane protein that acts as a chloride channel. Including its research by the National Neonatal Screening System (SNPN) caused a great impact on the morbidity and mortality of this disease, enabling early diagnosis and treatment. Meconium ileus (MI) is the earliest manifestation of the disease, occurring in 10% to 18% of patients. Objective: to describe a form of early presentation of CF with normal neonatal screening results. Clinical case: 18 months. Female, 33 weeks gestational age. Delay in the expulsion of meconium. On the third day of life, meconium ileus with intestinal obstruction, midgut volvulus and intestinal necrosis. Surgical resection is performed. Trypsin immunoreactive (TIR) normal at 7 and 23 days of age. Pancreatitis-associated protein (PAP) is not requested. Chronic malnutrition, severe bronchiolitis at 3 months, viral pneumonia at 7 and 11 months. Admission with a diagnosis of acute community pneumonia with respiratory failure. Sweat test altered on two occasions. Insufficient pancreatic elastase. Staphylococcus aureus and Pseudomonas aeruginosa were isolated in nasal exudate and respiratory secretions. Genetic study: Delta F508 mutation. With the CF diagnosis, a multidisciplinary approach, treatment and referral to a specialized center began. Conclusions: the existence of MI can provide false negatives in the IRR value, making PAP dosage necessary. The prognosis of these patients will depend on early diagnosis and timely therapeutic management at specialized centers.

Introdução: a fibrose cística (FC) é uma doença genética, multissistêmica, caracterizada pela disfunção das glândulas secretoras exócrinas secundária à mutação de uma proteína transmembrana que age como canal de cloreto. A inclusão da sua pesquisa no Sistema Nacional de Triagem Neonatal (SNPN) determinou grande impacto na morbimortalidade desta doença, permitindo diagnóstico e tratamento precoces. O íleo meconial (IM) é a manifestação mais precoce da doença, ocorrendo em 10 a 18% dos pacientes. Objetivo: descrever uma forma de apresentação precoce da FC com resultados normais de triagem neonatal. Caso clínico: 18 meses. Sexo feminino. 33 semanas de idade gestacional. Atraso na expulsão do mecônio. No terceiro dia de vida, íleo meconial com obstrução intestinal, vólvulo de intestino médio e necrose intestinal. A ressecção cirúrgica é realizada. Imunorreativo à tripsina (TIR) normal aos 7 e 23 dias de vida. A proteína associada à pancreatite (PAP) não é solicitada. Desnutrição crônica, bronquiolite grave aos 3 meses, pneumonia viral aos 7 e11 meses. Internação com diagnóstico de pneumonia comunitária aguda com insuficiência respiratória. Teste do suor alterado em duas ocasiões. Elastase pancreática insuficiente. Staphylococcus aureus e Pseudomonas aeruginosa foram isolados em exsudato nasal e secreções respiratórias. Estudo genético: mutação Delta F508. Com o diagnóstico de FC iniciou-se abordagem multidisciplinar, tratamento e encaminhamento para centro especializado. Conclusões: a existência de IM pode dar falsos negativos no valor da TIR, tornando necessária a dosagem de PAP. O prognóstico destes pacientes dependerá do diagnóstico precoce e do manejo terapêutico oportuno em centros especializados.

A tessitura dos discursos na construção diagnóstica da fibrose cística: uma perspectiva sobre acesso e barreiras / The intertwining of discourses in the diagnostic construction of cystic fibrosis: a perspective on access and barriers

Resumo As complexidades referidas na busca pela "exatidão" no diagnóstico da fibrose cística (FC) apontam para reflexões em torno de "o que é preciso" na atual conjuntura da "medicina de precisão". Analisamos os discursos de 19 atores sociais pertencentes à comunidade de especialistas na fibrose cística, explorando as acepções semânticas do vocábulo "precisão" e as barreiras ao diagnóstico e às inovações na terapêutica. Adotamos a análise crítica do discurso de Norman Fairclough a fim de alcançar as construções discursivas em torno da integralidade do cuidado, da garantia e oferta equitativa dos básicos sociais. O acesso foi identificado como categoria êmica quando nas arenas sociais de disputa estão as necessidades de saúde e o direito à vida.

Abstract The complexities referred to in the search for "accuracy" in the diagnosis of cystic fibrosis (CF) point to reflections around "what is needed" in the current situation of "precision medicine". We analyzed the discourses of 19 social actors belonging to the community of specialists in cystic fibrosis, exploring the semantic meanings of the word "precision", and the barriers to diagnosis and innovations in therapeutics. We adopted the critical discourse analysis (CDA) of Norman Fairclough in order to achieve the discursive constructions around the integrality of care, the guarantee and equitable supply of basic social needs. Access was identified as an emic category when in the social arenas of dispute are health needs and the right to life.

Bronchodilator response assessment through impulse oscillometry system and spirometry in children and adolescents with cystic fibrosis / Avaliação da resposta broncodilatadora por meio do sistema de oscilometria de impulso e espirometria em crianças e adolescentes com fibrose cística

ABSTRACT Objective: To investigate the effect of bronchodilator on the respiratory mechanics and pulmonary function of children and adolescents with cystic fibrosis. Methods: Cross-sectional study on clinically stable children and adolescents with cystic fibrosis aged from six to 15 years. Participants underwent impulse oscillometry and spirometry evaluations before and 15 minutes after bronchodilator inhalation. The Kolmogorov-Smirnov test was applied to verify the sample distribution, and the Student's t-test and Wilcoxon test were used to compare the data before and after bronchodilator inhalation. Results: The study included 54 individuals with a mean age of 9.7±2.8 years. The analysis showed a statistically significant improvement in impulse oscillometry and spirometry parameters after bronchodilator inhalation. However, according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommendations (2020 and 2021), this improvement was not sufficient to classify it as a bronchodilator response. Conclusions: The use of bronchodilator medication improved respiratory mechanics and pulmonary function parameters of children and adolescents with cystic fibrosis; however, most patients did not show bronchodilator response according to ATS/ERS recommendations.

RESUMO Objetivo: Investigar o efeito do broncodilatador na mecânica respiratória e função pulmonar de crianças e adolescentes com fibrose cística. Métodos: Estudo transversal em crianças e adolescentes com fibrose cística clinicamente estáveis, com idade entre seis e 15 anos. Os participantes realizaram avaliações por meio do sistema de oscilometria de impulso e espirometria antes e 15 minutos depois da inalação de broncodilatador. Foi aplicado o teste Kolmogorov-Smirnov para verificar a distribuição da amostra. Para comparar os dados antes e depois do broncodilatador foram utilizados os testes t de Student e Wilcoxon. Resultados: Participaram do estudo 54 indivíduos com média de idade de 9,7±2,8 anos. Houve melhora estatisticamente significativa nos parâmetros do oscilometria de impulso e espirometria após a inalação com broncodilatador. No entanto, de acordo com recomendações da American Thoracic Society (ATS) e European Respiratory Society (ERS) (2020 and 2021), essa melhora não foi suficiente para classificar como reposta broncodilatadora. Conclusões: O uso de medicamento broncodilatador melhorou a mecânica respiratória e função pulmonar de crianças e adolescentes com fibrose cística, no entanto a maioria da amostra não apresentou resposta ao broncodilatador de acordo com as recomendações da ATS/ERS.

Impact of COVID-19 social distancing recommendations on pulmonary function, nutritional status, and morbidity in patients with cystic fibrosis / Impacto das recomendações de distanciamento social por COVID-19 sobre a função pulmonar, estado nutricional e morbidade em pacientes com fibrose cística

ABSTRACT Objective: To evaluate the impact of COVID-19 social distancing recommendations on nutritional status, pulmonary function, and morbidity in patients with cystic fibrosis (CF). Methods: A retrospective cohort study including patients older than six years with a diagnosis of CF was performed. Demographic and clinical data, anthropometric measurements, pulmonary function, days of antibiotic use, and length of hospital stay were recorded. Variables were recorded at three time points relative to the baseline for implementation of social distancing measures: T-1 (14 months before implementation), T0 (baseline), and T1 (14 months after implementation). Delta (Δ) was calculated for each period: Δ1 (pre-pandemic T0-T-1) and Δ2 (pandemic T1-T0). Results: The study included 25 patients, with a mean age of 11.7±4.3 years. The mean forced expiratory volume in the first second (FEV1) was 85.6±23.6%, and body mass index (BMI) was 17.5±3.0 kg/m2. When comparing the two periods (Δ1 and Δ2), there was a significant increase in the FEV1/forced vital capacity (FVC) ratio (p=0.013) and in the forced expiratory flow between 25 and 75% of vital capacity (FEF25-75%) (p=0.037) in the pandemic period. There was also a significant reduction (p=0.005) in the use of antibiotics in the pandemic period compared with the pre-pandemic period. The Δ1 and Δ2 values did not differ significantly for BMI, FEV1, or length of hospital stay. Conclusions: COVID-19 social distancing recommendations had a positive impact (decrease) on morbidity (use of antibiotics) and small airway obstruction (FEF25-75%) in patients with CF.

RESUMO Objetivo: Avaliar o impacto das recomendações de medidas de distanciamento social por COVID-19 sobre estado nutricional, função pulmonar e morbidade em pacientes com fibrose cística (FC). Métodos: Estudo de coorte, retrospectivo, que incluiu pacientes com diagnóstico de FC e idade superior a seis anos. Foram registrados os dados demográficos, antropométricos, clínicos, de função pulmonar e o total de dias de uso de antibiótico e de hospitalizações. As variáveis foram registradas em três momentos relativos ao início das recomendações de distanciamento social: T-1 (14 meses antes), T0 (início das recomendações) e T1 (14 meses depois). Foram calculados deltas (Δ) para cada um dos períodos: Δ1 (pré-pandemia T0-T-1) e Δ2 (pandemia T1-T0). Resultados: Vinte e cinco pacientes, com média de idade de 11,7±4,3 anos, sendo 76% homozigotos para Δf508 e 28% colonizados por Pseudomonas aeruginosa, foram incluídos. A média do volume expiratório forçado no primeiro segundo (VEF1) foi de 85,6±23,6 (% do previsto) e o índice de massa corporal (IMC) foi de 17,5±3,0 kg/m2. Ao compararmos os períodos (Δ1 e Δ2), houve aumento significativo do VEF1/CVF (p=0,013) e do FEF25-75% (p=0,037) no período das recomendações de distanciamento. Também se observou redução significativa (p=0,005) do uso de antibióticos no período da pandemia em comparação ao período anterior a ela. Não houve diferenças significativas nos deltas para o IMC, VEF1 e dias de hospitalização. Conclusões: As recomendações de distanciamento social por COVID-19 tiveram impacto positivo (redução) sobre a morbidade (uso de antibióticos) e a obstrução de vias aéreas de menor calibre (FEF25-75%) em pacientes com FC.

Effect of Baihe Yuzi Prescription on CFTR， AQP， and ZIP Ion Channels and Oxidative Stress in Epididymis of Oligoasthenozoospermia Rats / 中国实验方剂学杂志

ObjectiveTo observe the effects of Baihe Yuzi prescription （BYP） on the cystic fibrosis transmembrane conductance regulator （CFTR）， aquaporin （AQP）， zinc/iron-regulated transporter-like protein （ZIP） and local oxidative stress in epididymis of oligoasthenozoospermia （OAS） rats， and to explore the mechanism of its intervention in OAS. MethodAfter 35 rats were acclimatized for 1 week， 7 rats were randomly selected as the normal group， and the remaining 28 rats were given tripterygium glycosides （TG） 30 mg·kg-1. After 4 weeks of modeling， they were randomly divided into 4 groups： model group， BYP low-dose group （LBYP）， BYP high-dose group （HBYP） and levocarnitine group， with 7 rats in each group. The rats in the normal group and model group were given normal saline at the same dosage. The levocarnitine group rats were given L-carnitine oral liquid （100 mg·kg-1） by gavage. The LBYP group rats were given BYP 6.3 g·kg-1， and the HBYP group rats were given BYP 12.6 g·kg-1 by gavage once a day for consecutive 4 weeks. After the end of the intervention， sperm count and motility of all rats were detected， the histopathological structure of epididymis was observed by hematoxylin-eosin （HE） staining， and the expressions of CFTR， AQP9， AQP3， ZIP8， ZIP12 and other proteins were detected by Western blot. The contents of α-glycosidase （α-GC）， sialic acid （SA）， carnitine， superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px） and malondialdehyde （MDA） were detected by enzyme-linked immunosorbent assay （ELISA）. Total zinc content was measured using an inductively coupled plasma mass spectrometer. Free zinc ion content was detected by zinc ion probes. ResultCompared with those in the normal group， the sperm count and motility of rats were decreased and the epididymal structure was disordered in the model group. The contents of α-GC and carnitine were decreased in epididymis （P<0.05）. MDA levels were increased， while SOD， GSH-Px and zinc levels were decreased （P<0.05）. The expressions of CFTR and ZIP12 in the head and cauda of the epididymis were down-regulated， and AQP3 expression was up-regulated. The expression of ZIP8 in the cauda epididymis was up-regulated （P<0.05）. Compared with the model group， BYP can significantly improve the sperm count and motility， the epididymal structure of OAS rats and the levels of α-GC and carnitine （P<0.05）. The expressions of CFTR and ZIP12 in the head and cauda of the epididymis were up-regulated， while the expressions of ZIP8 in the cauda epididymis and AQP3 in the head of the epididymis were decreased （P<0.05）. The SOD and GSH-Px levels and total zinc content in epididymis were increased， and the MDA levels were decreased （P<0.05）. ConclusionBYP may improve the sperm quality and repair epididymal tissue structure and function of OAS rats， by regulating the expressions of CFTR， AQP3， and ZIP12 ion channels and local antioxidant mechanism.

Evolución clínico funcional de pacientes con fibrosis quística tratados con lumacaftor/ivacaftor en un centro pediátrico. Serie de casos / Clinical and functional course of patients with cystic fibrosis treated with lumacaftor/ivacaftor at a children's hospital. A case series

Los moduladores de la proteína reguladora transmembrana de fibrosis quística (CFTR) tratan el defecto de esta proteína. El objetivo es describir la evolución de niños con fibrosis quística tratados con lumacaftor/ivacaftor. Se trata de una serie de 13 pacientes de 6 a 18 años con ≥ 6 meses de tratamiento. Se analizaron el volumen espiratorio forzado en el primer segundo (VEF1), puntaje Z del índice de masa corporal (IMC), antibioticoterapia/año, antes del tratamiento y durante 24 meses posteriores. A los 12 meses (9/13) y 24 meses (5/13), la mediana de cambio del porcentaje del predicho VEF1 (ppVEF1) fue de 0,5 pp [-2-12] y 15 pp [8,7-15,2], y del puntaje Z de IMC de 0,32 puntos [-0,2-0,5] y 1,23 puntos [0,3-1,6]. El primer año (11/13) la mediana de días de uso de antibiótico disminuyó de 57 a 28 (oral) y de 27 a 0 (intravenoso). Dos niños evidenciaron eventos adversos asociados.

Cystic fibrosis transmembrane regulator (CFTR) modulators treat defective CFTR protein. Our objective is to describe the course of children with cystic fibrosis treated with lumacaftor/ivacaftor. This is a case series of 13 patients aged 6 to 18 years with ≥ 6 months of treatment. Forced expiratory volume in the first second (FEV1), body mass index (BMI) Z-score, antibiotic therapy/year, before treatment and for 24 months after treatment were analyzed. At 12 months (9/13) and 24 months (5/13), the median change in the percent predicted FEV1 (ppFEV1) was 0.5 pp (-2­12) and 15 pp (8.7­15.2) and the BMI Z-score was 0.32 points (-0.2­0.5) and 1.23 points (0.3­1.6). In the first year, in 11/13 patients, the median number of days of antibiotic use decreased from 57 to 28 (oral) and from 27 to 0 (intravenous). Two children had associated adverse events.

Enfermedad hepática en la fibrosis quística pediátrica. Una revisión de los conocimientos actuales / Cystic fibrosis liver disease in children ­ A review of our current understanding

La fibrosis quística, la segunda enfermedad genética más frecuente, es el resultado de una proteína de canal mutada, la CFTR, que secreta iones de cloro que fluidifican las secreciones. La esperanza de vida en los pacientes ha aumentado en años recientes gracias a mejoras en el tratamiento. No obstante, las complicaciones hepáticas son la tercera causa de muerte y la comprensión de su fisiopatología es aún deficiente. Se considera que la obstrucción biliar secundaria a la presencia de secreciones espesas conduce a la cirrosis. Sin embargo, el ácido ursodesoxicólico no ha modificado la historia natural. Además, la presencia de hipertensión portal en ausencia de cirrosis no puede ser explicada. Se ha propuesto el rol de la CFTR como modulador de tolerancia inmune, que explica la presencia de una inflamación portal persistente que culmina en fibrosis. El eje intestino-hígado tendría un rol importante en la presentación y la progresión de esta enfermedad

Cystic fibrosis is the second most common genetic disease in infancy. It is the result of a mutated channel protein, the CFTR, which secretes chloride ions, fluidifying secretions. Recent improvements in the treatment have increased life expectancy in these patients. Nevertheless, liver involvement remains the third cause of death. Unfortunately, our understating of the physiopathology is still deficient. Biliary obstruction secondary to the presence of thick secretions is considered to lead to cirrhosis. However, treatment with ursodeoxycolic acid has not changed the natural history. Furthermore, the presence of portal hypertension in the absence of cirrhosis cannot be explained. Recently, the role of CFTR as modulator of immune tolerance has been proposed, which could explain the presence of a persistent portal inflammation leading to fibrosis, and the gut-liver axis would also have a role in disease presentation and progression.

Programa de actividades físico-terapéuticas para educandos con fibrosis quística

La investigación se realizó en el municipio Jiguaní, provincia de Granma, Cuba. Se inició, a partir de la limitada atención que reciben los educandos fibroquísticos en el contexto escolar; pues, en el sistema educativo cubano no hay evidencias de programas de actividades físico-terapéuticas que orienten la prescripción de ejercicios físicos y tengan en cuenta las posibilidades, potencialidades y necesidades de estos niños. La investigación tiene como objetivo elaborar un programa de actividades físico-terapéuticas, caracterizado por un enfoque integral físico-educativo que mejore la condición física orientada a la salud de educandos con fibrosis quística. Para su desarrollo, se efectuó un estudio correlacional, con diseño pre-experimental en el período comprendido entre septiembre 2019 y junio 2021. Se emplearon métodos teóricos, empíricos y estadístico-matemáticos, así como técnicas de investigación, entre ellos: analítico-sintético, hipotético-deductivo, sistémico estructural-funcional, revisión documental, observación estructurada, criterio de expertos, entrevista, triangulación metodológica y estadística descriptiva e inferencial. A partir de un muestreo intencional, se seleccionaron cuatro educandos con manifestaciones clínicas de las vías respiratorias, baja autoestima y escasa condición física, que representan el total de la población, para el 100 %, con una edad promedio de nueve años. En los resultados del experimento, mediante los indicadores evaluados con la implementación del programa de actividades físico-terapéuticas, se observaron cambios significativos en el 100 % de la muestra, con ello mejoró la condición física orientada a la salud en educandos con fibrosis quística.

A pesquisa foi realizada no município de Jiguaní, província de Granma, Cuba. Ela foi iniciada devido à atenção limitada que os alunos fibrocísticos recebem no contexto escolar, uma vez que no sistema educacional cubano não há evidências de programas de atividades físico-terapêuticas que orientem a prescrição de exercícios físicos e levem em conta as possibilidades, o potencial e as necessidades dessas crianças. O objetivo desta pesquisa é elaborar um programa de atividades físico-terapêuticas, caracterizado por um enfoque físico-educacional integral que melhore a condição física orientada para a saúde dos alunos com fibrose cística. Para seu desenvolvimento, foi realizado um estudo correlacional, com um desenho pré-experimental no período entre setembro de 2019 e junho de 2021. Foram utilizados métodos teóricos, empíricos e estatístico-matemáticos, bem como técnicas de pesquisa, incluindo: analítico-sintético, hipotético-dedutivo, estrutural-funcional sistêmico, revisão documental, observação estruturada, julgamento de especialistas, entrevista, triangulação metodológica e estatística descritiva e inferencial. A partir de uma amostragem intencional, foram selecionados quatro alunos com manifestações clínicas do trato respiratório, baixa autoestima e condição física ruim, representando 100% da população total, com idade média de nove anos. Nos resultados do experimento, por meio dos indicadores avaliados com a implementação do programa de atividades físico-terapêuticas, foram observadas mudanças significativas em 100% da amostra, melhorando assim a condição física voltada para a saúde dos alunos com fibrose cística.

The research was carried out in the Jiguaní municipality, Granma province, Cuba. It began, from the limited attention that fibrocystic students receive in the school context due to in the Cuban educational system there is no evidence of physical-therapeutic activity programs that guide the prescription of physical exercises and take into account the possibilities, potentialities and needs of these children. The objective of the research is to develop a program of physical-therapeutic activities, characterized by a comprehensive physical -educational approach that improves the health-oriented physical condition of students with cystic fibrosis. For its development, a correlational study was carried out, with a pre-experimental design in the period between September 2019 and June 2021. Theoretical, empirical and statistical-mathematical methods were used, as well as research techniques, including: analytical-synthetic, hypothetical-deductive, structural-functional systemic, documentary review, structured observation, expert judgment, interview, methodological triangulation and descriptive and inferential statistics. From an intentional sampling, four students with clinical manifestations of the respiratory tract, low self-esteem and poor physical condition were selected, representing the total population, for 100 %, with an average age of nine years. In the results of the experiment, through the indicators evaluated with the implementation of the program of physical-therapeutic activities, significant changes were observed in 100 % of the sample, thereby improving the health-oriented physical condition in students with cystic fibrosis.

La fibrosis quística en niños en el Ecuador / Cystic fibrosis in children in Ecuador

Objetivo: analizar la fibrosis quística en niños en el Ecuador. Metodología: Revisión sistemática de 21 publicaciones relacionadas al tema, específicamente 13 articulos de investigación en contexto ecuatoriano. Resultados y conclusión: En el Ecuador la incidencia de la enfermedad es de 1 por cada 11.110 habitantes y cada año nacen aproximadamente 23 niños con esta afección, teniéndose en cuenta las mutaciones en el CFTR, entorpecen el diagnóstico molecular, así como se ha estudiado un caso pediátrico de FQ con complicaciones en pancreatitis, siendo esto inusual en la población infantil, siendo considerable proseguir con investigaciones conducentes a tener una mejor referencia científica de la FQ en el Ecuador.

Objective: to analyze cystic fibrosis in children in Ecuador. Methodology: Systematic review of 21 publications related to the subject, specifically 13 research articles in the Ecuadorian context. Results and conclusion: In Ecuador the incidence of the disease is 1 for every 11,110 inhabitants and each year approximately 23 children are born with this condition, taking into account CFTR mutations, which hinder molecular diagnosis, as well as a study pediatric case of CF with complications in pancreatitis, this being unusual in the child population, it is important to continue with research leading to a better scientific reference of CF in Ecuador.

Transición en las enfermedades crónicas gastrointestinales. Del cuidado pediátrico al del adulto / Transition in chronic gastrointestinal diseases. From pediatric to adult care

Los avances tecnológicos y del conocimiento hicieron que un mayor número de pacientes con enfermedad crónica gastrointestinal pasen de ser atendidos por el pediatra al control por los médicos de adultos durante una de las etapas más vulnerables de la vida: la adolescencia. El Grupo de Trabajo de Transición del Comité de Gastroenterología de la Sociedad Argentina de Pediatría realizó una búsqueda de literatura exhaustiva y convocó a especialistas referentes del país, con el objeto de unificar los criterios basados en la evidencia y la experiencia. De esta manera, se proponen una serie de recomendaciones para todo el equipo de salud (pediatra, gastroenterólogo infantil, nutricionista, gastroenterólogo de adultos, psicólogo, enfermería), incluso para pacientes y familias, que faciliten el proceso de transición y optimicen el seguimiento, el control, la prevención de complicaciones y la calidad de vida de los pacientes con enfermedades crónicas gastrointestinales

Technological advances and the globalization of knowledge have led to a considerable increase in the number of patients with chronic gastrointestinal disease who transition from pediatric to adult care during one of the most vulnerable life stages: adolescence. The Transition Working Group of the Gastroenterology Committee of the Sociedad Argentina de Pediatría conducted an exhaustive literature search and summoned leading specialists in the most frequent chronic pathologies from all over the country to unify criteria based on evidence and experience. As a result, a series of recommendations are proposed for the whole health team (pediatrician, pediatric gastroenterologist, nutritionist, adult gastroenterologist, psychologist, and nurse) including patients and families, to facilitate the transition process, optimize follow-up, prevent complications, and improve the quality of life of patients with chronic gastrointestinal diseases.

Combined multi-channel intraluminal impedance measurement and pHmetry in the detection of gastroesophageal reflux disease in children with cystic fibrosis

Abstract Objective To assess the prevalence of GERD exclusively by means of multichannel intraluminal impedanciometry associated with pH monitoring (MIIpH) and compare it with respiratory symptoms in children with CF. To compare MIIpH with pHmetry alone to perform GERD diagnosis. Methods An analytical cross-sectional study was conducted with children diagnosed with CF who underwent MIIpH. Clinical and laboratory markers, including respiratory and digestive symptoms, were used for comparative analyses. High-resolution chest computed tomography was performed on patients with symptoms of chronic lung disease. Severity was classified according to the Bhalla score. Results A total of 29 children < 10 yo (18 girls) were evaluated; 19 of whom with physiological GER and 10 with GERD. Of the children with GERD, seven had predominantly acid GER, two acid+non-acid GER, and one non-acid GER. Three patients had GERD diagnosed only by MIIpH. Bhalla scores ranged from seven to 17.75 with no significant relationship with GERD. The number of pulmonary exacerbations was associated with a decrease in esophageal clearance regardless of the position in pHmetry and MIIpH. Conclusions The prevalence of GERD was 34% in children with CF. There was no association between respiratory disease severity and GER types. MIIpH detected 30% more patients with GERD than pHmetry.

Use of Methylene Blue to Treat Vasoplegia Syndrome in Cystic Fibrosis Patients Undergoing Lung Transplantation: A Case Series

Background: Several studies have demonstrated the utility of methylene blue (MB) to treat vasoplegic syndrome (VS), but some have cautioned against its routine use in lung transplantation with only two cases described in prominent literature. Cystic fibrosis patients commonly have chronic infections which predispose them to a systemic inflammatory syndrome-like vasoplegic response during lung transplantation. We present 13 cystic fibrosis patients who underwent lung transplantation and received MB for vasoplegic syndrome while on cardiopulmonary bypass, with or without inhaled pulmonary vasodilator therapy. Methods: Single?center, retrospective, case series analysis of cystic fibrosis patients who underwent lung transplant and received MB for vasoplegia. We defined the primary outcome as 30-day mortality, and secondary outcomes as primary graft failure, 1-year mortality, postoperative complications, and hemodynamic response to MB. Results: MB was associated with a significant increase in mean arterial pressure (MAP) (P < 0.001) in all patients, and 84.6% (11/13) of the patients had either a decrease or no change in vasopressor requirement. No patients developed acute primary graft dysfunction and there was 100% 30?day and 1?year survival. One patient required Extracorporeal membrane oxygenation (ECMO) for hypoxemia and 69% (9/13) of the patients had evidence of postoperative right ventricular dysfunction, but no patients required a right ventricular assist device. Conclusion: This case series demonstrates the effectiveness of MB in treating vasoplegia in cystic fibrosis patients during lung transplantation, without evidence of primary graft dysfunction, 30?day or 1?year mortality. The safety of MB regarding hypoxemia and increased pulmonary vascular resistance requires further investigation.

Five-year performance analysis of a cystic fibrosis newborn screening program in northeastern Brazil

Abstract Objective: To analyze the performance of the cystic fibrosis (CF) newborn screening (NBS) program over its first five years in a Brazilian northeastern state. Methods: A population-based study using a screening algorithm based on immunoreactive trypsinogen (IRT)/IRT. Data were retrieved from the state referral screening center registry. The program performance was evaluated using descriptive indicators such as the results of an active search, coverage, newborn's age at the time of blood sampling, the time between sample collection and its arrival at the laboratory, and the child's age at diagnosis of disease. Results: The public CF screening program covered 82.6% of the 1,017,576 births that occurred, with an accumulated five-year incidence of 1:20,767 live births. The median (25th-75th) age at diagnosis was 3.5 (2.3-7.3) months. The sampling before 7 days of life for the first IRT (IRT1) increased between 2013 and 2017 from 42.2 to 48.3%. Around 5% of IRT1 samples and 30% of the second samples were collected after 30 days of life. In the first and second stages of screening, 23.6% and 19.9% of the infants, respectively, were lost to follow-up. In both stages of screening, the samples were retained at the health units for a median (25th-75th) of 9.0 (7.0-13.0) days. Conclusions: The coverage by the CF-NBS program was satisfactory as compared to other Brazilian state rates and the percentage of IRT1 samples collected within the first week of life increased progressively. However, time of samples retention at the health units, inappropriate sampling, inherent methodological problems, and loss of follow-up need to improve.

Systematic review on fecal calprotectin in cystic fibrosis

Abstract Objectives: Fecal calprotectin is an inflammatory marker used for monitoring intestinal diseases. It has been studied as a marker of intestinal inflammation in cystic fibrosis (CF), a multi-systemic genetic disease caused by alterations to the CFTR gene. Manifestations of the disease favor a systemic inflammation not limited to the respiratory tract, therefore, calprotectin is a non-invasive and effective diagnostic method. The aim of the study was to perform a systematic review of the literature with a qualitative synthesis of studies. Sources: The articles were selected from PubMed, Web of Science, Scielo and Lilacs. Summary of the findings: Nine studies were selected for that qualitative synthesis, one was a randomized clinical trial, and eight were case-control or cohort designs. Most studies have indicated that calprotectin is a marker of systemic inflammation in CF and not just intestinal inflammation. Calprotectin is an aid in monitoring inflammatory bowel conditions in patients with cystic fibrosis. Conclusion: Further studies should be conducted to investigate the role of this marker in the systemic inflammation of CF.

El regulador de transmembrana de fibrosis quística (CFTR) disfuncional y sus efectos extrapulmonares / The dysfunction of transmembrane regulator in cystic fibrosis (CFTR) and its extrapulmonary effects

El daño del regulador de transmembrana de fibrosis quística (CFTR) puede causar una enfermedad grave fuera de los pulmones. El canal de cloruro (Cl-) ha sido el más estudiado, sin embargo, el bicarbonato (HCO3 -) tiene un rol muy importante en el comportamiento de las secreciones y la inflamación secundaria. El hecho de que CFTR funcione no sólo como un canal de Cl- sino también de HCO3- es un campo para la investigación y el desarrollo de fármacos para pacientes con daño genético o adquirido, este último frecuente en la población general. Algunos moduladores de CFTR pueden tener un beneficio terapéutico en el tratamiento de pancreatitis en ambas situaciones. La disfunción del CFTR a nivel renal puede resultar excepcionalmente en alcalosis metabólica y reducción del impulso ventilatorio. Hasta la fecha no está claro cuales serian sus efectos en los sistemas gastrointestinal y hepatobiliar.

Transmembrane regulator in cystic fibrosis (CFTR) can cause severe disease outside of the lungs. The chloride channel (Cl-) has been the most studied, however bicarbonate (HCO3 -) has a very important role in the behavior of secretions and secondary inflammation. The fact that CFTR works not only as a Cl- channel but also as an HCO3- channel is a field for research and development of drugs for patients with genetic or acquired damage, the latter frequent in the general population. Some CFTR modulators may have a therapeutic benefit in the treatment of pancreatitis in both situations. CFTR dysfunction at the renal level can exceptionally result in metabolic alkalosis and reduced ventilatory drive. To date it is not clear what its effects on the gastrointestinal and hepatobiliary systems would be.

Actualización en fibrosis quística: diabetes relacionada a fibrosis quística en la era de los moduladores del regulador de transmembrana de fibrosis quística (CFTR) / Update on cystic fibrosis/cystic fibrosis related diabete in the era of transmembrane regulator in cystic fibrosis (CFTR)

Las disglicemias, objetivadas en el test de tolerancia a la glucosa de 2 horas y en el monitoreo continuo de glicemia, son el factor de riesgo principal para el desarrollo de la diabetes relacionada a fibrosis quística (FQ) (DRFQ), la que constituiría la etapa final de un continuo de alteraciones del metabolismo de la glucosa en los pacientes con FQ. Estas disglicemias se deben tanto al daño directo de las células de los islotes pancreáticos productores de insulina, como al aumento de la resistencia a la insulina asociada al estado inflamatorio sistémico de la FQ. El uso cada vez más precoz de los moduladores del CFTR debiera contribuir a evitar el desarrollo de DRFQ y sus complicaciones. La siguiente revisión se enfoca en los efectos de los moduladores del CFTR en la tolerancia a la glucosa en pacientes con FQ.

Dysglycemia, observed in the 2-hour glucose tolerance test and in the continuous monitoring of glycemia, are the main risk factor for the development of diabetes related to cystic fibrosis (CF), which constitutes the final stage of a continuum of impaired glucose metabolism in people with CF. These dysglycemias are due both to direct damage to insulin-producing pancreatic islet cells, and to increased insulin resistance associated with the systemic inflammatory state of CF. The increasingly early use of CFTR modulators should help prevent the development of CRFD and its complications. The following review focuses on the effects of regulador de transmembrana de fibrosis quística (CFTR) modulators on glucose tolerance in people with CF.

Use of elexacaftor+tezacaftor+ivacaftor in individuals with cystic fibrosis and at least one F508del allele: a systematic review and meta-analysis / Uso de elexacaftor + tezacaftor + ivacaftor em indivíduos com fibrose cística com pelo menos um alelo F508del: revisão sistemática e meta-análise

ABSTRACT Objective: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. Methods: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, −0.16; 95% CI, −0.28 to −0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, −0.03; 95% CI, −0.08 to 0.01), and none of the studies reported deaths. Conclusions: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes.

RESUMO Objetivo: Avaliar o efeito do tratamento com a combinação de três moduladores da proteína cystic fibrosis transmembrane conductance regulator (CFTR, reguladora de condutância transmembrana em fibrose cística) - elexacaftor + tezacaftor + ivacaftor (ETI) - sobre desfechos clínicos importantes em indivíduos com fibrose cística. Métodos: Revisão sistemática e meta-análise de ensaios clínicos randomizados que compararam o uso de ETI em indivíduos com fibrose cística com pelo menos um alelo F508del com o uso de placebo ou de um comparador ativo como outras combinações de moduladores da CFTR. O estudo foi realizado seguindo as recomendações Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) e a metodologia Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO). Foram realizadas buscas nos seguintes bancos de dados: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials e ClinicalTrials.gov, desde a sua criação até 26 de dezembro de 2022. O risco de viés foi avaliado por meio da ferramenta de risco de viés da Cochrane, e a qualidade das evidências foi determinada com base no sistema Grading of Recommendations Assessment, Development and Evaluation (GRADE). Resultados: Foram identificados 54 estudos na busca primária. Destes, 6 preencheram os critérios de inclusão e foram analisados (1.127 pacientes: 577 pacientes intervenção e 550 pacientes controle). A meta-análise revelou que o uso de ETI aumentou o VEF1 em porcentagem do previsto [diferença de risco (DR): +10,47%; IC95%: 6,88-14,06], reduziu o número de exacerbações pulmonares agudas (DR: −0,16; IC95%: −0,28 a −0,04) e melhorou a qualidade de vida (DR: +14,93; IC95%: 9,98-19,89) e o IMC (DR: +1,07 kg/m2; IC95%: 0,90-1,25). Os eventos adversos não diferiram entre os grupos (DR: −0,03; IC95%: −0,08 a 0,01), e nenhum dos estudos relatou óbitos. Conclusões: Nossos achados demonstram que o tratamento com ETI melhora substancialmente os desfechos clinicamente significativos centrados no paciente.

Telehealth for children and adolescents with chronic pulmonary disease: systematic review / Telessaúde para crianças e adolescentes com doenças pulmonares crônicas: revisão sistemática

Abstract Objective: To revise the impact of telehealth on the quality of life, reduction in pulmonary exacerbations, number of days using antibiotics, adherence to treatment, pulmonary function, emergency visits, hospitalizations, and the nutritional status of individuals with asthma and cystic fibrosis. Data source: Four databases were used, MEDLINE, LILACS, Web of Science and Cochrane, as well as manual searches in English, Portuguese and Spanish. Randomized clinical trials, published between January 2010 and December 2020, with participants aged 0 to 20 years, were included. Data synthesis: Seventy-one records were identified after the removal of duplicates; however, twelve trials were eligible for synthesis. Included trials utilized: mobile phone applications (n=5), web platforms (n= 4), mobile telemedicine unit (n=1), software with an electronic record (n=1), remote spirometer (n=1), and active video games platform (n=1). Three trials used two tools, including telephone calls. Among the different types of interventions, improvement in adherence, quality of life, and physiologic variables were observed for mobile application interventions and game platforms compared to usual care. Visits to the emergency department, unscheduled medical appointments, and hospitalizations were not reduced. There was considerable heterogeneity among studies. Conclusions: The findings suggest that better control of symptoms, quality of life, and adherence to treatment can be attributed to the technological interventions used. Nevertheless, further research is needed to compare telehealth with face-to-face care and to indicate the most effective tools in the routine care of children with chronic lung diseases.

RESUMO Objetivo: Revisar o impacto da telessaúde na qualidade de vida, redução das exacerbações pulmonares, número de dias em uso de antibióticos, adesão ao tratamento, função pulmonar, visitas à emergência, hospitalizações e estado nutricional de indivíduos com asma e fibrose cística. Fontes de dados: Foram utilizadas quatro base de dados, sendo, MEDLINE, LILACS, Web of Science e Cochrane, além de pesquisas manuais nos idiomas inglês, português e espanhol. Foram incluídos ensaios clínicos randomizados, publicados no período de janeiro de 2010 a dezembro de 2020, com participantes de 0 a 20 anos. Síntese dos dados: Setenta e um registros foram identificados após a remoção das duplicatas e doze estudos foram elegíveis para síntese. Os ensaios utilizaram aplicativos para celular (n=5), plataformas da web (n= 4), unidade de telemedicina móvel (n=1), software com registro eletrônico (n=1), espirômetro remoto (n=1) e plataforma ativa de videogames (n=1). Três ensaios utilizaram duas ferramentas, incluindo chamadas telefônicas. Entre os diferentes tipos de intervenções, observou-se melhora na adesão, qualidade de vida e de variáveis fisiológicas para intervenções de aplicativos móveis e plataformas de jogos em comparação com os cuidados habituais. Visitas ao pronto-socorro, consultas médicas não agendadas e internações não foram reduzidas. Houve considerável heterogeneidade entre os estudos. Conclusões: Os achados sugerem que a melhora do controle dos sintomas, da qualidade de vida e da adesão ao tratamento podem ser atribuídos às intervenções tecnológicas utilizadas. No entanto, mais pesquisas são necessárias para comparar a telessaúde com o atendimento presencial e indicar as ferramentas mais efetivas na rotina de cuidados à população infantil com doenças crônicas pulmonares.