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Introduction Viral infections are associated with pulmonary exacerbations in children with Cystic Fibrosis (cwCF), but after 3 years of SARS-CoV-2 pandemic, whether cwCF are at higher risk of developing COVID-19 or its adverse consequences remains controversial. Methods We conducted an observational, multicenter, cross-sectional study of cwCF infected by SARS-CoV-2 between March 2020 and June 2022, (1 to 6 COVID-19 pandemic waves) in Spain. The study aimed to describe patients’ basal characteristics, SARS-CoV-2 clinical manifestations and outcomes, and whether there were differences across the pandemic waves. Results During study time, 351 SARS-CoV2 infections were reported among 341 cwCF. Median age was 8.5 years (range 0-17) and 51% were female. Cases were unevenly distributed across the pandemic, with most cases (82%) clustered between November 2021 and June 2022 (6 wave, also known as Omicron Wave due to the higher prevalence of this strain in that period in Spain). Most cwCF were asymptomatic (24.8%) or presented with mild Covid-19 symptoms (72.9%). Among symptomatic, most prevalent symptoms were fever (62%) and increased cough (53%). No multisystem inflammatory syndrome (MIS-C), persisting symptoms, long-term sequelae or deaths were reported. Conclusions Spanish current data indicate that cwCF do not experience higher risks of SARS-CoV-2 infection nor worse health outcomes or sequelae. Changes in patients’ basal characteristics, clinical courses and outcomes were detected across waves. While the pandemic continues, and new SARS-CoV-2 variants are being identified, a worldwide monitoring of COVID-19 in pediatric CF patients is needed.

Cystic fibrosis (CF) is the most common autosomal recessive disorder in the Caucasian population, with an incidence of 1:5000 live births. In 2011, the screening of CF was implemented in the Andalusian Public Health newborn screening program by using immunoreactive trypsinogen and chloride sweat test (IRT/IRT/sweat test) determinations. Since then, 79 children have been diagnosed with CF in our health area (Western Andalusia). The aim of this study was to evaluate the efficiency of this screening method and to examinate the characteristics of those CF infants who had a negative screening but who were later diagnosed. In the 2011-2021 period 462049 newborns were screened for CF using a two-step IRT determination and chloride sweat test. 63 infants were diagnosed with CF in our health area thanks to the screening, and 15 CF children had a negative screening result and were finally diagnosed by molecular sequencing of the CFTR gene. The most frequent symptoms that led to the diagnosis of those false negative (FN) patients were hyponatremic dehydration (mean age 9.75±1.5 months) and recurrent wheezing (mean age 24±14.5 months). The molecular analysis of the CFTR gene on those FN showed a diversity of genotypes, identifying more than 10 different mutations. Conclusion: The rate of FN patients obtained in this study is inadmissibly high, and the protocol used in this region has not been updated despite the advances in genetic testing in the past 10 years. An improvement on CF newborn screening should be implemented, adding molecular analysis of the CFTR gene. This article is protected by copyright. All rights reserved.

Background Cystic fibrosis (CF) bone disease (CFBD) has attracted considerable recent interest from researchers, although several aspects of CFBD pathophysiology remain poorly understood. The objective of this research was to investigate CFBD in children with CF and its relation to clinical and bone metabolism markers. Methods In a prospective observational study of 68 patients with CF and 63 healthy controls, we studied bone turnover biomarkers and bone mineral density (BMD). The biomarkers included osteocalcin, total-alkaline phosphatase, bone-alkaline phosphatase, N-terminal propeptide of type-1-procollagen, osteoprotegerin (OPG), interleukine-6, tumor necrosis factor alpha (TNF-α), type-1-collagen cross-linked C-telopeptide (CTX), parathormone (PTH), 25-vitamin D, 1,25-vitamin D, calcium and phosphorus. BMD was examined in lumbar spine, comparing two healthy Spanish populations. Two regression analyses were applied to any significant associations to evaluate predictors of BMD and of CF, expressed as odds ratios (OR) with 95% confidence intervals. Results After adjusting for age, sex, and height Z-score, gains in BMD LS in children and adolescents (6–16 years) with CF were not less than in healthy reference population. Patients with CF showed significant associations with different bone turnover biomarkers. Age, gender, body mass index, PTH, CTX and OPG were significant predictors of BMD (R2 = 0.866, p Conclusion A normal bone mineral density along with altered remodeling was found in CF patients with a normal nutritional status and without acute lung disease.

Background The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs. Methods We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1 Results The mean age was 26.65 (range of 10–45), while the mean ppFEV1 before the treatment was 32.4% and mean BMI was 19.9 kg/m2. We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor/ivacaftor, but no differences were found. However, a moderate association between days of intravenous antibiotic needed and the use of lumacaftor/ivacaftor (p = 0.001) was established. Indeed, under the lumacaftor/ivacaftor, patients required 5.8 days of intravenous antibiotic treatment compared to 14.9 days prior to study. Also, severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor/ivacaftor treatment (p = 0.003). Finally, 75% of the sample presented with AEs, which led 35% of the subjects to discontinue the treatment. Conclusions While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found.

Introduction Cystic fibrosis neonatal screening (CFNS), based on double determination of immunoreactive trypsinogen ([IRT] [IRT1/IRT2]), has been available in Andalusia since May 2011. If screening is positive, a sweat test is performed, and if that is positive or inconclusive, genetic testing is requested. Objective To analyze CFNS, based on results from the first 4.5 years of the program. Materials and methods Prospective descriptive study of neonates undergoing CFNS. IRT levels, sweat chloride, and mutations were recorded. Statistical analysis was performed using SPSS 12.0. Results Between May 2011 and December 2016, 474,953 neonates underwent CFNS. Of these, 1087 (0.23%) had elevated IRT2. Since CFNS was introduced, 73 cases of cystic fibrosis were diagnosed; 60 were diagnosed by positive CFNS, and 13 were diagnosed by other means. In one case, the patient developed a typical clinical picture of cystic fibrosis, but had not undergone CFNS at the decision of the parents; the remaining 12 had a negative CFNS (false negatives). Of these, one patient was diagnosed before symptoms developed, as his twin brother had a positive CFNS result; another had chloride at the upper limit of normal, and was subsequently diagnosed with genetic testing before symptoms appeared; and 10 patients developed clinical signs and symptoms. Excluding patients with meconium ileus, sensitivity and specificity of the CFNS program were 85.71% and 99.78%, respectively. The incidence of the disease in Andalusia is 1/6506 live births. Conclusion These results are a basis for reflection on possible areas for improvement of the CFNS algorithm, and thought may be given to the introduction of genetic studies to increase sensitivity and reduce false positives.

CF-COVID19-Spain Registry Group., [Background] Given the high incidence of confirmed infection by SARS-CoV-2 and mortality by COVID-19 in the Spanish population, its impact was analysed among persons with Cystic Fibrosis (CF) as a group at risk of a worse evolution. The possible causes of the incidence observed in them are explained and how CF Units have faced this health challenge is detailed., [Methods] Retrospective descriptive observational study, for which a Spanish CF Patients with Confirmed COVID-19 Registry is created, requesting information on number of people affected between 8 March–16 May 2020 and their clinical-demographic characteristics from the CF Units participating in the European Cystic Fibrosis Society Patient Registry (ECFSPR). The accumulated incidence is calculated, compared with that of the general population. Additionally, a survey (CF-COVID19-Spain) is carried out on prevention of SARS-CoV-2 infection, workings of CF Units and possible reasons for the incidence observed., [Results] COVID-19 was diagnosed in eight CF patients, one of whom had received a lung transplant. The accumulated incidence was 32/10000 in CF patients and 49/10000 in the general population. General death rate was 5.85/10000 while no CF patients included in the ECFSPR died. The characteristics of those affected and the results of the survey are described., [Conclusions] Despite being considered a disease at high risk of severe COVID-19, the low incidence and mortality in CF patients in Spain contrasts with the figures for the general population. The possible factors that would explain such findings are discussed, with the help of the results of the CF-COVID19-Spain survey.

Objective: To identify indication, timing and complications of tracheostomy in children below 14 years. Methods: medical record of patients who underwent tracheostomy between 1998 and 2018 was revised. Results: Fifty-nine children with chronic tracheostomy were included, mean age at time of tracheostomy 2.97 years. In thirty-four children (57.6%) tracheostomy was necessary for long-term mechanical ventilation, while in twenty-five was indicated to save severe airway organic or functional abnormalities. During the study, tracheostomy was removed in twenty children, while nine children died, one of them as a consequence of impossibility for tube re-insertion after a programmed change. In the last five years we observed an increased number of procedures (26 out of 59) with a shorter time of hospital admission before tracheostomy was performed. The most common tracheostomy complications were peristomal granulation tissue (8) and suprastomal granulation tissue (4). All patients but one were discharged at home and their parents took care of them. A multidisciplinary team was involved in the follow up, respiratory infection no related to tracheostomy or infection of the tracheostomy being the most frequent reason for consultation. No urgent direct laryngoscopy and bronchoscopy procedures were required. Children that did not need long-term mechanical ventilation were able to use a speaking valve at least when awake. Conclusion: Tracheostomy frequency is increasing lately, being in general well tolerated and manageable by parents at home. The majority of complications are related to minor infections, but occasionally severe complications may occur, warrantying expert control of airway.

Tracheal bronchus (TRB) has been generally considered an anatomical variant of the tracheobronchial tree without a precise pathological effect. Its prevalence is estimated to be between 0.2% to 3% of all children undergoing bronchoscopy and scientific information has been limited to case reports or small case series. Our working hypothesis was that TRB could trigger by itself recurrent or persistent respiratory symptoms. The objective of this retrospective and multicentre study of children with a diagnosis of TRB, coming from the main paediatric pulmonology units of Spain, was to determine the anatomical and clinical characteristics, including comorbidities, of TRB in childhood and their impact in the patients' clinical outcomes. One hundred thirty-three patients from 13 institutions were included in the study. Mean diagnostic age was 3.4 years and flexible bronchoscopy was the initial diagnostic method in 85% of cases. All TRB were located on the right wall of the trachea: 76% in the lower third and 24% in the carina. The most common clinical manifestations were obstructive bronchitis (53.3%) and recurrent pneumonia (46.6%), usually affecting the right upper lobe. Regarding associated anomalies, 33% had tracheomalacia, 32% congenital cardiovascular malformations, 28% gastroesophageal reflux, 22.5% congenital tracheal stenosis, and 8.3% Down syndrome. This series appears to be the most extensive published to date addressing this topic and, according to our data, TRB does not appear to be a mere incidental finding but is more likely linked to a wide range of congenital anomalies and contributes by itself to the recurrent respiratory symptomatology that these children exhibit.

Home heated humidified high-flow cannula therapy (HHHFC) is expensive and not always available. Domiciliary non-invasive ventilation (NIV), even in CPAP mode, may be poorly accepted by young non-collaborative patients and their families, due to interface problems or to leakage. Objective: to report our experience with HHHFC at home in young children. Methods: we tested a home CPAP equipment used with nasal cannulas to administer a high flow mixture of air and oxygen, humidified and warmed, as respiratory support in children with poor NIV acceptance and compliance. Gas flow for any pre-fixed CPAP level between 4 and 20 cmH2O was measured, with or without oxygen supplementation. Results: HHHFC therapy was applied to 9 pediatric patients, 4 females, mean age 12 months (range 2-45), mean follow up time 17.4 months (range 0.5-37), as home respiratory support during sleep time and respiratory exacerbations. Mean level of applied CPAP was 8.4 cmH2O (range 6-16), mean airflow measured was 7.8 L/min (range 6.3-11.85), which represented between 0.8 and 1.4 L/min/kg. HHHFC therapy was well tolerated and no side effects were reported. Reductions in number of hospital admissions, unscheduled visits and episodes of acute respiratory failure were observed. Sleep respiratory disorders improved in two patients. Feeding by nasogastric tube was not affected. Families felt that HHHFC respiratory support improved the quality of life of their children. Use of HHHFC was discontinued in two patients, was combined with NIV in four and continued with no changes in three. Conclusions: HHHFC therapy, when performed with CPAP devices, in selected patients, may offer the advantage of efficacy with a better tolerance than NIV.

SummaryObjective To date, available mortality trends due to cystic fibrosis (CF) have been limited to the analysis of certain countries in different parts of the world showing that mortality trends have been constantly decreasing. However, no studies have examined Europe as a whole. The present study aims to analyze CF mortality trends by gender within the European Union (EU) and to quantify potential years of life lost (PYLL). Design Deaths from the 27 EU countries were obtained from the statistical office of the EU from the years 1994–2010. Crude and age-standardized mortality rates (ASR) were estimated for women and men using the standard European population, expressed in deaths per 1,000,000 persons. The PYLL from ages 0 up to 30 years were estimated. Trends were studied by a joinpoint regression analysis. Results During the study period, 5,130 deaths (2,443 in males and 2,687 in females) were identified. Females had a slightly higher mortality rate than males, with a downward trend observed for both genders. In males, the ASR changed from 1.34 in 1994 to 1.03 in 2010. In females, the ASR changed from 1.42 in 1994 to 0.92 in 2010. The mean age at death and PYLL increased for both genders. The joinpoint analysis did not identify any significant joinpoint for either gender for ASR or PYLL. Conclusions Our data suggest a continued downward trend of CF mortality throughout the EU, with differences by country and gender. Pediatr Pulmonol. 2016;51:133–142. © 2015 Wiley Periodicals, Inc.

Resumen Introduccion Andalucia dispone de screening neonatal de fibrosis quistica (SNFQ) desde mayo 2011, basado en doble determinacion de tripsinogeno inmunorreactivo ([TIR] [TIR1/TIR2]). Si el screening es positivo realizamos un test del sudor y si es positivo o dudoso solicitamos genetica. Objetivo Analizar el SNFQ, basado en los resultados de los primeros 4,5 anos. Material y metodo Estudio descriptivo prospectivo de los neonatos sometidos a SNFQ. Se recogen los niveles de TIR, cloruro en sudor, mutaciones. Mediante SPSS12.0 se realizo analisis estadistico. Resultados Desde mayo 2011 a diciembre 2016, 474.953 neonatos fueron sometidos a SNFQ. Mil ochenta y siete (0,23%) presentaron TIR2 elevado. Desde la implantacion del SNFQ se diagnosticaron 73 casos con fibrosis quistica; 60 de ellos fueron diagnosticados mediante un SNFQ positivo, mientras que 13 no. Concretamente un paciente comenzo con clinica clasica de fibrosis quistica y se comprobo que no se habia realizado el SNFQ por decision paterna; los 12 restantes tuvieron un SNFQ negativo (falsos negativos). De estos, un paciente fue diagnosticado presintomaticamente al tener su hermano gemelo con SNFQ positivo; otro con cloruro en el limite alto de la normalidad se diagnostico presintomaticamente mediante genetica; 10 pacientes comenzaron clinicamente. Excluyendo los pacientes con ileo meconial, la sensibilidad y especificidad del programa de SNFQ asciende al 85,71 y 99,78% respectivamente. La incidencia de la enfermedad en Andalucia es de 1/6.506 recien nacidos vivos. Conclusion Los presentes resultados nos permiten reflexionar sobre posibles areas de mejoras adicionales del algoritmo del SNFQ, que debe pasar por la introduccion de estudios geneticos para asi aumentar la sensibilidad y disminuir los falsos positivos.

Resumen La fibrosis quistica es una enfermedad autosomica recesiva monogenica, de la que se han descrito ya mas de 1.900 mutaciones agrupadas en 6 clases y que constituye un ejemplo de lo que podria ser una enfermedad bien situada para poder beneficiarse de la medicina personalizada. En la actualidad, 2 enfoques muy diferentes tienen por objetivo corregir el defecto basico: la terapia genica, dirigida a corregir la alteracion genetica, y la terapia encaminada a corregir el defecto a nivel de la proteina CFTR. Esta ultima comienza a dar resultados prometedores con diversas moleculas en desarrollo. Ataluren (PTC124) es una molecula disenada para que los ribosomas se vuelvan menos sensibles a los codones de parada prematuros responsables de las mutaciones clase i . Lumacaftor (VX-809) es un farmaco corrector que esta dirigido a mutaciones de clase ii , entre las que figura la mas frecuente (Phe508del), con prometedores resultados. Ivacaftor (VX-770) es un farmaco potenciador, el unico comercializado hasta el momento, que ha demostrado una buena eficacia para la mutacion de clase iii , Gly551Asp, en ninos mayores de 6 anos y adultos. Ademas, diversos ensayos estan probando estos farmacos o la combinacion de ellos para otras mutaciones geneticas menos frecuentes. En los ultimos 5 anos, la CFTR ha sido designado como una diana terapeutica. Ivacaftor es el primer farmaco que trata el defecto basico de la fibrosis quistica, pero solo da respuesta a un escaso porcentaje de los pacientes. Se precisan nuevos farmacos capaces de restaurar la proteina CFTR causada por mutaciones mas comunes.

Cystic fibrosis is a single gene, autosomal recessive disorder, in which more than 1,900 mutations grouped into 6 classes have been described. It is an example a disease that could be well placed to benefit from personalised medicine. There are currently 2 very different approaches that aim to correct the basic defect: gene therapy, aimed at correcting the genetic alteration, and therapy aimed at correcting the defect in the CFTR protein. The latter is beginning to show promising results, with several molecules under development. Ataluren (PTC124) is a molecule designed to make the ribosomes become less sensitive to the premature stop codons responsible for class i mutations. Lumacaftor (VX-809) is a CFTR corrector directed at class ii mutations, among which Phe508del is the most frequent, with encouraging results. Ivacaftor (VX-770) is a potentiator, the only one marketed to date, which has shown good efficacy for the class iii mutation Gly551Asp in children over the age of 6 and adults. These drugs, or a combination of them, are currently undergoing various clinical trials for other less common genetic mutations. In the last 5 years, CFTR has been designated as a therapeutic target. Ivacaftor is the first drug to treat the basic defect in cystic fibrosis, but only provides a response in a small number of patients. New drugs capable of restoring the CFTR protein damaged by the most common mutations are required.

Background : Respiratory insufficiency in children with life-limiting and life-threatening conditions is common, it has a lasting impact, yet there is a paucity of evidence to guide clinicians in its management with home support. Objectives : Our aim was to review palliative indication of home mechanical ventilation (HMV) in Southwestern Spain. Methods : Descriptive cross-sectional study including pediatric patients (aged 0 to 18 years) who were being taken care by the HMV program at the University Hospital Virgen del Rocio in Seville between 2000 and 2015. Results : A total of 78 patients were analyzed, 22 on invasive ventilation (10 with 24 hours/day) and 56 on no invasive ventilation. Duration of HMV varies from 2 days to 15 years. According to standards for pediatric palliative care in Europe, 12 patients suffered from life-threatening illness, (group 1; 4 cancer, 8 no progressive lung disease), 17 had conditions in which premature death is inevitable (group 2; 3 mucopolysaccharidosis, 14 malformative syndrome or chromosomopathy), 38 had progressive conditions without curative options (group 3; 30 neuromuscular diseases, 8 neurological progressive disease of unknown origin), 7 had irreversible but not progressive conditions (group 4; cerebral palsy). When HMV was started 17 patients had severe cognitive impairment, and HMV was indicated to improve quality of life by reducing hospital visits. During follow up, 3 patients died and 3 were weaned from HMV (group 1). Only 4 patients were included in a pediatric palliative care program. Conclusions : Up to 95% of patients with HMV can benefit from palliative care. HMV in children with chronic conditions aims to ameliorate their quality of life, but may pose ethical dilemmas.

Summary Phlebectasia is an abnormal sacculofusiform dilatation, usually unilateral, which may affect any vein. It is infradiagnosed as it is generally asymptomatic. Sometimes it is diagnosed during the study of an intermittent mass. Phlebectasia of internal jugular vein is a rare disease, which mostly involved only the right side and it usually is a childhood disease. Its treatment is controversial. Nowadays a conservative approach to unilateral or bilateral asymptomatic phlebectasia is recommended. Symptomatic phlebectasia requires surgery. We present a case of a bilateral phlebectasia in a 23-month-old male child.

Aims: The presence of fungi in the airways of patients with cystic fibrosis (CF) is common, the most prevalent species being Aspergillus and Candida. However, it is unknown its role in the disease. The aim is to describe the changes over time of fungal microbiota and evaluate the clinical aspects related to them Methods: Prospective observational cohort study including children and adults with CF. Clinical and functional data and a sample of sputum at baseline and at 6 months were collected. The microbiological study was performed in sputum with conventional culture and a metagenomics approach using nested polymerase chain reaction and direct sequencing. The prevalence of fungal colonization by both techniques and the relationship with clinical variables of patients and their evolution are analysed Results: 63 CF patients were included, 46 adults and 17 children. In children, conventional cultivation detected no fungus, while metagenomics detected 14 (82.4%)cases. In adults, the metagenomic screening improved from 14 cases (30.4%) by culture to 32 (69.6%). The fungi were detected mainly Candida (38.1%) and Aspergillus (11.1%). In the basal visit, patients with isolates presented a lower FEV1 and a higher proportion of inhaled steroids use. At 6 months, these isolates were persistent in 47.6% and 11.1% presented new isolates in negative subjects. Patients with acquired fungus isolation presented a worse lung function FEV1 (-120 mL) as compared with persistent negative patients (+109 mL; p =0.088) Conclusions: Metagenomics studies identifies a larger population of fungal microbiota in CF that remains over time in a good proportion of patients. Newly acquired isolations have an impact on the disease progression.

Cystic fibrosis is a single gene, autosomal recessive disorder, in which more than 1,900 mutations grouped into 6 classes have been described. It is an example a disease that could be well placed to benefit from personalised medicine. There are currently 2 very different approaches that aim to correct the basic defect: gene therapy, aimed at correcting the genetic alteration, and therapy aimed at correcting the defect in the CFTR protein. The latter is beginning to show promising results, with several molecules under development. Ataluren (PTC124) is a molecule designed to make the ribosomes become less sensitive to the premature stop codons responsible for class i mutations. Lumacaftor (VX-809) is a CFTR corrector directed at class ii mutations, among which Phe508del is the most frequent, with encouraging results. Ivacaftor (VX-770) is a potentiator, the only one marketed to date, which has shown good efficacy for the class iii mutation Gly551Asp in children over the age of 6 and adults. These drugs, or a combination of them, are currently undergoing various clinical trials for other less common genetic mutations. In the last 5 years, CFTR has been designated as a therapeutic target. Ivacaftor is the first drug to treat the basic defect in cystic fibrosis, but only provides a response in a small number of patients. New drugs capable of restoring the CFTR protein damaged by the most common mutations are required.