SARS-CoV-2 infection in children with cystic fibrosis: A cross-sectional multicenter study in Spain. New waves, new knowledge.

INTRODUCTION: The association between viral infections and pulmonary exacerbations in children with cystic fibrosis (cwCF) is well established. However, the question of whether cwCF are at a higher risk of COVID-19 or its adverse consequences remains controversial. METHODS: We conducted an observational, multicenter, cross-sectional study of cwCF infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) between March 2020 and June 2022, (first to sixth 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 (sixth 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%). Infection occurring along the sixth wave was the only independent risk factor for being symptomatic. Just eight cwCF needed hospital admission. No multisystem inflammatory syndrome, 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, a worldwide monitoring of COVID-19 in pediatric CF patients is needed.

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. METHODOLOGY: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. RESULTS: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. CONCLUSIONS: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.

False negatives in the newborn screening for cystic fibrosis in Western Andalusia: Results from a 10-year experience.

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 462,049 newborns were screened for CF using a two-step IRT determination and chloride sweat test. Sixty-three 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.

Evaluation of bone metabolism in children with cystic fibrosis.

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 < 0,001). Moreover, we found that PTH (OR = 1.070; 95% CI 1.019-1.123), and TNFα (OR = 2.173; 95% CI 1.514-3.118) were significantly linked to CF, and calcium (OR = 0.115; 95% CI 0.025-0.524), 1,25-vitamin D (OR = 0.979; 95% CI 0.962 0.996) and OPG (OR = 0.189; 95% CI 0.073-0.489) were significant reduced. 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.

Resultados del cribado neonatal de Andalucía Occidental tras una década de experiencia / Results of the neonatal screening on Western Andalusia after a decade of experience

OBJETIVO: La principal justificación del trabajo fue describir nuestra experiencia en cribado neonatal y definir la prevalencia de cada una de las enfermedades incluidas en el programa de cribado neonatal de Andalucía, entre las que se encuentran el hipotiroidismo congénito, cribado ampliado expandido (aminoacidopatías, defectos de la beta-oxidación mitocondrial y acidurias orgánicas), fibrosis quística y enfermedad de células falciformes. MÉTODOS: El estudio se realizó en la Unidad del Laboratorio de Metabolopatías del Hospital Universitario Virgen del Rocío de Sevilla con muestras de recién nacidos de Andalucía Occidental (Cádiz, Córdoba, Huelva y Sevilla) y la ciudad autónoma de Ceuta. Para descartar hipotiroidismo congénito y cribado ampliado expandido se estudiaron un total de 435.141 recién nacidos, con fecha de inicio el 1 de abril de 2009. El cribado de fibrosis quística comenzó el 1 de mayo de 2011, siendo estudiados un total de 378.306 recién nacidos. Por último, el 26 de noviembre de 2018 se incorporó el cribado de anemia de células falciformes, que comprendió un total de 55.576 recién nacidos. La fecha fin de estudio fue el 31 de diciembre de 2019 para todas las patologías descritas anteriormente. El análisis estadístico se realizó usando el software IBM SPSS (versión 22, SPSS INC., EEUU). RESULTADOS: El estudio reveló una prevalencia de 1:1.565 recién nacidos para hipotiroidismo congénito, 1:1.532 para cribado ampliado expandido, 1:6.878 para fibrosis quística y 1:11.115 recién nacidos para enfermedad de células falciformes. CONCLUSIONES: El programa de cribado neonatal permite que se beneficien gran número de recién nacidos en la detección precoz de determinadas enfermedades congénitas graves y, con ello, mejora la morbimortalidad de aquellos que las padecen

OBJECTIVE: The main justification of this study was to describe our experience in neonatal screening and to define the prevalence of the diseases included in the neonatal screening program in Andalusia, among which are congenital hypothyroidism, expanded screening (aminoacidopathies, mitochondrial beta-oxidation defects and organic acidurias), cystic fibrosis, and screening for sickle cell anemia. METHODS: The study was carried out in the Metabolopathies Unit of the Virgen del Rocío Hospital in Seville with samples of newborns from Western Andalusia (Cádiz, Córdoba, Huelva and Seville) and autonomous city of Ceuta. A total of 435,141 newborns were studied (from the period from April 1st 2009 to December 31st 2019) to rule out congenital hypothyroidism and expanded screening; 378,306 for cystic fibrosis from May 1st 2011 to the same date described above. Finally, sickle cell anemia screening was included, which comprised a total of 55,576 newborns from November 26th, 2018 to the same period as the previous ones. Statistical analysis was performed using IBM SPSS software (version 22, SPSS INC., USA). RESULTS: The study revealed a prevalence of 1:1565 newborns for congenital hypothyroidism, 1:1532 newborns for extended screening, 1:6.878 newborns for cystic fibrosis, and a 1:11.115 newborns for sickle cell disease. CONCLUSIONS: The neonatal screening program allows a large number of newborns to benefit from the early detection of certain serious congenital diseases. This aim improves the morbidity and mortality of those who suffer from them

Lung Growth and Aging: A Complex and Increasingly Confounding Network / Desarrollo pulmonar y envejecimiento: una compleja red cada vez más desconcertante

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Spanish multicentre study on morbidity and pathogenicity of tracheal bronchus in children.

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.

Hemoptisis y bronquiolitis obliterante en niños con papilomatosis laríngea recurrente: reacciones adversas al cidofovir nebulizado / Hemoptysis and Bronchiolitis Obliterans in Children with Recurrent Respiratory Papillomatosis: Adverse Reactions to Nebulized Cidofovir

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Atelectasia persistente en paciente con fibrosis quística: ¿debemos tratarla siempre con antibioterapia? / Persistent Atelectasis in a Patient With Cystic Fibrosis: Are Antibiotics Always Needed?

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Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience.

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<40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months. 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 19.9kg/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.

Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience / Uso compasivo de lumacaftor/ivacaftor en fibrosis quística: experiencia española

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 < 40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125 mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months. 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

Introducción: La mutación causante de fibrosis quística (FQ) más frecuente es la deltaF508 (F508del), presente en el 28% de los pacientes españoles con FQ. Aunque la literatura sobre estudios en vida real en pacientes de FQ homocigotos para F508del tratados con lumacaftor/ivacaftor es escasa, pone de manifiesto la necesidad de contar con mejores estrategias para prevenir los efectos adversos (EA) relacionados con el tratamiento, así como del desarrollo de nuevos fármacos. Métodos: Se realizó un estudio observacional, retrospectivo multicéntrico para describir los efectos del tratamiento con lumacaftor/ivacaftor en vida real en España. Se incluyeron 20 pacientes con FQ, edad superior a los 6 años y ppFEV1 < 40%, procedentes de unidades de FQ de todo el país. Para los fines del estudio, fueron tratados con 2 comprimidos de lumacaftor/ivacaftor 200/125 mg/2 veces al día como parte de un programa de uso compasivo a lo largo de 2016. El criterio de valoración primario se midió en las muestras de todos los pacientes. Los datos de ppFEV1 se analizaron al inicio y cada 6 meses. Resultados: La mediana de edad fue de 26,65 (rango: 10-45), mientras que la mediana de ppFEV1 antes del tratamiento fue del 32,4% y la mediana del IMC 19,9 kg/m2. No se encontraron diferencias al analizar los cambios de ppVEF1 e IMC desde el inicio y durante el tratamiento con lumacaftor/ivacaftor. Sin embargo, se estableció una asociación moderada entre los días requeridos de antibiótico intravenoso y el uso de lumacaftor/ivacaftor (p = 0,001). De hecho, con lumacaftor/ivacaftor, los pacientes requirieron 5,8 días de tratamiento intravenoso con antibiótico, comparado con los 14,9 días previos al estudio. Además, el número de exacerbaciones pulmonares graves que requirieron hospitalización fue estadísticamente menor con lumacaftor/ivacaftor (p = 0,003). Por último, el 75% de la muestra presentó EA, lo cual supuso la discontinuación del tratamiento en un 35% de los casos. Conclusión: El tratamiento con lumacaftor/ivacaftor mejoró el número de exacerbaciones pulmonares severas, pero no supuso mejora ni en el ppFEV1 ni el IMC

Mycobacterium lentiflavum en pacientes con fibrosis quística: ¿colonizante o patogénico? / Mycobacterium Lentiflavum in Cystic Fibrosis Subjects. A Colonizer or a True Pathogen?

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Resultados del programa de screening neonatal de fibrosis quística en Andalucía tras 5 años de su implantación / Results of the Andalusian Cystic Fibrosis Neonatal Screening Program, 5 Years After Implementation

Introducción: Andalucía dispone de screening neonatal de fibrosis quística (SNFQ) desde mayo 2011, basado en doble determinación de tripsinógeno inmunorreactivo ([TIR] [TIR1/TIR2]). Si el screening es positivo realizamos un test del sudor y si es positivo o dudoso solicitamos genética. Objetivo: Analizar el SNFQ, basado en los resultados de los primeros 4,5 años. Material y método: Estudio descriptivo prospectivo de los neonatos sometidos a SNFQ. Se recogen los niveles de TIR, cloruro en sudor, mutaciones. Mediante SPSS12.0 se realizó análisis estadístico. 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 implantación del SNFQ se diagnosticaron 73 casos con fibrosis quística; 60 de ellos fueron diagnosticados mediante un SNFQ positivo, mientras que 13 no. Concretamente un paciente comenzó con clínica clásica de fibrosis quística y se comprobó que no se había realizado el SNFQ por decisión paterna; los 12 restantes tuvieron un SNFQ negativo (falsos negativos). De estos, un paciente fue diagnosticado presintomáticamente al tener su hermano gemelo con SNFQ positivo; otro con cloruro en el límite alto de la normalidad se diagnosticó presintomáticamente mediante genética; 10 pacientes comenzaron clínicamente. Excluyendo los pacientes con íleo meconial, la sensibilidad y especificidad del programa de SNFQ asciende al 85,71 y 99,78% respectivamente. La incidencia de la enfermedad en Andalucía es de 1/6.506 recién nacidos vivos. Conclusión: Los presentes resultados nos permiten reflexionar sobre posibles áreas de mejoras adicionales del algoritmo del SNFQ, que debe pasar por la introducción de estudios genéticos para así aumentar la sensibilidad y disminuir los falsos positivos

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, 1,087 (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 1/6,506 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

Tumores endobronquiales primarios en edad pediátrica / Primary Endobronchial Tumors in Childhood

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Results of the Andalusian Cystic Fibrosis Neonatal Screening Program, 5 Years After Implementation. / Resultados del programa de screening neonatal de fibrosis quística en Andalucía tras 5 años de su implantación.

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, 1,087 (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 1/6,506 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.