Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

Bacteria from bronchoalveolar lavage fluid from children with suspected chronic lower respiratory tract infection: results from a multi-center, cross-sectional study in Spain.

This cross-sectional study assessed the prevalence of bacteria isolated from Spanish children with suspected chronic lower respiratory tract infection (LRTI) for whom bronchoalveolar lavage (BAL) was indicated. BAL fluid (BALF) was collected from 191 children (aged ≥ 6 months to < 6 years, with persistent or recurrent respiratory symptoms, non-responders to usual treatment) and cultured. Nasopharyngeal swabs (NPSs) were also obtained and cultured to assess concordance of BALF and NPS findings in the same patient. Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis were identified from BALF with a bacterial load indicative of infection (> 104 colony-forming units/mL) in 10.5, 8.9, and 6.3% of children, respectively. Clinical characteristics were similar among participants, regardless of positivity status for any of the bacteria. Approximately 26% of pneumococcal isolates were PCV13 serotypes, and 96% of H. influenzae isolates were non-typeable (NTHi). Concordance between BALF and NPS isolates was 51.0% for S. pneumoniae, 52.1% for H. influenzae, and 22.0% for M. catarrhalis. CONCLUSION: S. pneumoniae, NTHi, and M. catarrhalis were the main bacteria detected in BALF and NPS. Children with suspected chronic LRTI may benefit from a vaccine protecting against NTHi. What is Known: • Chronic lower respiratory tract infection (LRTI) in children can cause high morbidity and is a major use of healthcare resources worldwide. Despite this, their etiology or potential preventive measures are poorly assessed. • Bronchoalveolar lavage can be used to determine bacterial etiology of chronic LRTI. What is New: • We used conventional and molecular techniques to show that Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis were present in the LRT of Spanish children with suspected chronic LRTI • Concordance between isolates from bronchoalveolar lavage fluid and nasopharyngeal swabs was low, suggesting that samples from the upper respiratory tract could not reliably predict the bacterial etiology of suspected chronic LRTI.

Long term follow-up of a tobacco prevention and cessation program in cystic fibrosis patients. / Seguimiento a largo plazo de un programa de prevención y cesación tabáquica en pacientes con fibrosis quística.

This study evaluates the impact over time of a telephone-based intervention in tobacco cessation and prevention targeting patients with cystic fibrosis (CF) in the Mediterranean region of Murcia, Spain. We conducted an experimental prospective study with a cohort of CF patients using an integrative smoking cessation programme, between 2008 and 2013. The target population included family members and patients from the Regional CF unit. The study included an initial tobacco exposure questionnaire, measurement of lung function, urinary cotinine levels, anthropomorphic measures and the administered intervention at specific time intervals. Of the 88 patients tracked through follow-up, active smoking rates were reduced from 10.23% to 4.55% (p = 0.06). Environmental tobacco exposure was reduced in non-smoker patients from 62.03% to 36.90% (p < 0.01) during the five year follow-up. Significant reductions in the gradient of household tobacco smoke exposure were also observed with a decrease of 12.60%, from 31.65% (n = 25/79) to 19.05% (n = 16/84) in 2013 (p = <0.01). Cotinine was significantly correlated with both active and passive exposure (p<0.01) with a significant reduction of cotinine levels from 63.13 (28.58-97.69) to 20.56 (0.86-40.27) ng/ml (p<0.01). The intervention to significantly increase the likelihood of family quitting (smoke-free home) was 1.26 (1.05-1.54). Telephone based interventions for tobacco cessation and prevention is a useful tool when applied over time. Trained intervention professionals in this area are needed in the environmental health approach for the treatment of CF.

Este estudio evalúa el impacto en el tiempo de una intervención telefónica de prevención y cesación tabáquica dirigida a pacientes con fibrosis quística (FQ) en la Región de Murcia, España. Estudio prospectivo experimental en una cohorte de pacientes con FQ utilizando un programa integrativo de cesación tabáquica, entre 2008 y 2013. La población diana incluye a pacientes y familiares de la unidad regional de FQ. El estudio incluyó un cuestionario inicial de exposición al tabaco, medición de la función pulmonar, niveles de cotinina en orina, medidas antropomórficas y la intervención realizada en intervalos de tiempo.De los 88 pacientes seguidos, la tasa de fumadores activos se redujo de 10,23% a 4,55% (p = 0,06). La exposición al humo ambiental de tabaco se redujo en los pacientes no fumadores de 62,03% a 36,90% (p < 0,01) durante los cinco años de seguimiento. Se observaron reducciones significativas en la exposición al humo ambiental de tabaco en los hogares, de 31,65% (n = 25/79) a 19,05% (n = 16/84) en 2013 (p = <0,01). La cotinina se correlacionó significativamente con la exposición al tabaco activa y pasiva (p < 0,01) con una reducción significativa de los niveles de cotinina de 63,13 (28,58-97,69) a 20,56 (0,86-40,27) ng/ml (p < 0,01). La intervención para aumentar significativamente la probabilidad de abandono familiar (hogar libre de humo) fue de 1,26 (1,05-1,54). La intervención telefónica mantenida en el tiempo es una herramienta útil para la prevención y cesación tabáquica. Profesionales entrenados en este modelo de intervención con enfoque en salud medioambiental son necesarios para mejorar el tratamiento de FQ.

Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

HLA-DRB1 and HLA-DQB1 genes on susceptibility to and protection from allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity pulmonary disease that affects both patients with cystic fibrosis (CF) and those with asthma. HLA-DRB1 alleles have previously been associated with ABPA-CF susceptibility; however, HLA-DQB1 allele associations have not been clearly established. The aim of the present study was to investigate HLA class II associations in patients with ABPA-CF and determine their roles in susceptibility or protection. Patients with ABPA-CF, patients with CF without ABPA, patients with asthma without ABPA (AST), and healthy controls were included in this study. DNA was extracted by automatic extractor. HLA-DRB1 and -DQB1 genotyping was performed by the Luminex PCR-SSOP method (One Lambda, Canoga Park, CA, USA). Allele specific PCR-SSP was also performed by high-resolution analysis (One Lambda). Statistical analysis was performed with SSPS and Arlequin software. Both HLA-DRB1*5:01 and -DRB1*11:04 alleles occurred with greater frequency in patients with ABPA-CF than in those with AST and CF and control subjects, corroborating previously published data. On the other hand, analysis of haplotypes revealed that almost all patients with ABPA-CF lacking DRB1*15:01 or DRB1*11:04 carry either DRB1*04, DRB1*11:01, or DRB1*07:01 alleles. In the HLA-DQB1 region, the HLA-DQB1*06:02 allele occurred more frequently in patients with ABPA-CF than in those with AST and CF and healthy controls, whereas HLA-DQB1*02:01 occurred less frequently in patients with ABPA-CF. These data confirm that there is a correlation between HLA-DRB1*15:01, -DRB1*11:04, DRB1*11:01, -DRB1*04 and -DRB1*07:01 alleles and ABPA-CF susceptibility and suggest that HLA-DQB1*02:01 is an ABPA-CF resistance allele.

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.

Analysis of the genotypic profile and its relationship with the clinical manifestations in people with cystic fibrosis: study from a rare disease registry.

BACKGROUND: Cystic fibrosis (CF) has a vast and heterogeneous mutational spectrum in Europe. This variability has also been described in Spain, and there are numerous studies linking CFTR variants with the symptoms of the disease. Most of the studies analysed determinate clinical manifestations or specific sequence variants in patients from clinical units. Others used registry data without addressing the genotype-phenotype relationship. Therefore, the objective of this study is to describe the genetic and clinical characteristics of people with CF and to analyse the relationship between both using data from the rare disease registry of a region in southeastern Spain. METHODS: A cross-sectional study was carried out in people with a confirmed diagnosis of CF registered in the Rare Diseases Information System (SIER) of the Region of Murcia (Spain). The patients were classified into two genotypes according to the functional consequence that the genetic variants had on the CFTR protein. RESULTS: There were 192 people diagnosed with CF reported in the Region of Murcia as of 31 December 2018. Seventy-six genotypes and 49 different variants were described, with c.1521_1523delCTT (p. Phe508del) being the most common in 58.3% of the CF patients and 37.0% of the alleles. In addition, 67% of the patients were classified as a high-risk genotype, which was associated with a lower percentage of FEV1 (OR: 5.3; 95% CI: 1.2, 24.4), an increased risk of colonization by Pseudomonas aeruginosa (OR: 7.5; 95% CI: 1.7, 33.0) and the presence of pancreatic insufficiency (OR: 28.1; 95% CI: 9.3, 84.4) compared to those with a low-risk genotype. CONCLUSIONS: This is the first study in Spain that describes the mutational spectrum and its association with clinical manifestations in patients with CF using data from a rare disease registry. The results obtained allow planning for the health resources needed by people with this disease, thus contributing to the development of personalized medicine that helps to optimize health care in CF patients.

Factors associated with clinical progression to severe COVID-19 in people with cystic fibrosis: A global observational study.

BACKGROUND: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen. RESULTS: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007). CONCLUSIONS: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2.

Geographic distribution and phenotype of European people with cystic fibrosis carrying A1006E mutation.

BACKGROUND: A1006E is a Cystic Fibrosis (CF) mutation that is still not widely known. We report phenotypic features and geographic distribution of the largest cohort of people with CF (pwCF) carrying A1006E to date. METHODS: Study of European pwCF carrying A1006E mutation, included in the European CF Society Patient Registry (ECFSPR). Genotype, ancestries and all variables recorded were compared to a cohort of F508del/F508del patients. Rate of decline in percentage-of-predicted FEV1 (ppFEV1) was also analyzed using the 2010-2017 ECFSPR. RESULTS: 44 pwCF carrying A1006E were reported (59% males), median age 33 years old (3-58), 54.5% Spanish and 40.9% Italian, most with ancestry in Murcia (Spain) and Lazio (Italy) regions. Compared to F508del homozygous, A1006E-pwCF were significantly older (75% vs. 52.5% ≥ 18 years old) and diagnosed at later median age (6.98 vs. 0.29 years); showed lower rates of meconium ileus (2.33% vs. 17.7%), pancreatic insufficiency (27.91% vs. 99.26%), diabetes (2.33% vs. 21.98%), liver disease (6.98% vs. 36.72%) and Pseudomonas aeruginosa chronic colonization (30.95% vs. 42.51%); and presented better nutrition (BMI z-score 0.44 vs. -0.43) and ppFEV1 (90.8% vs. 78.6%), with 18.9% (most >40 years old) having a ppFEV1<70%. Additional ppFEV1 decline (0.96% per year) was attributed to F508del/F508del genotype (p = 0.0007). None died or needed organ transplantation during the study period. CONCLUSIONS: A1006E-pwCF are mainly of Western Mediterranean Spanish and Italian descent. When compared with F508del/F508del-pwCF, they usually have a milder form of the disease, associated with pancreatic sufficiency and slower FEV1 decline. However, some will develop progressive respiratory impairment during adulthood.

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

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

Factors associated to functional recovery of left vocal fold motion impairment at two-years-old age in very preterm infants.

OBJECTIVE: To describe a cohort of neonates with left vocal fold motion impairment (LVFMI) and the factors associated to it in the neonatal period; procedures required during LVFMI treatment; and clinical outcomes at the age of 2-years. An additional objective was to study those factors which are likely to be most associated to functional recovery of LVFMI at this age. METHODS: A cohort of patients born in a tertiary care hospital with a diagnosis of left VFMI was included. Factors registered were: gender; clinical presentation at the time of examination; diagnosis of other laryngeal defects associated; data related to their neonatal period (gestational age, congenital heart defects corrective surgery required, neurologic disease, bronchopulmonary dysplasia, non-invasive ventilation required, invasive ventilation required, and tracheostomy required); treatment applied for LVFMI (tracheostomy and/or laryngeal surgery); need of language and hearing therapy; and outcomes considered by the pediatric otolaryngologist at the 2 years-old follow-up visit. RESULTS: A total of 56 patients with LVFMI diagnosis were included. Only 10 patients (17.9%) showed functional recovery from LVFMI at the age of 2 years. We found significant negative association between this recovery and language and hearing therapy (p = 0.03), which was also associated to psychomotor retardation (p < 0.001). Multivariate analysis produced similar results, being language and hearing therapy the only significant factor associated to a worse outcome (OR = 4.77 [CI95% 1.14; 20.08] p = 0.03). CONCLUSION: Psychomotor development retardation is negatively associated to functional recovery of full speech in a preterm infant's population with LVFMI diagnosis, regardless of other factors related to LVFMI etiology and severity.

A multimodal approach to detect and monitor early lung disease in cystic fibrosis.

Introduction: In the early stages, lung involvement in cystic fibrosis (CF) can be silent, with disease progression occurring in the absence of clinical symptoms. Irreversible airway damage is present in the early stages of disease; however, reliable biomarkers of early damage due to inflammation and infection that are universally applicable in day-to-day patient management have yet to be identified.Areas covered: At present, the main methods of detecting and monitoring early lung disease in CF are the lung clearance index (LCI), computed tomography (CT), and magnetic resonance imaging (MRI). LCI can be used to detect patients who may require more intense monitoring, identify exacerbations, and monitor responses to new interventions. High-resolution CT detects structural alterations in the lungs of CF patients with the best resolution of current imaging techniques. MRI is a radiation-free imaging alternative that provides both morphological and functional information. The role of MRI for short-term follow-up and pulmonary exacerbations is currently being investigated.Expert opinion: The roles of LCI and MRI are expected to expand considerably over the next few years. Meanwhile, closer collaboration between pulmonology and radiology specialties is an important goal toward improving care and optimizing outcomes in young patients with CF.

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.

BACKGROUND: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams. METHODS: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020. RESULTS: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease. CONCLUSIONS: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease.

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020.

BACKGROUND: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). METHODS: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. RESULTS: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133). CONCLUSIONS: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination.

Preschool Asthma Symptoms in Children Born Preterm: The Relevance of Lung Function in Infancy.

Background: The aim of the study is to assess whether lung function of infants born preterm predicts wheezing in pre-school age. Methods: A survey of the core wheezing questionnaire of the International Study on Asthma and Allergy in Children was administered to parents of preterm newborns, to whom lung function tests were performed at a corrected age of six months, and who, at the time of the survey, were between three and nine years of age. Results: Low values of all lung function parameters measured, except FVC, were predictors of wheezing at some time in life, (FEV0.5 OR: 0.62 (95%CI 0.39; 0.995); FEV0.5/FVC OR: 0.73 (0.54; 0.99)) FEF75 OR: 0.60 [0.37; 0.93]; FEF25-75 OR: 0.57 (0.37; 0.89)); and of wheezing in the past year (FEV0.5 OR: 0.36 (0.17; 0.76); FEV0.5/FVC OR: 0.59 (0.38; 0.93); FEF75 OR: 0.38 [0.19; 0.76]; FEF25-75 OR: 0.35 (0.17; 0.70). In addition, FEV0.5/FVC values lower than the lowest limit of normality, were predictive of hospital admissions due to wheezing (OR: 3.07; (1.02; 9.25)). Conclusions: Limited lung function in infancy is predictive of both future wheezing and hospitalization for a wheezing episode.

Impact of early caffeine therapy in preterm newborns on infant lung function.

OBJECTIVE: To know the effect of caffeine therapy on infant lung function in preterm infants with a gestational age less than 31 weeks. MATERIAL AND METHODS: Forced vital capacity (FVC), forced expiratory volume at 0.5 seconds (FEV0.5 ), and forced expiratory flows were measured by raised volume rapid thoracoabdominal compression technique; functional residual capacity was measured by plethysmography (FRCpleth ). Compliance of the respiratory system was measured by a single interruption technique (Crs). The Student t test was used to compare lung function measurements between the two groups: treated versus nontreated with caffeine. A multivariate analysis was carried out considering each and every lung function parameter (z-score) as the dependent variable; and gender, gestational age, birth weight (z-score), corrected age, invasive mechanical ventilation (yes/no), and bronchopulmonary dysplasia (BPD) diagnosis (yes/no) as independent ones. Additionally, stratified analyses by BPD diagnosis were performed. RESULTS: The multivariate analysis showed significant higher z-scores of FVC and FEV0.5 in preterm infants treated with caffeine (P = .004 and P = .024, respectively). This result only being significant in the group of non-BPD infants (P = .021 and P = .042), after stratifying by BPD diagnosis. Differences were not found in z-scores of FEV0.5/FVC, FEF75, FEF25-75, FRCpleth, nor Crs. CONCLUSION: Lung function (FVC and FEV0.5 ) is improved in infants born under 31 weeks of gestation when treated with caffeine. This improvement is driven by the group of infants who did not suffer from BPD. Overall, our results show that there is an early beneficial effect of caffeine treatment in infant lung function.

Impact of SARS-CoV-2 infection in patients with cystic fibrosis in Spain: Incidence and results of the national CF-COVID19-Spain survey.

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.

The global impact of SARS-CoV-2 in 181 people with cystic fibrosis.

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group.

[Follow-up protocol of patients with cystic fibrosis diagnosed by newborn screening]. / Protocolo de seguimiento de pacientes con fibrosis quística diagnosticados por cribado neonatal.

Newborn screening (NBS) for cystic fibrosis (CF) is well-established in many countries and provides the opportunity for an early diagnosis and treatment before the development of irreversible structural lung damage. In 1999, Catalonia, Castilla-León, and the Balearic Islands started the NBS programme for CF. In the last 10 years its implementation rapidly spread and all the autonomies offer the NBS programme for CF since 2015. There are many different strategies across Spain. It is believed that it is very opportune to have an updated and consensual guide for the diagnosis, follow-up, and treatment of patients diagnosed by neonatal screening.

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.