Inhaled aztreonam lysine in the management of Pseudomonas aeruginosa in patients with cystic fibrosis: real-life effectiveness.

BACKGROUND: Inhaled antibiotics have achieved or stabilised the clinical condition of patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection. We aimed to determine the effectiveness of aztreonam lysine inhaled solution (AZLI) in patients with CF and chronic P. aeruginosa infection. METHODS: A retrospective observational study was conducted on patients with CF and chronic P. aeruginosa infection who received AZLI between July 2012 and September 2018 inclusive in three Spanish hospitals in a routine clinical practice setting. The primary endpoint was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) compared with the previous 12 months, at the start of AZLI treatment and 12 months after starting the drug. Other variables analysed were exacerbations, hospitalisations, type and route of antibiotics prescribed, weight and body mass index (BMI) and adverse drug reactions. RESULTS: In a cohort of 52 patients, AZLI treatment led to stabilisation of FEV1, changing from a mean (SD) value of 55.60 (21.3)% at the start of treatment to 56.8 (20.4)% after 12 months of treatment (p=0.5296) in patients who had not previously received the drug. In addition, it significantly reduced exacerbations from a median (P25; P75) of 2.0 (1.0; 3.0) in the 12 months prior to AZLI to 1.0 (1.0; 2.0) in the 12 months after treatment initiation (p=0.0350). AZLI also reduced the need for other antibiotics and prevented a decrease in BMI, with an adequate safety profile. CONCLUSIONS: AZLI achieved stabilisation of lung function measured by FEV1 in patients with CF and chronic P. aeruginosa infection, along with an adequate safety profile.

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.

Prenatal Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Promising Way to Change the Impact of Cystic Fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is a potentially severe disease. The development of new therapies with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been a great advance in the management of this condition because they improve the function of the faulty CFTR protein rather than palliate its consequences. CFTR modulator therapy improves pancreatic and lung function and, therefore, quality of life, with greater benefits the sooner treatment is started. For this reason, the use of these therapies is being approved for increasingly younger patients. Only two cases of pregnant women taking CFTR modulator therapy with CF fetuses have been reported, suggesting that it could resolve meconium ileus (MI) prenatally and delay/prevent other consequences of CF. CASE PRESENTATION: We report a case of a healthy pregnant patient who underwent CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) in order to treat her fetus with CF (F508del homozygous CFTR mutation) and MI. Ultrasound findings suggestive of MI were observed at 24 weeks. Both parents were tested for CFTR mutations, and both were carriers of the F508del CFTR mutation. The fetus was diagnosed with CF by amniocentesis at 26+2 weeks. Maternal ETI therapy was initiated at 31+1 weeks, and no dilated bowel was observed at 39 weeks. There were no signs of bowel obstruction after birth. Maternal ETI treatment was continued during breastfeeding, with normal liver function. Immunoreactive trypsinogen in the newborn was 58.1 ng/mL, sweat chloride test was 80 mmol/L, and fecal elastase on the second day of life was 58 µg/g. CONCLUSION: Prenatal ETI treatment, as well as during breastfeeding, could solve, prevent, and/or delay CF complications.

Statistical Evaluation of Metaproteomics and 16S rRNA Amplicon Sequencing Techniques for Study of Gut Microbiota Establishment in Infants with Cystic Fibrosis.

Newborn screening for cystic fibrosis (CF) can identify affected but asymptomatic infants. The selection of omic technique for gut microbiota study is crucial due to both the small amount of feces available and the low microorganism load. Our aims were to compare the agreement between 16S rRNA amplicon sequencing and metaproteomics by a robust statistical analysis, including both presence and abundance of taxa, to describe the sequential establishment of the gut microbiota during the first year of life in a small size sample (8 infants and 28 fecal samples). The taxonomic assignations by the two techniques were similar, whereas certain discrepancies were observed in the abundance detection, mostly the lower predicted relative abundance of Bifidobacterium and the higher predicted relative abundance of certain Firmicutes and Proteobacteria by amplicon sequencing. During the first months of life, the CF gut microbiota is characterized by a significant enrichment of Ruminococcus gnavus, the expression of certain virulent bacterial traits, and the detection of human inflammation-related proteins. Metaproteomics provides information on composition and functionality, as well as data on host-microbiome interactions. Its strength is the identification and quantification of Actinobacteria and certain classes of Firmicutes, but alpha diversity indices are not comparable to those of amplicon sequencing. Both techniques detected an aberrant microbiota in our small cohort of infants with CF during their first year of life, dominated by the enrichment of R. gnavus within a human inflammatory environment. IMPORTANCE In recent years, some techniques have been incorporated for the study of microbial ecosystems, being 16S rRNA gene sequencing being the most widely used. Metaproteomics provides the advantage of identifying the interaction between microorganisms and human cells, but the available databases are less extensive as well as imprecise. Few studies compare the statistical differences between the two techniques to define the composition of an ecosystem. Our work shows that the two methods are comparable in terms of microorganism identification but provide different results in alpha diversity analysis. On the other hand, we have studied newborns with cystic fibrosis, for whom we have described the establishment of an intestinal ecosystem marked by the inflammatory response of the host and the enrichment of Ruminococcus gnavus.

Airway microbiota in patients with paediatric cystic fibrosis: Relationship with clinical status.

INTRODUCTION: New massive sequencing techniques make it possible to determine the composition of airway microbiota in patients with cystic fibrosis (CF). However, the relationship between the composition of lung microbiome and the clinical status of paediatric patients is still not fully understood. MATERIAL AND METHODS: A cross-sectional observational study was conducted on induced sputum samples from children with CF and known mutation in the CFTR gene. The bacterial sequences of the 16SrRNA gene were analyzed and their association with various clinical variables studied. RESULTS: Analysis of the 13 samples obtained showed a core microbiome made up of Staphylococcus spp., Streptococcus spp., Rothia spp., Gemella spp. and Granulicatella spp., with a small number of Pseudomonas spp. The cluster of patients with less biodiversity were found to exhibit a greater number of sequences of Staphylococcus spp., mainly Staphylococcus aureus (p 0.009) and a greater degree of lung damage. CONCLUSION: An airway microbiome with greater biodiversity may be an indicator of less pronounced disease progression, in which case new therapeutic interventions that prevent reduction in non-pathogenic species of the airway microbiota should be studied.

Airway microbiota in patients with paediatric cystic fibrosis: Relationship with clinical status / Microbiota respiratoria en pacientes pediátricos con fibrosis quística: relación con la situación clínica

Introduction: New massive sequencing techniques make it possible to determine the composition of airway microbiota in patients with cystic fibrosis (CF). However, the relationship between the composition of lung microbiome and the clinical status of paediatric patients is still not fully understood. Material and methods: A cross-sectional observational study was conducted on induced sputum samples from children with CF and known mutation in the CFTR gene. The bacterial sequences of the 16SrRNA gene were analyzed and their association with various clinical variables studied. Results: Analysis of the 13 samples obtained showed a core microbiome made up of Staphylococcus spp., Streptococcus spp., Rothia spp., Gemella spp. and Granulicatella spp., with a small number of Pseudomonas spp. The cluster of patients with less biodiversity were found to exhibit a greater number of sequences of Staphylococcus spp., mainly Staphylococcus aureus (p 0.009) and a greater degree of lung damage. Conclusion: An airway microbiome with greater biodiversity may be an indicator of less pronounced disease progression, in which case new therapeutic interventions that prevent reduction in non-pathogenic species of the airway microbiota should be studied

Introducción: Las nuevas técnicas de secuenciación masiva permiten determinar la composición de la microbiota de las vías respiratorias en pacientes con fibrosis quística (FQ). Sin embargo, la relación entre la composición de la microbiota pulmonar y el estado clínico de los pacientes pediátricos todavía no se ha establecido bien. Material y métodos: Se realizó un estudio transversal observacional en muestras de esputo inducido de niños con FQ y mutación conocida en el gen CFTR. Se analizaron las secuencias bacterianas del gen 16SrRNA y se estudió su asociación con diversas variables clínicas. Resultados: El análisis de las 13 muestras obtenidas mostró un microbioma central compuesto por Staphylococcus spp., Streptococcus spp., Rothia spp., Gemella spp. y Granulicatella spp., con un pequeño número de Pseudomonas spp. Se descubrió que el grupo de pacientes con menos biodiversidad mostraba un mayor número de secuencias de Staphylococcus spp., principalmente Staphylococcus aureus (p 0,009) y un mayor daño de la función pulmonar. Conclusión: La mayor biodiversidad del microbioma de vía respiratoria puede ser un indicador de menor progresión de la enfermedad, en cuyo caso deben estudiarse nuevas intervenciones terapéuticas que prevengan la disminución de especies no patógenas

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

Screening for symptoms of obstructive sleep apnea in children with severe craniofacial anomalies: assessment in a multidisciplinary unit.

OBJECTIVE: To assess the incidence of airway obstruction symptoms and the presence of obstructive sleep apnea in children with severe craniofacial anomalies by a proactive screening program using a standard questionnaire and cardiorespiratory polygraphy. PATIENTS AND METHODS: Children with severe craniofacial anomalies referred to our paediatric airway unit from February 2001 to June 2011 were eligible to be included in this retrospective, single centre study. Symptoms of airway obstruction were proactively investigated using the shorter version of the Pediatric Sleep Questionnaire (PSQ). Obstructive sleep apnea was assessed by means of cardiorespiratory polygraphy. Demographic data and reason for referral were also recorded. Primary outcomes were the prevalence of symptoms of airway obstruction and OSA. RESULTS: 44 children (24 girls) with severe craniofacial anomalies (15 Crouzon, 13 Apert, 9 Goldenhar, 5 Treacher-Collins, 2 Pfeiffer) were included, at a mean age of 5 years (range 8 months to 14 years). Reason for referral was routine follow up in 30 patients and overt OSA symptoms and signs in the remaining 14. PSQ results showed symptoms of airway obstruction in 82% of patients, being snoring the most frequent symptom (64.1%) followed by apneas (33.3%). Polygraphic studies showed inconclusive results in 8 children (18.2%), normal apnea-hypopnea index (AHI) in 16 (36.4%), mild obstructive sleep apnea in 9 (20.4%), moderate in 4 (9.1%) and severe obstructive sleep apnea in 7 (15.9%). CONCLUSIONS: Children with craniofacial anomalies have a high prevalence of symptoms of airway obstruction and obstructive sleep apnea that support a proactive screening strategy in this highly selected population.

The role of bronchoscopy in the management of patients with severe craniofacial syndromes.

PURPOSE: The purpose of this study is to assess the incidence of airway anomalies in children with severe craniofacial syndromes and to establish the role of bronchoscopy in the care of these patients. METHODS: Consecutive children with craniofacial syndromes, including both bony deformities of the skull and face, in which a bronchoscopy was performed between 1995 and 2010 were retrospectively reviewed. RESULTS: Thirty-six patients (22 boys, 14 girls; mean age, 39 months) were studied. Craniofacial synostosis was present in 21 patients (Crouzen syndrome, 11; Apert syndrome, 7, Pfeiffer syndrome, 3) and craniofacial dysostosis in 15 (Goldenhart syndrome, 8; Treacher Collins syndrome, 7). In 30 patients (83.3%), bronchoscopy was performed because of respiratory symptoms (apneic episodes, 22; respiratory distress, 13; stridor, 6; cyanosis, 1) and, in the remaining 6 (asymptomatic children), during guided tracheal intubation before a surgical procedure. Airway anomalies were found in 69.4% of patients (70% in symptomatic patients). Management consisted of tracheotomy in 13 patients, adenoidectomy/tonsillectomy in 13, glossopexy in 5, antireflux surgery in 3, and supraglottoplasty in 2. CONCLUSIONS: Airway anomalies occurred in 70% of children with severe craniofacial syndromes and respiratory symptoms. Bronchoscopy should be performed routinely in this selected group of patients, and the entire airway must be examined. Treatment should be tailored to each individual patient.