Consenso español para la prevención y el tratamiento de la infección bronquial por Pseudomonas aeruginosa en el paciente con fibrosis quística

Resumen Pseudomonas aeruginosa es el patogeno mas importante en la infeccion broncopulmonar en fibrosis quistica (FQ). Solo se erradica en la infeccion inicial, mientras que la reduccion de su carga bacteriana es el objetivo terapeutico en la infeccion cronica y exacerbaciones. El cribado neonatal y la farmacocinetica/farmacodinamica han cambiado el manejo del paciente con FQ. Se debe realizar un seguimiento microbiologico en los pacientes sin infeccion por P. aeruginosa. En la infeccion inicial se recomienda tratamiento inhalado (28 dias) con colistina (0,5-2 MU/8 h), tobramicina (300 mg/12 h) o aztreonam (75 mg/8 h) con o sin ciprofloxacino oral (15-20 mg/kg/12 h, 2-3 semanas). En la infe…

Oxidative stress in ciliated nasal epithelial cells from patients with primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) is a rare disorder characterized by dysfunction of respiratory cilia and impaired mucociliary clearance leading to recurrent airway infection and chronic inflammation appearing in childhood. Rationale and aims: Chronic inflammation has been associated to oxidative stress (OS). Moreover, evidence of increased OS in the airways of stable children with PCD has been shown (Zihlif, N. et al . Pediatr Pulmonol 2006; 41:509-14). We hypothesize that OS would be increased in ciliated nasal epithelial cells (CNEC) from patients with PCD. This study was aimed to assess the OS profile in CNEC isolated from children with PCD. Methods: CNEC were obtained from …

Knowledge of alpha-1 deficiency and primary ciliary dyskinesia by medical students and health professionals

Background: Under-diagnosis and delayed diagnosis are common features in rare diseases, which have negative effects on the patients9 prognosis. A possible explanation could be lack of awareness and education of the health professionals involved in the managements of these patients. Alpha-1-antitrypsin deficiency (AATD) and primary ciliary dyskinesia (DCP) are under-diagnosed rare diseases showing a median diagnosis delay of five to ten years. Methods: A survey was undertaken in paediatricians (general, paediatric pulmonologists and paediatric gastroenterologist) and medical school students to assess their knowledge on AATD and PCD. Results: A total of 624 surveys on AATD and 457 on PCD were…

Comparison of Physical Activity and Sedentary Behaviour between Schoolchildren with Cystic Fibrosis and Healthy Controls: A Gender Analysis

The purpose of this study was to examine differences in sports participation and the levels of physical activity (PA) and sedentary behaviour (SB) between schoolchildren with cystic fibrosis (CF) and a healthy control group (CG) taking into account the gender variable. PA and SB were measured with an accelerometer for 7 consecutive days in 44 children (24 girls

Implementation of a gene panel for genetic diagnosis of primary ciliary dyskinesia

Abstract Introduction Primary ciliary dyskinesia (PCD) is characterized by an alteration in the ciliary structure causing difficulty in the clearance of respiratory secretions. Diagnosis is complex and based on a combination of techniques. The objective of this study was to design a gene panel including all known causative genes, and to corroborate their diagnostic utility in a cohort of Spanish patients. Methods This was a multicenter cross-sectional study of patients with a high suspicion of PCD according to European Respiratory Society criteria. We designed a gene panel for massive sequencing using SeqCap EZ capture technology that included 44 genes associated with PCD. Results We includ…

Persistent tachypnea of infancy: Follow up at school age

Background Persistent tachypnea of infancy (PTI) is a rare pediatric lung disease of unknown origin. The diagnosis can be made by clinical presentation and chest high resolution computed tomography after exclusion of other causes. Clinical courses beyond infancy have rarely been assessed. Methods Patients included in the Kids Lung Register diagnosed with PTI as infants and now older than 5 years were identified. Initial presentation, extrapulmonary comorbidities, spirometry and clinical outcome were analyzed. Results Thirty-five children older than 5 years with PTI diagnosed as infants were analyzed. At the age of 5 years, 74% of the patients were reported as asymptomatic and did not develo…

LSC Abstract – Increased oxidative stress leads to telomere shortening in children with alpha-1 antitrypsin deficiency

Background: Oxidative stress (OS) is involved in the pathophysiology of AATD (Escribano A. et al. Thorax 2015; 70:82-3). In addition, it has been shown that OS accelerates telomere shortening which is associated to higher emphysema risk in COPD patients. Rationale and aims: Since AATD is characterised by chronic OS, we hypothesise that telomere shortening would be accelerated in AATD patients and would be associated with higher risk of developing lung disease. This study is aimed to assess the OS profile, the enzymatic antioxidant defence mechanisms and telomere length (TL) in children with AATD and to study its association with AAT phenotypes. Methods: OS parameters, the activity of the ma…

New Laboratory Protocol to Determine the Oxidative Stress Profile of Human Nasal Epithelial Cells Using Flow Cytometry

Several studies have shown the importance of oxidative stress (OS) in respiratory disease pathogenesis. It has been reported that the nasal epithelium may act as a surrogate for the bronchial epithelium in several respiratory diseases involving OS. However, the sample yields obtained from nasal biopsies are modest, limiting the number of parameters that can be determined. Flow cytometry has been widely used to evaluate cellular OS profiles. It has the advantage that analyses can be performed using a small amount of sample. Therefore, we aimed to set up a new method based on flow cytometry to assess the oxidative profile of human nasal epithelial cells which could be used in research on resp…

Knowledge of Rare Respiratory Diseases among Paediatricians and Medical School Students.

Alpha-1-antitrypsin deficiency (AATD) and primary ciliary dyskinesia (PCD) are underdiagnosed rare diseases showing a median diagnostic delay of five to ten years, which has negative effects on patient prognosis. Lack of awareness and education among healthcare professionals involved in the management of these patients have been suggested as possible causes. Our aim was to assess knowledge of these diseases among paediatricians and medical school students to determine which knowledge areas are most deficient. A survey was designed with questions testing fundamental aspects of the diagnosis and treatment of AATD and PCD. A score equal to or greater than 50% of the maximum score was set as th…

Telomere attrition in peripheral blood mononuclear cells of children with alpha-1 antitrypsin deficiency

Background: Our research group have demonstrated that oxidative stress (OS) is involved in the pathophysiology of alpha-1 antitrypsin deficiency (AATD) (Escribano A. et al. Thorax 2015;70:82-3). In addition, many evidences have shown that OS accelerates telomere shortening in several lung pathologies. Short telomeres have been associated to higher emphysema risk in COPD patients. Rationale: Since AATD is characterised by chronic OS, we hypothesise that telomere shortening would be accelerated in AATD patients and would be associated with higher risk of developing lung disease. Aims: To assess telomere length (TL) in AATD patients and to study its association with AAT phenotypes. Methods: TL…

PULMONARY AND CARDIAC COMPLICATIONS OF STAPHYLOCOCCAL OSTEOMYELITIS

Pulmonary complications of staph.osteomyelitis seem to be infrequent and are seldom related in wide reviews of this entity and in texts of infectious diseases.Cardiac complications are still more infrequently found.However our experience is far from this observation. We have found pneumonic interstitial infiltrates and/or asymptomatic pneumatoceles in about two thirds of children suffering from staph. osteomyelitis to whom we have taken a weekly chest radiograph while they were feverish.Severe forms are rare.Lately,however,we have treated 5 children with acute staph.osteomyelitis,aged 6 to 13,and whith severe pulmonary and cardiac complications.They had broad bone lesions which affected (1)…

IP-10 is an accurate biomarker for the diagnosis of tuberculosis in children.

Summary Objective Performance of IFN-γ assays in children is compromised. Therefore, we investigated the utility of IP-10 for the detection of active tuberculosis (TB) and latent tuberculosis infection (LTBI) diagnosis in children; comparing its positivity with QuantiFERON-TB Gold In-Tube (QFN-G-IT) and T-SPOT.TB. Methods We studied 230 children from three groups: active TB, screening (healthy children without known exposure to active TB patient screened at school or by their paediatrician) and contact-tracing studies. IFN-γ release was determined by QFN-G-IT and T-SPOT.TB. IP-10 was detected in QFN-G-IT supernatants by ELISA. Results When combining QFN-G-IT and IP-10 assays, positive resul…

Lack of effect of azithromycin on QT interval in children: a cohort study.

Macrolides are a group of antimicrobial drugs used widely, being well known for their adverse cardiac effects. Erythromycin and clarithromycin are most commonly associated with these conditions. In recent years, azithromycin (AZM) has been assessed because of its possible relation to arrhythmias (mainly QT interval prolongation) and risk of cardiovascular death.1 The pharmacodynamics of these effects is complex and the occurrence of cardiovascular death is unpredictable.2 However, all published manuscripts on the cardiac effects of AZM to date are cases in adults or …

Implementación de un panel de genes para el diagnóstico genético de la discinesia ciliar primaria

Resumen Introduccion La discinesia ciliar primaria (DCP) es una enfermedad caracterizada por una alteracion en la estructura ciliar que impide el correcto aclaramiento de las secreciones respiratorias. Su diagnostico es complejo y se basa en una combinacion de tecnicas. El objetivo de este estudio fue disenar un panel de genes incluyendo todos los genes causantes conocidos y comprobar su utilidad diagnostica en una cohorte de pacientes espanoles. Metodos Estudio transversal multicentrico de pacientes con sospecha elevada de DCP, aplicando los criterios de la European Respiratory Society. Diseno de un panel de genes para secuenciacion masiva con la tecnologia de captura SeqCap EZ technology,…

Type-Specific Antibodies to Pneumococcal Capsular Polysaccharide Acquired either Naturally or after Vaccination with Prevenar in Children with Underlying Chronic or Recurrent Lung Diseases

ABSTRACT The antibody response to capsular polysaccharides of pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F elicited either naturally or after vaccination with Prevenar was investigated in a cohort of children ( n = 163) with underlying chronic or recurrent lung diseases at risk of developing pneumococcal pneumonia and ultimately invasive disease. Serum concentrations of serotype-specific antibodies, as measured by enzyme-linked immunosorbent assay, in unvaccinated children ( n = 88) were higher in nasopharyngeal carriers ( n = 10) than in noncarriers ( n = 78) both at baseline and during follow-up. However, the antibody levels depended on the serotype and age of the children. Dur…

Ultrastructural patterns of primary ciliar dyskinesia syndrome.

Clinical presentation, ciliary ultrastructure, and nasal mucociliary transport by a radioisotopic technique were analyzed in 14 Kartagener syndrome patients. In this study the most common pattern was the absence of outer and inner dynein arms in 57% of cases. Also reported are 14% patients with short inner dynein arms. A total of 29% of the patients showed normal dynein arms. Mucociliary stasis was observed in 13 cases. Primary ciliary dyskinesia syndrome and Kartagener syndrome are clinically homogeneous and morphologically heterogeneous. The authors conclude that a typical clinical presentation with an altered mucociliary transport obtained by radioisotopic technique is diagnostic althoug…

Alpha-1 antitrypsin deficiency: outstanding questions and future directions

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. METHODS: In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. RESULTS: 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. CONCLUSIONS: 2) Several clinical and…

Diagnosis and treatment of bronchiectasis

Bronchiectasis is the end result of several different diseases that share principles of management. The clinical course usually involves chronic bronchial infection and inflammation, which are associated with progression. The cause of bronchiectasis should always be investigated, particularly when it can be treated. We recommend evaluating etiology, symptoms, bronchial colonization and infection, respiratory function, inflammation, structural damage, nutritional status, and quality of life in order to assess severity and to monitor clinical course. Care should be supervised by specialized units, at least when there is a history of chronic bronchial infection, recurrent exacerbations, or a c…

Espirometría forzada en preescolares sanos bajo las recomendaciones de la ATS/ERS: estudio CANDELA

Resumen: Introducción: actualmente no existen valores de referencia de espirometría forzada en preescolares sanos obtenidos según las recomendaciones publicadas por la American Thoracic Society (ATS) y la European Respiratory Society (ERS) en 2007. El objetivo del estudio es establecer valores espirométricos de referencia en niños preescolares sanos entre los 2 y los 7 años, según recomendaciones ATS/ERS. Material y método: estudio nacional, multicéntrico, descriptivo y transversal, en niños sanos de ambos sexos, mayores de 2 años y menores de 7. Las espirometrías forzadas se realizaron en laboratorios de función pulmonar de las 9 unidades de neumología pediátrica participantes. Los técnico…

Implementation of a gene panel for the genetic diagnosis of primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) is a disease characterized by an alteration in the ciliary structure that causes an abnormal clearance of respiratory secretions. Its diagnosis is complex and is based on a combination of different techniques. The objective of this study was to design a gene panel including all known caustive genes, and to verify the utility for diagnostic in a cohort of Spanish patients. Methods: Multicenter cross-sectional study of patients with high suspicion of PCD, applying the criteria of the European Respiratory Society. Design a gene panel for mass sequencing with SeqCap EZ technology, including 44 PCD-related genes. Results: 79 patients were included, 53…

Decreased glutathione and low catalase activity contribute to oxidative stress in children with α-1 antitrypsin deficiency: Table 1

Background Recent investigations in animal models have revealed oxidative stress and oxidative damage in the pathogenesis of alpha-1 antitrypsin deficiency (AATD). However, no data are available on the oxidative stress status and antioxidant enzyme activity in these patients. This study was aimed to analyse the oxidative stress profile and enzymatic antioxidant defence mechanisms in children with AATD. Methods Oxidative stress parameters and the activity of the main antioxidant enzymes were prospectively measured in serum of fifty-one children diagnosed with AATD and thirty-eight control individuals. Results Oxidative stress was increased in the serum of children with intermediate- (MZ; SZ)…

In vitro genome editing using CRISPR/Cas9 to edit SERPINA1 PiZ mutation

Introduction: The emergence some years ago of the CRISPR/Cas9 system allowed gene therapy to be specific, versatile, cheap and approachable to almost every laboratory. Due to these features, many different genetic diseases such as cystic fibrosis or β-thalassemia have been addressed in cellular models using the CRISPR/Cas9 genetic editing tool. Alpha-1 antytripsin deficiency (AATD) is a rare genetic condition that can provoke respiratory and hepatic symptoms. The Z allele of SERPINA1 gene is a well-characterised point mutation that can trigger the whole pathology. Henceforth, Z mutation is a suitable target for genetic edition using CRISPR/Cas9 in order to develop a gene therapy to treat AA…

Diagnóstico y tratamiento de las bronquiectasias

Bronchiectasis is the end result of several different diseases that share principles of management. The clinical course usually involves chronic bronchial infection and inflammation, which are associated with progression. The cause of bronchiectasis should always be investigated, particularly when it can be treated. We recommend evaluating etiology, symptoms, bronchial colonization and infection, respiratory function, inflammation, structural damage, nutritional status, and quality of life in order to assess severity and to monitor clinical course. Care should be supervised by specialized units, at least in cases of chronic bronchial infection, recurrent exacerbations, or when there is a ca…

New insights in primary ciliary dyskinesia

Introduction: Primary ciliary dyskinesia (PCD) is a rare genetic disease with an estimated prevalence of 1:20.000 births. It is characterized by abnormal motility of cilia, leading to impaired mucociliary clearance, and subsequent infection and chronic inflammation of the airways. PCD also affects spermatozoa and cilia in the Fallopian tubes, contributing to fertility issues; dyskinesia of embryonic nodal cilia causes a random distribution of the organs. Areas covered: An overview of the history, genetics, clinical manifestations in children and adults, diagnostic tests, treatments, and prognosis are reviewed. We also discuss current research and future prospects of PCD. Expert opinion: As …

Immunofluorescence Analysis as a Diagnostic Tool in a Spanish Cohort of Patients with Suspected Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive rare disease caused by an alteration of ciliary structure. Immunofluorescence, consisting in the detection of the presence and distribution of cilia proteins in human respiratory cells by fluorescence, has been recently proposed as a technique to improve understanding of disease-causing genes and diagnosis rate in PCD. The objective of this study is to determine the accuracy of a panel of four fluorescently labeled antibodies (DNAH5, DNALI1, GAS8 and RSPH4A or RSPH9) as a PCD diagnostic tool in the absence of transmission electron microscopy analysis. The panel was tested in nasal brushing samples of 74 patients with clinical suspic…

Recurrent wheezing during the first 3 years of life in a birth cohort of moderate-to-late preterm infants.

Background Data addressing short- and long-term respiratory morbidity in moderate-late preterm infants are limited. We aim to determine the incidence of recurrent wheezing and associated risk and protective factors in these infants during the first 3 years of life. Methods Prospective, multicenter birth cohort study of infants born at 32+0 to 35+0 weeks' gestation and followed for 3 years to assess the incidence of physician-diagnosed recurrent wheezing. Allergen sensitization and pulmonary function were also studied. We used multivariate mixed-effects models to identify risk factors associated with recurrent wheezing. Results A total of 977 preterm infants were enrolled. Rates of recurrent…

Antibiotic resistance and population structure of cystic fibrosis Pseudomonas aeruginosa isolates from a Spanish multi-centre study

The first Spanish multi-centre study on the microbiology of cystic fibrosis (CF) was conducted from 2013 to 2014. The study involved 24 CF units from 17 hospitals, and recruited 341 patients. The aim of this study was to characterise Pseudomonas aeruginosa isolates, 79 of which were recovered from 75 (22%) patients. The study determined the population structure, antibiotic susceptibility profile and genetic background of the strains. Fifty-five percent of the isolates were multi-drug-resistant, and 16% were extensively drug-resistant. Defective mutS and mutL genes were observed in mutator isolates (15.2%). Considerable genetic diversity was observed by pulsed-field gel electrophoresis (70 p…

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 im…

Spanish Consensus on the Prevention and Treatment of Pseudomonas aeruginosa Bronchial Infections in Cystic Fibrosis Patients

Pseudomonas aeruginosa is the main pathogen in bronchopulmonary infections in cystic fibrosis (CF) patients. It can only be eradicated at early infection stages while reduction of its bacterial load is the therapeutic goal during chronic infection or exacerbations. Neonatal screening and pharmacokinetic/pharmacodynamic knowledge has modified the management of CF-patients. A culture based microbiological follow-up should be performed in patients with no infection with P. aeruginosa. At initial infection, inhaled colistin (0,5-2 MU/tid), tobramycin (300 mg/bid) or aztreonam (75 mg/tid) with or without oral ciprofloxacin (15-20 mg/kg/bid, 2-3 weeks) are recommended. In chronic infections, trea…

Cystic fibrosis treatment: targeting the basic defect

ABSTRACTIntroduction: Cystic Fibrosis (CF) is a disease caused by different class mutations in the CF transmembrane conductance regulator (CFTR) gene. It can therefore benefit from a personalized medicine approach based on the individual genotype of each patient.Areas covered: This review provides a detailed overview of the current major development of new CF treatments that target the basic CF defect. The review summarizes gene therapy, mRNA repair strategies, read-through agents, and CFTR-modulators (potentiators, correctors, stabilizers, amplifiers and different combination therapies).Expert opinion: We are currently perhaps at the most exciting stage in the history of CF, with the poten…

International BEAT-PCD Consensus Statement for Infection Prevention and Control for Primary Ciliary Dyskinesia in collaboration with ERN-LUNG PCD Core NETWORK and patient representatives

Introduction In primary ciliary dyskinesia (PCD) impaired mucociliary clearance leads to recurrent airway infections and progressive lung destruction, and concern over chronic airway infection and patient-to-patient transmission is considerable. So far, there has been no defined consensus on how to control infection across centres caring for patients with PCD. Within the BEAT-PCD network, COST Action and ERS CRC together with the ERN-Lung PCD core a first initiative has now been taken towards creating such a consensus statement. Methods A multidisciplinary international PCD expert panel was set up to create a consensus statement for infection prevention and control (IP&C) for PCD, covering …

Plasma circulating miRNAs as diagnostic and prognostic biomarkers in alpha-1 antitrypsin deficiency

Introduction: Alpha-1 antitrypsin (AATD) deficiency is an inherited condition that leads to decreased circulating AAT levels, significantly increasing the risk of lung and liver disease. AATD is underdiagnosed. Severity of symptoms in AATD patients are highly variable and neither protein levels nor phenotype are sufficient to identify which patients will develop lung and/or liver disease. Therefore, new strategies and biomarkers for early diagnosis and prognosis of the disease are needed. Rationale and Aims: MicroRNAs (miRNAs) regulate gene expression and have been associated with the pathogenesis of various lung and liver diseases. Circulating miRNAs may serve as diagnostic and prognostic …

Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency.

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2–18 years) diagnosed with AATD and 18 controls (aged 3–16 years).Our results show that intermediate-risk (MZ; SZ) and …

Frequent detection of cytomegalovirus (CMV) DNA in the lower respiratory tract in CMV-seropositive pediatric patients with underlying chronic bronchopulmonary diseases lacking canonical immunosuppression

Abstract Cytomegalovirus (CMV) may be a relevant cause of morbidity in patients displaying various inflammatory diseases. In this study, it was investigated whether CMV DNA is detected in the lower respiratory tract and the systemic compartment in pediatric patients with chronic or recurrent bronchopulmonary diseases. A total of 42 lower respiratory tract specimens and 11 paired plasma samples from 42 patients were analyzed for the presence of CMV DNA by real‐time PCR. The respiratory specimens were also screened for the presence of respiratory viruses and human herpesvirus 6 (HHV‐6) and 7 (HHV‐7) by PCR methods. Quantitative bacterial and fungal cultures were performed. IL‐6 levels in the …

Vacuna anti-Pseudomonas

LSC Abstract – Oxidative stress in nasal epithelial cells from patients with primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) is a rare autosomal recessive inheritance disorder characterized by dysfunction of respiratory cilia and impaired mucociliary clearance, leading to respiratory problems appearing in childhood, decreased fertility and situs inversus in 50% of the cases. The deficient ciliary movement causes stasis of secretions in the airways leading to recurrent airway infection and chronic inflammation. Rationale and aims: Chronic inflammation has been associated to oxidative stress (OS). Moreover, evidence of increased OS in the airways of stable children with PCD has been shown (Zihlif, N. et al . Pediatr Pulmonol 2006; 41:509-14.). Therefore, we hypothesize t…