Silvia Gartner

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.

Spectrum of manifestations of Swyer-James-MacLeod syndrome.

PURPOSE The clinical and imaging findings of children with Swyer-James-MacLeod syndrome (SJMS) were reviewed to determine the incidence and type of bronchiectasis and analyze whether the clinical course of patients with bronchiectasis differed from that of patients without bronchiectasis. METHOD Our study population consisted of 13 patients. All had inspiratory/ expiratory chest X-ray films, chest CT, and lung scans. Eight underwent pulmonary function test. The results of these studies at diagnosis and during follow-up were analyzed and compared with the clinical features. RESULTS Bronchiectasis was demonstrated in nine patients, being saccular in five and cylindrical in four. Expiratory slices were helpful for demonstrating bilateral lung involvement that had not been suspected on inspiratory CT scans or conventional radiographs. The clinical features of the five patients with saccular bronchiectasis resembled those of patients with classic postviral bronchiectasis who suffered recurrent pulmonary infections; three of them underwent lobectomy. The remaining patients presented mild respiratory symptoms, with a spontaneous tendency toward improvement. CONCLUSION SJMS should be considered as a spectrum disease. Bronchiectasis is not a universal finding. The presence and type of bronchiectasis will influence clinical manifestations and prognosis. Patients without bronchiectasis or with cylindrical bronchiectasis had a lower incidence of pneumonia episodes than those with saccular bronchiectasis.

Upregulation of COX‐1 and COX‐2 in nasal polyps in cystic fibrosis

Background: Since abnormalities in prostanoid metabolism occur in the lower airway of patients with cystic fibrosis (CF), it is likely that they could also be detected in the nose. Methods: The degree of mRNA and protein expression of cyclo-oxygenase (COX) enzymes 1 (COX-1) and 2 (COX-2) was examined using quantitative reverse competitive polymerase chain reaction (RT-PCR) and Western blot analysis in the nasal polyps from 10 patients with CF, nasal polyps from 10 non-CF patients and 11 nasal mucosa specimens. The results are presented as 106 cDNA molecules/μg total RNA and the densitometric ratio between protein and β-actin. Results: COX-1 mRNA levels were significantly higher in CF nasal polyps (median 2.34, 25–75th percentiles 1.6–3.2) than in the nasal mucosa (0.78, 0.11–1.21), while there was no difference with non-CF nasal polyps (1.11, 0.80–3.15). COX-1 protein levels were significantly higher in CF nasal polyps (3.63, 2.71–4.27) than in nasal mucosa (1.55, 0.66–2.33) and non-CF nasal polyps (2.19, 1.72–3.68). COX-2 mRNA was significantly higher in CF nasal polyps (3.34, 2.42–7.05) than in nasal mucosa (1.69, 0.19–3.50). No differences were found in COX-2 mRNA expression between CF and non-CF polyps (1.38, 0.12–6.07). COX-2 protein levels were also significantly higher in CF nasal polyps (0.23, 0.04–0.34) than in non-CF nasal polyps (0.011, 0.009–0.016) or nasal mucosa (0.014, 0.014–0.016). Conclusions: Upregulation in the expression of COX-1 and COX-2 could explain the high production of prostanoids reported in CF. These findings raise questions regarding the potential use of selective or non-selective COX-2 non-steroidal anti-inflammatory treatment in CF.

Óxido nítrico exhalado en niños: un indicador no invasivo de la inflamación de las vías aéreas

En este articulo se presenta una revision academica sobre la aplicabilidad de la medida de la fraccion exhalada de oxido nitrico (FE NO ) en ninos. De acuerdo con las normas conjuntas de la American Thoracic Society/European Respiratory Society, se describen los metodos de medida on-line en ninos colaboradores y no colaboradores, los registros off-line sin control de flujo de exhalacion y con control de flujo de exhalacion mediante restrictor de flujo dinamico, y el registro off-line a respiracion corriente en ninos no colaboradores. Se revisan los valores de normalidad, fundamentalmente con los analizadores de la FE NO por quimioluminiscencia, mediante registro on-line de una unica respiracion (media geometrica: 9,7 ppb –partes por mil millones–; limite superior del intervalo de confianza del 95%: 25,2 ppb). Los valores de la FE NO superiores a 17 ppb aportan un 81% de sensibilidad y un 80% de especificidad para predecir asma de fenotipo eosinofilico. Se analiza la respuesta de la FE NO al tratamiento antiinflamatorio y al seguimiento del asma. Por ultimo, se comparan los resultados entre los analizadores por quimioluminiscencia y los electroquimicos, portatiles. Estos ultimos ofrecen la posibilidad, en ninos mayores de 5 anos, de un seguimiento adecuado y universal del oxido nitrico exhalado como indicador emergente de la inflamacion eosinofilica en la enfermedad asmatica, de modo que facilitan el diagnostico, el control evolutivo y el seguimiento terapeutico.

Exhaled Nitric Oxide in Children: A Noninvasive Marker of Airway Inflammation

This article is an academic review of the application in children of the measurement of fractional exhaled nitric oxide (FENO). We outline the joint American Thoracic Society/European Respiratory Society recommendations for online measurement of FENO in both cooperating children and children unable to cooperate, offline measurement with uncontrolled exhalation flow rate, offline measurement with controlled exhalation flow rate using a dynamic flow restrictor, and offline measurement during tidal breathing in children unable to cooperate. This is followed by a review of the normal range of values for single-breath online measurements obtained with a chemiluminescence FENO analyzer (geometric mean, 9.7 parts per billion [ppb]; upper limit of the 95% confidence interval, 25.2 ppb). FENO values above 17 ppb have a sensitivity of 81% and a specificity of 80% for predicting asthma of an eosinophilic phenotype. We discuss the response of FENO values to anti-inflammatory treatment and the use of this marker in the management of asthma. Results obtained with chemiluminescence and portable electrochemical analyzers are compared. The portable devices offer the possibility--in children over 5 years of age--of accurate and universal monitoring of exhaled nitric oxide concentrations, an emerging marker of eosinophilic inflammation in asthma that facilitates diagnosis, monitoring of disease progression, and assessment of response to therapy.

Fibrosis quística: consenso sobre el tratamiento del neumotórax y de la hemoptisis masiva y sobre las indicaciones del trasplante pulmonar

La fibrosis quística (FQ), con una incidencia de un caso cada 2.500 recién nacidos vivos, es la enfermedad hereditaria más frecuente en la raza caucásica. Se produce como consecuencia de la ausencia o la alteración de la función de una glucoproteína, llamada cystic fibrosis transmembrane conductance regulator (CFTR)1. La patogenia de la enfermedad no está aclarada, aunque parece ser que el círculo vicioso obstrucción-infeccióninflamación es el productor del daño pulmonar causante, a su vez, de las bronquiectasias quísticas y la fibrosis pulmonar propias de la enfermedad2. El diagnóstico de FQ se establece en el primer año de vida en el 70% de los casos, fundamentalmente por infecciones respiratorias agudas o persistentes o por malnutrición3. El tratamiento de la alteración pulmonar es uno de los pilares fundamentales para mejorar la supervivencia de estos enfermos. La expectativa de vida de los pacientes con FQ ha aumentado durante las últimas décadas debido, fundamentalmente, a la aparición de nuevos tratamientos y a la creación de unidades multidisciplinarias encargadas del cuidado de estos pacientes. A medida que aumenta la edad de los pacientes pueden ocurrir, con mayor frecuencia, una serie de complicaciones pulmonares graves, como el neumotórax y la hemoptisis masiva. La hemoptisis masiva tiene casi siempre su origen en las arterias bronquiales. La inflamación crónica que sufren las paredes bronquiales de los pulmones de los pacientes con FQ produce una hipertrofia de las mismas, junto con la formación de vasos nuevos. Esta hipervascularización conlleva una propensión al sangrado, especialmente durante las exacerbaciones infecciosas respiratorias. La forma de presentación de los neumotórax en la FQ no difiere de la que acontece en otras enfermedades respiratorias diferentes de este proceso. Es una complicación grave, con importante riesgo vital inmediato, pues ocurre fundamentalmente en los pacientes con afectación respiratoria importante3. El trasplante pulmonar debe ser la última opción terapéutica para los pacientes con una enfermedad pulmonar terminal. Con el objetivo de conseguir unas pautas consensuadas sobre el tratamiento del neumotórax y de la hemoptisis masiva en los pacientes con FQ, así como sobre las indicaciones y contraindicaciones del trasplante pulmonar en esta enfermedad, la Fundación Sira Carrasco, para ayuda contra la FQ organizó, el día 23 de abril de 1999, en Madrid, unos encuentros de consenso con profesionales especializados en el tratamiento de la FQ. Los resultados de esta discusión y los consensos alcanzados se detallan en el presente documento.

Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: Correlation with disease severity

Cystic fibrosis transmembrane conductance (CFTR) alterations are involved in the overproduction of prostaglandins (PG) in CF in vitro. We assessed the relationship between PGE-M and PGD-M urinary metabolites of PGE2 and PGD2 and CF severity. Twenty-four controls and 35 CF patients were recruited. PGE-M and PGD-M levels were measured by liquid chromatography/mass spectrometry and results were expressed as median and 25th-75th interquartile of ng/mg creatinine (Cr). PGE-M (15.63; 9.07-43.35ng/mg Cr) and PGD-M (2.16; 1.43-3.53ng/mg Cr) concentrations were higher in CF than in controls: PGE-M, (6.63; 4.35-8.60ng/mg Cr); PGD-M (1.23; 0.96-1.54ng/mg Cr). There was no correlation between metabolite levels and spirometric values. Patients with pancreatic insufficiency (n=29) had higher PGE-M levels (19.09; 9.36-52.69ng/mg Cr) than those with conserved function (n=6) (9.61; 5.78-14.34ng/mg Cr). PGE-M levels were associated with genotype severity: mild (7.14; 5.76-8.76, n=8), moderate (16.67; 13.67-28.62ng/mg Cr, n=5) and severe (22.82; 10.67-84.13ng/mg Cr). Our study confirms the key role of CFTR in the regulation of the cyclooxygenase pathway of arachidonic acid metabolism found in in vitro studies.

The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe

BACKGROUND Newborn screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. The aim of this study was to provide an update on NBS for CF in Europe and assess performance against the standards. METHODS Questionnaires were sent to key workers in each European country. RESULTS In 2016, there were 17 national programmes, 4 countries with regional programmes and 25 countries not screening in Europe. All national programmes employed different protocols, with IRT-DNA the most common strategy. Five countries were not using DNA analysis. In addition, the processing and structure of programmes varied considerably. Most programmes were achieving the ECFS standards with respect to timeliness, but were less successful with respect to sensitivity and specificity. CONCLUSIONS There has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

Óxido nítrico exhalado en niños menores de 4 años con bronquitis de repetición

BACKGROUND The objective of the study was to assess bronchial inflammation in preschool children with recurrent bronchitis by measuring exhaled nitric oxide. PATIENTS AND METHODS The study included patients under 4 years of age with at least 3 episodes of wheezing in the past year (n=63) and a control group (n=30). Exhaled nitric oxide was measured in samples collected offline during spontaneous tidal breathing with a face mask and stored in Mylar balloons. RESULTS The fractional exhaled nitric oxide concentration (FE(NO)) was higher in the group with bronchitis (mean [SD], 5.3 [1.3] parts per billion [ppb]) than in the control group (4.6 [1.1]ppb) (P=.02). There was a significant difference between the control group and children in the bronchitis group not treated with inhaled corticosteroids (P<.05), but not between controls and corticosteroid-treated patients. A relationship with eosinophil count was observed in that those with higher counts (>400 microL) had higher FE(NO) levels (P<.01). No relationship was observed between FE(NO) and a positive methacholine challenge test. Follow-up lasted at least 20 months. The initial FE(NO) level did not differ significantly according to whether patients were subsequently transient, infrequent, or frequent wheezers (5.2 [0.98]ppb, 5.6 [1.5]ppb, and 4.8 [1.34]ppb, respectively; P=.36). CONCLUSIONS In children under 4 years of age with recurrent wheezing bronchitis who were asymptomatic at study entry, a small increase in FE(NO) was observed although there was a good deal of overlap with the control group.