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.

Cost-effectiveness of omalizumab for the treatment of severe pediatric allergic asthma-Results of a real-life study in Spain.

BACKGROUND: Severe pediatric allergic asthma (SPAA) induces a huge economic burden in terms of direct, indirect, and intangible costs. The use of omalizumab for the treatment of these patients has produced a significant improvement in several clinical outcomes, but at the same time, the cost for the management of the disease has also increased. The aim of this report was to evaluate whether the use of omalizumab is cost-effective. METHODS: A sample of 426 children with SPAA from the ANCHORS (Asthma iN CHildren: Omalizumab in Real-life in Spain) study was used to calculate the incremental cost-effectiveness ratio (ICER) for the avoidance of moderate-to-severe exacerbations (MSE) and also for the improvement in childhood Asthma Control Test (c-ACT) or the Asthma Control Questionnaire (ACQ5). We retrospectively collected data on health encounters and drug consumption before and up to 6 years after the beginning of the treatment with omalizumab. RESULTS: The ICER per avoided MSE was €2107 after 1 year, and it consistently decreased to €656 in those followed up to 6 years. Similarly, the ICER for the minimally important difference in control tests showed a decrease from €2059 to €380 per each 0.5 points of improvement in ACQ5 and from €3141 to €2322 per each 3 points improvement in c-ACT, at years 1 and 6, respectively. CONCLUSION: The use of OMZ is a cost-effective option for most children with uncontrolled SPAA, especially those who have frequent exacerbations; the costs are progressively reduced in successive years of treatment.

Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.

BACKGROUND: Various studies have assessed omalizumab outcomes in the clinical practice setting but follow-up and/or number of patients included were limited. We aim to describe the long-term outcomes of pediatric patients with severe persistent allergic asthma receiving omalizumab in the largest real-life cohort reported to date. METHODS: ANCHORS was a multicenter, observational, retrospective cohort study conducted in 25 Pediatric Allergy and Pulmonology units in Spain. We collected data of patients < 18 years and initiating omalizumab between 2006 and 2018, from the year prior to omalizumab initiation to discontinuation or last available follow-up. The primary outcome was the evolution of the annual number of moderate-to-severe exacerbations compared with the baseline period. RESULTS: Of the 484 patients included, 101 (20.9%) reached 6 years of treatment. The mean ± standard deviation number of exacerbations decreased during the first year of treatment (7.9 ± 6.6 to 1.1 ± 2.0, P < .001) and remained likewise for up to 6 years. The other clinical parameters assessed also improved significantly during the first year and stabilized or continued to improve thereafter. The percentage of patients experiencing adverse events was consistently low, and the main reason for discontinuation was good disease evolution. CONCLUSION: In this large, long-term, observational study, moderate-to-severe exacerbations decreased significantly from the first year of treatment with omalizumab. The beneficial effect was maintained in the long term, along with a good safety profile. Our results position omalizumab as an effective long-term treatment in pediatric patients with severe persistent allergic asthma.

Long-term docosahexaenoic acid (DHA) supplementation in cystic fibrosis patients: a randomized, multi-center, double-blind, placebo-controlled trial.

BACKGROUND: Cystic fibrosis (CF) patients have an alteration in fatty acid (FA) metabolism, associated with increased omega-6 and low omega-3 FA. Previous studies on supplementation with omega-3 FA in CF had contradictory results, and to date there is no evidence to recommend routine use of omega-3 supplements in CF patients. We hypothesized that long-term supplementation with docosahexaenoic acid (DHA) will have beneficial effects in these patients, by reducing pulmonary, systemic and intestinal inflammation. METHODS: This was a randomized, double-blind, parallel, placebo-controlled trial. CF patients (age >2 months) were randomized to receive a seaweed DHA oil solution (50 mg/Kg/day) or matching placebo for 48 weeks. Primary outcomes were pulmonary (interleukin [IL]-8), systemic (IL-8) and intestinal (calprotectin) inflammatory biomarkers. Secondary outcomes included other pulmonary (IL-1ß, IL-6, neutrophil elastase, lactate and calprotectin) and systemic (serum-IL-1ß, IL-6) inflammatory biomarkers, as well as clinical outcomes (FEV1, pulmonary exacerbations, antibiotic use, nutritional status and quality of life). RESULTS: Ninety six CF patients, 44 female, age 14.6±11.9 years (48 DHA and 48 placebo) were included. At trial completion, there were no differences in all primary outcomes [serum-IL-8 (p=0.909), respiratory-IL-8 (p=0.384) or fecal calprotectin (p=0.948)], all secondary inflammatory biomarkers, or in any of the clinical outcomes evaluated. There were few adverse events, with similar incidence in both study groups. CONCLUSION: In this study, long-term DHA supplementation in CF patients was safe, but did not offer any benefit on inflammatory biomarkers, or in clinical outcomes compared with placebo. (NCT01783613).

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.

A comprehensive evaluation of omega-3 fatty acid supplementation in cystic fibrosis patients using lipidomics.

The evaluation of the benefits of omega-3 fatty acid supplementation in humans requires the identification and characterization of suitable biomarkers of its incorporation in the body. The reference method for the evaluation of omega-3, gas chromatography, is difficult to apply in clinical practice because of its low throughput and does not provide information about the incorporation of specific fatty acids in lipid species and the potential effects of supplementation on lipid classes. We used a quantitative lipidomic approach to follow the incorporation of omega-3 fatty acids into plasma lipids in cystic fibrosis patients (n=50) from a randomized controlled clinical trial after the supplementation of seaweed oil enriched with docosahexaenoic acid (DHA). Lipidomic analysis accurately showed the distribution of fatty acids in different lipid classes after omega-3 supplementation, and the performance in determining the compliance to supplementation was similar to that of gas chromatography coupled to mass spectrometry. Twelve months after fatty acid supplementation, DHA was predominantly incorporated into highly unsaturated cholesteryl esters (110.9±16.2 vs. 278.6±32.6 µM, mean±S.E.M.) and phosphatidylcholine (142.4±11.9 vs. 272.9±21.4 µM) and, to a lesser extent, into phosphatidylethanolamine (9.4±0.8 vs. 15.5±1.5 µM) and triglycerides (0.4±0.04 vs. 1.1±0.12 µM). In addition, a technique was developed for the fast measurement of the DHA/arachidonic acid ratio to simplify the follow-up of nutritional intervention with DHA-enriched foods. We conclude that lipidomics is a suitable approach for monitoring the incorporation of omega-3 fatty acids in nutritional studies.

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.

Evaluación de la medición de las resistencias pulmonares por técnica de interrupción / Assessing the measurement of airway resistance by the interrupter technique

Introducción. Las pruebas de función pulmonar permiten objetivar el grado de obstrucción bronquial en sujetos colaboradores. La medición de las resistencias pulmonares por métodos pasivos es muy útil en sujetos no colaboradores. El objetivo de este estudio fue evaluar la aplicabilidad de la medición de resistencias por interrupción (Rint) en la edad pediátrica, valorando su reproducibilidad, fabilidad y exactitud en relación con otras técnicas de medición de resistencias. Material y métodos. Estudio transversal en niños de entre 2 y 18 años, sanos y con patología obstructiva. Se midió la Rint con un aparato portátil y se comparó con las resistencias medidas por oscilometría y pletismografía. Se valoró la reproducibilidad de las mediciones y la infuencia de diferentes variables (uso de mascarilla o boquilla, sujeción de mejillas o uso de pinza nasal). Resultados. De 460 niños (47,6% menores de 7 años) se obtuvieron medidas válidas en el 82,6%. La reproducibilidad fue muy buena (CCI= 0,9412; p < 0,00001), sin encontrar diferencias entre las medidas obtenidas separadas en el tiempo (0,75 ± 0,3 contra 0,74 ± 0,28; p= 0,435). Ninguno de los factores antes mencionados afectó la reproducibilidad de las medidas. Los valores de resistencia obtenidos por pletismografía y oscilometría fueron superiores a los obtenidos por Rint, con una correlación positiva entre ambos. La correlación con la pletismografía disminuía cuanto mayor era el grado de obstrucción. Conclusiones. La medición de Rint es factible y reproducible, y se correlaciona bien con las resistencias medidas por oscilometría o pletismografía, por lo que sería de utilidad en los pacientes poco colaboradores. En los pacientes obstruidos, podría infraestimar la resistencia, difcultando su uso para el seguimiento de una patología obstructiva moderada-grave o en las pruebas de provocación bronquial.

Introduction. Pulmonary function tests allow an objective assessment of the degree of bronchial obstruction in collaborative subjects. The measurement of airway resistance using passive methods is very helpful in non-collaborative subjects. The objective of this study was to assess the applicability of measuring airway resistance by the interrupter technique (Rint) in pediatric subjects, determining its reproducibility, reliability and accuracy versus other techniques to measure airway resistance. Material and Methods. Cross-sectional study in healthy children and in children with an obstructive airway disease, all aged 2-18 years old. The Rint was measured using a portable device and results were compared to airway resistance measured by oscillometry and plethysmography. The reproducibility of measurements and the infuence of the different outcome measures (use of mask or mouthpiece, cheek support, or nose clip) were assessed. Results. Valid measurements were obtained in 82.6% of 460 children (47.6% younger than 7 years old). Reproducibility was very good (ICC= 0.9412; p <0.00001), and no differences were found among the measurements obtained at separate time intervals (0.75 ± 0.3 versus 0.74 ± 0.28; p= 0.435). None of the factors indicated before had an effect on the reproducibility of measurements. Resistance values obtained by plethysmography and oscillometry were higher than those obtained using the Rint, with a positive correlation between them. The higher the degree of airway obstruction, the worse the correlation with plethysmography. Conclusions. The Rint measurement is a plausible and reproducible technique, and has an adequate correlation with the resistance measurements obtained using oscillometry or plethysmography, thus making it useful for non-collaborative patients. In patients with airway obstruction, this technique could underestimate resistance, so it would be a hurdle to use it to follow-up subjects with a moderate to severe obstructive disease or in bronchial challenge tests.

Assessing the measurement of airway resistance by the interrupter technique.

INTRODUCTION: Pulmonary function tests allow an objective assessment of the degree of bronchial obstruction in collaborative subjects. The measurement of airway resistance using passive methods is very helpful in non-collaborative subjects. The objective of this study was to assess the applicability of measuring airway resistance by the interrupter technique (Rint) in pediatric subjects, determining its reproducibility, reliability and accuracy versus other techniques to measure airway resistance. MATERIAL AND METHODS: Cross-sectional study in healthy children and in children with an obstructive airway disease, all aged 2-18 years old. The Rint was measured using a portable device and results were compared to airway resistance measured by oscillometry and plethysmography. The reproducibility of measurements and the infuence of the different outcome measures (use of mask or mouthpiece, cheek support, or nose clip) were assessed. RESULTS: Valid measurements were obtained in 82.6% of 460 children (47.6% younger than 7 years old). Reproducibility was very good (ICC= 0.9412; p <0.00001), and no differences were found among the measurements obtained at separate time intervals (0.75 ± 0.3 versus 0.74 ± 0.28; p= 0.435). None of the factors indicated before had an effect on the reproducibility of measurements. Resistance values obtained by plethysmography and oscillometry were higher than those obtained using the Rint, with a positive correlation between them. The higher the degree of airway obstruction, the worse the correlation with plethysmography. CONCLUSIONS: The Rint measurement is a plausible and reproducible technique, and has an adequate correlation with the resistance measurements obtained using oscillometry or plethysmography, thus making it useful for non-collaborative patients. In patients with airway obstruction, this technique could underestimate resistance, so it would be a hurdle to use it to follow-up subjects with a moderate to severe obstructive disease or in bronchial challenge tests.

Right ventricular dysfunction in adolescents with mild cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF) patients the right ventricle (RV) suffers a progressive deterioration, but it is not clear when these changes begin. The aim of this study was to analyze the RV function in CF patients with mild respiratory disease. METHODS: Color-Doppler-Echocardiographic studies were prospectively performed in CF adolescent patients and an age-matched control group. Findings were correlated with pulmonary function tests (PFT), genotype, chronic bacterial colonization, pancreatic status and clinical scores. Only patients with mild CF were selected. RESULTS: Thirty seven CF patients and 40 healthy controls were recruited. In CF patients all echocardiographic parameters were abnormal compared to controls. Doppler analysis showed slightly elevated pulmonary artery pressure values, and abnormal relaxation and systolic function for all indexes. No correlation was found with any of the features studied. CONCLUSIONS: In CF patients, abnormalities in the structure and function of the RV may be present at early stages of the disease. These abnormalities are subclinical and do not correlate with clinical scores, PFT, genotype, chronic bacterial colonization or pancreatic insufficiency.

Atypical Pityriasis rosea in a black child: a case report.

INTRODUCTION: Pityriasis rosea is a self-limited inflammatory condition of the skin that mostly affects healthy children and adolescents. Atypical cases of Pityriasis rosea are fairly common and less readily recognized than typical eruptions, and may pose a diagnostic challenge. CASE PRESENTATION: We report the case of a 12-year-old black child that developed an intense pruritic papular eruption with intense facial involvement that was diagnosed of Pityriasis rosea and resolved after five weeks leaving a slight hyperpigmentation. CONCLUSION: Facial and scalp involvement, post-inflammatory disorders of pigmentation and papular lesions are characteristics typically associated to black patients with Pityriasis rosea. The knowledge of features found more frequently in dark-skinned population may be helpful to physicians for diagnosing an atypical Pityriasis rosea in these patients.