Baseline reticular basement membrane morphology is related to subsequent spirometry deterioration in pediatric chronic airway inflammation: a follow-up study.

Reticular basement membrane (RBM) thickening may occur in children with allergic bronchial asthma (BA), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD). Its functional consequences remain unknown. We investigated the relationship between baseline RBM thickness and subsequent spirometry. In our cohort follow-up study, patients aged 3-18 yr with BA, CF, and PCD and controls underwent baseline lung clearance index (LCI) measurement, spirometry, and endobronchial biopsy sampling. Total RBM and collagen IV-positive layer thickness were measured. Trends in forced vital capacity (FVC), forced expired volume in 1 s (FEV1), and FEV1/FVC were analyzed during follow-up, and their relationship to baseline characteristics was studied using univariate analysis and multiple regression models. Complete baseline data were available in 19 patients with BA, 30 patients with CF, 25 patients with PCD, and 19 controls. The RBM was thicker in patients with BA (6.33 ± 1.22 µm), CF (5.60 ± 1.39 µm), and PCD (6.50 ± 1.87 µm) than in controls (3.29 ± 0.55 µm) (all P < 0.001). The LCI was higher in patients with CF (15.32 ± 4.58, P < 0.001) and PCD (10.97 ± 2.46, P = 0.002) than in controls (7.44 ± 0.43). The median follow-up times were 3.6, 4.8, 5.7, and 1.9 years in patients with BA, CF, PCD, and controls, respectively. The z-scores of FEV1 and FEV1/FVC deteriorated significantly in all groups except in controls. In patients with CF and PCD, trends in FEV1 z-scores correlated with baseline LCI and RBM; in BA, it correlated with collagen IV. In multiple regression models, RBM morphology and ventilation inhomogeneity could predict up to 84.4% of variability in spirometry trends. In conclusion, baseline LCI value and RBM morphology may predict trends in subsequent spirometry.NEW & NOTEWORTHY This paper deals with the relationship between reticular basement membrane (RBM) morphology at baseline and follow-up spirometry in children with asthma, cystic fibrosis, and primary ciliary dyskinesia. For the first time, to our knowledge, the possibility to predict subsequent lung function development using selected baseline characteristics (reticular basement membrane morphology from endobronchial biopsy and ventilation inhomogeneity from nitrogen multiple breath washout test) is proposed. Corresponding predictive models are presented.

Complication rates in rigid vs. flexible endoscopic foreign body removal in children.

While foreign body aspiration remains a frequent and preventable cause of morbidity and mortality in children, recommendations on the appropriate removal technique do often not match the lived practice and expertise of the performing examiners. As there is a scarcity of data regarding success and complication rates of the procedure, the aim of this study was to set up a classification system for procedure-related complications, prospectively record and analyze them. Specialists in the field of foreign body removal contributed cases anonymously. Information regarding procedural details of the bronchoscopy, type, and severity of complications as well as patient characteristics were classified and recorded. Correlations were calculated using Pearson's Chi Square test. A total of 314 rigid and 178 flexible bronchoscopies were compared. Complications were categorized and their severity was defined by the anesthesiologist's assessment of whether to interrupt or terminate the procedure. The overall complication rate was similar in rigid vs. flexible bronchoscopy (19.1% vs. 24.2%, p = 0.232), while respiratory complications occurred significantly less frequent during rigid bronchoscopy (9.2% vs. 16.3%, p = 0.025). This is the largest pediatric case collection recording and comparing complications between rigid and flexible foreign body removal. The higher rate of respiratory complications in flexible bronchoscopy has been shown for the first time and validates some of the concerns about its use for foreign body removal. Flexible bronchoscopy is a safe procedure when extended respiratory monitoring and the possibility of an immediate switch to a secured airway are assured.

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients.

Effectiveness and Durability of mRNA Vaccine-Induced SARS-CoV-2-Specific Humoral and Cellular Immunity in Severe Asthma Patients on Biological Therapy.

Coronavirus disease 2019 (COVID-19) vaccines effectively elicit humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in healthy populations. This immunity decreases several months after vaccination. However, the efficacy of vaccine-induced immunity and its durability in patients with severe asthma on biological therapy are unknown. In this study, we evaluated the effectiveness and durability of mRNA vaccine-induced SARS-CoV-2-specific humoral and cellular immunity in severe asthma patients on biological therapy. The study included 34 patients with severe asthma treated with anti-IgE (omalizumab, n=17), anti-IL5 (mepolizumab, n=13; reslizumab, n=3), or anti-IL5R (benralizumab, n=1) biological therapy. All patients were vaccinated with two doses of the BNT162b2 mRNA vaccine with a 6-week interval between the doses. We found that this COVID-19 vaccination regimen elicited SARS-CoV-2-specific humoral and cellular immunity, which had significantly declined 6 months after receipt of the second dose of the vaccine. The type of biological treatment did not affect vaccine-elicited immunity. However, patient age negatively impacted the vaccine-induced humoral response. On the other hand, no such age-related impact on vaccine-elicited cellular immunity was observed. Our findings show that treatment of patients with severe asthma with biological therapy does not compromise the effectiveness or durability of COVID-19 vaccine-induced immunity.

Repeatability of lung clearance index in infants with cystic fibrosis and recurrent wheeze.

OBJECTIVES: To describe the short- and medium-term repeatability of lung clearance index at 2.5% (LCI2.5 ) in infants and calculate the number of patients needed to enroll in a study (N) using LCI2.5 as a primary outcome. METHODS: An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated. RESULTS: Forty infants with CF and 21 with RW were enrolled. Initial N2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI2.5 value. In clinically stable patients, LCI2.5 did not significantly change during the 8-month follow-up. Mean LCI2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intragroup differences of LCI2.5 and minimal difference to be detected would be 2.0. CONCLUSION: N2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies.

Lung function from school age to adulthood in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

The respiratory consequences of COVID-19 lasted for a median of 4 months in a cohort of children aged 2-18 years of age.

AIM: We focused on the clinical picture, severity and prognosis of children who experienced long-term respiratory issues after COVID-19. METHODS: This was a national Czech multicentre study of paediatric post-COVID syndrome, which used a standard protocol to evaluate structural and functional anomalies and exclude alternative diagnoses. From 6 January to 30 June 2021, 11 paediatric pulmonologists enrolled all paediatric referrals aged 2-18 years with persistent respiratory symptoms more than 12 weeks after COVID-19, namely cough, dyspnoea and chest pain. Medical histories were taken, and physical examinations, lung function testing, chest X-ray and blood tests were performed. RESULTS: The dominant symptoms in the 39 children (56.4% girls) were exertional dyspnoea (76.9%) and a chronic cough (48.7%), while dyspnoea at rest (30.8%) and chest pain (17.9%) were less prevalent. More than half (53.8%) reported more than 1 symptom, and 38.5% had abnormal results for 1 of the following tests: lung function, chest X-ray or D-dimers. The median age of the children was 13.5 years (interquartile range ±4.8 years), and the median recovery time was 4 months (range 1.5-8 months). CONCLUSION: Our initial data suggest that the long-term respiratory impact of COVID-19 was relatively mild in our cohort, with a favourable prognosis.

Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK.

BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.

Lung Resection in Children with Necrotizing Pneumonia: Outcome and Follow-up.

INTRODUCTION: The number of patients with necrotizing pneumonia has increased in recent years. The aim of this study is to review the incidence, management, and outcome of pediatric necrotizing pneumonia requiring surgical therapy and to prove that lung resection results in favorable development of patients. We hypothesize that overall lung function in children after lung resection does not differ from that of the healthy population. MATERIALS AND METHODS: A retrospective tertiary referral center study with a prospective follow-up spirometric study of patients with necrotizing pneumonia managed between January 2010 and December 2019 was performed. RESULTS: The study cohort consisted of 1,295 patients admitted to the pediatric department for community-acquired pneumonia; 47 patients developed necrotizing pneumonia, 36 of whom underwent parenchymal lung resection. A 5-year rise in the occurrence of necrotizing pneumonia requiring resection was 77%, with a significant increase in the last 3 years (p < 0.05). The median age at the time of surgery was 32.5 (interquartile range [IQR]: 32.25) months. Streptococcus pneumoniae was the most prevalent pathogen (83%), although 53.3% of these patients were vaccinated against the agent. In 67% of patients, preresection procedures were performed: drainage of pneumothorax (17%), drainage of empyema (46%), drainage of empyema with use of alteplase (25%), and thoracoscopic decortication (12%). Surgical procedures included lobectomy (72.2%), wedge resection (13.9%), bilobectomy (8.3%), and pneumonectomy (5.6%). The postoperative complication was bronchopleural fistula in three patients. There were two (5.5%) postoperative deaths due to multiple organ failure. The follow-up spirometry was performed 43.3 (median, IQR 23.8-66.7) months after surgical intervention. Normal lung function was detected in 35 (64.8%) patients, restrictive pattern in 6 (11.1%) patients, obstructive pattern in 11 (20.4%) patients, and combined in 2 (3.7%) patients. CONCLUSION: The number of patients with necrotizing pneumonia requiring resection has increased significantly in the last 3 years (p < 0.05). Aggressive surgical treatment results in significant clinical improvement in most cases and favorable lung function outcome. Long-term follow-up showed normal spirometry in 64.8% of cases.

Biologicals in childhood severe asthma: the European PERMEABLE survey on the status quo.

INTRODUCTION: Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. METHODS: Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. RESULTS: We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. CONCLUSION: Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.

Quantitative Assessment of Ciliary Ultrastructure with the Use of Automatic Analysis: PCD Quant.

The ciliary ultrastructure can be damaged in various situations. Such changes include primary defects found in primary ciliary dyskinesia (PCD) and secondary defects developing in secondary ciliary dyskinesia (SCD). PCD is a genetic disease resulting from impaired ciliary motility causing chronic disease of the respiratory tract. SCD is an acquired condition that can be caused, for example, by respiratory infection or exposure to tobacco smoke. The diagnosis of these diseases is a complex process with many diagnostic methods, including the evaluation of ciliary ultrastructure using transmission electron microscopy (the golden standard of examination). Our goal was to create a program capable of automatic quantitative analysis of the ciliary ultrastructure, determining the ratio of primary and secondary defects, as well as analysis of the mutual orientation of cilia in the ciliary border. PCD Quant, a program developed for the automatic quantitative analysis of cilia, cannot yet be used as a stand-alone method for evaluation and provides limited assistance in classifying primary and secondary defect classes and evaluating central pair angle deviations. Nevertheless, we see great potential for the future in automatic analysis of the ciliary ultrastructure.

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 diagnostic microbiology, infection prevention for specific pathogens considered indicated for treatment and segregation aspects. Using a modified Delphi process, consensus to a statement demanded at least 80% agreement within the PCD expert panel group. Patient organisation representatives were involved throughout the process. RESULTS: We present a consensus statement on 20 IP&C statements for PCD including suggested actions for microbiological identification, indications for treatment of Pseudomonas aeruginosa, Burkholderia cepacia and nontuberculous mycobacteria and suggested segregation aspects aimed to minimise patient-to-patient transmission of infections whether in-hospital, in PCD clinics or wards, or out of hospital at meetings between people with PCD. The statement also includes segregation aspects adapted to the current coronavirus disease 2019 (COVID-19) pandemic. CONCLUSION: The first ever international consensus statement on IP&C intended specifically for PCD is presented and is targeted at clinicians managing paediatric and adult patients with PCD, microbiologists, patient organisations and not least the patients and their families.

Evaluation of a Clinical Index as a Predictive Tool for Primary Ciliary Dyskinesia.

BACKGROUND: In primary ciliary dyskinesia (PCD) there is no single diagnostic test. Different predictive tools have been proposed to guide referral of high-risk patients for further diagnostic workup. We aimed to test clinical index (CI) on a large unselected cohort and compare its characteristics with other widely used tools-PICADAR and NA-CDCF. METHODS: CI, PICADAR, and NA-CDCF scores were calculated in 1401 patients with suspected PCD referred to our center. Their predictive characteristics were analyzed using receiver operating characteristics (ROC) curves and compared to each other. Nasal nitric oxide (nNO) was measured in 569 patients older than 3 years. RESULTS: PCD was diagnosed in 67 (4.8%) patients. CI, PICADAR, and NA-CDCF scores were higher in PCD than in nonPCD group (all p < 0.001). The area under the ROC curve (AUC) for CI was larger than for NA-CDCF (p = 0.005); AUCPICADAR and AUCNA-CDCF did not differ (p = 0.093). An overlap in signs and symptoms among tools was identified. PICADAR could not be assessed in 86 (6.1%) patients without chronic wet cough. For CI laterality or congenital heart defects assessment was not necessary. nNO further improved predictive power of all three tools. CONCLUSION: CI is a feasible predictive tool for PCD that may outperform PICADAR and NA-CFCD.

Management of asthma in childhood: study protocol of a systematic evidence update by the Paediatric Asthma in Real Life (PeARL) Think Tank.

INTRODUCTION: Clinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted. METHODS AND ANALYSIS: Standard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence. ETHICS AND DISSEMINATION: Ethics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank. PROSPERO REGISTRATION NUMBERS: CRD42020132990, CRD42020171624.

Transition of patients with interstitial lung disease from paediatric to adult care.

The European Cooperation in Science and Technology (COST) is a funding organisation for the creation of research networks, called COST Actions. COST Action 16125 was dedicated to European network for translational research in children's and adult interstitial lung disease. Working Group 5 of the COST Action CA16125 focussed on the problems of transition of children with interstitial lung diseases from paediatric to adult care. Results of this survey performed among members of the Working Group and some affiliated specialists showed highly variable and inadequate current system of transitions of these patients to adult care in most centres. In most centres there is no established and consistent procedure to guarantee appropriate transfer of information and prepare the patient for transition to a new specialist and a new team. Immediate action is therefore required. The Working Group has prepared a model procedure for the transition, based on protocols from several centres with established pathways, either for childhood interstitial lung disease or other chronic respiratory diseases.

Reflex zone stimulation reduces ventilation inhomogeneity in cystic fibrosis: A randomised controlled cross-over study.

BACKGROUND: The reflex zone stimulation technique (RST) activates complex motor responses and has a positive impact on the locomotor system. This technique may also indirectly affect breathing; however, the use of this technique as adjunct of the treatment of cystic fibrosis (CF) has not yet been characterised. METHODS: We performed a randomised controlled single-centre interventional trial to evaluate the short-term effects of RST on lung function in 21 paediatric CF patients with normal baseline spirometry. The effect of 30 min of RST was compared to that of sham therapy in a crossover design. The interventions were performed in random order and planned 6 months apart. The primary outcome was a change in global ventilation inhomogeneity after intervention, assessed by lung clearance index (LCI2.5 ) derived from a nitrogen multiple breath washout test. Secondary outcomes included changes in regional ventilation inhomogeneity (indices of acinar [Sacin*Vt] and conductive airway [Scond*Vt] inhomogeneity) and spirometry parameters (inspiratory capacity, forced vital capacity, and forced expiratory volume in 1 s). Trunk deformity was assessed by physiotherapists at study entry. RESULTS: After the RST intervention, the LCI2.5 (p = .004) and Scond*Vt (p = .009) decreased significantly, while inspiratory capacity increased (p = .012). In the sham-therapy group, none of the parameters changed significantly. Trunk deformity was seen in 76.5% of all patients, and 92.9% of those with trunk deformity showed a decrease in LCI2.5 after RST. CONCLUSION: RST has multiple positive short-term effects on lung function, especially in CF patients with trunk deformities.

Bronchodilating effects of a new beclometasone dipropionate plus formoterol fumarate formulation via pressurized metered-dose inhaler in asthmatic children: a double-blind, randomized, cross-over clinical study.

A new pediatric fixed combination of beclometasone dipropionate (BDP) 50 µg and formoterol fumarate (FF) 6 µg via pressurized metered-dose inhaler (pMDI) (CHF1535, Chiesi, Italy) was investigated. In a double-blind, randomized, placebo-controlled, cross-over study, a single CHF1535 administration using AeroChamber Plus™ spacer device (2 actuations, total dose BDP 100 µg/FF 12 µg) was compared to the same pMDI free combination in 56 asthmatic children aged ≥ 5 and < 12 years. Primary efficacy variable was forced expiratory volume during the first second (FEV1) area under the curve corrected by time over 12 h following morning dose (AUC0-12h). Further CHF1535 doses (50 µg/6 µg, 100 µg/12 µg, and 200 µg/24 µg) were also explored. Adverse events, electrocardiogram, and vital signs were monitored for safety. CHF1535 was non-inferior to free combination [adjusted mean difference (95% CI) 0.004 L (- 0.050, 0.041] with lower confidence limit greater than the limit set at 0.1 L. FEV1 AUC0-12h of each CHF1535 dose vs placebo were 0.037 L (p = 0.160), 0.119 L (p < 0.001), and 0.094 (p < 0.001) for 50/6, 100/12, and 200/24, respectively. No safety signals were found.Conclusion: CHF1535 was as effective as free combination BDP/FF, with a trend towards a dose-related response. All treatments were safe.Trial registration: ClinicalTrials.gov ID: NCT01584492 What is Known: •Inhaled pressurized metered-dose solutions (pMDI) are the preferred treatment for pediatric asthma. •Combination therapy of inhaled corticosteroids and long-acting ß2- agonists is a well-established approach to control airway inflammation and airway obstruction also in pediatric patients. What is New: •A novel pediatric pMDI fixed combination of beclomethasone dipropionate 50 µg and formoterol fumarate 6 µg (CHF 1535) was non-inferior to the free combination at the same dose in pulmonary function over the 12-h post-dose period in asthmatic children, with trend towards a dose-related response.

Access to medicines for rare diseases: beating the drum for primary ciliary dyskinesia.

Primary ciliary dyskinesia, a rare disease causing bronchiectasis, lacks a sound evidence base for treatment. @beatpcd proposes 1) forming a PCD European clinical trial network to address this situation and 2) conducting n-of-1 trials to access medication. https://bit.ly/3j5blfM.

Viral infections and wheezing-asthma inception in childhood: is there a role for immunomodulation by oral bacterial lysates?

Severe and recurrent infections of the respiratory tract in early childhood constitute major risk factors for the development of bronchial hyper-responsiveness and obstructive respiratory diseases in later life. In the first years of life, the vast majority of respiratory tract infections (RTI) leading to wheezing and asthma are of a viral origin and severity and recurrence are the consequence of a greater exposure to infectious agents in a period when the immune system is still relatively immature. Therefore, boosting the efficiency of the host immune response against viral infections seems to be a rational preventative approach. In the last decades it has been demonstrated that living in farm environments, i.e. early-life exposure to microbes, may reduce the risk of allergic and infectious disorders, increasing the immune response efficacy. These findings have suggested that treatment with bacterial lysates could promote a nonspecific immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. Experimental and clinical studies showing the reduction of RTI frequency and severity in childhood and elucidating the involved mechanisms can support this hypothesis.

Impact of COVID-19 on Pediatric Asthma: Practice Adjustments and Disease Burden.

BACKGROUND: It is unclear whether asthma may affect susceptibility or severity of coronavirus disease 2019 (COVID-19) in children and how pediatric asthma services worldwide have responded to the pandemic. OBJECTIVE: To describe the impact of the COVID-19 pandemic on pediatric asthma services and on disease burden in their patients. METHODS: An online survey was sent to members of the Pediatric Asthma in Real Life think tank and the World Allergy Organization Pediatric Asthma Committee. It included questions on service provision, disease burden, and the clinical course of confirmed cases of COVID-19 infection among children with asthma. RESULTS: Ninety-one respondents, caring for an estimated population of more than 133,000 children with asthma, completed the survey. COVID-19 significantly impacted pediatric asthma services: 39% ceased physical appointments, 47% stopped accepting new patients, and 75% limited patients' visits. Consultations were almost halved to a median of 20 (interquartile range, 10-25) patients per week. Virtual clinics and helplines were launched in most centers. Better than expected disease control was reported in 20% (10%-40%) of patients, whereas control was negatively affected in only 10% (7.5%-12.5%). Adherence also appeared to increase. Only 15 confirmed cases of COVID-19 were reported among the population; the estimated incidence is not apparently different from the reports of general pediatric cohorts. CONCLUSIONS: Children with asthma do not appear to be disproportionately affected by COVID-19. Outcomes may even have improved, possibly through increased adherence and/or reduced exposures. Clinical services have rapidly responded to the pandemic by limiting and replacing physical appointments with virtual encounters.