Proinflammatory pattern in the lower airways of non-asthmatic obese adolescents.

BACKGROUND: Obesity is known to be a pro-inflammatory condition affecting multiple organs. Obesity as a systemic pro-inflammatory state, might be associated with bronchial inflammation in non-smoking adolescents with a BMI ≥ 30 kg/m2 without evidence of concomitant chronic diseases. MATERIALS AND METHODS: We studied non-asthmatic obese patients (n = 20; median age 15.8 years; BMI 35.0 kg/m2) compared to age matched healthy control subjects (n = 20; median age 17.5 years; BMI 21.5 kg/m2). Induced sputum differential cell counts and sputum mRNA levels were assessed for all study subjects. Serum levels of CRP, IL-6, and IL-8 were measured. Further, IL-5, IL-6, IL-8, IL-13, IL-17, TNF-α, IFN-γ, and IP-10 protein levels were analyzed in induced sputum was. RESULTS: Serum CRP levels, sputum inflammatory cell load and sputum eosinophils differed significantly between obese and non-obese subjects, for sputum neutrophils, a correlation was shown with BMI ≥ 30 kg/m2. Differences were also observed for sputum mRNA expression of IL6, IL8, IL13, IL17, IL23, and IFN-γ, as well as the transcription factors T-bet, GATA3, and FoxP3. CONCLUSIONS: Increased bronchial inflammation, triggered by systemic or local inflammatory effects of obesity itself, may account for the higher rates of airway disease in obese adolescents.

Are Questionnaires Helpful To Predict Exercise-Induced Bronchoconstriction (EIB) And Exercise-Induced Laryngeal Obstruction (EILO)?

OBJECTIVE: Exercise induced laryngeal obstruction (EILO) is an important differential diagnosis to exercise induced bronchoconstriction (EIB) and diagnosed via continuous laryngoscopy while exercising (CLE). However, availability of CLE is limited to specialized centres. And without CLE EILO is often misdiagnosed as EIB. Therefore it is essential to carefully preselect potential EILO candidates. Aim of this study was to investigate whether two short questionnaires -Asthma Control Test (ACT) and Dyspnea Index (DI) evaluating upper airway-related dyspnea- can differentiate between EIB and EILO. METHODS: Patients with dyspnea while exercising were analysed with an exercise challenge in the cold chamber (ECC) to diagnose EIB in visit 1 (V1), as appropriate a CLE in visit 2 (V2, 4-6 weeks after V1) and ACT and DI in V1 and V2. EIB patients were treated with asthma medication after V1. RESULTS: Complete dataset of 36 subjects were gathered. The ACT showed lower values in V2 in EILO compared to EIB patients. A lack of improvement in ACT in V2 after asthma medication of EIB patients is suspicious for additional EILO diagnosis. The DI showed higher values in V1 in EILO compared to EIB patients. A score≥30 can predict a positive CLE reaction. CONCLUSION: ACT and DI are valuable tools in preselecting CLE candidates to assure timely diagnostic despite limited diagnostic capabilities.

MicroRNA Profiling of the Inflammatory Response after Early and Late Asthmatic Reaction.

A high proportion of house dust mite (HDM)-allergic asthmatics suffer from both an early asthmatic reaction (EAR) and a late asthmatic reaction (LAR) which follows it. In these patients, allergic inflammation is more relevant. MiRNAs have been shown to play an important role in the regulation of asthma's pathology. The aim of this study was to analyze the miRNA profile in patients with mild asthma and an HDM allergy after bronchial allergen provocation (BAP). Seventeen patients with EAR/no LAR and 17 patients with EAR plus LAR, determined by a significant fall in FEV1 after BAP, were differentially analyzed. As expected, patients with EAR plus LAR showed a more pronounced allergic inflammation and FEV1 delta drop after 24 h. NGS-miRNA analysis identified the down-regulation of miR-15a-5p, miR-15b-5p, and miR-374a-5p after BAP with the highest significance in patients with EAR plus LAR, which were negatively correlated with eNO and the maximum decrease in FEV1. These miRNAs have shared targets like CCND1, VEGFA, and GSK3B, which are known to be involved in airway remodeling, basement membrane thickening, and Extracellular Matrix deposition. NGS-profiling identified miRNAs involved in the inflammatory response after BAP with HDM extract, which might be useful to predict a LAR.

Dual Role of microRNA-146a in Experimental Inflammation in Human Pulmonary Epithelial and Immune Cells and Expression in Inflammatory Lung Diseases.

microRNA (miR)-146a emerges as a promising post-transcriptional regulator in various inflammatory diseases with different roles for the two isoforms miR-146a-5p and miR-146a-3p. The present study aimed to examine the dual role of miR-146a-5p and miR-146a 3p in the modulation of inflammation in human pulmonary epithelial and immune cells in vitro as well as their expression in patients with inflammatory lung diseases. Experimental inflammation in human A549, HL60, and THP1 via the NF-kB pathway resulted in the major upregulation of miR-146a-5p and miR-146a-3p expression, which was partly cell-specific. Modulation by transfection with miRNA mimics and inhibitors demonstrated an anti-inflammatory effect of miR-146a-5p and a pro-inflammatory effect of miR-146a-3p, respectively. A mutual interference between miR-146a-5p and miR-146a-3p was observed, with miR-146a-5p exerting a predominant influence. In vivo NGS analyses revealed an upregulation of miR-146a-3p in the blood of patients with cystic fibrosis and bronchiolitis obliterans, while miR-146a-5p levels were downregulated or unchanged compared to controls. The reverse pattern was observed in patients with SARS-CoV-2 infection. In conclusion, miR-146a-5p and miR-146a-3p are two distinct but interconnected miRNA isoforms with opposing functions in inflammation regulation. Understanding their interaction provides important insights into the progression and persistence of inflammatory lung diseases and might provide potential therapeutic options.

Severe bronchial hyperresponsiveness along with house dust mite allergy indicates persistence of asthma in young children.

BACKGROUND: Significant risk factors for persistence of asthma later in life are family history of allergies, early allergic sensitization and bronchial hyperresponsiveness (BHR). The evolution of BHR in young children without allergic sensitization and with house dust mite allergy (HDM) was investigated. METHODS: In this retrospective analysis, electronic charts of 4850 young children with asthma and wheezy bronchitis between 2005 and 2018 were reviewed in order to study all patients ≤6 years with BHR assessed by methacholine provocation tests (MCT) at least once (n = 1175). Patients with more than two follow-up measurements were divided in group 1 (no allergic sensitization; n = 110) and group 2 (HDM allergy; n = 88). Additionally, skin prick test, exhaled nitrite oxide (eNO), and asthma treatment were analyzed. RESULTS: Forty-seven patients of group 1 aged median 4.3 years and 48 patients of group 2 aged median 4.7 years showed initially severe BHR <0.1 mg. At follow-up, patients with HDM were more likely to show persistence of severe BHR than non-sensitized patients (severe BHR group 1: n = 5 (10.6%) vs. group 2: n = 21 (43.8%), p < .001). In addition, 89.4% of group 1 had mild to moderate or no BHR, compared to only 56.2% of group 2. There was a significant difference in eN0 (median group 1: 9 ppb vs. group 2: 26 ppb, p < .001), at last follow-up. Age, sex, and asthma therapy had no effect on BHR. CONCLUSION: In young children without sensitization BHR normalizes, whereas HDM allergy indicates a persistence of asthma beyond infancy.

Peripheral polyneuropathy in children and young adults with ataxia-telangiectasia.

BACKGROUND AND PURPOSE: Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A-T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age-dependent neuropathy in A-T. METHODS: In this prospective study, 42 classical A-T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age- and gender-matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed. RESULTS: In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001). CONCLUSIONS: In A-T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A-T cohort demonstrates that development of neuropathy in A-T differs in the upper and lower extremities.

Aerosol measurement identifies SARS-CoV 2 PCR positive adults compared with healthy controls.

BACKGROUND: SARS-CoV-2 is spread primarily through droplets and aerosols. Exhaled aerosols are generated in the upper airways through shear stress and in the lung periphery by 'reopening of collapsed airways'. Aerosol measuring may detect highly contagious individuals ("super spreaders or super-emitters") and discriminate between SARS-CoV-2 infected and non-infected individuals. This is the first study comparing exhaled aerosols in SARS-CoV-2 infected individuals and healthy controls. DESIGN: A prospective observational cohort study in 288 adults, comprising 64 patients testing positive by SARS CoV-2 PCR before enrollment, and 224 healthy adults testing negative (matched control sample) at the University Hospital Frankfurt, Germany, from February to June 2021. Study objective was to evaluate the concentration of exhaled aerosols during physiologic breathing in SARS-CoV-2 PCR-positive and -negative subjects. Secondary outcome measures included correlation of aerosol concentration to SARS-CoV-2 PCR results, change in aerosol concentration due to confounders, and correlation between clinical symptoms and aerosol. RESULTS: There was a highly significant difference in respiratory aerosol concentrations between SARS-CoV-2 PCR-positive (median 1490.5/L) and -negative subjects (median 252.0/L; p < 0.0001). There were no significant differences due to age, sex, smoking status, or body mass index. ROC analysis showed an AUC of 0.8918. CONCLUSIONS: Measurements of respiratory aerosols were significantly elevated in SARS-CoV-2 positive individuals, which helps to understand the spread and course of respiratory viral infections, as well as the detection of highly infectious individuals.

Association between Polyunsaturated Fatty Acid Profile and Bronchial Inflammation in Bronchiolitis Obliterans.

Introduction: Bronchiolitis obliterans (BO) is a chronic lung disease, which occurs after an insult to the lower airways, in particular after airway infections or after stem cell transplantation, and which results in persistent inflammation. N-3 and n-6 polyunsaturated fatty acids (PUFA) have been shown to influence the inflammatory processes in chronic inflammatory conditions. Since BO is maintained by persistent pulmonary inflammation, a disbalanced n-6/n-3 fatty acid profile could support the inflammatory process in patients with BO and therefore, could become an approach to new therapeutic options. Methods: Twenty-five patients with BO (age: 13; 7-39) and 26 healthy controls (age: 19; 7-31) participated in the study. Lung function (forced viral capacity (FVC), forced expiratory volume 1 (FEV1), residual volume (RV)), and lung clearance index (LCI) were measured. Induced sputum was analyzed for cytology and cytokine levels (IL-1ß, IL-6, IL-8, TNF-α) using cytometric bead array (CBA). The PUFA profile was determined in the serum and induced sputum by gas chromatography. Results: Patients presented with significantly lower FVC and FEV1 as well as higher RV and LCI measurements compared to the control group. Apart from a massive airway inflammation indicated by elevated numbers of total cells and neutrophils, the CBA analysis showed significantly increased levels of IL-1ß, IL-6, and IL-8. The analysis of PUFA in sputum and serum revealed a significant difference in the ratio between the n-6 PUFA arachidonic acid (AA) and the n-3 PUFA docosahexaenoic acid (DHA) (AA : DHA). Furthermore, the AA : DHA ratio significantly correlated with the inflammatory cytokines in induced sputum. Conclusion: Lung function in BO is significantly impaired and associated with uncontrolled neutrophil-dominated airway inflammation. Furthermore, the imbalance in the AA/DHA ratio in favor of n-6 PUFA demonstrates a pro-inflammatory microenvironment in the cell membrane, which correlates with the inflammatory cytokines in induced sputum and might be an option for an anti-inflammatory therapy in BO.

Methacholine and FeNO Measurement in Patients with Habit Cough.

BACKGROUND: Chronic cough is one of the most common symptoms in childhood. Making a definite diagnosis is a challenge for all pediatricians especially in patients when cough is without an organic cause like in habit cough. PATIENTS AND METHODS: In this retrospective analysis, all electronic outpatient charts of the Division of Allergology and Pneumology, between January 1, 2010 and December 31, 2019 were reviewed in order to study all children with potential habit cough. All children underwent the following diagnostic algorithms, skin prick test (SPT), measurement of fractional exhaled nitric oxide (FeNO), spirometry and methacholine challenge test (MCT). The value of a normal MCT and FeNO measurement for diagnosing habit cough was investigated. RESULTS: The chart review revealed 482 patients with chronic cough>4 weeks. Of these, 99 (20.5%) with suspected habit cough were collected. 13 patients had to be excluded for other diagnosis and a complete data set was available in 55 patients. 33 (60.0%) of 55 patients were SPT negative and 22 (40.0%) had sensitization to common allergens. Five patients had elevated FeNO≥20 ppb and three showed severe bronchial hyperresponsiveness<0.1 mg methacholine, challenging the diagnosis of habit cough. CONCLUSION: A normal FeNO and MCT can help confirm the clinical diagnosis of habit cough. However, in patients with positive MCT and/or elevated FeNO habit cough can be present. Especially in patients with elevated FeNO and severe BHR cough variant asthma and eosinophilic bronchitis have to be ruled out.

Bronchial inflammation biomarker patterns link humoral immunodeficiency with bronchiectasis-related small airway dysfunction.

BACKGROUND: The progression of chronic destructive lung disease in patients with humoral immunodeficiency (ID) and concomitant development of bronchiectasis is difficult to prevent. Lung function tests in these patients typically show bronchial obstruction of the small airways in combination with increased air trapping in the distal airways, which is consistent with small airway dysfunction. OBJECTIVE: The objective was to assess the grade of chronic lower airway inflammation and small airway dysfunction from induced sputum and the corresponding local pro-inflammatory mediator pattern to discriminate patients affected by bronchiectasis-related Small Airway Dysfunction (SAD). METHODS: In a prospective design, 22 patients with ID (14 CVID, 3 XLA, 3 hyper-IgM syndrome, 1 hyper-IgE syndrome and low IgG levels due to treatment with rituximab and 1 SCID after BMT and persistent humoral defect) and 21 healthy controls were examined. Lung function, Fraction Expiratory Nitric Oxide (FeNO) and pro-inflammatory cytokine levels were compared in subsets of patients with (ID + BE) and without bronchiectasis (ID) pre-stratified using high-resolution computed tomography (HRCT) scans and control subjects. RESULTS: Analysis of induced sputum showed significantly increased total cell counts and severe neutrophilic inflammation in ID. The concomitant SAD revealed higher total cell numbers compared to ID. Bronchial inflammation in ID is clearly mirrored by pro-inflammatory mediators IL-1ß, IL-6 and CXCL-8, whilst TNF-α revealed a correlation with lung function parameters altered in the context of bronchiectasis-related Small Airway Dysfunction. CONCLUSIONS: In spite of immunoglobulin substitution, bronchial inflammation was dominated by neutrophils and was highly increased in patients with ID + BE. Notably, the pro-inflammatory cytokines in patients with ID were significantly increased in induced sputum. The context-dependent cytokine pattern in relation to the presence of concomitant bronchiectasis associated with SAD in ID patients could be helpful in delimiting ID patient subgroups and individualizing therapeutic approaches.

EAACI position paper on the clinical use of the bronchial allergen challenge: Unmet needs and research priorities.

Allergic asthma (AA) is a common asthma phenotype, and its diagnosis requires both the demonstration of IgE-sensitization to aeroallergens and the causative role of this sensitization as a major driver of asthma symptoms. Therefore, a bronchial allergen challenge (BAC) would be occasionally required to identify AA patients among atopic asthmatics. Nevertheless, BAC is usually considered a research tool only, with existing protocols being tailored to mild asthmatics and research needs (eg long washout period for inhaled corticosteroids). Consequently, existing BAC protocols are not designed to be performed in moderate-to-severe asthmatics or in clinical practice. The correct diagnosis of AA might help select patients for immunomodulatory therapies. Allergen sublingual immunotherapy is now registered and recommended for controlled or partially controlled patients with house dust mite-driven AA and with FEV1 ≥ 70%. Allergen avoidance is costly and difficult to implement for the management of AA, so the proper selection of patients is also beneficial. In this position paper, the EAACI Task Force proposes a methodology for clinical BAC that would need to be validated in future studies. The clinical implementation of BAC could ultimately translate into a better phenotyping of asthmatics in real life, and into a more accurate selection of patients for long-term and costly management pathways.

Evaluating Children and Adolescents with Suspected Exercise Induced Asthma: Real Life Data.

OBJECTIVE: Exercise-induced bronchoconstriction (EIB) occurs frequently in children and adolescents and may be a sign of insufficient asthma control. EIB is often evaluated by respiratory symptoms, spirometry, eNO measurement and methacholine testing (MCT) instead of time consuming exercise test. Aim of this study was to analyse the amount of patients for which an exercise challenge in a cold chamber (ECC) was needed for a clear EIB diagnosis, to characterize EIB phenotypes and the incidence of exercise induced laryngeal obstruction (EILO) in a large cohort of patients with EIB. METHODS: A retrospective analysis was performed in 595 children and adolescents (mean age 12.1 years) with suspected EIB from January 2014 to December 2018. Complete data sets of skin prick test, spirometry, eNO and MCT were available from 336 patients. RESULTS: An ECC to confirm the EIB diagnosis was performed in 125 (37.2%) of patients. Three EIB phenotypes were detected: group 1: EIB without allergic sensitization (n=159); group 2: EIB with other than house dust mite (HDM) sensitization (n=87) and group 3: EIB with HDM sensitization (n=90). MCT and eNO showed significant differences between the subgroups: An eNO>46 ppb and/or a MCT<0.1 mg was found in 23.9% vs. 50.6% vs. 57.8% in group 1-3, respectively. Significantly more patients suffered from EILO in group 1 compared to group 2 and 3 (n=13 vs. n=1). CONCLUSION: EIB without sensitization is as often as EIB with sensitization. In patients without sensitization, EILO has to be considered as a possible cause of symptoms during exercise.

Antibiotic Use in Paediatric Patients Hospitalized with Acute Severe Asthma.

BACKGROUND: Antibiotic use during asthma exacerbations in paediatric patients is not routinely recommended but common practise in out-patient and in-patient settings. Objective of this study was to analyse frequency of antibiotic use during acute severe asthma exacerbations, antibiotic classes utilized and clinical decision-making. METHODS: All in-patient admissions over 10 years in a single German Children's University hospital due to acute severe asthma were included in this retrospective analysis. Age, length of stay, oxygen supplementation, treatment, laboratory parameters and chest x-rays of all patients ranging from 1 to 17 years were analysed. RESULTS: 580 hospital admissions were included in this study. Overall antibiotic use was high but decreased with age (1-5 years 69,6%, 6-11 years 57,6% and 12-17 years 39,7%, p<0.001). Analysis of antibiotic treatment without clear indication showed a consistently lower treatment rate of 28.3%, with macrolides being the most common antibiotic class. Younger age significantly decreased, whereas, increase of CrP value, use of oxygen supplementation and concomitant fever all significantly increased the odds ratio (OR 0.967; 4.366, 2.472 and 2.011 respectively) of receiving antibiotic treatment without clear indication. CONCLUSION: Antibiotic treatment without clear indication during acute severe asthma is common in this German single-centre cohort. Clinical parameters of more severe disease affect clinician's decision to administer antibiotics despite evidence of bacterial infection or improved outcome.

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease.

Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.

The incidence and type of cancer in patients with ataxia-telangiectasia via a retrospective single-centre study.

Ataxia-telangiectasia (A-T) is a hereditary immune system disorder with neurodegeneration. Its first neurologic symptoms include ataxic gait in early childhood, with slowly progressive cerebellar ataxia, oculomotor apraxia, oculocutaneous telangiectasia, and progressive muscle weakness. Neonatal screening for severe T-cell deficiency was recently found to diagnose A-T patients with a significantly reduced naïve T-cell pool. Our study includes 69 A-T patients between 8 January 2002 and 1 December 2019. Nineteen cases of cancer were diagnosed in 17 patients (25%), with a median overall survival [OS; 95% cumulative indcidence (CI)] of 26·9 years for the entire cohort. The 15-year OS of 82·5% (72-95%) was significantly decreased among A-T patients with malignancies, who had a median OS of 2·11 years, with a two-year-estimated OS of 50·7% (31-82%). Haematological malignancies were the major causes of death within the initial years of life with a 15 times increased risk for death [HR (95% CI): 6·9 (3·1-15.2), P < 0·001] upon malignancy diagnosis. Male patients with A-T are at a higher cancer risk than their female counterparts. This manuscript highlights the need for cancer surveillance and prevention, as well as optimal treatment in this cohort.

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

AR101 Oral Immunotherapy for Peanut Allergy.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Effects of the SARS-CoV2-Lockdown on Pediatric Care in the Rhine-Main Area.

BACKGROUND: The effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and lockdown on pediatric diseases and care are not well characterized in Germany. PATIENTS AND METHODS: To investigate the effects of the lockdown on pediatric medical care in the Rhine-Main area, a survey asking 115 pediatricians and an analysis of the inpatient admissions at the Department for Children and Adolescents Goethe-University, Frankfurt in April 2020 compared to April 2019 was performed. RESULTS: 65/115 (56.5%) pediatricians answered the survey. Pediatricians estimated the reduction of patient consultations in April 2020 vs. 2019 by 40% (median), however, according to their practice administration software, patient visits decreased by 30%. The median number of cases with the diagnosis J21 (acute bronchitis) were significantly less in April 2020 vs. April 2019 (50 vs. 10 cases per pediatrician; p<0.001). Simultaneously, hospital admissions decreased by 43.7% from 402 total cases in April 2019 to 226 cases in April 2020. Hospital admissions due to acute respiratory tract infections or asthma exacerbations as well as neonatal and oncological disorders were significantly reduced compared to the previous year (83.7; 38.1 and 22.1% respectively less to 2019). CONCLUSION: The lockdown in April 2020 resulted in significantly fewer visits to pediatricians in general practice and hospital admissions, especially for acute respiratory tract infections. The health and economic consequences are discussed.

The MiR-320 Family Is Strongly Downregulated in Patients with COVID-19 Induced Severe Respiratory Failure.

A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0-3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-ß signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.

Immune competence and respiratory symptoms in patients with ataxia telangiectasia: A prospective follow-up study.

Ataxia telangiectasia is a multi-system disorder characterized by progressive cerebellar ataxia, malignancies, chronic pulmonary disease and immunodeficiency. The aim of our study was to determine the immune competence and prevalence of respiratory infections and/or chronic cough in classical A-T patients compared to age-matched healthy controls. STUDY DESIGN: We recruited 20 classical A-T not treated by immunoglobulins and 21 healthy age-matched control patients. The caregivers were advised to keep a daily diary with the following items (daytime and nighttime cough, runny nose, fever), number of cold episodes, number of antibiotic treatments. RESULTS: Patients with A-T showed significant differences compared to healthy controls in symptom score, daytime and nighttime cough, days with symptoms and missed days in kindergarten/school. Severe infections with hospitalization occurred rarely. Respiratory symptoms did not correlate with immunoglobulin levels in A-T patients. CONCLUSIONS: Mild symptoms like chronic cough were present in A-T patients, possibly indicating ongoing silent crippling disease.