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Background Lung function testing in small children is cumbersome. However, reduced variability of tidal breathing recorded using impedance pneumography (IP) during sleep was recently found to be a potential objective marker of wheeze in children aged 1‐5 years. We aimed to investigate how an acute bronchial obstruction (BO) and its severity, and recovery thereof reflect in expiratory variability index (EVI). Methods EVI was measured using a wearable IP system (Ventica®) during sleep in 40 healthy controls (aged 1.5‐5.9 years) and 30 patients hospitalized due to acute BO (aged 1.3‐5.3 years). In healthy controls, EVI was measured for 1‐3 nights at their homes. Patients were measured for several nights during hospitalization, as practically feasible, and at home 2 and 4 weeks post‐discharge. Results We received 79 EVI results from 39 controls and 139 from 30 patients. 90% had previous BO episodes, 30% used asthma controller medication before and 100% after hospitalization. Compared to controls, EVI was significantly lower during hospitalization (P

Health care workers (HCW) are at increased risk of a latent tuberculosis infection (LTBI) due to occupational exposure to Mycobacterium tuberculosis. In order to investigate the mutual influence of a TH1 type immune response caused by LTBI and T helper 2 (TH2) type immune response caused by allergy, we conducted a study examining the prevalence of common inhaled allergen sensitization in the HCW population with different levels of exposure to tuberculosis (high and low). HCW with possible exposure to tuberculosis (TB) were tested with QuantiFERON-TB Gold (QFT-G) and tuberculin skin test (TST), while skin prick test (SPT) was performed for inhaled allergens. The antigen (Ag) response at QFT-G was inversely correlated with participants` allergy anamnesis (p= 0.039). Sensitization to inhaled allergens (positive SPT and number of positive allergens at SPT) was more prominent in the low exposure group (p= 0.006 and p= 0.0065, respectively). Ag response at QFT-G test was significantly higher in participants with no medical history of allergy (p= 0.048). Our results demonstrate that exposure to TB and LTBI are associated with inhaled allergen sensitization in HCW, possibly inhibiting allergic sensitization by mediating the T-helper type 1 (Th1) immune response.

PANDAS, or pediactric autoimmune neuropsychiatric disorder associated with Streptococcus pyogenes, is characterized by an acute onset of neuropsychiatric symptoms which seem unexplainable. These symptoms usually include obsessive-compulsive disorder, and a variety of tics, that appear in children before puberty. The aim of this study was to compare the clinical manifestations of our patients with PANDAS to the latest studies and report our findings. This retrospectiove study included 20 patients with valid clinical features of PANDAS who were treated and followed at Srebrnjak Children’s Hospital between 2014 and 2019. Our examinees were children before puberty which fullfilled the main criterion of early-onset and at least two major criteria – obsessions/compulsions (OCD) and neuromotor dysfunction (tics, hyperactivity). We retrospectively analized all the data with special focus on neuropsychiatric symptoms. In 5-year period a total of 20 children, 16 (80%) male and 4 (20%) female, aged 3 to 11 years (median age 6,5) were followed up under the diagnosis of PANDAS. Only one patient had a burdened perinatal history (prematurity, short-term mechanical ventilation, neuromotor habilitation). Family history of tics and autoimmune disorders was positive in N=5 (25%). All patients had OCD and tics with acute onset of symptoms. Elevated levels of antistreptolysin titers were found in all but one patient (95%). Anti-DNAse-B levels were tested in 7 patients and was elevated in 4 (57%). Attention disordes were present in N=17 (85%) and 4 (20%) patients had sleeping difficulties. Speech difficulties were detected in N=5 (25%). Decline in school performance was also commun in children attending school N=10 (71%). None of the patients had pathological changes in EEG, and those with neuroimaging studies (N=12 or 60%) did not have any speciffic findings. First-line antibiotics were given to 15 (75%) patients. In 5 (25%) patients a full regression of symptoms was registered, 10 (50%) had partial improvement, 5 (25%) had no response.In 7 (35%) patients intravenous immunoglobulins (IVIG) were given after initial antibiotic treatment with incomplete regression. Tics persisted in 11 patients and 4 had tics with behavioral difficulties. In 7 patients treated with IVIG we proceeded with parenteral antibiotics because of partial symptom regression and 2 were given corticosteroids (still followed). We observed a higher rate of full symptom regression with first-line parenteral antibiotics and some of them improved after IVIG. Further research on larger cohorts of patients are necessary for better management of this clinical entity.

Periostin is a matricellular protein upregulated in response to IL-4 and IL-13, that have a role in development of allergic diseases. Previous studies reported that periostin can be a non-invasive biomarker of T2-driven inflammatory response in asthma in adults, with inconsistent results in children. None of the studies examined the association of serum periostin levels with asthma symptoms in children who have been infected with respiratory syncytial virus (RSV) in the first two years of life. The aim of this study was to determine the usefulness of serum periostin levels as a potential biomarker for asthma, especially recent asthma symptoms in children. This prospective study observed 72 children from birth. RSV infection was confirmed with positive serum specific RSV Immunoglobulin G (IgG) at one and/or two years of age. Asthma was diagnosed according to International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire at 10 years of age. Fractional exhaled nitric oxide (FeNO), lung function, skin prick test and blood samples for analysis of specific immunoglobulin E (sIgE) on standard pallet of inhalant allergens, total IgE (tIgE) and periostin were provided. At 10 years of age, asthma was diagnosed in 23 (31.9%) of the observed children. In 15 (20.8%) of them who reported asthma symptoms during the last 12 months, median serum periostin levels were 40.04 ng/ml. In 57 (79.2%) children who were free of asthma symptoms in the last 12 months, mean serum periostin levels were 30.57 ng/ml. Serum periostin levels correlated significantly with recent asthma symptoms (Kendall’s Tau-B = 0.236, p = 0.016). Serum periostin levels significantly correlated with asthma symptoms during the last 12 months in 10-year-old children who were infected with RSV during their first two years of life. Our preliminary results suggest that serum periostin level may be useful in diagnosing asthma in children, especially those with recent asthma symptoms and history of RSV infection in infancy.

Objective − The aim of study was to evaluate the effects of parental smoking and tobacco smoke exposure (TSE) on asthma symptoms in children, and to raise awareness of the detrimental effects of TSE for asthmatic children.Methods − A modified and validated questionnaire on TSE was completed by 76 parents and their children who were being treated at Srebrnjak Children’s Hospital for asthma. Patients filled in a standardized ACT questionnaire about their asthma symptoms, whereas parental smoking data were derived from a questionnaire filled in by the parents. The answers were structured as ordinal and categorical variables. The non-parametric Mann-Whitney U test and Kruskal-Wallis test were performed.Results −There are statistically significant differences in the frequency of asthma symptoms in children depending on whether household members smoked cigarettes, with statistically significant differences in the frequency of asthma symptoms in children depending on whether their parents smoked cigarettes outside the house, only in one/certain room or everywhere in the house. 34.1% of smoking parents vs 9.4% of nonsmoking parents allow smoking in a car while the child is riding in it. 40.9% of parents who smoke vs 21.9% of non-smoking parents believe that their child is exposed to tobacco smoke somewhere other than in their household or car.Conclusion − TSE is associated with more symptoms and worse asthma control in asthmatic children.

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., This study reveals enormous differences in therapy with biologicals for childhood severe asthma across Europe, and demonstrates the urgent need for harmonisation in medication choice, definition of therapy success and how/when to discontinue treatment https://bit.ly/3tnJMTY

Objective: Pharmacogenetic studies have recognized specific genes that highly correlate with response to inhaled corticosteroids (ICS) treatment in asthma patients. Among the genes identified, we selected glucocorticoid-induced transcript 1 (GLCCI1) and stress-induced phosphoprotein 1 (STIP1) to evaluate the impact of these gene polymorphisms on ICS treatment response in Tunisian asthmatics. Methods: We analyzed four single nucleotide polymorphisms (SNPs): two in GLCCI1 (rs37972 and rs37973), and two in STIP1 (rs2236647 and rs2236648), which are genes associated with susceptibility to asthma and response to ICS in a Tunisian cohort. The SNPs were genotyped using reverse transcriptase polymerase chain reaction (RT- PCR) techniques. Results: This case-control study consisted of 230 adult asthmatic patients and 236 healthy subjects. Seventy-five asthmatics were selected and followed through 12 weeks of routine treatment. The T allele rs2236648 in STIP1 was associated with allergic asthma (OR = 0.38, 95%CI = 0.20-0.69, p = 0.001). The rs37972 and rs37973 of GLCCI1 were associated with a higher risk of asthma (p < 0.001). The T allele rs37972 and G allele rs37973 were correlated with a strong risk for developing severe asthma (p < 0.001). Asthma patients carrying the rs37973 GG genotype had less improvement in the forced expiratory volume in one second (FEV1) than those with the AA or AG genotypes after 12 weeks of treatment (p < 0.001). Also, the G allele of rs37973 was associated with worse response to ICS after 12 weeks of treatment (p < 0.001). Conclusion: The rs37972 and rs37973 polymorphisms can serve as potential asthma risk biomarkers in a Tunisian population.

Having a penicillin allergy label associates with worse healthcare outcomes and increased treatment costs.1-3 However, whether penicillin allergy testing is cost‐saving remains unclear, particularly as there is heterogeneity in the practice of such testing.4 Therefore, we developed an online questionnaire to assess the practice and cost perceptions of diagnostic tests used in penicillin allergy evaluation. Regarding cost perceptions, we asked respondents to estimate material, personnel, and facilities costs of performing each assessed diagnostic test. We also asked for estimates on the total paid amounts for each performed test (ie, perceived reimbursements by the State, insurance companies, or patients). Respondents provided a level of confidence (low, medium, or high) for each reported cost estimate. This questionnaire targeted drug allergy experts in Europe—we contacted European Network of Drug Allergy members by email, as well as first, last, and/or corresponding authors of publications in the field of drug allergy (our search was limited to publications of the last 10 years).

Despite widely and regularly used therapy asthma in children is not fully controlled. Recognizing the complexity of asthma phenotypes and endotypes imposed the concept of precision medicine in asthma treatment. By applying machine learning algorithms assessed with respect to their accuracy in predicting treatment outcome, we have successfully identified 4 distinct clusters in a pediatric asthma cohort with specific treatment outcome patterns according to changes in lung function (FEV1 and MEF50), airway inflammation (FENO) and disease control likely affected by discrete phenotypes at initial disease presentation, differing in the type and level of inflammation, age of onset, comorbidities, certain genetic and other physiologic traits. The smallest and the largest of the 4 clusters- 1 (N = 58) and 3 (N = 138) had better treatment outcomes compared to clusters 2 and 4 and were characterized by more prominent atopic markers and a predominant allelic (A allele) effect for rs37973 in the GLCCI1 gene previously associated with positive treatment outcomes in asthmatics. These patients also had a relatively later onset of disease (6 + yrs). Clusters 2 (N = 87) and 4 (N = 64) had poorer treatment success, but varied in the type of inflammation (predominantly neutrophilic for cluster 4 and likely mixed-type for cluster 2), comorbidities (obesity for cluster 2), level of systemic inflammation (highest hsCRP for cluster 2) and platelet count (lowest for cluster 4). The results of this study emphasize the issues in asthma management due to the overgeneralized approach to the disease, not taking into account specific disease phenotypes.

Asthma in children is a heterogeneous disease manifested by various phenotypes and endotypes. The level of disease control, as well as the effectiveness of anti-inflammatory treatment, is variable and inadequate in a significant portion of patients. By applying machine learning algorithms, we aimed to predict the treatment success in a pediatric asthma cohort and to identify the key variables for understanding the underlying mechanisms. We predicted the treatment outcomes in children with mild to severe asthma (N = 365), according to changes in asthma control, lung function (FEV1 and MEF50) and FENO values after 6 months of controller medication use, using Random Forest and AdaBoost classifiers. The highest prediction power is achieved for control- and, to a lower extent, for FENO-related treatment outcomes, especially in younger children. The most predictive variables for asthma control are related to asthma severity and the total IgE, which were also predictive for FENO-based outcomes. MEF50-related treatment outcomes were better predicted than the FEV1-based response, and one of the best predictive variables for this response was hsCRP, emphasizing the involvement of the distal airways in childhood asthma. Our results suggest that asthma control- and FENO-based outcomes can be more accurately predicted using machine learning than the outcomes according to FEV1 and MEF50. This supports the symptom control-based asthma management approach and its complementary FENO-guided tool in children. T2-high asthma seemed to respond best to the anti-inflammatory treatment. The results of this study in predicting the treatment success will help to enable treatment optimization and to implement the concept of precision medicine in pediatric asthma treatment.

Maternal nutrition and lifestyle in pregnancy are important modifiable factors for both maternal and offspring&rsquo, s health. Although the Mediterranean diet has beneficial effects on health, recent studies have shown low adherence in Europe. This study aimed to assess the Mediterranean diet adherence in 266 pregnant women from Dalmatia, Croatia and to investigate their lifestyle habits and regional differences. Adherence to the Mediterranean diet was assessed through two Mediterranean diet scores. Differences in maternal characteristics (diet, education, income, parity, smoking, pre-pregnancy body mass index (BMI), physical activity, contraception) with regards to location and dietary habits were analyzed using the non-parametric Mann&ndash, Whitney U test. The machine learning approach was used to reveal other potential non-linear relationships. The results showed that adherence to the Mediterranean diet was low to moderate among the pregnant women in this study, with no significant mainland&ndash, island differences. The highest adherence was observed among wealthier women with generally healthier lifestyle choices. The most significant mainland&ndash, island differences were observed for lifestyle and socioeconomic factors (income, education, physical activity). The machine learning approach confirmed the findings of the conventional statistical method. We can conclude that adverse socioeconomic and lifestyle conditions were more pronounced in the island population, which, together with the observed non-Mediterranean dietary pattern, calls for more effective intervention strategies.

Background: Environmental interactions are very complex in childhood asthma, and we hypothesized that even a short-term exposure to an allergy safe outdoor environment (AllSOE) combined with pulmonary rehabilitation program (PRP) could exert significant beneficial effects. Our aim was to test the effects of 2-week PRP provided in an AllSOE in children with mild to moderate asthma. Methods: 110 children (aged 7.5–17 years, 46% girls), with partially or totally controlled asthma, attended the PRP at the Island of Lošinj (Croatia) supervised by a multidisciplinary team (pediatric pulmonologist, sports medicine specialist, physiotherapist and kinesiologist). Each child had an adjusted intensity of physical activity with at least 2 h of exercise per day. Body height and weight, spirometry, fraction of exhaled nitric oxide (FeNO), running distance during free running test (FRT) and the decline in lung function after FRT (exercise-induced bronchoconstriction- EIB) were measured at baseline and after PRP. Results: A significant improvement in running distance (from 903 ± 272 m to 968 ± 289 m ; p < 0.001), a decrease of FeNO (from 37 ± 32 ppb to 25 ± 17 ppb ; p < 0.001) were determined after PRP. There were no significant changes in lung function and EIB, except EIB in the fourth quartile (significant EIB at baseline) where EIB significantly decreased (p < 0.001) after PRP. Conclusion: Two weeks of PRP in an AllSOE significantly improved exercise capacity and reduced airway inflammation and airway hyperreactivity showing that even a short-term PRP within a proper environment could be effective and affordable management strategy for children and adolescents with mild to moderate asthma.

BACKGROUND: Treatment of drinking water may decrease microbial exposure. OBJECTIVE: To investigate whether bacterial load in drinking water is associated with altered risk of allergic diseases. METHODS: We recruited 1, 110 schoolchildren aged 6-16 years between 2011 and 2013 in Požega-Slavonia County in Croatia, where we capitalized on a natural experiment whereby individuals receive drinking water through public mains supply or individual wells. We obtained data on microbial content of drinking water for all participants ; 585 children were randomly selected for more detailed assessments, including skin prick testing. Since water supply was highly correlated with rural residence, we compared clinical outcomes across four groups (Rural/Individual, Rural/Public, Urban/Individual, Urban/Public). For each child, we derived quantitative index of microbial exposure (bacterial load in the drinking water measured during the child's first year of life). RESULTS: Cumulative bacterial load in drinking water was higher (median [IQR]: 6390 [4190-9550] vs. 0 [0-0] ; p

Background: Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX- 0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX- 0171 in children admitted to hospital with RSV lower respiratory tract infection. Methods: This double-blind, randomised, placebo- controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web- based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49. Findings: Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX- 0171, and 42 received placebo ; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7- 28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7] ; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9] ; p92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4] ; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1] ; difference in least- squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug. Interpretation: Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation.

BACKGROUND The aim of this study was to assess sleep architecture and respiration during sleep in children with intractable epileptic encephalopathies using overnight video-polysomnography (V-PSG). ----- MATERIAL AND METHODS Between 2015 to 2017 overnight V-PSG recordings were made for 31 children (22 boys and 9 girls) with intractable epileptic encephalopathy with a mean age of 6.78±3.61 years and a mean body mass index (BMI) of 15.83±3.16 kg/m3. Thirty-one healthy children were matched for sex, age, and BMI as the control group. The phases of sleep studied included rapid eye movement (REM) sleep, and non-REM (NREM) phases NREM 1, NREM 2, and NREM 3. Respiratory function during sleep was evaluated. ----- RESULTS Children with epileptic encephalopathies receiving antiepileptic treatment had significantly decreased total sleep time (TST) (p=0.038), significantly increased percentage of NREM1 (p=0.033), and a significantly lower percentage of total REM (p

Allergic rhinitis is a common health problem in both children and adults. The number of patients allergic to ragweed (Ambrosia artemisiifolia) is on the rise throughout Europe, having a significant negative impact on the patients' and their family's quality of life. Allergen-specific immunotherapy (AIT) has disease-modifying effects and can induce immune tolerance to allergens. Both subcutaneous immunotherapy and sublingual immunotherapy with ragweed extracts/preparations have clear positive clinical efficacy, especially over pharmacological treatment, even years after the treatment has ended. AIT also has very good safety profiles with extremely rare side effects, and the extracts/preparations used in AIT are commonly well tolerated by patients. However, patient adherence to treatment with AIT seems to be quite low, mostly due to the fact that treatment with AIT is relatively time-demanding and, moreover, due to patients not receiving adequate information and education about the treatment before it starts. AIT is undergoing innovations and improvements in clinical efficacy, safety and patient adherence, especially with new approaches using new adjuvants, recombinant or modified allergens, synthetic peptides, novel routes of administration (epidermal or intralymphatic), and new protocols, which might make AIT more acceptable for a wider range of patients and novel indications. Patient education and support (eg, recall systems) is one of the most important goals for AIT in the future, to further enhance treatment success.

Background Diagnosing asthma in children is a challenge and using a single biomarker from exhaled breath condensate (EBC) showed the lack of improvement in it. Objective The aim of this study was to assess the diagnostic potential of a pattern of simple chemical biomarkers from EBC in diagnosing asthma in children in a real-life setting, its association with lung function and gastroesophageal reflux disease (GERD). Methods In 75 consecutive children aged 5–7 years with asthma-like symptoms the following tests were performed: skin prick tests, spirometry, impulse oscillometry (IOS), exhaled NO (FENO), 24-hour oesophageal pH monitoring and EBC collection with subsequent analysis of pH, carbon dioxide tension, oxygen tension, and concentrations of magnesium, calcium, iron and urates. Results No significant differences were found for individual EBC biomarkers between asthmatics and non-asthmatics (p > 0.05 for all). A pattern of six EBC biomarkers showed a statistically significant (p = 0.046) predictive model for asthma (AUC = 0.698, PPV = 84.2%, NPV = 38.9%). None to moderate association (R2 up to 0.43) between EBC biomarkers and lung function measures and FENO was found, with IOS parameters showing the best association with EBC biomarkers. A significantly higher EBC Fe was found in children with asthma and GERD compared to asthmatics without GERD (p = 0.049). Conclusions An approach that involves a pattern of EBC biomarkers had a better diagnostic accuracy for asthma in children in real-life settings compared to a single one. Poor to moderate association of EBC biomarkers with lung function suggests a complementary value of EBC analysis for asthma diagnosis in children.

Background: Diminished variability of the expiratory flow profiles measured using impedance pneumography (IP) during night’s sleep is associated with lower airway obstruction (LAO) in young children with recurrent wheeze (Seppa et al. ERJ Open Res 2019, accepted). Aims and Objectives: We aimed to investigate, how an acute LAO and recovery thereof reflects on the change in expiratory variability index (EVI) in a longitudinal setting. Methods: EVI was measured using a wearable IP system (Ventica, Revenio Research Ltd., Vantaa, Finland) during sleep at night in healthy controls (both sexes aged 4.3 [1.5-6.0] y) and patients hospitalised due to acute LAO (both sexes, aged 3.5 [1.3-6.0] y). In-patients were measured for several nights, as practically feasible, and for 1-2 nights at home after first and second control visit (2 and 4 weeks post-discharge). The controls were measured for 1-3 nights at their homes. Results: We received 79 recordings from 37 controls and 141 from 29 patients. Compared to the controls, EVI of the patients was lower during the in-patient period (rank sum p Conclusions: EVI shows to be a sensitive, objective marker of acute LAO prone to change with the clinical status in children aged 1-5 years.

Osteoarthritis (OA) is a degenerative joint disease accompanied by pain and loss of function. Adipose tissue harbors mesenchymal stem/stromal cells (MSC), or medicinal signaling cells as suggested by Caplan (Caplan, 2017), used in autologous transplantation in many clinical settings. The aim of the study was to characterize a stromal vascular fraction from microfragmented lipoaspirate (SVF-MLA) applied for cartilage treatment in OA and compare it to that of autologous lipoaspirate (SVF-LA). Samples were first stained using a DuraClone SC prototype tube for the surface detection of CD31, CD34, CD45, CD73, CD90, CD105, CD146 and LIVE/DEAD Yellow Fixable Stain for dead cell detection, followed by DRAQ7 cell nuclear dye staining, and analyzed by flow cytometry. In SVF-LA and SVF-MLA samples, the following population phenotypes were identified within the CD45− fraction: CD31+CD34+CD73±CD90±CD105±CD146± endothelial progenitors (EP), CD31+CD34−CD73±CD90±CD105−CD146± mature endothelial cells, CD31−CD34−CD73±CD90+CD105−CD146+ pericytes, CD31−CD34+CD73±CD90+CD105−CD146+ transitional pericytes, and CD31−CD34+CD73highCD90+CD105−CD146− supra-adventitial-adipose stromal cells (SA-ASC). The immunophenotyping profile of SVF-MLA was dominated by a reduction of leukocytes and SA-ASC, and an increase in EP, evidencing a marked enrichment of this cell population in the course of adipose tissue microfragmentation. The role of EP in pericyte-primed MSC-mediated tissue healing, as well as the observed hormonal implication, is yet to be investigated.

Common ragweed is a highly allergenic invasive species in Europe, expected to become widespread under climate change. Allergy to ragweed manifests as eye, nasal and lung symptoms, and children may retain these throughout life. The dose-response relationship between symptoms and pollen concentrations is unclear. We undertook a longitudinal study, assessing the association between ragweed pollen concentration and allergic eye, nasal and lung symptoms in children living under a range of ragweed pollen concentrations in Croatia. Over three years, 85 children completed daily diaries, detailing allergic symptoms alongside daily location, activities and medication, resulting in 10,130 individual daily entries. The daily ragweed pollen concentration for the children's locations was obtained, alongside daily weather and air pollution. Parents completed a home/lifestyle/medical questionnaire. Generalised Additive Mixed Models established the relationship between pollen concentrations and symptoms, alongside other covariates. Eye symptoms were associated with mean daily pollen concentration over four days (day of symptoms plus 3 previous days); 61 grains/m3/day (95%CI: 45, 100) was the threshold at which 50% of children reported symptoms. Nasal symptoms were associated with mean daily pollen concentration over 12 days (day of symptoms plus 11 previous days); the threshold for 50% of children reporting symptoms was 40 grains/m3/day (95%CI: 24, 87). Lung symptoms showed a relationship with mean daily pollen concentration over 19 days (day of symptoms plus 18 previous days), with a threshold of 71 grains/m3/day (95%CI: 59, 88). Taking medication on the day of symptoms showed higher odds, suggesting responsive behaviour. Taking medication on the day prior to symptoms showed lower odds of reporting, indicating preventative behaviour. Different symptoms in children demonstrate varying dose-response relationships with ragweed pollen concentrations. Each symptom type responded to pollen exposure over different time periods. Using medication prior to symptoms can reduce symptom presence. These findings can be used to better manage paediatric ragweed allergy symptoms.

Every agent used during the perioperative period may be involved and have the potential to trigger both allergic, IgE and non-IgE reaction as well as non-specific (non-allergic) reactions. In many cases, an allergic mechanism cannot be ruled out and systematic investigations should be tested of all drugs and agents the patient was exposed to prior to the reaction. The complexity of agents used for anaesthesia and surgery present challenges when attempting to identify the culprit drugs and select proper testing to better recognition of trigger. The diagnosis of preoperative anaphylactic or anaphylactoid reaction is clinical and based upon the presence of characteristic symptom and signs that begin suddenly and developed rapidly in most cases. Elevations of mast cell mediators such as tryptase and histamine in the blood can help to distinguish anaphylaxis from other disorders that present with similar clinical picture. The secondary investigations of adverse perioperative drug reactions are highly specialised and include skin testing, in vitro testing and in some cases challenge tests. Any suspected reaction during anaesthesia must be extensively investigated and these diagnostic tests should be done in specialised centres. The cooperation between anaesthesiologists and allergists is necessary to provide the necessary diagnostic tests to identify the responsible drug, to carry out prevention and to provide recommendations for future anesthetic procedures.

BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency. Although most people with selective IgAD (sIgAD) are asymptomatic, many patients often suffer from recurrent respiratory infections and different allergic disorders. Our aim was to investigate connection between subtypes of sIgAD and incidence of respiratory and allergic disorders, as well as connection with lung function changes in children. METHODS: Children with IgAD where divided into two groups ; severe IgAD in patients was defined as serum IgA level

The objective of the study was to assess the potential mechanisms by which the microbiome influences immune responses in allergy and asthma, especially during early childhood and to evaluate the evidence of respiratory and gut microbiota dysbiosis. The development and progression of allergy and asthma may depend on individual susceptibility, allergen exposure, infections, and exposure to indoor and outdoor air pollution. In recent years there has increasingly been an emphasis on the importance of microbiota in the regulation of immune response and the development of atopic diseases, as well as asthma. Commensal microbes are necessary for the induction of a balanced and tolerogenic immune system especially at an early age. An insufficiency of early life exposure to the environmental microbiota necessary for colonization of the gastrointestinal and/or respiratory tracts results in the development of asthma and allergic diseases. On the other hand, disturbed physiological flora in the digestive and respiratory tract also increase the risk for development and progression of asthma and allergy (allergic march). Microbiota in the gut and lungs may influence both the onset and progression of childhood asthma. These microbiota can be modulated by various environmental factors, including the type of delivery, early-life microbial exposures, diet, antibiotics. Conclusion – Intervention regarding airway microbiome, particularly in early life, might be a strategy for prevention or treatment of asthma and allergies. Further investigations are needed to improve our understanding of the role of the microbiome in inflammation, and to clarify the effect of the regulation of lung and gut microbiota and its influence on the prevention or treatment of allergic diseases and asthma.

The aim of the study was to assess sleep architecture and breathing in sleep in children with Down syndrome. The study was conducted by using overnight video-polysomnography (V-PSG) in children with Down syndrome and age-matched children from the general population. Analysis of polysomnographic parameters revealed that compared to the norms of healthy age- and maturitymatched children from the general population, children with Down syndrome had significantly shorter sleep latency (p=0.007), shorter total sleep time (p=0.004), lower sleep efficiency (p=0.010), less NREM1 sleep phase (p=0.0002), less NREM3 sleep phase (p=0.034), less REM sleep (p=0.034) in favour of more NREM2 phase but not significantly (p=0.069), and spent more time awake after sleep onset (p=0.0002). Children with Down syndrome had significantly more obstructive sleep apnoeas and hypopnoeas per hour (higher obstructive sleep apnoeas and hypopnoeas index) (p=0.008), but less central sleep apnoea per hour (lower central apnoeas index) (p=0.041), which led to the nonsignificantly lower total apnoea- hypopnoea index (p=0.762) in children with Down syndrome. The mean and longest apnoea duration did not differ significantly between these two groups. Children with Down syndrome had a significantly lower mean and nadir oxygen saturation (p=0.008 and p=0.001, respectively). In conclusion, the majority of respiratory complications in children with Down syndrome can be prevented by raising awareness of sleep disturbances in children with Down syndrome among their parents and health care providers and by introducing early routine V-PSG in the follow up of these children.

The aim of the study was to assess sleep architecture and breathing in sleep in children with Down syndrome. The study was conducted by using overnight video-polysomnography (V-PSG) in children with Down syndrome and age-matched children from the general population. Analysis of polysomnographic parameters revealed that compared to the norms of healthy age- and maturitymatched children from the general population, children with Down syndrome had significantly shorter sleep latency (p=0.007), shorter total sleep time (p=0.004), lower sleep efficiency (p=0.010), less NREM1 sleep phase (p=0.0002), less NREM3 sleep phase (p=0.034), less REM sleep (p=0.034) in favour of more NREM2 phase but not significantly (p=0.069), and spent more time awake after sleep onset (p=0.0002). Children with Down syndrome had significantly more obstructive sleep apnoeas and hypopnoeas per hour (higher obstructive sleep apnoeas and hypopnoeas index) (p=0.008), but less central sleep apnoea per hour (lower central apnoeas index) (p=0.041), which led to the nonsignificantly lower total apnoea-hypopnoea index (p=0.762) in children with Down syndrome. The mean and longest apnoea duration did not differ significantly between these two groups. Children with Down syndrome had a significantly lower mean and nadir oxygen saturation (p=0.008 and p=0.001, respectively). In conclusion, the majority of respiratory complications in children with Down syndrome can be prevented by raising awareness of sleep disturbances in children with Down syndrome among their parents and health care providers and by introducing early routine V-PSG in the follow up of these children., Cilj: Istražiti arhitektoniku spavanja i disanja tijekom sna u djece s Downovim sindromom. Metode: Cjelonoćna videopolisomnografija (V-PSG) u skupini djece s Downovim sindromom i u onoj iz opće populacije odgovarajuće dobi i zrelosti. Rezultat: Analiza polisomnografskih parametara pokazala je da djeca s Downovim sindromom, u usporedbi s normativima u zdrave djece u općoj populaciji, odgovarajuće dobi i zrelosti, imaju značajno kraću latenciju spavanja (SL) p=0,007, kraće ukupno vrijeme spavanja (TST) p=0,004, nižu efikasnost spavanja (SE) p=0,010, manje NREM1 faze spavanja p=0,0002, manje NREM3 faze spavanja p=0,034, manje REM spavanja p= 0,034 (na račun više površnog NREM2 spavanja, ali ne statistički značajno, p=0,069) i da provode više vremena budni nakon započimanja spavanja (p=0,0002). Djeca s Downovim sindromom imaju značajno više opstruktivnih apneja i hipopneja po satu spavanja (viši OAHI) p=0,008, ali imaju manje centralnih apneja po satu spavanja (niži CAI) p=0,041, što pridonosi statistički neznačajno nižem ukupnom AHI-u (p=0,762) u djece s Downovim sindromom. Prosječno i najdulje trajanje apneja nije se značajno razlikovalo između dviju skupina. Djeca s Downovim sindromom su imala značajno niže i prosječne i nadir saturacije kisika (p=0,008 i p=0,001). Zaključak: Možemo prevenirati većinu respiratornih komplikacija u djece s Downovim sindromom podizanjem svjesnosti njihovih roditelja o poremećajima spavanja u te djece, ali i zdravstvenih djelatnika, te uključivanjem rutinske cjelonoćne videopolisomnografije u njihovo praćenje.