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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.

Anti-inflammatory treatment is the pharmacological cornerstone of asthma management. However, for a long time, short-acting beta-agonists (SABAs) have been proposed as rescue medications in all treatment steps and as monotherapy for milder asthma. This was based on the unproven assumption that symptom relief requires only bronchodilation. Herein, we describe the evolution of the Inhaled corticosteroid (ICS) Containing resCUE (IC-CUE; ICQ) algorithm by tracing its origins and projecting it into the future.

Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.

Hereditary angioedema (HAE), an inherited deficiency offunctional C1 esterase inhibitor (C1-INH), is characterized byrecurrent episodes of disabling and often painful swelling insubcutaneous and/or submucosal tissues.1HAE attacks aregenerally unpredictable, but triggers for an attack can includehaving a dental or medical procedure (eg, surgery), other trauma,or stress. A preemptive management plan for patients under-going these types of situations may reduce the risk of HAE at-tacks. Recommendations include administration of short-termprophylaxis in patients with HAE before invasive medical pro-cedures, especially those involving the upper airways or digestivetract, with C1-INH concentrate typically the medication ofchoice.

BACKGROUND Children with adenoid hypertrophy (AH) have impaired respiratory system defense mechanisms, such as mucociliary clearance. We hypothesized that AH negatively affects one of the most important aspects of mucociliary clearance-ciliary beat frequency (CBF) and that adenoidectomy could potentially restore this essential defence mechanism of the airways. This study evaluated the influence of AH and endoscopic adenoidectomy on the CBF of the nasal respiratory epithelium in children. METHODS This prospective study included 64 children with confirmed AH aged 3 to 18 years and 43 age- and sex-matched healthy controls. Nasal CBF was analyzed using a digital high-speed video microscope and the software application Ciliary Analysis (NI LabVIEW). The preoperative adenoid size was assessed according to Cassano. Clinical symptoms of chronic rhinosinusitis were evaluated using the SNOT-20 questionnaire. RESULTS Children with AH had a median CBF of 5.35 ± 1.06 Hz. Six months after surgery, the median CBF was significantly higher (6.48 ± 0.88 Hz; P

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

We report a 2-year-old patient with Netherton syndrome presenting with generalized exfoliative erythroderma, ichthyosiform dermatitis, trichorrhexis invaginata, hypernatremic dehydration, failure to thrive, and recurrent respiratory infections. Molecular analysis of SPINK5 identified a novel mutation (c.1530CA). Our case report also verifies and supports the safety and efficacy of subcutaneous immunoglobulin substitution in chronic generalized skin disorders associated with primary immunodeficiencies such as Netherton syndrome.

DiGeorge syndrome (DGS) is a primary immunodeficiency disease characterized by multiple clinical features, including congenital heart defects, typical facial appearance, hypocalcemia, and immunodeficiency associated to thymic hypoplasia. A subset of patients with DGS may also have contemporary allergic diseases, possibly in the context of T cell dysregulation. Our work presents an unusual case of DGS in coincidence with severe allergic asthma successfully treated by humanized monoclonal anti-IgE antibody, omalizumab. Biological therapy with omalizumab is indicated as an add-on treatment for poorly controlled asthma in patients with severe persistent allergic asthma aged 6 years and above, who meet strict criteria. While data available from clinical trials suggest that omalizumab is generally well-tolerated, a little is known about its efficacy and tolerability in the context of underlying immunodeficiency. We reported for the first time that omalizumab could be safely effective in treatment of severe allergic asthma in patients with DGS, without modification of immunological parameters.

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.

Background Hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling attacks. A European treatment registry was established to review the adverse event profile and efficacy of recombinant human C1 esterase inhibitor (rhC1-INH) for HAE attacks. Methods Individuals with C1-INH-HAE were enrolled following a decision to treat with rhC1-INH and provision of written informed consent. Medical history and baseline HAE information were collected at screening. Healthcare providers entered data on HAE attacks, response to treatment, and adverse events using a web-based questionnaire. Results From July 1, 2011, through December 1, 2019, 71 patients with C1-INH-HAE (30 male/41 female; mean age, 47.3 years; age range, 19–78 years) in 9 countries reported 2356 attacks and were treated with rhC1-INH. Before registry entry, patients, including 20 (28.2%) who were on maintenance therapy/prophylaxis at registry enrollment, experienced a mean of 25 HAE attacks per year (median, 16 [range, 0–185]). Most treated HAE attacks were abdominal (46.1%), followed by peripheral (38.3%), oro-facial-pharyngeal (14.8%), urogenital (3.2%), and laryngeal (2.6%). The mean rhC1-INH dose was 3307 U (43.3 U/kg). Patients reported symptom improvement within 4 h for 97.8% of attacks (2305/2356) with rhC1-INH; most attacks (99.8%; 2351/2356) required only 1 dose. Five attacks were treated with a second dose (total rhC1-INH dose administered for attack, 4200 U). No hypersensitivity, thrombotic/thromboembolic events, or drug-related serious adverse events were reported. Conclusion The rhC1-INH treatment registry provided real-world data on the treatment of 2356 HAE attacks that were consistent with clinical trial data of rhC1-INH in patients with C1-INH-HAE.

PURPOSE OF REVIEW: Matrix metalloproteinases (MMPs) are a family of over 20 zinc-dependent proteases with different biological and pathological activities, and many have been implicated in several diseases. Although nonselective MMP inhibitors are known to induce serious side-effects, targeting individual MMPs may offer a safer therapeutic potential for several diseases. Hence, we provide a concise overview on MMP-12, given its association with pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and other progressive pulmonary fibrosis (PPF), which may also occur in coronavirus disease 2019. RECENT FINDINGS: In asthma, COPD, and PPF, increased MMP-12 levels have been associated with inflammation and/or structural changes within the lungs and negatively correlated with functional parameters. Increased pulmonary MMP-12 levels and MMP-12 gene expression have been related to disease severity in asthma and COPD. Targeting MMP-12 showed potential in animal models of pulmonary diseases but human data are still very scarce. SUMMARY: Although there may be a potential role of MMP-12 in asthma, COPD and PPF, several pathophysiological aspects await elucidation. Targeting MMP-12 may provide further insights into MMP-12 related mechanisms and how this translates into clinical outcomes; this warrants further research.

BACKGROUND: Patients with non-cystic fibrosis bronchiectasis (BE) have frequent exacerbations that are causes of significant morbidity and sometimes mortality, and which it is desirable to prevent. AIM: We aimed to assess the effects of pleuran on the incidence and duration of exacerbations in patients with BE. METHODS: A prospective, observational, open-label, and active-controlled study was realized as a comparison of the frequency and duration of exacerbations between a group of patients with BE (30 patients, 14 males and 16 females, aged 44–72 years) who received a combination supplement containing pleuran 100 mg, Vitamin C 60 mg and zinc 5 mg over a 3-month period and a group of patients with BE (31 patients, 15 males and 16 females, aged 45–74 years) treated over a 3-month period with a combination supplement containing Vitamin C 60 mg and zinc 5 mg. RESULTS: Over the study period, altogether 46 exacerbations were documented (19 in the patients receiving pleuran and 27 in the patients who did not receive pleuran), nine of which required hospital treatment (four in the patients receiving pleuran [21.5%] and five in the patients who did not receive pleuran [18.6%]). The mean number of exacerbations over the study period was significantly lower in the patients receiving pleuran (0.6 ± 0.4) as compared to the mean number in the patients who did not receive pleuran (0.8 ± 0.3) (p = 0.0297). The mean duration of exacerbations, expressed in days, needed for cure or clinical improvement in the patients receiving pleuran (11.2 ± 1.7 days) was significantly shorter than that of exacerbations in the patients who did not receive pleuran (12.4 ± 1.3 days) (p = 0.0029). We found significantly lower incidence and significantly shorter duration of exacerbations in the patients with BE who received pleuran as compared to their incidence and duration in the patients with BE who did not receive pleuran. CONCLUSION: Our findings indicated a need for further investigations in this domain to define the possible role of pleuran in the prevention of BE exacerbations.

Currently, the world is facinga global pandemicwith a new coronavirus SARS-CoV- 2 (Severe Acute Respiratory Syndrome CoronaVirus Type 2) causing infectious disease named COVID-19 (CoronaVirus Infectious Disease 2019). Comparing the clinical presentation and epidemiological characteristics of COVID-19 with previous coronavirus-associated respiratory diseases (SARS-CoV1 and MERS) revealedsome remarkable findings and differences. Moreover, the clinical course of SARS-CoV-2 infection showed the complexity of COVID-19 profile with the variable clinical presentations.

Severe acute respiratory syndrome caused by a novel 2019 coronavirus (SARS-CoV2) represents one of the most studied infectious diseases of today. The number of scientific reports and publications increases exponentially day by day. While the majority of infected subjects are asymptomatic or show mild symptoms, there is an important proportion of patients who requires hospitalization and, sometimes, intensive care. Immune response to novel coronavirus is complex, involves both innate and adaptive immunity, and is biphasic. Significant differences were observed when comparing severe and non-severe patients. Analysis of the reported results from clinical trials clearly show an involvement of specific cellular immunity (predominantly leucopenia, decreased counts of CD3+, CD4+, and CD8+ T lymphocytes, changes of T cell compartment) and the so-called cytokine storm, which is associated with worsening of symptoms and the promotion of lung damage. An interesting finding regarding eosinopenia that can have both diagnostic and prognostic value is reported by some authors. Examination of selected immune parameters could help to identify severe patients with the risk of unfavorable course of the disease, predict the prognosis and recognize improvement in the clinical status. Moreover, detailed analysis of the immune changes could help to select novel prospective therapeutic strategies.

Exposure to tobacco smoke is associated with a higher risk of respiratory tract diseases. The aim of this study was to determine the influence of passive smoking on selected characteristics of children with adenoid hypertrophy. Sixty-one children with adenoid hypertrophy were enrolled in the prospective study. Differences in bacterial colonisation of middle nasal meatus and nasopharynx and changes in selected laboratory immune and inflammatory markers according to the tobacco smoke exposure were analysed. Exposure to tobacco smoke was associated with significantly higher colonisation of pathogenic bacteria and polymicrobial growth of pathogenic bacteria (≥ 2 bacteria) in middle nasal meatus compared to non-exposed children (P = 0.045, P = 0.032, respectively). Identification of pathogenic bacteria in the middle nasal meatus did not correlate with isolation of pathogenic bacteria in the nasopharynx in either group of children. Parameters of humoral immunity in serum, IgA and IgG, were detected at higher concentrations in children exposed to tobacco smoke (P = 0.047, P = 0.031, respectively). Differences in selected parameters of cellular immunity in peripheral blood according to passive smoking were not observed. Tobacco smoke exposure is related to increased colonisation by pathogenic bacteria in middle nasal meatus and elevation of IgA and IgG in peripheral blood, but does not seem to influence markers of cellular immunity parameters in children with adenoid hypertrophy. Avoidance of passive smoking could be recommended as a universal preventive strategy against microbial colonisation of the upper airways and development of various inflammatory diseases in children, e.g. adenoid hypertrophy.L’effetto del fumo passivo sulla colonizzazione batterica delle alte vie aeree e su determinati parametri di laboratorio nei bambini.L’esposizione al fumo di sigaretta è associato ad un alto rischio di sviluppare malattie del tratto respiratorio. L’obiettivo di questo studio è stato quello di determinare l’influenza del fumo passivo su determinate caratteristiche dei bambini con ipertrofia adenoidea. Sessantuno bambini con ipertrofia adenoidea sono stati arruolati in questo studio prospettico. Sono stati analizzati differenze nella colonizzazione batterica del meato medio e del nasofaringe e cambiamenti di determinati parametri di laboratorio immunologici e di marker dell’infiammazione in relazione all’esposizione al fumo di tabacco. L’esposizione al fumo è stata associata in maniera significativa alla colonizzazione di batteri patogeni e alla crescita polimicrobica di batteri patogeni (≥ 2 batteri) nel meato nasale medio, rispetto ai bambini non esposti (P = 0,045, P = 0,032, rispettivamente). L’identificazioene di batteri patogeni nel meato medio non è stata accompagnata all’isolamento di batteri patogeni nel nasofaringe di entrambi i gruppi di bambini. Parametri sierici dell’immunità umorale, quali IgA e IgG, sono risultati notevolmente più elevati nei bambini esposti (P = 0,047, P = 0,031, rispettivamente). Tuttavia non sono state trovate differenze nei parametri sierici riguardanti l’immunità cellulare. In conclusione l’esposizione al fumo di tabacco sembra essere correlata ad un incremento della colonizzazione da parte di batteri patogeni del meato medio e ad un aumento delle IgA e delle IgG nel sangue periferico, mentre non sembra influenzare i markers dell’immunità cellulare nei bambini con ipertrofia adenoidea. Evitare il fumo passivo dovrebbe essere raccomandato come strategia preventiva universale contro la colonizzazione microbica delle alte vie aeree e lo sviluppo di svariate malattie infiammatorie dei bambini, come ad esempio l’ipertrofia adenoidea.

The skin is the largest multifunctional organ in the human body, serving as an excellent barrier against chemical and biological hazards [...]

Resumen Introduccion La base genetica del asma bronquial es compleja y es probable que en su desarrollo contribuyan diversos genes a traves de sus efectos principales e interacciones genicas. Las citocinas participan en diferentes aspectos del asma, determinando el tipo, la gravedad y los resultados patogenicos. Durante las crisis, los asmaticos alergicos muestran concentraciones significativamente mas altas de citocinas proinflamatorias, tales como interleucinas y quimiocinas. En los ultimos anos, se ha observado que las citocinas y sus receptores son muy polimorficos, por lo que investigamos los polimorfismos del gen promotor de la interleucina 6 en las posiciones −174G/C (rs1800795) y −572G/C (rs1800796) en el asma infantil. Metodos Analizamos los polimorfismos del gen promotor de la interleucina 6 en pacientes con asma bronquial y ninos sanos mediante el analisis de polimorfismos en la longitud de los fragmentos de restriccion amplificados por reaccion en cadena de la polimerasa. Resultados Se observo una asociacion significativa entre el polimorfismo en −174G/C y el asma bronquial (OR = 3,4; IC 95%: 2,045-5,638; p IL-6 −174G/C (OR = 4,1; IC 95%: 2,308-7,280; p −7 ). Conclusiones El polimorfismo de la interleucina 6 se asocia con el asma bronquial, especialmente con el fenotipo atopico. En pacientes asmaticos, la expresion y la secrecion de interleucinas pueden resultar afectadas por polimorfismos genicos, lo que podria tener efectos modificadores de la enfermedad en la via aerea y modificar la respuesta terapeutica.

The genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene-gene interactions. Cytokines contribute to different aspects of asthma, as they determine the type, severity and outcomes of asthma pathogenesis. Allergic asthmatics undergoing an asthmatic attack exhibit significantly higher levels of pro-inflammatory cytokines, such as interleukins and chemokines. In recent years, cytokines and their receptors have been shown to be highly polymorphic, and this prompted us to investigate interleukin 6 promoter polymorphisms at position -174G/C (rs1800795) and at -572G/C (rs1800796) in relation to asthma in children.Interleukin 6 promoter polymorphisms were analyzed in bronchial asthma patients and healthy children using polymerase chain reaction-restriction fragment length polymorphism analysis.We observed a significant association between polymorphism at -174G/C and bronchial asthma (OR=3.4, 95% CI: 2.045-5.638, P.001). Higher associations between polymorphism at IL-6 -174G/C and bronchial asthma were observed in atopic patients (OR=4.1, 95% CI: 2.308-7.280, P8.10Interleukin 6 polymorphism is associated with bronchial asthma, particularly its atopic phenotype. Expression and secretion of interleukins in asthmatic patients may be affected by genetic polymorphisms, and could have a disease-modifying effect in the asthmatic airway and modify the therapeutic response.

Background : The aim of this study was to determine the frequency of atopy and the influence of atopy on bacterial colonization of upper airway in children with adenoid hypertrophy. Material and methods : Forty children were enrolled in the prospective study. Presence of atopy was diagnosed by skin-prick test. Differences in bacterial colonization of middle nasal meatus and nasopharynx according to the presence of atopy were analyzed. Resu lts: Atopy was diagnosed in 75% children with adenoid hypertrophy. Presence of atopy was associated with significantly more often colonization of pathogenic bacteria ( Streptococcus pneumoniae, Hemophillus influaenzae, Moraxella catarrhalis, Staphylococcus aureus ) in the middle nasal meatus but not in nasopharynx ( P = 0.045, P = 0.483, respectively). Identification of pathogenic bacteria in middle nasal meatus did not correlate with isolation of pathogenic bacteria in nasopharynx in both groups of children. Conclusion : There is a high incidence of atopy in children with adenoid hypertrophy. Atopy is related to increased colonization by pathogenic bacteria in middle nasal meatus but not in nasopharynx.

Vaccination against varicella rapidly reduces disease incidence, resulting in reductions in both individual burden and societal costs. Despite these benefits, there is no standardization of varicella immunization policies in Europe, including countries in Central and Eastern Europe (CEE).This systematic literature review identified publications on the epidemiology of varicella, its associated health and economic burden, and vaccination strategies within the CEE region, defined as Albania, Bosnia-Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, Slovakia, and Slovenia. Twenty-six studies were identified from a search of PubMed, Embase®, and MEDLINE® biomedical literature databases, supplemented by gray literature and country-specific/global websites.Limited information exists in published studies on the burden of varicella in CEE. The wide variability in incidence rates between countries is likely explained by a lack of consistency in reporting systems. Funded universal varicella vaccination (UVV) in CEE is currently available only in Latvia as a one-dose schedule, but Hungary together with Latvia are introducing a two-dose strategy in 2019. For countries that do not provide UVV, introduction of vaccination is predicted to provide substantial reductions in cases and rates of associated complications, with important economic benefits.

Background International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD. Methods 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics. Results The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype. Conclusions Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases with serious impact on quality of life. β-Glucans are natural substances with potent immunomodulatory and anti-inflammatory activity.In a multicentre open split-body study, we studied the effect of Imunoglukan P4H® cream in a group of 105 patients with AD (39 males, 37%). Evaluation of subjective (visual analogue scale, VAS) and objective (EASI score, eczema area and severity index) characteristics of AD was carried out.In total, 80 patients (76.2%) completed the study. Topical β-glucan application resulted in the significant improvement of both objective and subjective symptoms of AD. On the application side, significant decline in the number of days with AD exacerbation and its severity was observed. Moreover, the subjects experienced decline of pruritus on the β-glucan half of the body (VAS score: 1.68 vs. 1.95, p 0.001). During the study, the continual and significant decline of EASI scores on the site of β-glucan application was observed (V4: 1.57 vs. 1.85, p 0.001). The preparation was in general well tolerated.This is the first study evaluating and confirming the potential use of β-glucan-based cream as a supportive complementary therapy of atopic dermatitis.

Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent episodes of subcutaneous/submucosal edema, which may be preceded by erythema marginatum (EM) as a prodromal symptom. Our aim was to analyze the changes occurring in the parameters of the coagulation system during the development of EM and HAE attacks.Eight C1-INH-HAE patients (1 male, 7 females, median age: 41.7 years) were studied. Blood samples were obtained from all patients (during symptom-free periods, EM, and HAE attacks), as well as from 20 sex- and age-matched healthy controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, Factor V, Factor VII, Factor X, Factor XI, and Factor XII levels were measured.D-dimer levels were significantly lower, whereas aPTT was significantly prolonged in healthy controls vs. the values measured during the symptom-free period (p = 0.0497; p = 0.0043), in the presence of EM (p = 0.002; p = 0.0002), or during HAE attacks (p 0.0001; p = 0.0002). We observed the following differences between samples taken during HAE attacks vs. in symptom-free periods: D-dimer levels were significantly elevated (p = 0.0391), while aPTT was significantly shorter during HAE attacks (p = 0.0159). D-dimer levels were significantly higher during EM than in symptom-free periods (p = 0.0078). Comparing the samples drawn during EM or during HAE attacks, there were no significant differences in the study parameters.D-dimer levels were elevated during EM and this suggests that EM may be part of the HAE attack. Nevertheless, further research into the complement and kinin-kallikrein systems is needed in more patients for a better understanding of the pathomechanism of EM.

OBJECTIVE The use of biodegradable materials represents a new option in the treatment of paediatric facial skeleton fractures. The benefits of a resorbable system include reductions in time for long-term stability, diminished immobilisation period, and elimination of painful procedures for implant removal. The resorption of the material did not influence bone repair and growth. Bioresorbable plates and screws get completely excreted through physiological routes. MATERIAL AND METHODS The age of the patients ranges from that of pre-schoolers till 18 years. The mean age of boys and girls was 12.18 (range 4-18 years) and 13.59 (range 5-18 years), respectively. RESULTS During the ten-year period, 168 children and adolescents, 136 boys and 32 girls, were treated. The conservative treatment was performed in 67 patients (39.9 %). Open surgical reduction was performed in 101 patients (60.1 %). Bioresorbable plates were applied in 44 patients (43.6 % of surgically treated). CONCLUSION The implementation of biodegradable osteosynthetic materials is optimal for the treatment of fractures of the middle third of the facial skeleton, lower part of the upper third of the facial skeleton, mandibular body and parasymphysis (Tab. 3, Fig. 3, Ref. 31).

Autoinflammatory disorders (AID) are characterized by spontaneous attacks of acute inflammation with a broad spectrum of clinical symptoms. Ongoing inflammation and reoccurrence of acute flares can lead to the development of amyloidosis. One group of AID is represented by monogenic periodic fever syndromes while familial Mediterranean fever (FMF) is the most common form of AID from this group. Its prevalence in Central and Eastern Europe was reported to be very low. We report a case of FMF patient with a very severe clinical course of FMF and intolerance to colchicine, which is a gold standard for FMF treatment. The clinical effect of the application of anakinra was insufficient and accompanied with side effects and low tolerability. Switching to canakinumab (human monoclonal antibody against IL-1β) at dose of 150 mg every 4 weeks induced a rapid remission of the disease activity and inflammatory markers. However, due to relapse of acute flares after three weeks from application, the escalation of dose to 300 mg every 4 weeks induced a complete remission of symptoms and significantly improved the quality of life. This is the first report of successful canakinumab administration in FMF patient in Central and Eastern Europe, a region with very low incidence of FMF (Tab. 1, Ref. 16).

β-glucans are derived from a variety of sources including yeast, grain and fungus and belong to the class of drugs known as biological response modifiers. They possess a broad spectrum of biological activities that enhance immunity in humans. One promising area for β-glucans’ application is dermatology, including wound care. Topical applications of β-glucans are increasing, especially due to their pluripotent properties. Macrophages, keratinocytes and fibroblasts are considered the main target cells of β-glucans during wound healing. β-glucans enhance wound repair by increasing the infiltration of macrophages, which stimulates tissue granulation, collagen deposition and reepithelialization. β-glucan wound dressings represent a suitable wound healing agent, with great stability and resistance to wound proteases. This review summarizes the current knowledge and progress made on characterizing β-glucans’ wound healing properties in vitro and in vivo and their safety and efficacy in managing non-healing wounds or other chronic dermatological conditions and diseases.

"Çalışmada 57 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır.” Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers. Federal Ministry of Education & Research (BMBF) - IFB/CCI: 01EO1303 - E:med/SysInflame: 012X1306F - DZIF: 8000805-3 German Research Foundation (DFG) - FR 2821/6-1

Bronchial asthma is one of the most common chronic inflammatory diseases of the airways. In the pathogenesis of this disease, the interplay among the genes, intrinsic, and extrinsic factors are crucial. Various combinations of the involved factors determine and modify the final clinical phenotype/endotype of asthma. Oxidative stress results from an imbalance between the production of reactive oxygen species and reactive nitrogen species and the capacity of antioxidant defense mechanisms. It was shown that oxidative damage of biomolecules is strongly involved in the asthmatic inflammation. It is evident that asthma is accompanied by oxidative stress in the airways and in the systemic circulation. The oxidative stress is more pronounced during the acute exacerbation or allergen challenge. On the other hand, the genetic variations in the genes for anti-oxidative and pro-oxidative enzymes are variably associated with various asthmatic subtypes. Whether oxidative stress is the consequence of, or the cause for, chronic changes in asthmatic airways is still being discussed. Contribution of oxidative stress to asthma pathology remains at least partially controversial, since antioxidant interventions have proven rather unsuccessful. According to current knowledge, the relationship between oxidative stress and asthmatic inflammation is bidirectional, and genetic predisposition could modify the balance between these two positions—oxidative stress as a cause for or consequence of asthmatic inflammation.

Aim. Primary immunodeficiencies (PID) are becoming a recognized public health problem worldwide. The most important subgroup of these disorders are the antibody deficiencies. X-linked agammaglobulinaemia was the first described entity of this group and is characterised by early onset of recurrent bacterial infections, profound deficiency of all immunoglobulin isotypes and markedly reduced number of peripheral B-lymphocytes. Case report. We report the case of a 10-year old boy with X-linked agammaglobulinaemia caused by a previously non-described mutation in BTK gene with typical clinical presentation but delayed diagnosis. Following diagnosis, substitution therapy with intravenous immunoglobulins was started and the clinical status of the patient improved. Conclusion. We reported a case of X-linked agammaglobulinaemia with delayed diagnosis despite the typical anamnestic signs for primary humoral immunodeficiency. The disease was caused by a previously non-reported mutation in the BTK gene. Measurement of serum immunoglobulins should be performed in all children with recurrent, complicated respiratory infections as a screening test for humoral immunodeficiencies.

Summary Objectives Bronchial asthma is a chronic respiratory disease characterized by airway inflammation. There is increasing evidence that neurotrophins play an important role in the development and maintenance of neurogenic airway inflammation in chronic allergic diseases. Working Hypothesis Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and has several important functions in the airways. There are only a few reports on the association between genetic variations in the BDNF gene and various allergic diseases, and the results are generally conflicting. Therefore, we aimed to study the functional polymorphism Val66Met (also called rs6265 or G196A) in the BDNF gene in a group of asthmatic children and healthy controls. Study Design, Patient-Selection, and Methodology We studied 248 asthmatic patients (aged 12.28 ± 0.24 years) and 249 healthy children (aged 13.14 ± 0.48 years). Analysis of the Val66Met polymorphism of the BDNF gene was performed by polymerase chain reaction (PCR) and PCR products were digested by PmlI. Results The prevalence of the Val66Met polymorphisms (Val/Val, Val/Met, and Met/Met) was 61.7%, 33.5%, and 4.8% in asthmatics, respectively, and 47.0%, 51.8%, and 1.2% in healthy subjects, respectively. We observed a significant association of the Met/Met variant genotype with asthmatics (OR = 4.17, 95% CI = 1.16–14.96, P = 0.018). The Val/Met genotype was protective against bronchial asthma (OR = 0.69, 95% CI = 0.48–0.99, P = 0.045), especially in girls (OR = 0.34, 95% CI = 0.20–0.59, P = 0.001). Conclusion Specific BDNF gene polymorphism may contribute to bronchial asthma susceptibility. Our study suggested the positive association between selected functional BDNF polymorphism (rs6265) and asthma in children. Pediatr Pulmonol. 2015; 50:631–637. © 2014 Wiley Periodicals, Inc.

β-glucans are a group of biologically active polysaccharides of natural origin with a proven pleiotropic immunomodulation effect. Their efficacy has been confirmed in the therapeutic treatment and prevention of various infectious diseases, secondary immune defects and also of oncologic disorders. Allergic diseases are one of the most frequent diseases and their prevalence continues to increase. They develop as a consequence of dysregulation of the immune system, especially when there is failure in the equilibrium of the response of TH1/TH2 lymphocytes towards TH2. New therapeutic approaches in the treatment of immunopathological conditions (e.g. allergic or oncologic) are directed to restoring the equilibrium among different T lymphocyte subpopulations. Based on in vitro experiments, and also on animal and human clinical studies, there is much evidence for the importance of β-glucans in the treatment and also prevention of allergic diseases; this opens new perspectives on the use of this widespread and popular group of natural substances.

Introduction Patients with hereditary angioedema (HAE) are at risk for an acute attack after medical procedures. Short-term prophylaxis may minimize this risk. This study evaluated recombinant C1 esterase inhibitor (rhC1-INH) as short-term prophylaxis. Methods Patients with angioedema were treated with rhC1-INH prior to medical procedures/stressful life events; HAE attacks were recorded through 2 days and >2-7 days postprocedure. Results Fifty-one patients (median age, 44 years [range, 17-73 years]; 62.7% female; 92.2% HAE type 1) were included. A median rhC1-INH dose of 3075 IU (range, 2100-4200 IU) was administered as prophylaxis, median of 60 minutes prior, for 70 procedures (52.9% [n=37] dental [median, 60 minutes preprocedure]); 30.0% [n=21] surgical [median, 45 minutes preprocedure]; 15.7% [n=11] endoscopy [median, 30 minutes preprocedure, and 1.4% [n=1] stressful life event). Majority (n=48; 68.6%) of 70 cases had rhC1-INH administered 10-65 minutes preprocedure: 25 of 48 (52.1%) dental, 16 (33.3%) surgical, and 7 (14.6%) endoscopy. Nineteen (27.1%) cases involved long-term prophylaxis (danazol/tranexamic acid). Overall, 97.1% (68/70) of cases did not have an HAE attack within 2 days postprocedure; 91.4% (64/70) during >2-7 days postprocedure. For 2 attacks occurring within 2 days, rhC1-INH was administered 230 minutes and ≥24 hours preprocedure, respectively. No adverse events were reported. As a self-control group, 76.9% of 26 cases with no long-term/short-term prophylaxis preprocedure had an attack within 2 days postprocedure. Conclusions Short-term prophylaxis with rhC1-INH, administered within several hours preprocedure, was efficacious and safe in adolescents/adults and reduced the risk of an HAE attack postprocedure.

Resumen Introduccion El asma bronquial es una enfermedad compleja en la que los factores geneticos, los factores ambientales y la lesion oxidativa son responsables del inicio y la modulacion de su progresion. Si fracasan los mecanismos antioxidantes, las especies reactivas del oxigeno afectan a las biomoleculas, lo que se sigue de la progresion de la enfermedad. La catalasa es uno de los antioxidantes enzimaticos endogenos mas importantes. En el presente estudio examinamos la hipotesis de que un aumento de la lesion oxidativa y el polimorfismo en el gen CAT (region promotora -262 C/T) se asocian a asma bronquial infantil. Pacientes y metodos En ninos sanos (249) y ninos asmaticos (248) se efectuo una genotipificacion de los polimorfismos en el gen CAT usando la reaccion en cadena de la polimerasa-polimorfismo de longitud de fragmentos de restriccion. Mediante espectrofotometria, en los ninos se analizaron los marcadores de lesion oxidativa: el contenido de grupos sulfhidrilo y de sustancias reactivas al acido tiobarbiturico. Resultados El genotipo TT de la catalasa fue mas frecuente entre pacientes asmaticos (22,6%) que en ninos sanos (4,8%) (odds ratio = 5,63; intervalo de confianza del 95% = 2,93–10,81; p Conclusiones Los resultados del presente estudio sugieren que el polimorfismo del gen de la catalasa podria participar en la aparicion de asma bronquial y en el aumento de la lesion oxidativa en ninos asmaticos. La variacion genetica de los antioxidantes enzimaticos podria modular el riesgo de la enfermedad.

Recurrent respiratory tract infections (RRTIs) present a very important problem in paediatric praxis. As true immunodeficiencies are rare, one of the most important factors assumed to contribute to increased respiratory morbidity is atopy. Several preparations of natural origin have been used for the prevention of RRTIs, and some of the most effective immunomodulators are biologically active polysaccharides – e.g. s-glucans. In our randomised, double-blind, placebo-controlled study, we investigated the prevalence of atopy in a group of children with RRTIs and the potential anti-allergic effect of pleuran (s-glucan isolated from Pleurotus ostreatus) on basic laboratory markers of allergic inflammation. We confirmed that atopy may be an important factor contributing to the increased respiratory morbidity in children with RRTIs. The active treatment with pleuran resulted in a significant reduction of peripheral blood eosinophilia and stabilised the levels of total IgE in serum. This was more evident in atopic subjects. Pleuran showed a potential anti-allergic effect. This previously non-described effect could expand the application of this natural immunomodulator also as a complementary adjuvant therapy in allergic patients. Copyright © 2013 John Wiley & Sons, Ltd.

The composition and function of human milk is unique and gives a basis for the development of modern artificial milk formulas that can provide an appropriate substitute for non-breastfed infants. Although human milk is not fully substitutable, modern milk formulas are attempting to mimic human milk and partially substitute its complex biological positive effects on infants. Besides the immunomodulatory factors from human milk, research has been focused on the composition and structure of human milk fat with a high content of β-palmitic acid (sn-2 palmitic acid, β-palmitate). According to the available studies, increasing the content of β-palmitate added to milk formulas promotes several beneficial physiological functions. β-palmitate positively influences fatty acid metabolism, increases calcium absorption, improves bone matrix quality and the stool consistency, and has a positive effect on the development of the intestinal microbiome.

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.