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Asthma is divided into various distinct phenotypes on the basis of clinical characteristics, physiological findings, and triggers, and phenotyping is usually performed in a hypothesis-driven univariate manner. However, phenotyping can also be performed using computer algorithms to evaluate hypotheses-free relationships among many clinical and biological characteristics. We aimed to identify asthma phenotypes based on multiple demographic, clinical, and immunological characteristics.Cluster analysis in R v3.5.0 was performed using asthma patient data. A total of 170 adult patients with asthma (diagnosed according to the GINA recommendations) were recruited to the study. All patients completed questionnaires about their smoking history and underwent physical examination, spirometry, skin-prick test, blood sample collection to evaluate peripheral blood cell counts and serum IgE, periostin, and interleukin (IL)-33 levels, as well as body mass index measurements. Data normality was checked with histograms and QQ plots. Hierarchical clustering was performed using Ward's linkage with Ward's clustering criterion. The optimal number of clusters was validated using the Dunn criterion as well as by comparing different clustering algorithms using the clValid package.Three clusters characterizing asthma phenotypes were identified: (1) early-onset, highly atopic, and eosinophilic asthma associated with male sex and high levels of IL-33 and periostin; (2) late-onset, eosinophilic asthma associated with female sex and low levels of IL-33 and periostin; and (3) late-onset, obese, neutrophilic asthma associated with female sex, persistent airway obstruction, and very low IL-33 and periostin levels.

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.

Background The occurrence of allergic conditions, for example allergic asthma, rhinitis, and atopic dermatitis, is rising worldwide. These allergic conditions are associated with poor life quality. Vitamin D is proposed to be linked with increased risk and severe forms of allergic diseases. Aims This review article aimed to evaluate the vitamin D level role and polymorphisms of vitamin D receptor gene (VDR) in atopy. Methods & Materials We analyzed publications that were focusing on levels of vitamin D and/or polymorphism analysis of vitamin D receptor gene in allergic asthma, rhinitis, and atopic dermatitis patients. Results We noticed that levels of vitamin D are extensively studied in atopy by many research groups, however, polymorphisms of vitamin D receptor gene and their link with levels of vitamin D lack comprehensive data. There is evidence that vitamin D may be associated with anti‐inflammatory effects in allergic diseases. Some of VDR polymorphisms also may play a role in pathogenesis of these diseases. However, the data from different studies are controversial. Discussion The results of different studies are usually inconsistent, most probably due to populational bias or differences in methodology. Even though, more evidence shows a positive impact of vitamin D on the risk and outcomes of allergic diseases, especially atopic dermatitis, and asthma. Conclusions There is controversial data about the level of vitamin D and its role in atopy; however, more evidence shows a positive impact on the risk and outcomes of allergic diseases., Some evidence suggests that vitamin D is linked with increased risk and more severe forms of allergic diseases. Therefore, this review article aimed to evaluate the role of vitamin D level and vitamin D receptor gene (VDR) polymorphisms in atopy. We found that vitamin D levels in atopy are extensively studied by many research groups, however, vitamin D receptor gene polymorphisms and their link with vitamin D levels lack comprehensive data. Even though, more evidence shows a positive impact on the risk and outcomes of allergic diseases, especially atopic dermatitis and asthma.

Background Allergic rhinitis is one of the most prevalent allergic diseases worldwide which diagnosis is based on typical clinical signs and positive results of allergic tests. Selection and evaluation of treatment is based mainly on subjective symptoms. Objective measurement of patients’ complaints is necessary for proper documentation and follow-up. There are no short simple validated questionnaire assessing nasal symptoms in patients with allergic rhinitis in Lithuania. Total nasal symptoms score (TNSS) is a brief questionnaire which evaluate the severity of main symptoms of allergic rhinitis widely used in different countries. Our aim was to translate the TNSS in the Lithuanian language and to validate it. Methods Prospective cross-cultural adaption and validation study was performed. Linguistic validation of TNSS was performed and validity and reliability were assessed. Patients with chronic allergic and non-allergic rhinitis and healthy individuals were included in this study. Patients had to complete translated version of TNSS. Patients with allergic rhinitis additionally were asked to fill Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Results Seventy-six individuals were involved into the study: 16 with non-allergic rhinitis (NAR) (21.1%), 49 with allergic rhinitis (AR) (64.5%) and 11 healthy individuals (14.5%). Cronbach’s α was 0.87. TNSS score was significantly higher in patients with NAR and AR compared with healthy individuals (3.56 ± 2.28 vs. 4.28 ± 2.46 vs. 0.27 ± 0.91). Positive significant correlation was found between TNSS score and RQLQ score (rs = 0.77, p Conclusions The Lithuanian version of the TNSS proved to be a valid instrument for assessing nasal symptoms in patients with allergic rhinitis.

Drug-induced hypersensitivity syndrome (DiHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug-induced reaction characterized by various symptoms: skin rash, fever, lymph node enlargement and internal organ involvement, which starts within 2 weeks to 3 months after drug initiation. It is challenging to diagnose this syndrome due to the variety of cutaneous and visceral symptoms. Different mechanisms have been implicated in its development, including genetic susceptibility associated with human leucocyte antigen (HLA) loci, detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation, and reactivation of human herpes, including Epstein-Barr virus and human herpes virus (HHV)-6 and HHV-7. The most frequently reported causes of DiHS/DRESS are antiepileptic agents, allopurinol and sulfonamides. We report a case of DiHS/DRESS induced by second-line treatment for tuberculosis, prothionamide and para-aminosalicylic acid, and Epstein-Barr virus re-infection. Patch testing, which was performed in this case, is not fully standardized, but it can be helpful and a safe way to evaluate and diagnose DiHS/DRESS.

Background\ud \ud Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as “may contain traces of” is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin.\ud \ud \ud \ud Methods\ud \ud MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results.\ud \ud \ud \ud Results\ud \ud In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds.\ud \ud \ud \ud Conclusion\ud \ud Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement “this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product” for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.

Atopic diseases, such as atopic dermatitis (AD), allergic asthma (AA), and allergic rhinitis (AR), are increasingly becoming a worldwide issue. This atopic triad originates at an early age and on a multifactorial basis, causing significant discomfort to susceptible individuals. The global case number is now reaching new highs, so exploring immune system regulation and its components is becoming critical. One cytokine, interleukin-32 (IL-32), is involved in inflammation and regulation of the immune system. It has nine isoforms that show varying degrees of expression, both intracellularly and extracellularly. IL-32 is secreted by immune cells, such as monocytes, macrophages, natural killer cells, and T cells, and by nonimmune cells, including fibroblasts, keratinocytes, and endothelial cells. Its production is regulated and augmented by microorganisms, mitogens, and other cytokines. Early studies demonstrated that IL-32 was an immune regulator that functioned to protect against inflammatory diseases, including AD, AA, and AR, and proposed a proinflammatory role for IL-32 in immune regulation and symptom exacerbation. However, several later reports suggested that IL-32 is downregulated in inflammatory diseases and exerts an anti-inflammatory effect. This review article focuses on recent findings regarding the detrimental and protective roles of IL-32 in development and management of inflammatory diseases. The exact role of IL-32 in AD, AA, and AR still remains to be elucidated. Future research should explore new avenues of IL-32 functionality in human inflammatory diseases.

Hintergrund: Mehr als eine Milliarde Menschen leiden an chronischen Atemwegserkrankungen wie Asthma, COPD, Rhinitis und Rhinosinusitis. Diese verursachen enorme Belastungen und gelten als schwerwiegende nicht übertragbare Erkrankungen. Viele Patienten sind noch unbehandelt und die Kosten der Untätigkeit sind nicht akzeptabel. Am 23. März 2018 fand in Vilnius eine Konferenz unter der Schirmherrschaft des Gesundheitsministeriums und verschiedener wissenschaftlicher Fachgesellschaften statt, auf der multisektorale Versorgungswege vorgeschlagen wurden, die angeleitetes Selbstmanagement, mHealth und Luftverschmutzung bei der Versorgung bestimmter chronischer Atemwegserkrankungen (Rhinitis, chronische Rhinosinusitis, Asthma und COPD) einschließen. Das Treffen schloss mit der Erklärung von Vilnius, die von den Teilnehmern des EU-Gipfels zu chronischen Atemwegserkrankungen unter der Federführung von Euforea entwickelt wurde. Schlussfolgerung: Die Erklärung von Vilnius ist ein wichtiger Schritt im Kampf gegen die weltweite Luftverschmutzung und ihre Auswirkungen für Patienten mit chronischen Atemwegserkrankungen und sie spielt im Hinblick auf die EU-Gesundheitsstrategie eine wichtige Rolle, da sie einen Zusatznutzen zu dem bereits vorhandenen Wissen über die öffentliche Gesundheit liefert.

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.

Introduction: Recently described interleukin (IL) 22 can play the role in the development of allergic airway diseases. However, it is not known if this cytokine acts as proinflammatory or anti-inflammatory agent. Aim: To evaluate link between IL-22 and IL-10, IL-13, and severity of symptoms in patients with allergic asthma and/ or persistent allergic rhinitis caused by house dust mite. Methods: Patients with diagnosed allergic asthma (according to GINA) and/ or persistent allergic rhinitis (according to ARIA and symptoms duration ≥ 2 years) were studied. Allergy was assessed by skin prick. IL-22, IL-13 and IL-10 levels were measured in serum and nasal lavage using commercial ELISA kit. All patients completed total nasal symptom score (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Patients with asthma additionally – Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Test (ACT). Results: The study comprised 18 patients with allergic rhinitis (AR) and 9 with allergic rhinitis and allergic asthma (ARA). Serum IL-22 positively correlated with serum IL-10, but not with IL- 13 in all studied patients (rs=0.52, p Conclusions: Our study demonstrated possible anti-inflammatory effect of IL-22 in allergic airway diseases caused by house dust mite.

The immune system plays an important role in the pathogenesis of many disorders, including allergic airway diseases. There are studies suggesting that interleukin (IL)-22 can be important in the development of these diseases. However, it is not known if this cytokine acts as proinflammatory or anti-inflammatory agent. This systematic review aimed to analyze level and role of IL-22 in patients with allergic airway diseases in comparison with healthy individuals. Systematic review included only observational studies with patients having allergic rhinitis and/or allergic asthma. The primary outcome measure was IL-22 level in patients with allergic asthma and/or allergic rhinitis. A total of 95 articles were found. Overall, 6 articles were included in systematic review. Five of these studies showed that IL-22 was increased in patients with allergic airway diseases compared with control group. Majority of studies revealed relation between IL-22 level and severity of allergic asthma and allergic rhinitis. Some studies showed positive relation between IL-22 level and total immunoglobulin E (IgE), specific IgE, and eosinophil count in nasal mucosa. IL-22 level is increased in children and adults with allergic airway diseases and is likely to be associated with proinflammatory features.

Chronic cough is a common symptom of various chronic diseases. However, the vast majority of individuals with conditions that are commonly associated with cough, such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. It is known that in the pathogenesis of cough, the nervous system plays a vital role. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature. The aim of this article is to review the most recent data about the role of the immune system in the pathogenesis of chronic cough.

IL-33 is a recently discovered cytokine which plays an important role in asthma pathogenesis. AIM To evaluate serum IL-33 in patients with asthma and healthy controls, and to evaluate the association of IL-33 with different asthma phenotypes. METHODS Patients with asthma (n = 115) and healthy subjects (n = 85) were included in the study. Subjects with asthma were divided into groups according to their phenotype: allergic/non-allergic, eosinophilic/non-eosinophilic, obese/non-obese and severity according to GINA (mild, moderate and severe). The concentration of IL-33 in serum was measured by standardized enzyme-linked immunosorbent assay. RESULTS The level of IL-33 was significantly higher in patients with asthma when compared to healthy subjects (672.73 ± 104.47 pg/mL vs 268.52 ± 27.56 pg/mL, P

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer related death worldwide. Tumor-infiltrating macrophages are believed to play an important role in growth, progression, and metastasis of tumors. In NSCLC, the role of macrophages remains controversial; therefore, we aimed to evaluate the distribution of macrophages (M1 and M2) in tumor islets and stroma and to analyze their relations to patients’ survival. Lung tissue specimens from 80 NSCLC patients who underwent surgical resection for NSCLC (pathological stage I-III) and 16 control group subjects who underwent surgery because of recurrent spontaneous pneumothorax were analyzed. Immunohistochemical double staining of CD68/iNOS (markers for M1 macrophages) and CD68/CD163 (markers for M2 macrophages) was performed and evaluated in a blinded manner. The numbers of M1 and M2 macrophages in tumor islets and stroma were counted manually. Predominant infiltration of M1 and M2 macrophages was observed in the tumor stroma compared with the tumor islets. M2 macrophages predominated over M1 macrophages in the tumor tissue. Tumor islets-infiltrating M1 macrophages and the number of total tumor-infiltrating M2 macrophages were independent predictors of patients survival: high infiltration of M1 macrophages in tumor islets was associated with increased overall survival in NSCLC (P

PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity was investigated in 1438 unrelated subjects from Latvia, Lithuania and Taiwan. In general, polymorphism of each individual locus showed tendencies similar to determined previously in HapMap populations. Main differences concern Taiwanese and include presence of rs2277460 rare allele A not found before in Asians and absence of rs2295827 rare alleles homozygotes TT observed in all other human populations. Observed patterns of SNPs and haplotype diversity were compatible with expectation of neutral model of evolution. Linkage disequilibrium between the rs2295826 and rs2295827 was detected to be complete in Latvians and Lithuanians (D´ = 1; r2 = 1) and slightly disrupted in Taiwanese (D´ = 0.978; r2 = 0.901). Population differentiation (FST statistics) was estimated from pairwise population comparisons of loci variability, five locus haplotypes and PSMA6 and PSMC6 two locus haplotypes. Latvians were significantly different from all Asians at each of 5 SNPs and from Lithuanians at the rs1048990 and PSMC6 loci. Lithuanian and Asian populations exhibited similarities at the PSMC6 loci and were different at the PSMA6 and PSMA3 SNPs. Considering five locus haplotypes all European populations were significantly different from Asian; Lithuanian population was different from both Latvian and CEU. Allele specific patterns of transcription factor binding sites and splicing signals were predicted in silico and addressed to eventual functionality of nucleotide substitutions and their potential to be involved in human genome evolution and geographical adaptation. Current study represents a novel step toward a systematic analysis of the proteasomal gene genetic diversity in human populations., Highlights • SNPs in PSMA6, PSMC6 and PSMA3 differentiate Latvian and Taiwanese populations. • rs2277460, rs1048990 and rs2348071 differentiate Lithuanians and Taiwanese. • Lithuanians and Taiwanese are similar in rs2295826, rs2295827 diversity. • rs1048990, rs2295826 and rs2295827 differentiate Latvians and Lithuanians.

Summary The role of T lymphocytes in pathogenesis of chronic inflammatory airway diseases – asthma and chronic obstructive pulmonary disease (COPD) has been emphasized in recent years: the importance of αβ T-cells (CD8+ and CD4+) has been widely described. A substantial fraction of γδ T-cells is a composite part of pulmonary T lymphocytes. Specific localisation of γδ T-cells in epithelium/mucosa-rich tissues implies their potential role in local inflammatory immune response, which occurs in chronic inflammatory airway diseases. An investigation was made of the T-lymphocyte subsets in induced sputum (IS), in bronchoalveolar lavage (BAL) and in peripheral blood from 20 patients with COPD (stages II–III; GOLD), 18 patients with asthma (persistent mild to moderate; GINA) and 14 healthy subjects. Relationship of γδ T-cells with lung function and smoking history was analysed. COPD patients had significantly higher numbers of CD8+T-cells in the airways of smokers compared to ex-smokers in the COPD group. A significant positive correlation was found between CD8+T-cells and pack-years of smoking. Differently, the COPD patients had significantly lower relative and absolute numbers of γδ T-cells in IS and in BAL compared to those from asthma or healthy subjects. The quantity of γδ T-cells negatively correlated with forced expiratory volume in 1 s and smoking (pack-years) only in COPD group. Our findings indicate a different local inflammatory response in COPD patients and in asthmatic groups. The reduced amount of γδ T-cells in IS and in BAL from COPD patients raises the hypothesis about their important role in pathogenesis of COPD.

Asthma is a chronic inflammatory airway disease with an increase in the prevalence worldwide. This is gene-by-environment disease, with multifactor pathogenesis, which has not been well established yet. IL-33 is a recently discovered cytokine with dual function. It can act as a traditional cytokine as well as an intracellular nuclear factor. Polymorphisms of genes encoding proteasomes could influence IL-33 effect in asthma. Aim: to evaluate serum IL-33 concentration in Lithuanian asthma patients with different PSMA6 gene polymorphisms. Methods: Patients with asthma (n=145; mean age 46.4±15.3yrs) and healthy subjects (n=150; mean age 41.0±14.4yrs) were involved in study. DNA from peripheral blood was extracted using Qiagen (Germany) DNA blood mini kit standardized protocol. SNPs of PSMA6 gene were evaluated using allele specific amplification and cleaved amplified polymorphic sequence methods: rs2277460 in promoter region (-110C>A) and rs1048990 in 59UTR region (-8C>G). IL-33 levels in serum were measured with Human IL-33 ELISA Kit according to the manufacturer9s protocol. Results: Analysis of all studied subjects showed that CA genotype is associated with higher concentration of IL-33 in comparison to CC genotype (1051.8 ± 298.3 pg/ml vs 573.4 ± 97.3 pg/ml, p G) and IL-33 level. Conclusions: Patients with PSMA6 gene CA genotype have higher levels of IL-33 than subjects with other genotypes. These results suggest that presence of this genotype is associated with more expressed inflammation.

Introduction. Non-small cell lung cancer (NSCLC) remains the most common cause of cancer related death worldwide. Tumor infiltrating macrophages are believed to play essential role in the immune response to cancer cells. Study aim was to evaluate the tumor infiltrating macrophages (M1 and M2) and to analyze their relations to patients9 survival. Methods. We recruited 80 patients with primary NSCLC (stages I-III) with median age 66 years (ranges 45-77). Paraffin-embedded sections of surgically resected tumor were analyzed. Immunohistochemical double staining of CD68/iNOS (markers for M1 macrophages) and CD68/CD163 (markers for M2 macrophages) was performed and evaluated in blinded manner. Quantitative evaluation of these cells was done in 10 most representative high-power fields (HPFs ×400 magnification) per tissue section. Results . Predominant infiltration of M1 and M2 macrophages was observed in tumor stroma compared to tumor islets (P Conclusions. Our study demonstrated that tumor islets infiltrating M1 macrophages are associated with improved NSCLC patients9 survival, while increased total number of tumor infiltrating M2 macrophages is associated with poor survival.

Interleukin-32 (IL-32) is a newly described cytokine which is expected to have an important role in autoimmune disorders. It was shown that chronic obstructive pulmonary disease (COPD) has a component of autoimmunity, though the role of IL-32 in its pathogenesis is not known. The aim of this study was to estimate IL-32 concentrations in serum, induced sputum (IS) supernatant and bronchoalveolar lavage (BAL) fluid from patients with COPD, and to compare asthma patients with and healthy subjects. Outpatients with COPD (63.7 ± 8.4 years, n = 51), asthma (58.3 ± 12.4 years, n = 31), and healthy subjects (59.8 ± 8.2 years, n = 9) were studied. The levels of IL-32 in serum, BAL fluid, and IS supernatant samples were analyzed by ELISA. Concentrations of IL-32 were higher in all the studied materials from patients with COPD (BAL 22.46 ± 2.48 pg/ml, IS 19.66 ± 1.69 pg/ml, serum 26.77 ± 2.56 pg/ml) in comparison with patients with asthma (BAL 6.25 ± 1.08 pg/ml, IS 5.82 ± 1.15 pg/ml, serum 6.09 ± 1.16 pg/ml, p < 0.05 respectively) as well as healthy subjects (BAL 4.21 ± 1.13 pg/ml, IS 3.59 ± 0.66 pg/ml, serum 4.63 ± 1.03 pg/ml, p < 0.05 respectively). Moreover, the level of IL-32 was higher in COPD smokers than in COPD ex-smokers in investigated respiratory tissue compartments and serum, and correlated with smoking history. Increased level of IL-32 in serum, IS supernatant, and BAL fluid from patients with COPD in comparison with asthma patients and healthy subjects suggest that IL-32 may play an important role in the pathogenesis of COPD, which depends on the smoking history.

Asthma is one of the most common chronic respiratory diseases with an increasing prevalence and financial burden worldwide. This disease affects individuals in all countries and all ethnic groups; however, prevalence rates of asthma have been reported to vary significantly between different regions. To understand the origin of asthma and to manage it effectively, it is necessary to analyze the genetic and environmental factors that cause these geographic differences. Therefore, we aimed to review published data from the investigations of asthma patients in Eastern Europe, represented by Latvia and Lithuania, and of patients from Eastern Asia represented by Taiwan. We hope that some of the common factors can be identified and different variants can be compared among these three countries for development of a new strategy to prevent childhood asthma.

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P

Background: Alphal-antitrypsin (AAT) deficiency is an under-diagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The objective of the present screening was to estimate the AAT gene frequency and prevalence and to identify AAT deficiency cases in a large cohort of Lithuanian patients with COPD. Methods: A nationwide program of AAT deficiency was conducted in 1167 COPD patients, defined according to the GOLD criteria. Patients were collected from outpatient clinics in five different Lithuanian regions (Kaunas, Vilnius, Siauliai, Klaipeda and Alytus). AAT serum concentrations were measured by nephelometry; PI-phenotypes characterized by isoelectric-focusing. Results: Mean age and FEV1 were 62.0 (10.3) and 54.7% (10.9), respectively. Ninety-one AAT deficiency genotypes (40 MZ, 39 MS, 1 SS, 3 SZ and 8 ZZ) were identified. Catculated PI*S and PI*Z frequencies, expressed in per 1000, were 18.8 (95% CI: 13.9-25) and 25.3 (95% CI: 19.4-32.7), respectively. The calculated AAT gene prevalence (Hardy-Weinberg principle) was: 1/1.09 for MM, 1/28 for MS, 1/2814 for SS, 1/20 for MZ, 1/1049 for SZ and 1/1565 for ZZ. Calculated Odds ratio (OR) for PI*Z in COPD vs. Lithuanian healthy people was of 1.87 (P = 0.004). Conclusion: The OR for each genotypic class demonstrated a significant increase of MZ, SZ and ZZ genotypes in COPD patients. The results of the present study, with a significant number of ZZ individuals detected, support the general concept of targeted screening for AAT deficiency in countries like Lithuania, with a large population of COPD patients and tow awareness among care-givers about this genetic condition. (C) 2008 Elsevier Ltd. All rights reserved. (Less)

Cough reflex sensitivity has not been studied extensively in patients with chronic obstructive pulmonary disease (COPD). The aim of the study was to evaluate cough reflex sensitivity to capsaicin in current and former smokers with COPD and examine its association with potentially protussive mediators. Fifteen active smokers and 18 ex-smokers with moderate to severe COPD, 14 healthy active smokers, and 13 healthy never smokers were enrolled. Capsaicin aerosol was administered in order of ascending concentration until the concentrations inducing two or more coughs (C(2)) and five or more coughs (C(5)) were attained. The concentrations of leukotriene E(4) (LTE(4)), leukotriene B(4) (LTB(4)), and interleukin-8 (IL-8) in bronchoalveolar lavage (BAL) fluid were analyzed by ELISA. Cough reflex sensitivity in COPD smokers [mean log C(2) = 1.20 +/- 0.23 (SEM) microM; log C(5) = 1.85 +/- 0.21 microM] did not differ from that in COPD ex-smokers (log C(2) = 1.15 +/- 0.14 microM; log C(5) = 2.10 +/- 0.19 microM; p > 0.05). Mean C(2) and C(5) in both COPD groups were significantly lower than in healthy active smokers, but higher compared with the healthy never-smokers. BAL fluid concentrations of LTE(4) and LTB(4) were similar in all groups. IL-8 concentrations did not differ between COPD smokers, COPD ex-smokers, and healthy active smokers, but were significantly higher in all three groups compared with healthy never smokers. Cough reflex sensitivity to capsaicin does not differ between smokers and ex-smokers with COPD.

Background: Airway inflammation is associated with an increased expression and release of inflammatory reactants that regulate processes of cell migration, activation and degranulation. The purpose of this study was to quantify bronchial lavage (BAL) fluid and serum levels of chemokine (IL-8), secretory leukocyte protease inhibitor (SLPI), soluble intracellular adhesion molecules-1 (sICAM-1) and sCD14, as surrogate markers of inflammatory and immune response in asthma and chronic obstructive pulmonary disease (COPD) patients with similar disease duration time. Methods: Biomarkers in serum and BAL fluid from asthma (n = 13) and COPD (n = 25) patients were measured using commercially available ELISA kits. Results: We found that in asthma and COPD groups the concentrations of IL-8 and SLPI are significantly higher in BAL fluid than in serum, while levels of sICAM-1 and sCD14 in BAL fluid are significantly lower than in serum. Of these 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma (P < 0.05). In both groups, BAL IL-8 correlated with SLPI (r = 0.577, P < 0.01 and r = 0.589, P < 0.05, respectively). In patients with COPD the BAL sICAM-1 correlated with sCD14 (r = 0.576, P < 0.01), while in asthma patients BAL sICAM-1 correlated with FEV,/FVC (r= 0.418, P < 0.01). Moreover, in asthma patients the serum SLPI correlated with sCD14 (r=0.688, P < 0.01) and serum sICAM-1 negatively correlated with FEV1/FVC (r= -0.582, P < 0.05). Conclusion: Our findings point to the importance of selecting a correct biological fluid when analyzing specific biomarkers, and also show that of 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma. 2007 Published by Elsevier Ltd. (Less)

Previous studies have shown that healthy cigarette smokers have diminished cough reflex sensitivity compared to healthy nonsmokers. We have recently demonstrated that cough reflex sensitivity is enhanced soon after smoking cessation, suggesting that diminished cough sensitivity in smokers results from chronic cigarette smoke-induced desensitization of airway cough receptors. In this study, we evaluated cough reflex sensitivity to capsaicin (C(5)) in 11 chronic smokers who had discontinued smoking for at least 2 weeks, and then resumed smoking. Two weeks after smoking cessation there was a significant enhancement of cough reflex sensitivity; mean (+/-SEM) log C(5) decreased from 1.77+/-0.18 to 1.47+/-0.14 (p=0.01). All subjects resumed smoking after 2-12 weeks of abstinence. Repeat capsaicin cough challenge was performed 14-23 days after resumption of smoking. Mean log C(5) increased compared to the last value obtained during the smoking cessation period: 1.42+/-0.15 vs. 1.77+/-0.16 (p=0.0004). Mean log C(5) after resumption of smoking returned to almost exactly the baseline value. Our findings suggest that the sensitivity of airway cough receptors is a dynamic phenomenon, promptly affected and modulated by changes in environmental conditions, such as the presence or absence of cigarette smoke.

Introduction. It is believed that patient9s immune cells affect tumor development. Immunosuppressive lymphocytes represented by CD4+Foxp3+T cells participate in immunosurveillance in lung cancer and in the immunological tolerance. Study aim was to investigate tumor infiltrating T cells (CD4+Foxp3+, CD4+ and CD8+) in NSCLC. Methods: We studied 48 NSCLC patients (stages I-III) with median age 65.5 years (ranges 46-77) and 10 control group individuals (patients without NSCLC) with median age 20 years (ranges 20-77). Immunohistochemical analysis of surgical lung biopsy samples was performed. Quantitative evaluation of CD4+Foxp3+, CD4+ and CD8+ T cells in tumor islets and stroma was analyzed in 10 most representative high-power fields (HPFs x 400 magnification) per tissue section. Results. Greater amount of CD4+Foxp3+ T cells was found in NSCLC tumor tissue comparing with control group patients (50[11-92] vs. 9[7-10], P Conclusions. Increased amount of CD4+Foxp3+, CD4+ and CD8+ T cells in non-small cell lung cancer tumor tissue was observed.

To investigate polymorphisms of proteasomal genes PSMA6 (rs1048990 and rs2277460), PSMC6 (rs2295826 and rs2295827) and PSMA3 (rs2348071) in Lithuanian patients with asthma.One-hundred forty-six asthma patients and 150 control subjects were studied. DNA was extracted from peripheral blood samples. Five single nucleotide polymorphisms (SNP's) of the three proteasomal genes were analyzed using allele-specific amplification or the cleaved amplified polymorphic sequence method.While certain alleles and genotypes of PSMA6 rs2277460 and rs1048990 and PSMA3 rs2348071 SNP's occurred more frequently in asthma patients than in controls, no statistically significant differences in alleles or genotypes of PSMA6, PSMC6 or PSMA3 were observed between asthma patients and control subjects. However, when male and female study subjects were considered separately, we found that the CG genotype of PSMA6 rs1048990 is significantly more frequent in male asthma patients compared to male control subjects.We found no significant differences in frequencies of selected five proteasomal gene PSMA6, PSMC6 and PSMA3 SNP's between asthma patients and control subjects overall. Among male subjects, however, the CG PSMA6 rs1048990 genotype was significantly more frequent in asthma patients compared with control subjects.

Essential role of beta(2)-adrenoreceptor (beta(2)AR) in airway relaxation is well established. Nevertheless, beta(2)AR seems playing an actual role in allergy and inflammation. Interaction between beta(2)AR and proinflamatory cytokines in airway smooth muscle has been revealed. Being located on proinflamatory cells, beta(2)ARs may influence function of these cells in vivo. It was clear established, that stimulation of beta(2)AR inhibits release of proinflamatory mediators from mast cells, influences T-cell growth and function, eosinophil survival and function, including GM-CSF- or PAF-induced degranulation. Stimulation of beta(2)ARs, located on alveolar macrophages and epithelial cells, has ambiguity influence on their regulation and function, including phagocytosis and mediator secretion, in vivo. Vascular responses, resulting in inhibition of plasma exudation were confirmed, but modulation of sensory nerves via beta(2)AR is not certain yet. beta(2)AR-agonists are effective in treatment of immediate allergic reactions, but desensitisation of beta(2)ARs on inflammatory cells may result in paradoxical effects, especially in asthma. In summary, it is clear that beta(2)ARs may play an anti-inflammatory role in vitro. Unfortunately, in vitro data have shown limited applicability in vivo; therefore further research in this field is required.

Background Eosinophils develop from CD34 + bone marrow progenitors, and evidence increasingly suggests that these progenitors are recruited to the airways in atopic asthmatics after allergen challenge. Moreover, it has been shown that the number of CD34 + progenitors in bronchial tissue correlates with asthma severity. To date, however, little is known about how these cells are recruited into the airways. Objective Our aim was to evaluate the role of 2 chemokines, eotaxin-1 and/or eotaxin-2, in the recruitment of newly produced and CD34 + eosinophils to the airways after allergen exposure. Methods BALB/c mice sensitized and exposed to ovalbumin were pretreated intraperitoneally or intranasally with a neutralizing anti-eotaxin-1 and/or anti-eotaxin-2 antibody. A thymidine analogue, 5-bromo-2′-deoxyuridine (BrdU), was used to mark newly produced cells. Bronchoalveolar lavage (BAL), blood, and bone marrow were collected 24 hours after the final exposure. Results Anti-eotaxin-1 and/or anti-eotaxin-2 given intranasally (ie, locally to airways) significantly decreased BAL eosinophils. This decrease was paralleled with a decrease in both BrdU + and CD34 + eosinophils. In contrast, systemically administered (ie, intraperitoneally) anti-eotaxin-1 and/or anti-eotaxin-2 resulted in a significant decrease in BAL eosinophils only when the combined treatment was of a sufficiently high dosage to produce measurable concentrations in the airways. Furthermore, neither of the treated groups showed any significant decrease in blood or bone marrow eosinophils. Conclusion Both eotaxin-1 and eotaxin-2 are involved locally within the airways in the regulation of the recruitment of newly produced and CD34 + eosinophils after allergen exposure.

Chronic obstructive pulmonary disease (COPD) is characterised by limited bronchial reversibility and chronic neutrophilic inflammation. However, in some cases of COPD, eosinophilic inflammation is present. We investigated the relationship between reversibility to beta2-agonist with atopy and neutrophil activation in patients with stable COPD. For this purpose, 38 outpatients with COPD (mean age: 64 years) 12 with asthma (mean age: 51 years) and 13 healthy controls (mean age: 49 years) were tested using increasing doses of inhaled salbutamol (up to 3100 microg). According to their reversibility, COPD patients were divided into two groups: reversible COPD (deltaFEV1or = 12% pred, n = 16) and non-reversible COPD (deltaFEV112% pred, n = 22). Atopy, assessed by skin prick, was found at similar frequencies in both COPD groups. Total serum IgE was higher in COPD patients vs. controls, but did not differ significantly between the COPD groups. The blood eosinophil count was significantly higher in the reversible COPD group than in the non-reversible COPD, and correlated with deltaFEV % pred (Rs = 0.54, P0.05), as well as in asthmatics. The non-reversible COPD group had a higher level of spontaneous neutrophil activation (by reduction of nitroblue tetrazolium) versus controls. We conclude that airway reversibility in COPD patients is associated with the degree of blood eosinophilia, but not with the degree of blood neutrophil activation.

Background: The For Angioedema Subcutaneous Treatment (FAST)-2, a phase III, double-blind, randomized, multicenter, placebo-controlled study (ClinicalTri als.gov identifier: NCT00500656), established the efficacy and safety of single injections of icatibant, a bradykinin B2 receptor antagonist, in the treatment of hereditary angioedema (HAE) attacks. Here, we evaluate the efficacy and safety of repeated treatment with icatibant in adult patients experiencing HAE attacks during the FAST-2 open-label extension (OLE) phase. Methods: Patients completing the controlled phase were eligible to participate in the OLE phase and receive open-label icatibant (30 mg subcutaneously) for the treatment of cutaneous, abdominal, and/or laryngeal HAE attack(s) severe enough to warrant treatment. Time to onset of symptom relief was calculated for each attack. Descriptive analyses (median, 95% CIs) were performed for all attacks; post hoc analyses were conducted in patients with at least five icatibanttreated attacks throughout the FAST-2 OLE phase. Safety was also monitored. Results: Fifty-four patients received icatibant for 374 attacks (176 cutaneous, 168 abdominal, and 30 laryngeal). For cutaneous and/or abdominal attacks (attacks 2–5), the median times to onset of symptom relief ranged between 2.0 and 2.5 h. For all laryngeal attacks, the median times to regression (start of improvement) of symptoms ranged between 0.3 and 4.0 h. Post hoc analyses showed that the overall median time to onset of symptom relief was 2.0 h. Overall, 89.8% of attacks resolved with a single icatibant injection. No drug-related serious adverse events were reported. Conclusions: These findings have demonstrated the efficacy and safety of repeated icatibant treatment for HAE attacks.

INTRODUCTION Chronic obstructive pulmonary disease (COPD) has been recently defined as a systemic pulmonary inflammatory disease, and congenital α1 antitrypsin deficiency is one of the well-established genetic risk factors for chronic obstructive pulmonary disease. The aim of our study was to evaluate the possible associations of α1 antitrypsin with inflammatory markers - CRP, sCD14, TNF-α, sTNFR-1, and sTNFR-2 - in patients with COPD with different α1 antitrypsin genotypes. MATERIAL AND METHODS Serum biomarkers from patients (n = 355) with COPD, defined according to the GOLD criteria, were analyzed using commercial ELISA kits; α1 antitrypsin concentrations were determined by nephelometry, and α1 antitrypsin phenotyping was carried out by means of isoelectric focusing. RESULTS No significant differences in CRP, TNF-α, sTNFR-1, sTNFR-2, and sCD14 levels were found comparing COPD patients with different genotypes. In patients without α1 antitrypsin deficiency (PI*MM), a significant negative correlation between lung function (FEV(1)) and serum α1 antitrypsin (r = -0.522, p = 0.03) and CRP concentration (r = -0.590, p = 0.011) was detected. The level of α1 antitrypsin positively correlated with: a) CRP concentration (r = 0.671, p = 0.005), b) sCD14 (r = 0.510, p = 0.008) and c) sTNFR-1 (r = 0.567, p = 0.007). CONCLUSIONS In patients without α1 antitrypsin deficiency, the positive association of α1 antitrypsin concentration with CRP, sCD14, and sTNFR-1 and the negative association with FEV(1) show the importance of α1 antitrypsin as a marker of systemic inflammation.

Despite the importance of cigarette smoking as a cause of respiratory symptoms and disease, until recently there has been little attention on the effect of smoking on cough reflex sensitivity. Recent studies have shown that in otherwise healthy smokers, cough reflex sensitivity is diminished relative to that of nonsmokers. One proposed mechanism, chronic cigarette smoke-induced desensitization of airway cough receptors, is supported by the demonstration that smoking cessation leads to prompt enhancement of cough reflex sensitivity, even after many years of smoking. Furthermore, resumption of cigarette smoking promptly results in suppression of cough reflex sensitivity. These observations have introduced the concept that cough reflex sensitivity in humans is a dynamic phenomenon, able to be modulated by the presence or absence of stimuli such as cigarette smoke, even after prolonged exposure.

Chronic airway inflammation is most important pathological finding in asthma. Cigarette smoking may modify type of inflammation as well as may influence disease severity and response to the treatment.Thus the aim of this study was to investigate whether cigarette smoking may have an influence on the levels of eotaxin-1, eotaxin-2, eotaxin-3 and IL-5 in patients with stable mild/moderate asthma.45 steroid naive asthmatics (mean age: 55.2 +/- 2.2 yrs) and 23 "healthy" smokers and non-smokers control subjects (mean age: 54.4 +/- 9.7 yrs) were investigated. Asthmatics were divided into two subgroups according to their smoking histories: asthmatic smokers (n = 19) who currently smoke and have a history of10 pack-years and asthmatic never-smokers (n = 26). BAL and induced sputum were performed. Cytospins of induced sputum and BAL were stained with May-Grunwald-Giemsa for differential cell counts. Eotaxin-1, eotaxin-2, eotaxin-3 and IL-5 concentrations in serum, sputum and BAL supernatant was measured using a commercial ELISA kit.In sputum supernatant from asthma smokers was significantly higher concentration of eotaxin-1 than in non-smokers asthmatics (203.4 +/- 10.0 vs. 140.2 +/- 9.5 respectively, p0.05). In non-smokers asthma patients levels of BAL eotaxin-1 strongly related to percent and absolute numbers of BAL eosinophils and neutrophils (Rs = 0.737 and Rs = 0.514 respectively, p0.05). The number and percent of sputum neutrophils and eosinophils, obtained from smokers asthmatics, significantly correlated with eotaxin-2 concentration in sputum supernatant (Rs = 0.58 and Rs = 0.75 respectively, p0.05). IL-5 levels in the serum and sputum from asthmatic never-smokers were significantly higher than they were from asthmatic smokers and "healthy" smokers. Asthmatic never-smokers showed a significantly higher amount of IL-5 in serum and sputum than the asthmatic smokers showed.This study showed the elevated levels of sputum eotaxin-1 as well as serum, sputum and BAL eotaxin-2 in asthmatic smokers without a significant increase of eosinophils compared to asthmatic never-smokers. The eotaxin concentrations were related not only with number of eosinophils but also with the number of neutrophils in all the studied tissue compartments. The data herein permits a suggestion that smoking may influence change in asthmatic airway inflammation by stimulating the production of eotaxins.

Chronic obstructive pulmonary disease (COPD) and asthma are defined as chronic inflammatory airway diseases. There is increasing evidence that systemic inflammation may be involved in their pathogenesis too. We aimed to investigate the C-reactive protein levels in plasma of patients with COPD, asthma and control subjects and to evaluate associations of C-reactive protein levels with pulmonary function and smoking history. Material and methods. We investigated 87 persons: 41 with COPD, 30 with asthma, and 16 controls. Clinical evaluation, pulmonary function tests, C-reactive protein concentration measurement, body mass index and smoking history evaluation were performed. Results. We determined significantly higher C-reactive protein concentrations in COPD patients compared with asthma patients and controls (8.37±1.14 vs 3.14±0.67 and 2.39±0.59 mg/L, respectively, P&lt, 0.001). Creactive protein concentrations in smokers and ex-smokers with COPD were significantly higher than in COPD non-smokers (8.38±1.52 and 10.4±2.22 vs 4.10±0.86 mg/L, respectively, 0.05). In COPD patients, C-reactive protein level correlated with FEV1 (R=–0.463, P=0.002), FEV1/FVC (R=–0.449, P=0.003), and pack-years (R=0.572, P=0.001). There was no correlation between C-reactive protein level and analyzed parameters in asthmatics and control group. Conclusions. Our data support the hypothesis that systemic inflammation plays a role in the pathogenesis of COPD, and cigarette smoking might influence this inflammation.