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Andrea Vukić Dugac,1,2 Mirna Vergles,3 Sanda Škrinjarić Cincar,4 Ljiljana Bulat Kardum,5 Marina Lampalo,1 Sanja Popović-Grle,1,2 Jelena Ostojić,6 Tatjana Tokić Vuksan-Ćusa,7 Žarko Vrbica,8,9 Emilija Lozo Vukovac,10 Neven Tudorić11 1Clinic for Respiratory Diseases, University Hospital Centre Zagreb, Zagreb, Croatia; 2School of Medicine, University of Zagreb, Zagreb, Croatia; 3Department of Pulmonology, Clinical Hospital Dubrava, Zagreb, Croatia; 4Faculty of Medicine, University of Osijek, Osijek, Croatia; 5Department of Pulmonology, Clinical Hospital Centre Rijeka, Rijeka, Croatia; 6Pulmonary Outpatient Clinic, Special Hospital for Pulmonary Diseases, Zagreb, Croatia; 7Department of Internal Medicine, Karlovac General Hospital, Karlovac, Croatia; 8Department of Internal Medicine, Dubrovnik General Hospital, Dubrovnik, Croatia; 9University Study Programme Nursing, University of Dubrovnik, Dubrovnik, Croatia; 10Department of Pulmonology, University Hospital Split, Split, Croatia; 11Pulmonary Outpatient Clinic, St. Catherine Specialty Hospital, Zagreb, CroatiaCorrespondence: Neven Tudorić, St. Catherine Specialty Hospital, Branimirova Ul. 71E, Zagreb, 10000, Croatia, Tel +385915832449, Email neven.tudoric@gmail.comIntroduction: Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) lead to poor outcomes and increased burden for patients and healthcare systems. The Global Initiative for COPD (GOLD) includes specific recommendations for AECOPD interventions, discharge criteria, and follow-up. Aligning the AECOPD discharge letters (DL) with GOLD guidelines could facilitate dissemination of recommendations among general practitioners (GPs).Purpose: This study was conducted to assess the compliance of DL with the GOLD recommendations in Croatia.Methods: Pre-pandemic DL of patients presenting for AECOPD to emergency room (ER) were analyzed and stratified by clinical decision to hospitalize (HDL) or discharge patients for outpatient treatment (ERDL). Experienced pulmonologists checked the information from DL against guidelines by using online study-specific questionnaires.Results: In total, 225 HDL and 368 ERDL were analyzed. In most cases, the GOLD ABCD categories (85% HDL, 92% ERDL) or the spirometry-based degree of severity (90% HDL, 91% ERDL) were not included. The number of AEs in the previous year was recorded, but the specific frequent exacerbator phenotype not explicitly stated. The AE phenotype was included in two thirds of HDL and one third of ERDL. The blood eosinophil count was frequently available, but not considered decision-relevant information. Adjustments of previous maintenance therapy, mostly escalation, were recommended in 58.4% HDL and 27.9% ERDL, respectively. Education on proper use of inhalers was recommended only in 15.6% of HDL. Smoking cessation measures were advised in 23.1% HDL and 7.9% ERDL; pulmonary rehabilitation in 35.6% HDL and 0.8% ERDL. Early follow-up was frequently advised (> 50%), but rarely appointed.Conclusion: Significant deficiencies in compliance with the GOLD guidelines were identified, translating into a missed opportunity for GPs to become acquainted with GOLD recommendations. These findings emphasize the necessity to increase compliance with guidelines first at specialist level and consequent standardization of DL.Keywords: COPD, GOLD guidelines, acute exacerbation, discharge record

The aim of this study was to establish the impact of air transport on blood samples packaged with and without cooling elements and effect of outdoor temperature on sample quality. Venous samples from 38 blood donors in winter and 36 in summer were tested for hemolysis and complete blood count. One tube per subject was kept in controlled conditions at +4 °C. Two sets of tubes were sent by plane from Zagreb to Brussels, one with and one without cooling elements, and another two sets were sent to London following the same principle. Packages with cooling elements were stored in controlled warehousing conditions at airports (+2 °C to +8 °C), whereas packages without cooling elements were stored in ambient warehouse conditions. Data loggers were used for temperature monitoring. Our research revealed statistically significant differences in several hematologic parameters when comparing the samples stored in controlled laboratory conditions and those transported by plane. These differences were more pronounced in the samples transported during the summer. Transport conditions without cooling elements had additional negative impact on the sample quality. Transport of samples using cooling elements and controlled warehousing conditions at airports are sometimes not sufficient to maintain laboratory storage conditions., (Sestre Milosrdnice University Hospital.)

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313) , HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

Background: The aim of this study was to determine the distribution of ABO and RhD blood group phenotypes in the general population in the Republic of Croatia and among hospitalized patients with severe COVID-19., Materials and Methods: Data on ABO and RhD blood groups of all blood donors in Croatia (who donated blood during the period 2015-2020) and patients and pregnant women tested at the Croatian Institute of Transfusion Medicine during the 2-year period, 2019-2020, were obtained from the e-Delphyn blood bank information system. A total of 614,673 results were analyzed in this group. The other group consisted of 780 COVID-19 patients hospitalized with severe COVID-19. Data are presented as total number and percentages and a comparison of proportions test was performed., Results: The most frequent ABO phenotype in the general population is A (38%), followed by O (37%), B (18%) and AB (7%). RhD positive individuals accounted for 81% of the general population and RhD negative for the other 19%. Among COVID-19 patients, phenotype A was the most frequent (42%), followed by phenotypes O (32%), B (17%) and AB (9%). Thus blood group A was significantly more common among COVID-19 patients than among the general population, whereas blood group O was significantly less frequent., Discussion: This study provides the first official results of the distribution of ABO and RhD blood group phenotypes in the general population in Croatia. Moreover, this study confirms other researchers' observations about the predominance of the A blood group phenotype among COVID-19 patients.

Aims: Biologics have been proven efficacious for patients with severe asthma (SA). It is essential to diagnose such individuals correctly. This study was designed to survey pulmonologists to identify barriers to early diagnosis and subsequent appropriate use of biologics for SA in Croatia., Methods: A pulmonologist group with expertise in SA developed the initial list of questions, with the final questionnaire created according to a 2-round Delphi method. The resulting survey consisted of 23 items consequently divided into 4 domains: 1) Pulmonologists' demographics and professional experiences; 2) Concerns about asthma management; 3) Attitudes toward SA diagnosis; and 4) Beliefs and attitudes regarding the use of biologics in managing SA. The given answers represented the respondents' estimates., Results: Eighty-four surveys were analyzed, with pulmonologists observing that general practitioners often inaccurately diagnose asthma and treat acute exacerbations. Although specialist centers are capably and correctly equipped, the time to diagnose patients with SA is approximately 3.5 months, with initial use of biologics delayed an additional 2 months. The primary indications for prescribing biologics are conventional therapy with oral glucocorticoids (91.7%) and frequent acute exacerbations (82.1%). In addition to improper diagnosis (64.3%), many patients with SA do not receive the indicated biologics owing to strict administrative directives for reimbursement (70.2%) or limited hospital resources (57.1%)., Limitations: The limitations of this survey include the subjective nature of the collected data, the relatively small sample size, and the lack of the biologic efficacy evaluation., Conclusions: Croatian pulmonologists observed that a significant number of patients with SA who are eligible for biologics are not prescribed them, largely because of an inaccurate and/or delayed diagnosis, a delayed referral to a specialist center, highly restrictive criteria for reimbursement, and/or institutional budgetary limitations., Competing Interests: The project was funded by AstraZeneca for logistical and medical writing support. SPG has received compensation for advisory board membership from AstraZeneca, Boehringer Ingelheim, Novartis, Pliva-Teva, GlaxoSmithKline, Berlin-Chemie, Sanofi, Providens, Pharmas, and Medis; has received a grant from Novartis; and has received fees for lectures at symposia organized by AstraZeneca, Boehringer Ingelheim, Novartis, Pliva-Teva, GlaxoSmithKline, Berlin-Chemie, Sanofi, MSD, Pfizer, UCB Pharma, Providens, Pharmas, and Medis. ML received lecturing/consulting fees from Pliva/Teva and lecturing fees from Providens, AstraZeneca, Sandoz, Novartis, Berlin-Chemie, and GlaxoSmithKline. SSC received fees from Boehringer Ingelheim, Providens, Novartis, GlaxoSmithKline, AstraZeneca, Alkaloid, Salvus, Medis, Teva-Pliva, Roche, and Sanofi Genzyme. LBK received lecturing/consultancy fees from AstraZeneca, Boehringer Ingelheim, Roche, Pliva, Sanofi Aventis, and Novartis; lecturing fees from Sandoz, Providens, Berlin-Chemie, Abbott, Oktal Pharma, and Salvus; and received consultancy fees from GlaxoSmithKline. IG received consultancy fees from Boehringer Ingelheim, AstraZeneca, and Novartis; and lecturing fees from MSD, Teva, and Sandoz. EBK received lecturing/consulting fees from Boehringer Ingelheim, AstraZeneca, Chiesi, GlaxoSmithKline, Abbott, and Sandoz. MV received lecturing fees from GlaxoSmithKline, Pliva, Providens, AstraZeneca, Salveo, Alkaloid, and Boehringer Ingelheim. NT received lecturing/consulting fees from Boehringer Ingelheim, AstraZeneca, Berlin-Chemie Menarini, Chiesi, GlaxoSmithKline, Meda, Novartis, and Sandoz. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Asthma is the most common respiratory disease. It has multiple phenotypes thatcan be partially differentiated by measuring the disease's specific characteristics-biomarkers. The pathogenetic mechanisms are complex, and it is still a challenge to choose suitable biomarkers to adequately stratify patients, which became especially important with the introduction of biologicals in asthma treatment. Usage of biomarkers and an understanding of the underlying pathobiological mechanisms lead to the definition of endotypes. Asthma can be broadly divided into two endotypes, T2-high and T2-low. The right combination of various biomarkers in different phenotypes is under investigation, hoping to help researchers and clinicians in better disease evaluation since theindividual approach and personalized medicine are imperative. Multiple biomarkers are superior to a single biomarker.

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B (TrkB) receptor might contribute to normal lung functioning and immune responses; however, their role in asthma remains unclear. Plasma BDNF concentrations, as well as BDNF and NTRK2 ( TrkB gene) polymorphisms, were investigated in 120 asthma patients and 120 healthy individuals using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. The genotype and allele frequencies of BDNF Val66Met (rs6265) and NTRK2 rs1439050 polymorphisms did not differ between healthy individuals and asthma patients, nor between patients grouped according to severity or different asthma phenotypes. Although plasma BDNF concentrations were higher among healthy subjects carrying the BDNF Val66Met GG genotype compared to the A allele carriers, such differences were not detected in asthma patients, suggesting the influences of other factors. Plasma BDNF concentration was not affected by NTRK2 rs1439050 polymorphism. Asthma patients had higher plasma BDNF concentrations than control subjects; however, no differences were found between patients subdivided according to asthma severity, or Type-2, allergic, and eosinophilic asthma. Higher plasma BDNF levels were observed in asthma patients with aspirin sensitivity and aspirin-exacerbated respiratory disease. These results suggest that plasma BDNF may serve as a potential peripheral biomarker for asthma, particularly asthma with aspirin sensitivity.

Aim ABO blood group genotypes are established as a genetic factor in pathophysiology of various diseases, such as cardiovascular disorders, cancers, infectious diseases and there is rising evidence of their involvement in other conditions. The aim of this study was to determine if ventilatory changes of lung function in asthma, measured by biomarkers/parameters, are connected to certain ABO blood group genotypes in Croatia. Methods A case-control study included 149 patients with asthma and 153 healthy individuals (blood donors). ABO genotyping on five main alleles was performed using PCR-SSP method. All patients had spirometry performed and severity of asthma was estimated. Clinical parameters of spirometry (FEV1, FEV/FVC, PEF), biomarkers FeNO, IgE and pO2 were measured. The χ2 test, Fisher's test, Kruskal-Wallis test and Spearman's correlation coefficients with p<0.05 were used as statistically significant. Results There was no determined statistically significant difference in both ABO genotypes and phenotypes between patient and control groups. Comparison of the lung function in different ABO phenotypes in asthmatic patients also did not show any statistically significant differences in FEV1 values, FEV/FVC ratio or PEF. Statistically significant differences in oxygenation between different ABO blood types have not been noticed (p=0.326). Differences in quantitative values of biomarkers (FeNO and IgE) between different ABO blood phenotypes in patients with asthma were not significant, except for IgE that had marginal values (p=0.074). Conclusion No correlation was found between certain ABO blood group genotypes and parameters/biomarkers of ventilatory dysfunction in patients with allergic and nonallergic asthma., (Copyright© by the Medical Assotiation of Zenica-Doboj Canton.)

During a two-year period (2001-2003), 464 patients were treated for tuberculosis at Jordanovac Department for Lung Diseases in Croatia. Besides pulmonary tuberculosis in 97.7% of patients, patients were also treated for tuberculous pleurisy (0.9%), tuberculous laryngitis (0.6%), tuberculous meningitis (0.2%), tuberculous pericarditis (0.2%) and urogenital tuberculosis (0.4%). Out of the total number of patients, 57.3% declared themselves to be active smokers (men were predominant and made up to 80.8%) and 20.9% to be active alcohol consumers. Both risk factors, i.e. smoking and alcohol consumption, were present in 15.1% of all patients. The most common comorbidities were diabetes mellitus (30.4%), cardiac diseases (11.2%) and chronic obstructive pulmonary disease (8.0%). Lung carcinoma was the most common malignant disease (n=51), with Mycobacterium tuberculosis isolated in 33% of them. Seventy-two of 464 (15.5%) patients had recurrences of tuberculosis. Of these, 30.5% had one of the risk factors (20.8% were smokers and 9.7% consumed alcohol), while 32.5% of patients had both risk factors. In conclusion, cigarette smoking was proved to be the most significant risk factor for development of pulmonary tuberculosis and its recurrence.

Background: Asthma is one of the most common chronic diseases in the world. Obesity is the most common comorbidity of asthma and is connected to incidence and course of the disease. Obesity is associated with non-allergic asthma phenotype, but this relation could be influenced by gender. The aim of our study was to determine the relationship between BMI and asthma and to explore possible gender differences., Subjects and Methods: Study included 149 patients with asthma (examined group) and 153 healthy blood donors (control group). Data from the medical records of patients with asthma were used, and all included subjects had their BMI calculated using standard formula. Data were analyzed using descriptive statistics methods. Data with non-parametric distribution were analysed with Mann-Whitney U test and showed through medians with corresponding interquartile ranges. Statistical significance of BMI differences between non-allergic asthma, allergic asthma and control groups were analyzed by one-way analysis of variance - ANOVA. The results were interpreted at a significance level of P<0.05., Results: The comparison between median BMI values of two groups shows that examined group of patients with astma has significantly higher median BMI value in comparison with control group (P=0.035). Correlation was stronger for women than men (P=0.002 vs P=0.898). Incresed BMI of the examined group of patients with asthma was not asociated with non-allergic asthma (P=0.085). However, when stratified according to gender, there was a strong association of increased BMI with non-allergic asthma in women (P<0.001)., Conclusion: Patients with asthma in our study have higher BMI in comparison to healthy individuals, which contributes to hypothesis that BMI is a risk factor for development of asthma. We found that possible effect that BMI has on asthma is stronger in women, since there was a strong association between increased BMI and non-allergic asthma only in women.

Tobacco consumption is one of the most common preventable cause of premature deaths worldwide. Persisting effects of exposure to tobacco smoke on children and adolescents are apparent during pregnancy and in early infancy, passive exposure to environmental tobacco smoke in home and elsewhere, and active smoking during adolescence. While, lung development in these stages of growth is not complete, tobacco smoke puts children and adolescents in danger of severe respiratory diseases and may interfere with the growth of their lungs. Active tobacco consumption by adolescents may have immediate adverse health outcomes such as addiction, impaired lung growth or reduced lung function. Much of the current evidence comes from longitudinal and cross-sectional longitudinal observational studies and propose that the strongest associations with smoke exposure are in the pregnancy and early childhood. The association of nicotine with respiratory system among children and adolescents is less clearly understood and the evidence primarily comes from in vitro and animal studies.

Asthma is a chronic inflammatory disease that is characterized by reversible obstruction of airways, bronchial hyper-reactivity and airway remodeling. The etiology of asthma is multifactorial, with inheritance playing an important role. The aim of our study was to investigate the importance of biomarkers of asthma and the role of plasminogen activator inhibitor-1 (PAI-1) gene as a genetic factor that could be involved in the pathogenesis of asthma. The research was conducted at Jordanovac University Department for Lung Diseases and Croatian Institute of Transfusion Medicine. The research included 149 patients with asthma and 89 healthy individuals. We collected demographic data of both study groups, determined asthma severity using GINA guidelines, and the values of biomarkers and PAI-1 by using laboratory techniques. Based on the results, we concluded that patients with allergic phenotype of asthma were younger, had better lung function and higher levels of IgE. By observing FeNO values, we were not able to distinguish asthmatic patients that had been diagnosed with obstruction of airways from asthmatic patients with normal lung function because FeNO indicates the inflammatory component of disease. The 4G/5G polymorphism of PAI-1 gene did not show any statistically significant difference in the distribution of 4G/4G, 4G/5G and 5G/5G between the group of asthmatic patients and control group.

Plasminogen activator inhibitor-1 (PAI-1) is a glycoprotein which has a role in tissue remodelling after inflammatory processes. The objective is to investigate the frequency of PAI-1 gene polymorphism (4G/5G) in patients with a lung ventilation dysfunction in asthma and allergic rhinitis. Genomic DNA was isolated and genotypes of polymorphism of PAI-1 4G/5G and ABO were determined using the methods of RT-PCR and PCR-SSP. Study group includes 145 adult patients diagnosed with chronic asthma, with all clinically relevant parameters and the laboratory markers of pO 2 , IgE and eosinophils in sputum and nasal swab. In the processing of data, appropriate statistical tests (Kolmogorov-Smirnov test, median, interquartile ranges, χ 2 and Mann-Whitney U tests) were used. Patients with symptoms of allergic rhinitis were significantly younger and had an almost four time higher levels of IgE (P = 0.001), higher pO 2 (P = 0.002) and PEF (P = 0.036), compared to those who do not have these symptoms. Genotype PAI 4G/4G is significantly more common in patients with allergic rhinitis (28.1% vs. 16.1%; P = 0.017) compared to the genotype 5G/5G. Carriers of the genotype 4G/5G also have a borderline statistical significance. There were no statistically significant difference in the incidence of allergic rhinitis in the carriers of any ABO genotypes. The frequency of PAI genotype 4G/4G is significantly more common in patients with allergic rhinitis. The results suggest that the carriers of at least one 4G allele are at a higher risk for developing symptoms of allergic rhinitis in asthma.