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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 test the hypothesis that glutathione- S-transferase (GST) genotypes were associated with COPD. GSTP1, GSTM1 and GSTT1 genotypes were determined by DNA methods and GST activity spectrophotometrically in older male Caucasian Croats (non- -smokers, ex-smokers, and smokers) with stable COPD (n = 30) and sex/age matched controls (n = 60). The distribution of GSTP1 genotypes and alleles in controls vs. COPD showed a statistical difference (p < 0.05). The odds ratio of CC/CT+TT (wild type GSTP1 exon 6 vs. joint heterozygous and mutant homozygous GSTP1 exon 6) was 10.000 and statistically different (p = 0.002). In this study, the GSTP1 mutant genotype of exon 5 (GG), as well as GSTP1 mutant and heterozygous genotypes of exon 6 (TT and CT), were suggested to be genetic contributors to COPD susceptibility. Null GSTM1, null GSTT1 and joint GSTM1/GSTT1 null genotypes were not disease associated. Serum GST was not associated with GST genotypes and COPD or smoking history in our study subjects. Conclusions drawn from the study should be further supported and clarified by studies with larger sample sizes.

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.

Chronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case−control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493&#95;N592S, and rs5744174&#95;F616L) indicated the minor allele of rs2072493&#95;N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493&#95;N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.

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.

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.

What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature., Case Summary: We present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research.
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Objective: The aim of our study was to investigate impact of active and passive smoking on total and specific serum IgE levels and on incidence of developing allergic diseases (i.e. asthma, rhinitis) in a group of Croatian adolescents., Methods: Our study consisted of random sample of one hundred fifty-five (155) voluntary pupils (80 males and 75 females), with mean age of 16.72 +/- 1.25 years, from one high school in the city of Varazdin (north-west part of Croatia). Their smoking habits were examined by interview administered by a single trained survey worker while diagnosis of allergic disease (i.e. asthma and allergic rhinits) had to be previously confirmed by physician. Total and specific serum IgE levels were determined using enzyme-linked immunosorbent assay (ELISA) method in Central Laboratory of Clinic for lung diseases Jordanovac, Zagreb (Croatia)., Results: Statistically significant higher prevalence of allergic diseases was found in the group of passive smokers as opposed to nonsmokers (chi2=9.29, p=0.002) as well as in active smokers compared to nonsmokers (chi2=4.45, p=0.034). Also, total IgE (IU/ml) was significantly higher in passive smokers when compared to non-smokers (t=13.039, p<0.01), and in passive smokers as opposed to active smokers as well (t=4.960, p<0.01), while difference in its level between active smokers and non-smokers was not statistically significant. The level of specific IgE to Dermatophagoides pteronyssinus between active smokers, passive smokers and non-smokers resulted to be not statistically significant., Conclusions: Results of the study indicate that clinical manifestations of allergic diseases are more frequent in smokers (both active and passive) than in nonsmokers. Our investigation leads us to a presumption of a possibly more harmful effect of passive than active smoking in the adolescent high school population. Statistically highest IgE level in passive smokers as opposed to non-smokers or smokers could be attributed to longer duration of exposure to tobacco smoke in passive smokers and tobacco's potential cumulative effect on allergic senzitisa-tion, although investigations with more precised and detailed mesures including higher number of participants are warranted.

Chronic obstructive pulmonary disease (COPD) is already the world's fourth most common cause of mortality and likely to become the third in a few year's time. Because it is an inflammatory airway disease with altered host immune response, infectious complications are frequent. Acute exacerbations of COPD (AECOPD) significantly worsen the patient's general health, accelerating disability. Each exacerbation leads progressively to further deterioration of lung function. Among the various causes of AECOPD, including viruses, bacteria and air pollution, a bacterial etiology is most common (50-69%). The management of AECOPD remains extremely challenging and places a heavy economic burden on health care institutions. The decision to administer antibiotics in AECOPD is multifactorial, the most important considerations being severity of the COPD stage and patient performance status, clinical symptoms (increased dyspnea, sputum volume and sputum purulence), severity of current and previous exacerbations, comorbidity and current smoking. Exacerbations which require hospital admission are associated with significant in-patient mortality. AECOPD patients presenting with worsening dyspnea, increased sputum volume and purulence should be offered antimicrobial therapy. If treating with antibiotics, treatment must include coverage for Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis in all cases, but other bacteria (such as Gram-negatives) may need to be covered depending on the condition of the patient. Antibiotics, particularly macrolides and fluoroquinolones, when administered under suitable conditions, shorten the clinical course and prevent severe deterioration. possible complications resulting from untreated severe AECOPD surpass the potential risks from the use of antibiotic therapy. Additional anti-inflammatory and immunomodulatory actions of some antibiotics may contribute to their efficacy in AECOPD.

Life-threatening hemoptysis is very rare and, fortunately, not many physicians have experienced it. The unpredictability of massive hemoptysis is often underestimated in seemingly stable patients and becomes fatal within a few minutes. The current definitions of massive and/or life-threatening hemoptysis in the medical literature are inadequate and the specific recommendations for the management of such conditions, based on sporadic case reports, are inadequate as well. We report herein a case of active tuberculosis-related exsanguinating hemoptysis (>1500 mL of blood within minutes) in a 26-year-old male, which illustrates the essential issues in the management of this condition; the pertinent literature is also reviewed. After a cardiac arrest with successful resuscitation, in an effort to reduce the risk of recurrent hemoptysis, we introduced a bronchial blocker (i.e., a Fogarty catheter), as guided by a fiberoptic bronchoscope, into the right main bronchus through several days earlier performed percutaneous tracheostomy because of patient's respiratory insufficiency. Several factors played a crucial role in the patient's survival. The main purpose of this case report is to contribute to the management of hemoptysis that leads to exsanguination within minutes and the originality of this report entails the introduction of bronchial blocker through the percutaneous tracheal cannula.

Allergic rhinitis (AR) is a major chronic respiratory disease because of its prevalence, its impacts on the quality of life, economic burden and links with asthma. A significant relationship between the severity of rhinitis and prevalence of asthma in allergic patients was found both in patients suffering from seasonal rhinitis and in those suffering from perennial-allergic rhinitis (PAR) and asthma. The aim of the study was to investigate allergy phenotypes in patients with intermittent allergic rhinitis (IAR) and persistent allergic rhinitis (PAR) in residents of Zagreb, and to determine if there were any other differences in the clinical (in vivo) and diagnostic (in vitro) presentations of the phenotype of subjects suffering from different types of rhinitis. 205 subjects were divided into 2 groups, 102 with IAR sensitized to ragweed pollen (Ambrosia elatior) and 103 with PAR sensitized to house dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae). The diagnosis was based on a detailed medical history, examination and diagnostic tests (spirometry, reversibility after appliance of salbutamol, skin prick test, and total IgE). Rhinitis symptoms in subjects with IAR were significantly different than in those with PAR. Sneezing and a runny, itchy nose were frequently present in the IAR group, but not in the PAR group. Prevalence of the coexistence of asthma was higher in the PAR group (35:57%), as well as more severe clinical phenotype of asthma. The covariation of sensitization was similar (70:74%). The most frequent sensitization in the IAR group was found to house dust mite (38%), and in the PAR group to animal dander (40%). The clinical presentation of the IAR was different from that of the PAR. The prevalence of coexisting asthma was significantly higher in the PAR group. The covariation of sensitization was similar.

Setting: Patients of five randomly selected general practitioners in Split, Croatia., Objective: To investigate knowledge about tuberculosis (TB) and to identify target groups for information, education and communication activities., Design: Cross-sectional survey based on a structured questionnaire using a convenience sampling among subjects aged > or =18 years. Data were stratified by sex, age group, educational background, personal monthly income and contact with TB patients. TB knowledge scores were determined from the number of correct answers to 12 selected questions., Results: The questionnaires were completed by 386 subjects. No statistically significant differences were observed between females and males with respect to age, educational background or contact with TB patients, except for personal income, which was higher in males (P < 0.001). The mean TB knowledge score was 9.4 +/- 1.98 (range 1-12, median 10). A low score was associated with the youngest age group, 18-29 years (P = 0.018), and with <12 years of education (P = 0.002)., Conclusion: Educational background and age groups of respondents were important determinants of TB knowledge. Although the study sample showed a satisfactory level of knowledge, the results demonstrated several misconceptions that need to be clarified. Uncertainties in core TB knowledge need to be addressed choosing less educated and young people as specific target groups.

Magnesium is one of the most important factors for regulation of inflammatory response as well as muscle function, and COPD is a multicomponent disease characterized by abnormal inflammatory response of the lungs with systemic muscle dysfunction. Because polymorphonuclear (PMN) cells are significantly represented in the pathogenesis of COPD, concentrations of total (tMg) and ionised magnesium (iMg) were determined in plasma and isolated PMN cells in 46 patients in stable phase of COPD (past smokers, current smokers, and non-smokers), 24 healthy smokers and 37 healthy non-smokers. In the same samples concentrations of total (tCa) and ionised calcium (iCa) were determined, due to the antagonism of magnesium towards calcium. We found decreased biological active iMg in PMN compared to the group of healthy non-smokers (5.42, 1.98-17.31 micromol/10(9) cells vs. 7.50, 3.27-15.15 micromol/10(9) cells, p < 0.05). In the plasma and isolated PMN of the patients the ratio of total calcium/total magnesium (tCa/tMg) was significantly increased (2.89, 2.15-3.86 and 1.19, 0.07-9.87) compared to the group of healthy non-smokers (2.65, 2.19-3.44 and 0.67, 0.14-2.40, p < 0.05) and to the group of healthy smokers (2.58, 2.26-3.24 and 0.66, 0.14-2.85, p < 0.05). In the group of patients the concentration of tCa was significantly increased in all samples compared to the healthy group of non-smokers and healthy smokers. The results of univariant logistic regression analysis for smoking, concentration of tCa and ratio of tCa/tMg in PMN showed high odds ratio for COPD status. These results raise a possibility that intracellular polymorphonuclear value of magnesium could be a distinctive marker for COPD risk disclosure among smokers.

Background: Altered muscle amino acid metabolism resulting in skeletal muscle dysfunction is one of the systemic effects of chronic obstructive pulmonary disease (COPD) associated with systemic oxidative stress and inflammation. The aim of the study was to investigate the existence and extent of changes in the activities of the enzymes catalyzing transamination reactions (aminotransferases), the enzyme involved in bone rearrangement (alkaline phosphatase), and the enzyme reflecting hypoxia that is characteristic of these patients (lactate dehydrogenase). In addition, the effect of cigarette smoking on these enzyme activities was also assessed., Methods: Enzyme activities such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase were determined by standard analysis in sera of 29 COPD patients (FEV(1) = 46.6 +/- 12.1%) and 58 healthy subjects (21 nonsmokers, 17 ex-smokers and 20 smokers)., Results: The activity of aspartate aminotransferase and alanine aminotransferase was significantly decreased, and the activity of lactate dehydrogenase increased in sera of COPD patients as compared with the group of healthy nonsmokers. According to centile values, the activity of alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase was increased in 50, 5, and 50% of COPD patients, respectively., Conclusions: Study results revealed significant changes in the activities of transamination enzymes in patient sera, thus supporting the reports on altered amino acid metabolism in skeletal muscle in COPD. The elevated activity of alkaline phosphatase provides additional evidence for altered bone rearrangement in these patients. Smoking was not found to have any major effect on these enzyme activities in the present study.