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The nutritiol status of patients with chronic obstructive pulmory disease (COPD) is a significant factor that influences the prognosis of the disease. This observatiol study aimed to alyze the nutritiol status of COPD patients and assess the associations between nutritiol status, disease severity, and exercise capacity in four different regions of Croatia. In this multicenter study, 534 COPD patients were recruited and evaluated concerning fat-free mass (FFM), FFM index (FFMI), skeletal muscle mass index (SMMI), phase angle (PhA), pulmory function tests, and the 6-minute walk test (6MWT). There were 325 (60.9%) male and 209 (39.1%) female patients with a mean age of 66.7±8.4 years. Most patients (73.2%) exhibited a moderate to severely abnormal obstructive pattern and had a reduced 6MWT distance (396.5±110.8 m). Among the participants, 32.8% were overweight and 22.3% were obese, and they had satisfactory values for nutritiol status variables (FFM, FFMI, SMMI, PhA). There were no statistical differences between the centers in terms of nutritiol status variables. There was a significantly positive correlation of forced expiratory volume in one second with body mass index (BMI) (r=0.148, p=0.001), PhA (r=0.256, p=0.00), FFM (r=0.365, p=0.00), and SMMI (r=0.238, p=0.00). However, there was no significant correlation of the 6MWT with BMI (r=-0.049, p=0.254), FFM (r=0.065, p=0.133), and SMMI (r=-0.007, p=0.867). The data alysis demonstrated that our patients were not underweight and that there was no significant difference between the centers in terms of BMI, FFM, FFMI, SMMI, and PhA. This lack of significant difference was observed even though one of the regions studied was Mediterranean.

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). This study was conducted to assess the compliance of DL with the GOLD recommendations in Croatia. 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. 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. 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.

Background: Distinguishing chronic obstructive pulmonary disease (COPD) from asthma–COPD overlap (ACO) remains challenging due to shared clinical and inflammatory features. Interleukin-13 (IL-13) is implicated in airway inflammation and remodeling and may represent a potential treatable trait. This study aimed to evaluate whether serum IL-13 could differentiate between COPD and ACO or define ACO subtypes and to explore its relationship with clinical and phenotype parameters. Materials and Methods: We conducted a cross-sectional bicentric study in 215 COPD and ACO patients recruited from outpatient clinics. The study measured blood IL-13 levels in COPD vs. ACO patients, across five ACO subtypes, and evaluated IL-13’s ability to predict ACO. Additionally, correlations were explored among endotype (IL-13) and different phenotype traits (e.g., fractional exhaled nitric oxide (FeNO), sputum eosinophilia, serum total immunoglobulin E (tIgE) levels, blood eosinophilia, and neutrophilia) and clinical outcomes (annualized exacerbation rate, symptom scores, and pulmonary function parameters). Results: No significant differences in IL-13 levels were found between COPD and ACO patients or among ACO subtypes. IL-13 did not predict ACO occurrence. We observed a weak correlation between IL-13 and tIgE levels in the entire cohort. Additionally, there was a weak correlation between IL-13 and FeNO in patients with eosinophil counts exceeding 300 cells/μL, as well as between IL-13 and age in the COPD cohort. No correlation was found between IL-13 and other phenotypic features or clinical outcomes in the overall cohort, including within both COPD and ACO groups. Conclusions: IL-13 cannot differentiate between COPD and ACO or ACO’s subtypes.

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. 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. 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%). 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.

We analyzed for associations between a variable number of tandem repeat (VNTR) polymorphism in the Family with sequence similarity 46, member A (FAM46A) gene and a single nucleotide polymorphism (rs3117582) in the BCL2-Associated Athanogene 6 (BAG6) with non small cell lung cancer in Croatian and Norwegian subjects. A total of 503 (262 Croatian and 241Norwegian) non small cell lung cancer patients and 897 controls (568 Croatian and 329 Norwegian) were analyzed. We found that the frequency of allele b (three VNTR repeats) of FAM46A gene was significantly increased in the patients compared to the healthy controls in the Croatian and the combined Croatian and Norwegian subjects. Genotype frequencies of cd (four and five VNTR repeats) and cc (four VNTR repeats homozygote) of the FAM46A gene were significantly decreased in the patients compared to the healthy controls in the Croatian and Norwegian subjects, respectively. Logistic regression analyses revealed FAM46A genotype cc to be an independent predictive factor for non small cell lung cancer risk in the Norwegian subjects after adjustment for age, gender and smoking status. This is the first study to suggest an association between the FAM46A gene VNTR polymorphisms and non small cell lung cancer. We found also that BAG6 rs3117582 SNP was associated with non small cell lung cancer in the Norwegian subjects and the combined Croatian-Norwegian subjects corroborating the earlier finding that BAG6 rs3117582 SNP was associated with lung cancer in Europeans. Logistic regression analyses revealed that genotypes and alleles of BAG6 were independent predictive factor for non small cell lung cancer risk in the Norwegian and combined Croatian-Norwegian subjects, after adjustment for age and gender.

We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio = 2.42, 95% Confidence Interval = 1.34-4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval = 1.26-9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease.

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren’s syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD.

Ingileif Jonsdottir, Kari Stefansson and colleagues show that variants in the HLA class II region contribute to tuberculosis risk in populations of European ancestry. They propose that the associated variants influence disease risk by altering expression of HLA class II molecules presenting protective M. tuberculosis antigens to T cells. Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually 1 . To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10 −13 ) and PTB (OR = 1.25, P = 5.8 × 10 −12 ), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10 −12 )—both located between HLA - DQA1 and HLA - DRB1 —and a missense variant encoding p.Ala210Thr in HLA - DQA1 (MAF = 19.1%, rs9272785), associated with M . tuberculosis infection ( P = 9.3 × 10 −9 , OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia ( P < 5.9 × 10 −4 ). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M . tuberculosis antigens to T cells.

Background Main risk factor for the development of chronic obstructive pulmonary disease (COPD) is smoking, although only less than 1/3 of smokers develop clinically manifest COPD. COPD’s progressive nature with high disability and mortality makes it plausible to detect it as early as possible thus allowing for an early intervention. The only tool for an early diagnosis that could be used on the global scale is spirometry, even though symptoms and deprivation of health related quality of life (HRQoL) precede relevant spirometric changes. Existing HRQoL questionnaires are too complicated or not developed for an early detection of COPD. The aim of our study was to develop a new simple HRQoL tool that will allow (alone or in combination with other markers) early detection of patients with COPD. Methods A multicenter prospective cohort study recruiting 500 subjects at risk for COPD (smokers/ex-smokers ≥20 pack-years, 40–65 years, both sexes, with no prior diagnosis of COPD) will be carried out in two phases: (1) cross-sectional - development and validation of a new questionnaire; and (2) prospective - follow-up of a cohort of patients at risk for COPD. Subjects were recruited by 25 GPs and assessed for COPD by dedicated pulmonologists in 7 hospital centers using a predefined protocol: HRQoL, history, physical, blood sampling, exhaled breath temperature (EBT), lung function, 6-min walk test (6MWT). Patients without COPD and those in GOLD stage 1 at initial assessment will be reassessed for disease progression by the same pulmonologist after 2 and 5 years. Discussion This is one of the first cohort studies attempting to establish the incidence of COPD in the pre-symptomatic stage before significant end organ damage. We intend to assess the validity, predictability and discriminative power (‘healthy’ smokers vs. pre-symptomatic phase in newly developed COPD) of newly developed HRQoL tool alone or in combination with other markers; EBT, lung function, 6MWT, genomics, transcriptomics, proteomics). We expect that the results of this study can improve our understanding of the development of COPD, identify some new underlying pathophysiological pathways, and offer to sensitive smokers/ex-smokers new preventive and early intervention measures thus improving the management of COPD. Trial registration Clinicaltrial.gov NCT01550679 retrospectively registered February 28, 2012.