What is pre-COPD and do we know how to treat it?

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The lung damage in COPD is associated with an enhanced chronic inflammatory response in the airways and lung tissue to harmful particles or gases. Early detection and treatment of COPD can help manage symptoms and slow the progression of the disease. AREAS COVERED: Status of knowledge regarding early diagnosis, definition of pre-COPD, possible new tools for early diagnosis, possibilities of early treatment, and the results of studies in this population are discussed. Literature search (2014-2024) was done in PubMed, EMBASE, and WoS databases using the keywords COPD, early diagnosis, treatment, smoking, prevention; with additional search of literature in found articles. EXPERT OPINION: No early case-finding programs have been proposed or validated, so we still have many patients diagnosed in the late stage of the disease. Clinically manifest COPD is characterized as typically progressive and irreversible with current therapeutic options. If we aim to reduce the mortality and morbidity from COPD we should target these steps: Prevention; Early diagnosis; Form registries of persons at risk for COPD development; Diagnose preclinical COPD; and discover new preventive therapeutic interventions.

Breathlessness and "exacerbation" questions predictive for incident COPD (MARKO study): data after two years of follow-up.

Aims: To determine the predictability of the MARKO questionnaire and/or its domains, individually or in combination with other markers and characteristics (age, gender, smoking history, lung function, 6-min walk test (6 MWT), exhaled breath temperature (EBT), and hsCRP for the incident chronic obstructive pulmonary disease (COPD) in subjects at risk over 2 years follow-up period). Participants and Methods: Patients, smokers/ex-smokers with >20 pack-years, aged 40-65 years of both sexes were recruited and followed for 2 years. After recruitment and signing the informed consent at the GP, a detailed diagnostic workout was done by the pulmonologist; they completed three self-assessment questionnaires-MARKO, SGRQ and CAT, detailed history and physical, laboratory (CBC, hsCRP), lung function tests with bronchodilator and EBT. At the 2 year follow-up visit they performed: the same three self-assessment questionnaires, history and physical, lung function tests and EBT. Results: A sample of 320 subjects (41.9% male), mean (SD) age 51.9 (7.4) years with 36.4 (17.4) pack-years of smoking was reassessed after 2.1 years. Exploratory factor analysis of MARKO questionnaire isolated three distinct domains (breathlessness and fatigue, "exacerbations", cough and expectorations). We have determined a rate for incident COPD that was 4.911/100 person-years (95% CI [3.436-6.816]). We found out that questions about breathlessness and "exacerbations", and male sex were predictive of incident COPD after two years follow-up (AUC 0.79, 95% CI [0.74-0.84], p < 0.001). When only active smokers were analyzed a change in EBT after a cigarette (ΔEBT) was added to a previous model (AUC 0.83, 95% CI [0.78-0.88], p < 0.001). Conclusion: Our preliminary data shows that the MARKO questionnaire combined with EBT (change after a cigarette smoke) could potentially serve as early markers of future COPD in smokers.

Are We Missing the Opportunity to Disseminate GOLD Recommendations Through AECOPD Discharge Letters?

Introduction: 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.

Early detection of COPD patients in GOLD 0 population: an observational non-interventional cohort study - MARKO study.

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.

Development and the initial validation of a new self-administered questionnaire for an early detection of health status changes in smokers at risk for chronic obstructive pulmonary disease (MARKO questionnaire).

AIM: To develop and do an initial validation of a new simple tool (self-administered questionnaire) that would be sensitive and specific enough to detect early changes in smokers leading to future development of chronic obstructive pulmonary disease (COPD). METHODS: 224 consecutive participants (50.9% women), with mean±standard deviation age of 52.3±6.7 years, 37.5±16.7 pack-years smoking history (85.8% active smokers), and no prior diagnosis of COPD were recruited. The MARKO questionnaire was self-administered twice; at the general practitioner's office and after 2-4 weeks at the tertiary care hospital. Participants were assessed for COPD by a pulmonologist after filling in a quality of life (QoL) questionnaires, history-taking, physical examination, lung function test, 6-minute walk test, and laboratory tests. They were divided into four subgroups: "healthy" smokers, symptomatic smokers, and smokers with mild and moderately severe COPD. RESULTS: Psychometric analyses indicated that the 18-item questionnaire had a very good internal consistency (Cronbach's alpha=0.91) and test-retest reliability for a four week period (c=0.89, 95% confidence interval [CI] 0.85-0.92, Lin's concordance). A significant correlations of MARKO scores were found with two QoL questionnaires; r=0.69 (P<0.001) and r=0.81 (P<0.001). Receiver operating characteristic curve analysis showed an area under the curve of 0.753 (95% CI 0.691-0.808, <0.001), with a sensitivity of 71.83% and specificity of 64.24% to discriminate "healthy" smokers from other subgroups. CONCLUSION: Based on psychometric analyses and high convergent validity correlation with already validated QoL questionnaires, the newly developed MARKO questionnaire was shown to be a reliable self-administered short health status assessment tool.

Diagnostic accuracy of a pocket screening spirometer in diagnosing chronic obstructive pulmonary disease in general practice: a cross sectional validation study using tertiary care as a reference.

BACKGROUND: COPD-6™ is a lung function testing device for a rapid pre-spirometry testing to screen-out at-risk individuals not having COPD and indicating those at risk. The aim of this study was to validate COPD-6™ lung function testing (index test) in general practice in discriminating patients with COPD out of the population at risk - smokers/ex-smokers with no previous diagnosis of COPD, using measurements at tertiary care as reference standard. METHODS: Consecutive 227 subjects (115 women, 185 smokers/42 ex-smokers, ≥20 pack-years) with no previous diagnosis of COPD, aged 52.5 (SD 6.8) years from 26 general practitioners (GPs) were recruited, lung function tested with COPD-6™, referred to the tertiary institution for repeated COPD-6™ testing followed by spirometry with a bronchodilator (salbutamol), examination, and pulmonologist consultation for the diagnosis and severity of COPD. RESULTS: COPD was diagnosed in 43 subjects (18.9 %), with an AUC of 0.827 (95 % CI 0.769-0.875, P < 0.001) for the diagnosis of COPD when lung function was measured using COPD-6™ in GP's office with a specificity of 100 % (95 % CI, 97.95-100 %) but a very low sensitivity of 32.56 % (95 % CI, 20.49-47.48 %). Significant agreement for forced expiratory volume in 1 s measured at GP's office and at lung function lab was found (mean difference 0.01 L, p = 0.667) but not for other measured parameters (p < 0.001 for all). CONCLUSIONS: Our study results point out that active case finding in a population at risk for COPD should be instituted (almost 20 % of undiagnosed COPD). Based on our results lung function testing with COPD-6™ can substitute spirometry testing in cases where it is not readily available to the patient/physician taken into account that the traditional FEV1/FEV6 cutoff value of <0.7 is not the only criterion for diagnosis and/or further referral. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01550679 Registered 28 September 2014, retrospectively registered.

Exhaled Breath Temperature as a Novel Marker of Future Development of COPD: Results of a Follow-Up Study in Smokers.

Although only less than one-third of smokers develop COPD, early marker(s) of COPD development are lacking. The aim of this research was to assess the ability of an average equilibrium exhaled breath temperature (EBT) in identifying susceptibility to cigarette smoke so as to predict COPD development in smokers at risk. The study was a part of a multicenter prospective cohort study in current smokers (N = 140, both sexes, 40-65 years, ≥20 pack-years) with no prior diagnosis of COPD. Diagnostic workup includes history, physical, quality of life, hematology and highly sensitive CRP, EBT before and after smoking a cigarette, lung function with bronchodilator test, and 6-minute walk test. Patients without a diagnosis of COPD and in GOLD 1 stage at initial assessment were reassessed after 2 years. COPD was additionally diagnosed based on lower level of normal (LLN) lung function criteria. Utility of EBT for disease progression was analyzed using receiver operator curve (ROC) and logistic regression analyses. Change in EBT after smoking a cigarette at initial visit (ΔEBT) was significantly predictive for disease progression (newly diagnosed COPD; newly diagnosed COPD + severity progression) after 2 years (p < 0.05 for both). ΔEBT had an AUC of 0.859 (p = 0.011) with sensitivity of 66.7% and specificity of 98.1% for newly diagnosed COPD using LLN criteria. We conclude that EBT shows potential for predicting the future development of COPD in current smokers. This was best seen using LLN to diagnose COPD, adding further evidence to question the use of GOLD criteria for diagnosing COPD.

Intraregional differences in asthma prevalence and risk factors for asthma among adolescents in Split-Dalmatia County, Croatia.

BACKGROUND: Our aim was to assess the differences in intraregional prevalence of asthma in adolescents in Split-Dalmatia County to determine asthma risk factors in our population and estimate the specificity and sensitivity of the questionnaire used. MATERIAL/METHODS: We conducted the study using the European Community Respiratory Health Survey II short questionnaire supplemented by some questions from the International Study of Asthma in Childhood questionnaire. The participants suspected to have asthma were invited for examination by an asthma specialist who established the final diagnosis of asthma according to the medical history, physical examination, skin-prick tests, and peak flow measurements. RESULTS: A total of 4027 students (51.2% male) participated in the study. According to the prevalence of wheezing during the last 12 months, asthma prevalence was estimated at 9.7%. The total prevalence of asthma confirmed by an asthma specialist in the selected population was 5.60% (95% CI, 4.93-6.36%); 6.18% in Split (95% CI, 5.37-7.09), 5.63% in Imotski (95% CI, 3.48-8.58), and 2.90% in Sinj (95% CI, 1.67-4.68) (P=0.0028). We found sensitization to aeroallergens and peanuts, and active smoking to be independent risk factors for asthma. CONCLUSIONS: Split-Dalmatia County has moderate asthma prevalence, with a significant intraregional difference. Asthma prevalence estimated by a questionnaire (9.7%) overestimates the prevalence of asthma confirmed by an asthma specialist (5.6%) in adolescents in Croatia. Our data confirmed the need of a more complex questionnaire to evaluate the accurate prevalence of current asthma or the need for subsequent clinical evaluation of the questionnaire obtained data. Allergic sensitization to aeroallergens and active smoking were important risk factors for asthma.

Necrotising sarcoid granulomatosis of the spinal cord: case report.

We report a patient who presented with leg weakness and cervical lymphadenopathy. Thoracical magnetic resonance imaging showed an inhomogenously increased signal in the thickened portion of the cord. Multilevel laminectomy and spinal cord biopsy revealed granulomatous infiltrations with necrosis. Review of the histopathological finding established the diagnosis of necrotising sarcoid granulomatosis (NSG) of the spinal medulla, cytological FNA diagnosis of the neck lymph node was granulomatous inflammation with necrosis, but histopathological analysis of the same neck lymph node disclosed granulomatous inflammation without necrosis. On further radiographic chest evaluation mediastinal lymphadenopathy was found. Immunophenotyping of lymphocytes in bronchoalveolar lavage fluid (BALF) was indicative of sarcoidosis. After the administration of corticosteroid therapy the patient's clinical condition improved, and laryngeal and mediastinal lymph nodes subsided with minor changes remaining in the spinal medulla, which, based upon MR assessment, were considered to be irreversible. To our knowledge, this is the first described case with finding of granulomatous inflammation with and without vasculitis in various organs, consistent with the Churg's study who believes NSG to be a histological variant of sarcoidosis.

Correlation between cholelithiasis and gallbladder carcinoma in surgical and autopsy specimens.

Gallbladder (GB) cancer is the most common malignant lesion of the biliary tract. The decision for a cholecystectomy in asymptomatic cholelithiasis as a measure of the secondary prevention of gallbladder cancer is based on the data of incidence and selected predictive factors for a specific population. A consecutive series of 3351 cholecystectomies in five year period was reviewed. That data was compared with the data from 2395 consecutive autopsies from the same period. Possible risk factors for gallbladder cancer were analysed. In surgical specimens, the incidence of gallbladder carcinoma was 0.62%. Of those, 24% were in patients younger than 60 years and 95.24% were associated with cholelithiasis. In autopsy material, in cases in which cholelithiasis was present, the incidence of gallbladder carcinoma was 3.4%. All cases were in patients older than 60 years and all were associated with cholelithiasis. Correlation between cholelithiasis and gallbladder carcinoma was most significant for women in the surgical group while it was not as strong for men or in the autopsy group. The results vary whether we analyse surgical or autopsy material, but in both cases female gender and the duration of cholelithiasis were significant risk factors. In our population GB cancer is not uncommon in elderly women with gall stones and is diagnosed in advanced stage if one waits for symptoms.

Different phenotypes of intermittent and persistent respiratory allergy in Zagreb, Croatia.

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.

[Guidelines for diagnosis and management of asthma in adults of the Croatian Respiratory Society]. / Smjernice Hrvatskoga pulmoloskog drustva za dijagnosticiranje i lijecenje astme u odraslih.

The global use of guidelines for proper diagnosis and management of asthma was worldwide aimed toward obtaining effective control of asthma. Until now, the most often used guidelines in Croatia were the ones issued by the Global Initiative for Asthma (GINA). Their implementation significantly improved and uniformed the diagnosis and management of asthma at different levels of the national health system. The obtained level of knowledge has enabled the making of local guidelines which acknowledge economic, cultural and even traditional specificities of Croatia. It was supposed that Croatian medical professionals would more effectively use guidelines they actively supported to prepare and which were appropriated to local work environment and medicines available. Therefore, based on current scientific evidence, the Croatian Respiratory Society has prepared Croatian Guidelines for Diagnosis and Management of Asthma in Adults purposed for wide use among Croatian doctors and other health professionals.

Between stigma and dawn of medicine: the last leprosarium in Croatia.

In an attempt to reconstruct the function of the last leprosarium in Croatia, situated in the little town of Metkovic in the Neretva valley, we used local folk tales and compared them with different data sources, such as register of deaths in the Roman Catholic parishes in Metkovic and the nearby village of Vidonje, archived local newspapers, building documents, and different artifacts from the beginning of the 20th century. We identified individuals and families who were treated in the leprosarium during its existence from 1905, when it was built, until 1925, when it was closed down. We analyzed why the Neretva river valley was chosen for the isolation of lepers. It seems that the geographical position of the region, close to the endemic seat of the disease in the neighboring Bosnia, was more important for the decision to build the leprosarium than the incidence of leprosy or some recent outbreak of the disease in Croatia. Building of leprosariums, such as this one in Metkovic, was a part of tradition of separating lepers from human community. This was considered as a socially and medically justified behavior in a time when it was not possible to identify the cause of leprosy and apply the proper treatment.