Monocyte related haematological indices in acute exacerbations of COPD - a new biomarker?

C-reactive protein (CRP) and leukocyte count are standard tools for recognising inflammation in COPD patients. This study aimed to find if there is a pattern in monocyte related haematological indices - monocyte to neutrophil ratio (MNR) and monocyte to lymphocyte ratio (MLR) - which could be helpful in differentiating COPD patients in need for hospitalization due to acute exacerbation of COPD or differentiating frequent COPD exacerbators from non-frequent COPD exacerbators. The study included 119 patients with COPD and 35 control subjects, recruited at the Clinic for Respiratory Diseases Jordanovac, University Hospital Centre Zagreb, Croatia. Complete blood count was performed on Sysmex XN-1000, CRP on Cobas c501, and Fbg on BCS XP analyser. Data were analysed with MedCalc statistical software. The COPD patients were divided into three groups - frequent exacerbators (FE), non-frequent exacerbators (NFE), patients hospitalized for acute COPD exacerbations (HAE) and the control group were healthy smokers (HS). A statistically significant difference was found in the values of MNR while comparing these groups of patients: FE vs HAE (p<0.000), NFE vs HAE (p<0.000) and HS vs HAE (p<0.001); and for the values of MLR: FE vs HAE (p<0.022), NFE vs HAE (p<0.000) and HS vs HAE (p<0.000). As MLR and MNR have shown the statistical difference comparing the group of HAE to NFE, FE and HS, MLR and MNR could be valuable and available markers of acute COPD exacerbations and need for hospitalization.

Lipid profile and atherogenic indices in patients with stable chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Limited number of studies investigated lipid profile in chronic obstructive pulmonary disease (COPD) with inconsistent results. This study aimed to investigate lipid parameters in sera of patients with stable COPD and their associations with disease severity, smoking, comorbidities and therapy. METHODS AND RESULTS: The study included 137 COPD patients and 95 controls. Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assessed. Non-HDL-C (NHC), atherogenic coefficient (AC), TG/HDL-C, atherogenic index of plasma (AIP), Castelli's risk index I and II (CRI-I, CRI-II), and monocyte to HDL ratio (MHR) were calculated. HDL-C and MHR were increased, while other lipid parameters and indices were decreased in COPD patients compared to healthy individuals. Smoking did not influence lipid parameters. However, lipid profile was altered only in more severe disease stages. AC, CRI-I and CRI-II showed positive association with lung function parameters in COPD patients, and negative with COPD multicomponent indices (ADO, BODCAT, BODEx, CODEx and DOSE). Combined model that included CRI-II, C-reactive protein, fibrinogen and white blood cells showed great diagnostic performances, and correctly classified 72% of study participants with an AUC of 0.800 (0.742-0.849), P < 0.001. Bronchodilator monotherapy and statins have opposite impact on TC, LDL-C and NHC, while TG, TG/HDL-C and AIP were increased in COPD patients with cardiovascular diseases. CONCLUSION: Lipid disbalance is present in COPD, and it seems to occur later as the disease progresses. Further studies are needed to illuminate the underlying mechanism of dyslipidaemia.

The Influence of Depression, Anxiety and Stress on Changes in Locomotor Parameters in Patients Who Are Prone to Develop COPD.

BACKGROUND: Depression and anxiety are the most prevalent diseases that contribute to global disability, especially if they are not early recognised and properly treated. They occur as part of many chronic diseases, often remain unrecognised at an early stage, and significantly contribute to the progression of the underlying disease reducing the quality of life in these patients. Numerous studies have shown that anxiety / depression and dyspnea are the leading symptoms in patients with COPD that are associated with high morbidity and mortality. The aim of this study was to determine the relationship between the degree of depression, anxiety and stress, using DASS- 21 scale, and changes in locomotor parameters in smokers who are prone to develop COPD. SUBJECTS AND METHODS: The study included 164 patients, smokers and non-smokers, who underwent spirometry, 6-minute walk test and bicycle ergometer. They were all measured for body weight, height, waist circumference, pulse, blood pressure and each patient completed DASS-21, CAT and IPAQ questionnaire. RESULTS: The results of the IPAQ questionnaire indicated a statistically significant difference in the physical activity of smokers and non-smokers. A statistically significant was found between DASS-21 and patients physical activity (p=0.0001), 6-minute walk test (r=-0.186, p=0.017), VO2 max (r=-0.220, p=0.005) and weekly calorie consumption (r=-0.222, p=0.004). CONCLUSION: According to the results of the study, an increased degree of anxiety, depression and stress is an important factor influencing changes in locomotor parameters in smokers who are prone to develop COPD.

Health Sequelae of Tobacco Exposure in Childhood and Adolescence.

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.

THE ROLE OF CIGARETTE SMOKING AND ALCOHOL CONSUMPTION IN PULMONARY TUBERCULOSIS DEVELOPMENT AND RECURRENCE.

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.

ADAPTATION AND VALIDATION OF THE CAMBRIDGE PULMONARY HYPERTENSION OUTCOME REVIEW (CAMPHOR) FOR CROATIA.

Pulmonary hypertension (PH) is a chronic disease which severely impairs quality of life (QoL). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the first disease-specific tool to assess patient-reported symptoms, functioning and QoL in PH patients. The aim of this study was to adapt and validate the CAMPHOR for use in Croatia. The adaptation process involved three stages: translation (bilingual and lay panel), cognitive debriefing interviews with patients and psychometric validation. For the latter stage, a postal survey was conducted with 50 patients to examine the reliability and validity of the adapted scale. All three scales of the Croatian CAMPHOR demonstrated excellent internal consistency (Symptoms = 0.93; Activity limitations = 0.94; QoL = 0.92) and test-retest reliability correlations (Symptoms = 0.90; Activity limitations = 0.95; QoL = 0.90). Predicted correlations with the SF-36 scales provided evidence for construct validity of the CAMPHOR scales. Evidence for known group validity was shown by the ability of the scales to distinguish between participants based on patient-perceived general health and disease severity. The Croatian version of the CAMPHOR is a valid and reliable tool for use in clinical routine and clinical research.

Cigarette Smoke Induces Activation of Polymorphonuclear Leukocytes.

INTRODUCTION: Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke may stimulate inflammatory response and activate polymorphonuclear leukocytes (PMN) thus resulting in secretion of cellular proteases. The aim of our study was to explore the effect of cigarette smoke extract (CSE) on the release of matrix metalloproteinase-9 (MMP-9) from PMN. METHODS: The study included 23 patients with stable COPD and 9 healthy controls. PMN were isolated from blood of all participants and exposed to 4% CSE or basal culture medium (0% CSE) for 20 h. MMP-9 concentration in PMN culture media was measured using the ELISA method. RESULTS: Exposure of PMN to 4% CSE did not cause cytotoxic effects, as determined by no changes in lactate dehydrogenase (LDH) activity in PMN culture media when compared to untreated PMN (P = 0.689). In basal conditions, PMN of COPD patients released significantly more MMP-9 compared with PMN of healthy controls (P = 0.016). However, concentration ratio of MMP-9 released from PMN exposed to 4% CSE or 0% CSE of each participant was significantly higher for healthy subjects than for COPD patients (P = 0.025). CONCLUSION: Cigarette smoke induces activation of PMN in healthy controls. However, chronically activated PMN in COPD patients could not be further stimulated by in vitro exposure to CSE. Constantly raised amount of MMP-9 released into the tissues may be involved in the degradation of extracellular matrix in the lungs as seen in COPD patients.

Dyspnea from Neuropsychyatric Perspective: a Narrative Review.

Dyspnea or breathlessness is a term primarily used in respiratory medicine. Nevertheless, in the last fifteen years, studies from other fields focus on the affective component of this complex phenomenon due to the frequent observation that psychological states can cause or be caused by dyspnea. Research so far shows that besides the biological component, dyspnea has a strong emotional and psychosocial determinant. This means that apart from its biological factors, dyspnea and its intensity are affected by emotions, personality, anxiety and depression, etc. Individuals with psychiatric disorders, in the same conditions, will evaluate their dyspnea as more intense and disturbing compared to individuals without psychiatric comorbidity. Emotional states in healthy individuals can amplify the sense of dyspnea which is of extreme importance for clinical practice in order to consider the whole person and not just the symptom which is being presented. Also, dyspnea seems to be frequent complaint in some groups of patients with psychiatric disorders (e.g.panic disorder), where the fear of suffocation is presented as clinical symptom. Futher research of dyspnea as a complex, multicomponent phenomenon, can contribute to better treatment options and better differential diagnosis concerning possible psychiatric background of physical symptoms.

Pharmacogenomics and tailored polypharmacy: an 80-year-old lady with rosuvastatin-associated rhabdomyolysis and maprotiline-related Ogilvie's syndrome
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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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Polymorphism 4G/5G of the plasminogen activator inhibitor 1 gene as a risk factor for the development of allergic rhinitis symptoms in patients with asthma.

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 pO2, 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 pO2 (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.

Evaluation of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry in Identification of Nontuberculous Mycobacteria.

BACKGROUND/AIMS: Species-level identification of nontuberculous mycobacteria (NTM) is important in making decisions about the necessity and choice of antimicrobial treatment. The reason is predictable clinical significance and the susceptibility profile of specific NTM species. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is recognized as a diagnostic tool for routine identification of bacteria and yeasts in the clinical laboratory based on protein fingerprint analysis. The aim of the study was to evaluate MALDI-TOF MS in the identification of NTM. METHODS: A total of 25 NTM isolates from liquid cultures were identified with both polymerase chain reaction (PCR)-based hybridization assay and MALDI-TOF MS at the University Hospital Center Zagreb. RESULTS: PCR-based hybridization assay identified 96% (24/25) and MALDI-TOF MS 80% (20/25) of tested NTM isolates. Five isolates with no reliable MALDI-TOF MS identification belonged to the Mycobacterium avium-intracellulare complex. Seventy percent (14/20) of NTM isolates successfully identified with MALDI-TOF MS had a score higher than 2.0, indicating reliable species identification. CONCLUSION: MALDI-TOF MS is a promising tool for the identification of NTM. With a further improvement of the protein extraction protocol, especially regarding the M. avium-intracellulare complex, MALDI-TOF MS could be an additional standard method for identification of NTM.

Gamma-glutamyltransferase and C-reactive protein in stable chronic obstructive pulmonary disease.

Systemic inflammation and oxidative stress are the most important features of chronic obstructive pulmonary disease (COPD). The presence of oxidative stress in the airways of smokers, the largest population of COPD patients, is a consequence of direct inhalation of cigarette smoke and increased inflammation-related production of reactive oxygen species. On the other hand, oxidative stress appears to be the key component of many processes associated with chronic inflammation. We intend to examine whether serum C-reactive protein (CRP) concentration and gamma-glutamyltransferase (GGT) activity might be used as auxiliary markers in monitoring level of oxidative stress and inflammation in clinically stable COPD. We also investigated influence of cigarette smoking on these two systemic parameters. Catalytic activity of GGT and concentration of CRP were determined in sera of COPD patients (N = 109) and in healthy controls (N = 51) by using standard spectrophotometric method and immunoturbidimetric method, respectively. Concentration of CRP and activity of GGT were increased in COPD patients, as compared to healthy controls (p < 0.05). We found a significant positive correlation between those two parameters in COPD patients (r = 0.202, p = 0.0371). Our results showed no difference in GGT activity (p = 0.606) or CRP concentration (p = 0.573) between groups of patients when subdivided according to the severity of the disease. Smoking did not have a significant impact on CRP and GGT values in COPD patients and healthy controls. We showed an increase of serum CRP and GGT values in COPD patients, and we suggest that serum GGT activity might also represent an inflammation/oxidative stress marker. It seems that COPD patients present higher serum CRP and GGT values than healthy subjects independently from their smoking habits.

Periodontal disease increases risk for chronic obstructive pulmonary disease.

The aim of this study was to explore whether a periodontal disease could be a risk indicator for a chronic obstructive pulmonary disease (COPD). The examined group comprised 93 patients with COPD (mean age 65.8 years). The control group comprised 43 systemically healthy individuals (mean age 62.1 years). Respiratory and periodontal conditions were examined in both groups. COPB subjects had significantly worse periodontal conditions than controls (p < 0.05) with regard to each parameter of periodontal condition, except for gingival inflammation. COPD patients had higher Plaque Index than control patients (82.84 +/- 22.81 vs. 57.15 +/- 26.96; p < 0.001), higher periodontal depth (3.02 +/- 0.92 vs. 2.57 +/- 0.79 mm; p = 0.007), higher gingival recession (1.97 +/- 1.09 vs. 0.91 +/- 0.79 mm; p < 0.001), and higher mean clinical attachment loss (CAL) (4.12 +/- 1.74 vs. 2.91 +/- 1.27 mm; p < 0.001). Multiple logistic regression model, after controlling for other risk indicators, showed that periodontal disease, presented as CAL > or = 4 mm at > or = 60% sites, was associated with odds ratio of 3.2 (95% CI 1.0-9.8) for the COPB group. Data suggest that periodontal disease could be a risk indicator for COPD.

[Pharmacotherapy of severe asthma]. / Lijecenje teske astme.

Severe asthma affects 5-10% of the asthma population. Exact pathophysiology of severe asthma mechanisams is complex and not fully understood. Cellular inflammation of the airways with neutrophils is a characteristic feature and is considered relevant to the pathogenesis of the disease, but all components of the airway wall have been reported to be thickened in severe asthma with or without cellular inflammation. Clinically it usually involves women with severe non-allergic asthma, late onset of asthma patients and aspirin induced asthma. Severe asthma rarely affects allergic asthma patients. Although majority of adults with mild or moderate asthma can be treated by inhaled glucocorticoids either alone or in combination with beta 2 agonists bronchodilators, patients with severe asthma require high doses of inhaled glucocorticoids or continuous oral use of glucocorticoids. Treatment of severe asthma should be started with high doses of inhaled steroids, 2000 microg of beclomethasone or its equivalents in addition to long acting beta 2 agonists, leukotriene receptor antagonists, theophylline and long acting anticholinergic drugs. Due to significant short-term and longterm oral glucocorticoids side effects it is essential to emphasize the importance of alternative therapies in severe asthma: treatment with omalizumab, macrolide antibiotics, tumor necrosis factor alpha inhibitors, cytokine receptors inhibitors and bronchial thermoplasty. Although there is a significant improvement in the treatment of severe asthma, the challenge remains to determine therapeutic strategy for appropriate phenotype in view of the heterogeneity of severe asthma.

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.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

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.

Characteristics of severe asthma patients on biologics: a real-life European registry study.

Background: The use of anti-interleukin-5 (IL5) for severe asthma is based on criteria from randomised controlled trials (RCTs), but in real-life patients might not fulfil the eligibility criteria but may benefit from biologics. We aimed to characterise patients starting anti-IL5(R) in Europe and evaluate the discrepancies between initiation of anti-IL5(R) in real life and in RCTs. Materials and methods: We performed a cross-sectional analysis with data from the severe asthma patients at the start of anti-IL5(R) in the Severe Heterogeneous Asthma Research collaboration Patient-centred (SHARP Central) registry. We compared the baseline characteristics of the patients starting anti-IL5(R) from 11 European countries within SHARP with the baseline characteristics of the severe asthma patients from 10 RCTs (four for mepolizumab, three for benralizumab and three for reslizumab). Patients were evaluated following eligibility criteria from the RCTs of anti-IL5 therapies. Results: Patients starting anti-IL5(R) in Europe (n=1231) differed in terms of smoking history, clinical characteristics and medication use. The characteristics of severe asthma patients in the SHARP registry differed from the characteristics of patients in RCTs. Only 327 (26.56%) patients fulfilled eligibility criteria of all the RCTs; 24 patients were eligible for mepolizumab, 100 for benralizumab and 52 reslizumab. The main characteristics of ineligibility were: ≥10 pack-years, respiratory diseases other than asthma, Asthma Control Questionnaire score ≤1.5 and low-dose inhaled corticosteroids. Conclusion: A large proportion of patients in the SHARP registry would not have been eligible for anti-IL5(R) treatment in RCTs, demonstrating the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma.

Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis.

Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93 mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.