SEVERE ASTHMA FORUM 7TH INTERNATIONAL SOUTHEAST MEETING ON SEVERE ASTHMA 4. - 5. April 2025, Bled SEVERE ASTHMA FORUM 7TH INTERNATIONAL SOUTHEAST MEETING ON SEVERE ASTHMA SPOMLADANSKO STROKOVNO SREČANJE ZDRUŽENJA PNEVMOLOGOV SLOVENIJE Proceedings of Scientific Congress 4. – 5. April 2025, Bled Organiser: Slovenian Respiratory Society Organising committee: Mitja Košnik, Robert Marčun, Sabina Škrgat Scientific Committee: Sabina Škrgat, Peter Korošec, Ramesh Kurukulaaratchy, Stefano Del Giacco, Marina Lampalo, Sanja Hromiš, Peter Kopač, Natalija Edelbaher, Katja Mohorčič Editors and reviewers: Mitja Košnik, Sabina Škrgat Electronic edition SEVERE ASTHMA FORUM 7TH INTERNATIONAL SOUTHEAST MEETING ON SEVERE ASTHMA SPOMLADANSKO STROKOVNO SREČANJE ZDRUŽENJA PNEVMOLOGOV SLOVENIJE Organizer: Slovenian Respiratory Society Date: 4-5 April 2025 Location: Hotel Rikli Balance Bled Amgen AstraZeneca Berlin Chemie MSD Sanofi Boehringer Ingelheim Chiesi IRIS Medis Pliva Teva Roche SCIENTIFIC PROGRAMME FRIDAY 5TH OF APRIL, 2025 08.30-08.40: Introduc1on (Sabina Škrgat, Mitja Košnik) 08.40-09.45: Basic science in severe asthma: what is new (Peter Korošec, Ramesh Kurukulaaratchy) 08.40-09.05: Peter Korošec: Basic science in severe asthma: Pathophysiology and mechanisms (Invited plenary lecture) 09.05-09.30: Ma1ja Rijavec: Basic science in severe asthma: Biomarkers and gene1cs (Invited plenary lecture) 09.30-09.45: Discussion 09.45-11.15: ProblemaEc case reports with discussion/workshop-1 st part (Ramesh Kurukulaaratchy, Sabina Škrgat) 9.45-10.05: Saša Rink: Development of Allergic Bronchopulmonary Mycosis During Benralizumab Treatment 10.05-10.25: Žiga Pile1č: Steroid burden in asthma – a case report 10.25-10.45: Anamarija Štajduhar, Marina Lampalo: Complicated asthma in an obese pa1ent 10.45-11.05: Ivan Čekerevac: Hypereosinophilia and severe asthma 11.05-11.15: Addi1onal discussion 1me (if needed) 11.15-11.35: Coffee break 11.35-13.20: PerspecEves and clinical outcomes in severe asthma (Stefano Del Giacco, Mihaela Zidarn) 11.35-12.05: Ramesh Kurukulaaratchy: Comorbidi1es and Mul1morbidity – Important New Perspec1ves in Severe Asthma (Invited plenary lecture) 12.05-12.30: Stefano Del Giacco: Remission in asthma (Invited plenary lecture) 12.30-12.55: Sabina Škrgat: Outcomes and challenges in severe asthma with fungal senzi1sa1on (Invited plenary lecture) 12.55-13.20: Discussion 13.20- 13.40: Satellite symposium AstraZeneca Stefano Del Giacco, Unlocking Airways: Benralizumab's Pioneering Role in Severe Asthma Management 13.40-14.30: Lunch 14.30-16.30: Reports from clinics and real life studies (Peter Kopač, Branislava Milenković) 14.30-14.45: Sanja Hromiš: Weight-adjusted biologic therapy – are there some benefits? (Invited lecture) 14.45-15.00: Mirna Vergles: A new rhythm in severe asthma management: extending the intervals for biologics? (Invited lecture) 15.00-15.15: Irena Šarc: Biologic Therapy in eosinophil COPD: Insights from Our Clinical Experience. (Invited lecture) 15.15-15.30: Peter Kopač: The Significance of Eosinophil Loca1on in Severe Asthma: Insights from Induced Sputum (Invited lecture) 15.30-15.45: Luka Kunej, Škrgat Sabina: Clinical and molecular response to dupilumab treatment in pa1ents with eosinophilic asthma (Invited lecture) 15.45-16.15: Discussion 16.15-16.35: Satellite symposium AstraZeneca Mark Kačar, Saša Rink, Natalija Edelbaher: TSLP - This Special Lijle Protein, what it does and how it can help us. 16.30-17.00 Coffee break Parallel secEon I 17.00-18.15 ProblemaEc case reports with discussion-2nd part. (Ivan Čekerevac, Željko Vrbica) 17.00-17.20: Marija Gomerčić Palčić: Pa1ent with Severe Eosinophilic Asthma and CRSwNP Who Developed EGPA While Being Treated with Benralizumab 17.20-17.40: Jasmina Bošnjić: Asthma and pulmonary embolism 17.40-18.00: Špela Kosi: The Importance of Diagnosing and Trea1ng OSA in Pa1ents with Severe Asthma 18.00-18.15 Addi1onal discussion 1me (if needed) 18:15-19:05 Satellite symposium Sanofi. From Clinical Trials to Real Life: How Dupilumab is Changing PracEce (Jure Urbančič) Jure Urbančič: Introduc1on: T2I is the common denominator Mirna Vergles: Severe asthma: Can clinical remission be achieved? Mihkel Plaas. Is precision medicine possible for CRSwNP? Panel discussion Parallel secEon II 17:00-19:10 DROBOCELIČNI RAK (Katja Mohorčič, Zala Leštan Ramovš) 17:00 Duška Vidovič: Drobnocelični rak pljuč: kje smo in kam gremo ? (Invited lecture) 17:10 Katja Adamič: Urgentna stanja pri bolnikih z rakom pljuč (Invited lecture) 17:25 Dimitrij Kuhelj: Vstavitev opornice v zgornjo votlo veno (Invited lecture) 17:40 Eva Ćirić: Ali je drobnocelični rak pljuč lahko ozdravljiva bolezen? (Invited lecture) 17:55 Loredana Mrak: Kaj je novega v sistemski terapiji drobnoceličnega raka pljuč? (Invited lecture) 18:10 Razprava 18:30 SATELITSKI SIMPOZIJ ASTRAZENECA Marina Čakš: Izkušnje zdravljenja z imunoterapijo pri slovenskih bolnikih z drobnoceličnim rakom pljuč 18:50 SATELITSKI SIMPOZIJ MSD Urška Janžič: Neželeni učinki imunoterapije 20.00: Dinner SATURDAY 05.04.2025 ComorbidiEes in severe asthma and MDT approach Part 1 (Matevž Harlander, Natalija Edelbeher) 8.15-8.35: Miodrag Janić: Diabetes/obesity/severe asthma (Invited lecture) 8.35-8.55 Hočevar Alojzija: EGPA from reumatologist perspec1ve (Invited lecture) 8.55-9.15 Urbančič Jure: EIT specialist in severe asthma pa1ent (Invited lecture) 9.15-9.35 Ana Komlenić : Psychologist- Basic personality traits of severe asthma pa1ents and their impact on treatment outcomes (Invited lecture) 9.35-9.50 Discussion: part 1 9:50 Satellite symposium Berlin-Chemie Peter Kopač: Airway Remodeling in Asthma and the Effects of Mepolizumab Treatment Part 2: (Ramesh Kurukulaaratchy, Sanja Hromiš) 10.05-10.30 Ziherl Kris1na: The Challenge of Comorbid OSA in Pa1ents with Severe and Difficult-to-Treat Asthma (Invited plenary lecture) 10.30-10.55 Matjaž Fležar: Func1onal algorithm for severe airway disease; from diagnosis to follow-up and feno1piza1on (Invited plenary lecture) 10.55-11.15 Discussion: part 2 11.15 End of the conference and closing remarks (Sabina Škrgat) Farewell cocktail KAZALO BASIC SCIENCE IN SEVERE ASTHMA: PATHOPHYSIOLOGY AND MECHANISMS ................................................... 7 BASIC SCIENCE IN SEVERE ASTHMA: BIOMARKERS AND GENETICS .................................................................... 8 DEVELOPMENT OF ALLERGIC BRONCHOPULMONARY MYCOSIS DURING BENRALIZUMAB TREATMENT ...................................................................................................................................................... 9 STEROID BURDEN IN ASTHMA – A CASE REPORT .............................................................................................. 10 COMPLICATED ASTHMA IN AN OBESE PATIENT - A CASE REPORT ...................................................................... 12 HYPEREOSINOPHILIA AND SEVERE ASTHMA .................................................................................................... 13 COMORBIDITIES AND MULTIMORBIDITY - IMPORTANT NEW PERSPECTIVES IN SEVERE ASTHMA ....................... 14 OUTCOMES AND CHALLENGES IN SEVERE ASTHMA WITH FUNGAL SENZITISATION ........................................... 15 WEIGHT-ADJUSTED BIOLOGIC THERAPY – ARE THERE SOME BENEFITS? ........................................................... 17 A NEW RHYTHM IN SEVERE ASTHMA MANAGEMENT: EXTENDING THE INTERVALS FOR BIOLOGICS? ................................................................................................................................................... 19 BIOLOGIC THERAPY IN EOSINOPHILIC COPD: INSIGHTS FROM OUR CLINICAL EXPERIENCE ............................. 20 THE SIGNIFICANCE OF EOSINOPHIL LOCATION IN SEVERE ASTHMA: INSIGHTS FROM INDUCED SPUTUM ......................................................................................................................................................... 27 IMMUNOLOGICAL PATHWAYS IN SEVERE T2 ASTHMA PATIENTS DURING DUPILUMAB TREATMENT .................................................................................................................................................... 29 PATIENT WITH SEVERE EOSINOPHILIC ASTHMA AND CRSWNP WHO DEVELOPED EGPA WHILE BEING TREATED WITH BENRALIZUMAB ............................................................................................................ 31 ASTHMA AND PULMONARY EMBOLISM: CASE REPORT ..................................................................................... 32 THE IMPORTANCE OF DIAGNOSING AND TREATING OSA IN PATIENTS WITH SEVERE ASTHMA ........................... 33 ROLE OF OTORHINOLARYNGOLOGIST IN SEVERE ASTHMA PATIENT ................................................................. 34 EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS – A RHEUMATOLOGICAL PERSPECTIVE ....................... 35 DIABETES/OBESITY/SEVERE ASTHMA .............................................................................................................. 37 BASIC PERSONALITY TRAITS OF SEVERE ASTHMA PATIENTS AND THEIR IMPACT ON TREATMENT OUTCOME ...................................................................................................................................................... 38 THE CHALLENGE OF COMORBID OSA IN PATIENTS WITH DIFFICULT-TO-TREAT ASTHMA .................................... 39 FUNCTIONAL ALGORITHM FOR SEVERE AIRWAY DISEASE: FROM DIAGNOSIS TO FOLLOW-UP AND PHENOTYPING ........................................................................................................................................ 44 CO-USE OF DUAL BIOLOGIC THERAPIES IN PATIENT WITH SEVERE ASTHMA AND ANKYLOSING SPONDYLITIS: SAFETY PROFILE ....................................................................................................................... 45 DROBNOCELIČNI RAK PLJUČ: KJE SMO IN KAM GREMO? ................................................................................... 46 URGENTNA STANJA V DIAGNOSTIKI PLJUČNEGA RAKA ..................................................................................... 48 VSTAVITEV OPORNICE V ZGORNJO VOTLO VENO .............................................................................................. 54 ALI JE DROBNOCELIČNI RAK PLJUČ LAHKO OZDRAVLJIVA BOLEZEN? ............................................................... 56 KAJ JE NOVEGA V SISTEMSKI TERAPIJI DROBNOCELIČNEGA RAKA PLJUČ? ......................................................... 59 BIOLOGIC TREATMENT WITH RESLIZUMAB IN SEVERE ASTHMA WITH FUNGAL SENSITIZATION: A CASE REPORT OF CLINICAL RESPONSE ........................................................................................................... 62 INVITED PLENARY LECTURE BASIC SCIENCE IN SEVERE ASTHMA: PATHOPHYSIOLOGY AND MECHANISMS Peter Korosec. University Clinic of Respiratory and Allergic Diseases, Golnik; Faculty of Pharmacy, University of Ljubljana BACKGROUND Type 2 immunity is a pa?ern of immunity characterized by the acHvaHon of TH2 cells and group 2 innate lymphoid cells (ILC2s) that produce the type 2 cytokines IL-4, IL-5, IL-9, and IL-13, with the inclusion of eosinophils and /or mast cells and is primarily known for its detrimental roles in type 2 (T2) asthma. On the other hand, non-T2 asthma involves the acHvaHon of various pathways in mulHple types of immune cells, including acHvaHon of and the possible release of cytokines and chemokines from macrophages, neutrophils, dendriHc cells, and especially epithelial cells. METHODS To describe several novel mechanisms of regulaHon and funcHon of T2 immune cells in asthma, focusing on ILC2s, TH2, mast cells, and neuroimmunology. To describe novel mechanisms pivotal in iniHaHng and amplifying the inflammatory response, ulHmately contribuHng to the development and progression of non-T2 asthma. RESULTS The development of chronic allergic airway pathology is a?ributed to the epigeneHc acquisiHon of memory by ILC2s, the infiltraHon of mucosal Hssues by stemlike memory TH2 cells, and Hssue-resident memory TH2 cells. Further, mast cells can be regulated by lipids and are not just the sources but also the targets of lipids. There seem to be interacHons between type 2 immune cells and peripheral neurons, including neuronal control of immune homeostasis in the lung and mulHsynapHc neuronal pathways for airway constricHon in asthma. Novel molecular mechanisms of non-T2 asthma include inflammasome acHvaHon, type I, II, and III IFN response upon respiratory viral infecHon, IL-6 signaling pathway, and alarmins and epithelial-derived cytokines, like TSLP and IL-33, which, in addiHon to driving T2 inflammaHon in asthma, may also contribute to non-T2 asthma. CONCLUSIONS The use of advanced technologies, single-cell RNA sequencing, and ILC experimental geneHc models has fueled these mechanisHc developments, which are significant for novel discoveries in clinical medicine, including further drug development for severe asthma. INVITED PLENARY LECTURE BASIC SCIENCE IN SEVERE ASTHMA: BIOMARKERS AND GENETICS MaFja Rijavec University Clinic of Respiratory and Allergic Diseases Golnik, Slovenia Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia Severe asthma remains a significant clinical challenge, impacHng morbidity, mortality, and healthcare resource uHlizaHon, despite accounHng for a small proporHon of overall asthma prevalence. Asthma is a complex, highly heterogeneous disease with mulHple phenotypes and endotypes, and current diagnosHc tools o`en fall short of fully addressing its variability. This highlights the increasing need for new diagnosHc, predicHve, and prognosHc biomarkers to enable more personalized treatment strategies. Recent advances in the understanding of asthma’s heterogeneity and immunopathogenesis have facilitated the idenHficaHon of precise disease pathways, which, in turn, support the development of targeted therapies. Biomarkers can improve early diagnosis of asthma, allowing for prompt intervenHon that can prevent disease progression, reduce complicaHons, and improve long-term outcomes. Reliable biomarkers also aid in monitoring disease acHvity and treatment efficacy in real-Hme, enabling be?er disease management. This approach can ulHmately reduce hospitalizaHons, emergency visits, and the overall healthcare costs associated with poorly controlled asthma. For paHents with severe asthma, who o`en fail to respond to standard therapies, the idenHficaHon of novel biomarkers is crucial for guiding the development of specialized treatments. Biomarkers are being invesHgated across various levels, from clinical presentaHons and paHent characterisHcs to biochemical, immunologic, geneHc, and epigeneHc factors (such as DNA methylaHon and microRNAs). Some biomarkers are already clinically available, albeit the majority are sHll candidate biomarkers. Understanding the molecular mechanisms underlying different asthma endotypes—such as eosinophilic versus neutrophilic asthma—has provided insights into the variable response to treatments and is key to more precise management. Biomarkers linked to frequent exacerbaHons and severe asthma (e.g., IL-6, IL-1β, specific miRNAs, and geneHc variants) have the potenHal to significantly enhance paHent management. Biologic therapies, guided by these biomarkers, represent a promising shi` towards personalized treatment, improving paHent outcomes, reducing exacerbaHons, and enhancing quality of life. For example, biomarkers associated with T2-high asthma (e.g., FeNO, eosinophils, total IgE, IL-4, IL-5, IL-13, periosHn) can help tailor therapies aimed at reducing eosinophilic inflammaHon. Conversely, biomarkers associated with T2-low asthma (e.g., Th17 cells, neutrophils, YKL-40) can guide the use of treatments targeHng neutrophilic or Th17-driven inflammaHon. Ongoing research is focused on refining exisHng biomarkers and discovering new ones, with the goal of further opHmizing treatment precision. However, challenges remain in accurately predicHng responses due to the complexity of asthma’s pathophysiology. ConHnued research into biomarkers and geneHc factors is essenHal for realizing the full potenHal of biological treatments and opHmizing care for paHents with severe asthma. DEVELOPMENT OF ALLERGIC BRONCHOPULMONARY MYCOSIS DURING BENRALIZUMAB TREATMENT Saša Rink. Department of Pulmonary Diseases and Allergy, University Medical Centre Ljubljana INTRODUCTION Allergic bronchopulmonary mycosis (ABPM) is an umbrella term for hypersensiHvity reacHons to various fungal species, with Aspergillus fumigatus being the most common cause in allergic bronchopulmonary aspergillosis (ABPA). ABPA is well-defined by elevated blood eosinophils (BEC >500 × 10⁶/L), increased total serum IgE (>500 IU/mL), and specific IgE/IgG to Aspergillus (1). CASE HISTORY A 69-year-old woman with severe asthma was evaluated for biologic therapy due to frequent exacerbaHons and lung funcHon decline. She had chronic sinusiHs without nasal polyposis and a history of ABPA in long-term remission, with blood eosinophil count (BEC 500x106), negaHve specific IgE/IgG for Aspergillus and Candida, normal total IgE (150 IU/mL), and FEV1 1580 ml (62%). HRCT showed mild bronchiectasis and mucus plugging without acHve ABPA. Benralizumab was iniHated, leading to symptom improvement, no exacerbaHons, a rise in FEV1 2560 ml (105%), and a BEC of 0. However, a`er six months, she developed producHve cough, gradual decline of FEV1 2370 ml (96%), and increasing total IgE (316 IU/mL), though sputum analysis showed no fungal or bacterial growth. HRCT revealed worsening bronchiectasis and new bronchoceles indicaHn possible ABPA flare up. At one year, despite well-controlled asthma and BEC 0, total IgE had increased significantly (3160 IU/mL), with sensiHzaHon to both Aspergillus and Candida. FleeHng opaciHes appeared on HRCT, and bronchoscopy revealed thick mucus and Schizophyllum growth. She later disclosed significant mold exposure at her holiday home. Itraconazole was added to her asthma treatment. CONCLUSION Systemic corHcosteroids remain the mainstay of ABPM treatment, with anHfungal therapy recommended for refractory cases. Biologic therapies, parHcularly anH IL-5 agents, offer a steroid-sparing opHon (2,3). Despite benralizumab treatment and absent peripheral eosinophilia, our paHent developed ABPM caused by Schizophyllum commune - a fungus found in decaying wood that has the ability to trigger IgE-mediated immune responses, o`en cross-reacHng with other fungal species like Aspergillus (4). This case highlights the complexity ABPM and the need for tailored management strategies. LITERATURE 1. Agarwal R, Sehgal IS, Muthu V, et al. Revised ISHAM-ABPA working group clinical pracAce guidelines for diagnosing, classifying and treaAng allergic bronchopulmonary aspergillosis/mycoses. Eur Respir J 2024; 63(4):2400061. 2. Darragh K, Akuthota P. CorAcosteroid-sparing effect of biologics in paAents with allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol. 2024 May;132(5):650-652. doi: 10.1016/j.anai.2024.01.010. Epub 2024 Jan 15. PMID: 38232815. 3. Chen X, Zhi H, Wang X, Zhou Z, Luo H, Li J, Sehmi R, O'Byrne PM, Chen R. Efficacy of Biologics in PaAents with Allergic Bronchopulmonary Aspergillosis: A SystemaAc Review and Meta-Analysis. Lung. 2024 Aug;202(4):367-383. doi: 10.1007/s00408-024-00717-y. Epub 2024 Jun 19. PMID: 38898129. 4. Takahashi H, Hamakawa M, Ishida T, Watanabe A. Allergic bronchopulmonary mycosis in Schizophyllum commune with posiAve Aspergillus-specific IgE anAbodies: A case report. Respirol Case Rep. 2024 Jul 16;12(7):e01433. doi: 10.1002/rcr2.1433. PMID: 39015483; PMCID: PMC11250149. STEROID BURDEN IN ASTHMA A CASE REPORT – Žiga PileFč. Department of pneumology, Novo mesto General Hospital BACKGROUND Steroids are the cornerstone of asthma treatment. Inhaled glucocorHcoids (ICS) have the primary role in controlling symptoms, reducing airway inflammaHon and exacerbaHon risk while oral glucocorHcoids (OCS) are used either to treat exacerbaHons or to maintain disease control when other intervenHons have failed (1,2). While awareness of both short- and long-term OCS therapy burden is rising with experts suggesHng minimising exposure to OCS and acHve screening for possible side-effects (1,3–5), knowledge of systemic side effects of ICS is sparser. Evidence is emerging of not only adrenal gland suppression (6,7) but also major adverse cardiovascular events, pneumonia and pulmonary embolism risk being increased, especially with higher doses or longer Hme of ICS use (8). Using high doses (500-1000 mcg of fluHcasone propionate or equivalent (1,9)) of ICS corresponds to systemic effects of approximately 2-4 mg prednisolone daily (10), which confers a high cumulaHve steroid burden with longer exposure. IniHaHng biological therapy in severe asthma paHents has been shown as an effecHve steroid-sparing intervenHon (1,11) CASE REPORT I present a 69-year-old female, never smoker, reHred asthma nurse, with childhood onset asthma, arterial hypertension and celiac disease. Asthma has been treated with oral prednisolone for 29 years and later 20 years with medium to high-dose ICS. Last 30 years asthma has been prone to exacerbaHons with frequent bouts of OCS. Prolonged OCS treatment was needed in recent years for Covid pneumonia and later PneumocysHs jirovecii infecHon. As a result, she has developed adrenal insufficiency, steroid diabetes, osteoporosis, obesity. Mild posiHonal obstrucHve sleep apnoea and treatment-resistant atrial fibrillaHon were discovered. Her eosinophil count was perpetually low, no fungal sensiHzaHon or allergies were discovered, inhalaHon technique and adherence were always good. Even on highest doses of inhaled medicaHons exacerbaHons were frequent and stabilised only on OCS. In April 2024 anH-TSLP therapy was iniHated. Asthma has been stable since then. DIRECTIONS FOR FUTURE RESEARCH More data is needed on systemic effects of ICS treatments, especially high-dose, which are o`en used to avoid maintenance OCS prescripHon. Guidelines should be updated accordingly and focus also on high-dose ICS sparing intervenHons. Awareness should also be raised with other specialists to recognise and promptly refer severe asthma paHents with OCS use and frequent exacerbaHon history to a specialised centre. LITERATURE 1. GINA 2024 [Internet]. [cited 2025 Mar 11]. Available from: hips://ginasthma.org/wp-content/uploads/2024/05/GINA- 2024-Strategy-Report-24_05_22_WMS.pdf 2. Bleecker ER, Menzies-Gow AN, Price DB, Bourdin A, Sweet S, MarAn AL, et al. SystemaAc Literature Review of Systemic CorAcosteroid Use for Asthma Management. Am J Respir Crit Care Med. 2020 Feb 1;201(3):276–93. 3. Lefebvre P, Duh MS, Lafeuille MH, Gozalo L, Desai U, Robitaille MN, et al. Acute and chronic systemic corAcosteroid-related complicaAons in paAents with severe asthma. J Allergy Clin Immunol. 2015 Dec;136(6):1488–95. 4. Marques J, Duarte-Ramos F, Ferreira MB, Lima R, Lopes C, Sokolova A, et al. OpAmizing the use of systemic corAcosteroids in severe asthma (ROSA II project): a naAonal Delphi consensus study. Pulmonology. 2023;29(6):555–63. 5. Suehs CM, Menzies-Gow A, Price D, Bleecker ER, Canonica GW, Gurnell M, et al. Expert Consensus on the Tapering of Oral CorAcosteroids for the Treatment of Asthma: A Delphi Study. 2020; 6. Woods CP, Argese N, Chapman M, Boot C, Webster R, Dabhi V, et al. Adrenal suppression in paAents taking inhaled glucocorAcoids is highly prevalent and management can be guided by morning corAsol. European Journal of Endocrinology. 2015 Nov;173(5):633–42. 7. Beuschlein F, Else T, Bancos I, Hahner S, Hamidi O, Van Hulsteijn L, et al. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of GlucocorAcoid-induced Adrenal Insufficiency. The Journal of Clinical Endocrinology & Metabolism. 2024 Jun 17;109(7):1657–83. 8. Bloom CI, Yang F, Hubbard R, Majeed A, Wedzicha JA. AssociaAon of Dose of Inhaled CorAcosteroids and Frequency of Adverse Events. Am J Respir Crit Care Med. 2025 Jan 1;211(1):54–63. 9. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. InternaAonal ERS/ATS guidelines on definiAon, evaluaAon and treatment of severe asthma. Eur Respir J. 2014 Feb;43(2):343–73. 10. Daley-Yates PT. Inhaled corAcosteroids: potency, dose equivalence and therapeuAc index. Brit J Clinical Pharma. 2015 Sep;80(3):372–80. 11. Kyriakopoulos C, Gogali A, Markozannes G, KosAkas K. Biologic agents licensed for severe asthma: a systemaAc review and meta-analysis of randomised controlled trials. Eur Respir Rev. 2024 Apr 30;33(172):230238. COMPLICATED ASTHMA IN AN OBESE PATIENT - A CASE REPORT Anamarija Štajduhar. Marina Lampalo. Ena Tolić. Clinic for Pulmonary Diseases Jordanovac, Clinical Hospital Center Zagreb Obesity represents a global health issue. Adipose Hssue is a metabolically acHve organ, and obese paHents with asthma have greater everyday impairment than lean asthma paHents. Here, we present a case of an obese female paHent with severe asthma and a challenge that poses a treatment of such paHent. A 51-year-old paHent who was diagnosed with non-allergic eosinophilic asthma at the age of 14. She is a professional cleaner, a lifelong non-smoker, and was hospitalized several Hmes for asthma in childhood and at least 1 to 2 Hmes a year in adulthood. ComorbidiHes include Cushing's syndrome, osteoporosis, arterial hypertension, adiposity, and type 2 diabetes. The highest recorded blood eosinophil values were 1800 cells/mcL, and she tested negaHve for allergies. Her symptoms include dry cough and exercise intolerance. She is dependent on the use of oral corHcosteroids as well as high doses of inhaled corHcosteroids. Over the years, BMI has varied from 28 kg/m2 to 42 kg/m2. Pulmonary funcHon is severely impaired – FVC 47% (1.52 L), FEV1 19% (0.49 L), FEV1/FVC 0.32 with normal diffusion capacity for CO and FeNO values. Chest CT scan showed diffuse bilateral small peribronchial infiltrates in the lung parenchyma with deformed bronchi with thickened walls. Echocardiographic findings were nonsignificant. Pulmonary rehabilitaHon was performed several Hmes. UlHmately, a mulHdisciplinary team decided to start treatment with mepolizumab. A`er 70 cycles of mepolizumab, the number of eosinophils in the blood normalized (10 cells/mcL), but with further need for prednisone, annual asthma exacerbaHons and permanently reduced lung funcHon (FVC 51%, FEV1 25%, FEV1/FVC 0.40). The therapy was switched to tezepelumab in 2024. The paHent's condiHon has been improving (ACT 25), she has started to lose weight, but due to sleep hypopnea (AHI 10) and long-term oxyhemoglobin desaturaHon (SpO2 <80% 40 min), BIPAP was introduced along with home oxygen therapy. The paHent is currently without exacerbaHons, in a stable asthma phase, and an a?empt to disconHnue oral corHcosteroids is imminent. In conclusion, obesity-related changes in the respiratory system aggravate asthma, causing frequent and severe exacerbaHons and worse quality of life. It is an issue that needs to be promptly addressed as part of the everyday care of asthma paHents. HYPEREOSINOPHILIA AND SEVERE ASTHMA Ivan Čekerevac. Faculty of Medical Sciences University of Kragujevac; Clinic for pulmonology, University Clinical Center Kragujevac INTRODUCTION Hypereosinophilia is defined as an absolute peripheral blood eosinophil count that is >1,500 cells/μL on two occasions, at least 1 month apart, or in the presence of significant Hssue eosinophilia. Hypereosinophilic syndrome (HES) be reserved for cases that fulfil the definiHon of HE and have otherwise unexplained organ dysfuncHon/damage. HES may be classified into primary (neoplasHc) and secondary (reacHve). SomeHmes in paHents with T2 high severe asthma and hypereosinophilia we have suspicion or red flags for other diseases. CASE REPORT: A 47-year-old woman with a background of asthma for about 4 years consulted an allergist because of eosinophils up to 1000/ μL. She was on a regular therapy FluHcasone/Vilanterol 92/22mcg and SAMA/SABA as needed and had parHally controlled asthma. Laboratory tests related to tumor markers, immunology including ANCA and stool examinaHon for parasites were negaHve. Specific IgE to inhaled allergens, as well as the rhino-provocaHon test, were also negaHve. In the next few months, the dose of the same inhaler was increased to a high. We saw the paHent for the first Hme in January 2025 with a history that she had two moderate exacerbaHons of asthma in the last three months treated with systemic corHcosteroids. She menHoned having a severe cough and audible wheezes but no associated upper respiratory tract symptoms. Laboratory examinaHon revealed increased peripheral blood eosinophil numbers (2300 /μL). The fracHon of exhaled nitric oxide (FeNO) was elevated (62 ppb). Pulmonary funcHon test showed obstrucHve pulmonary dysfuncHon (FEV1 69% ,FEV1/FVC 68%). We admi?ed her to the hospital and repeated eosinophils were 1800/ μL , IgE total 183, ANCA were negaHve. Chest CT scans showed crazy paving consolidaHon dominant subpleural/the appearance of ground-glass opaciHes with thickening of the wall of segmental bronchi. Flexible bronchoscopy with transbronchial biopsy was performed for diagnosHc purposes. Histological finding included epithelium with dominated by goblet cells and smooth muscle hypertrophy/hyperplasia. CT of the sinuses showed signs of pansinusiHs (all paranasal caviHes filled with thick contents), without nasal polyposis. A bone marrow biopsy was performed with findings in support of reacHve eosinophilia (up to 20%). An EMG was performed without signs of sensorimotor peripheral neuropathy or mononeuriHs mulHplex. We decided to administer Reslizumab (3mg/kg) per month and two months later her asthma was under control, spirometry was normal, blood eosinophils 140/ μL and no significant infiltraHon on chest x-ray. Conclusion: IdenHficaHon of a comprehensive set of red flags (lung infiltrates etc.) in paHents with severe asthma and hypereosinophilia can be used to raise the suspicion of other diseases, primarily EGPA and HES. Pulmonologists should maintain high awareness to the disease with paHents presenHng with asthma, especially when they are uncontrolled or severe and have high BECs. Key words: hyperosinophilia, severe asthma INVITED PLENARY LECTURE COMORBIDITIES AND MULTIMORBIDITY - IMPORTANT NEW PERSPECTIVES IN SEVERE ASTHMA Prof Ramesh J Kurukulaaratchy. University of Southampton, United Kingdom BACKGROUND There is increasing awareness that comorbidiHes are frequently present in paHents with difficult-to-treat/ severe asthma. However their impacts on asthma paHents remain poorly understood as does the concept of how they combine in the form of mulHmorbidity. AIMS The aims of this talk are to: 1: Understand the nature and impacts of comorbidiHes associated with difficult-to-treat/severe asthma. 2: Consider comorbidiHes as treatable traits in difficult-to-treat/ severe asthma. 3: Recognise mulHmorbidity profiles/ phenotypes in difficult-to-treat/ severe asthma. 4: Consider the concept of a mulHmorbidity index to improve understanding of asthma impacts. 5: Appreciate impacts of mulHmodal approaches to mulHmorbidity in difficult-to-treat/ severe asthma. FINDINGS ComorbidiHes are commonplace in paHents with difficult-to-treat/severe asthma. They (both individually and collecHvely) show detrimental impacts on asthma outcomes including maintenance oral steroid need, asthma exacerbaHon, lung funcHon and asthma control. They may negaHvely influence long-term asthma control, impair biologic remission, negaHvely impact quality of life and impose significant health economic burden. In parallel, recogniHon of comorbidiHes in asthma care is subopHmal. However, many comorbidiHes can be regarded as “treatable super traits” that detrimentally impact paHents with asthma, but which can be addressed to help improve paHent outcomes. A new concept is the recogniHon that comorbidiHes in asthma usually occur in combinaHon within a framework of mulHmorbidity. Recent work in the Severe Heterogeneous Asthma Research CollaboraHon: PaHent-Centred (SHARP) has idenHfied mulHmorbidity clusters and categories in severe asthma paHents that show different clinical manifestaHons. There is also emerging evidence of the ability of a mulHmorbidity index to provide an alternaHve holisHc perspecHve that highlights worse asthma outcome risk in severe asthma paHents. Furthermore, studies have shown the benefits of addressing comorbidiHes/ mulHmorbidity within a comprehensive treatable traits approach in paHents with severe asthma. CONCLUSIONS: Look for comorbidiHes in difficult-to-treat/ severe asthma and you will find them; find and you should address them, address them and you will improve your paHents' outcomes. INVITED PLENARY LECTURE OUTCOMES AND CHALLENGES IN SEVERE ASTHMA WITH FUNGAL SENZITISATION Sabina Škrgat. Department of Pulmonary Diseases and Allergy, University Medical Centre, Ljubljana Medical Faculty, University of Ljubljana BACKGROUND Fungal sensiHzaHon is common in asthma, with prevalence varying across studies. It appears to be higher in severe asthma than in mild asthma, with reported rates ranging from 35% to 75% (1). SensiHzaHon to Aspergillus fumigatus is associated with a spectrum of condiHons (2): - A. fumigatus sensiHzaHon (AFS) is defined by increased IgE levels or a posiHve skin prick test for A. fumigatus. - A. fumigatus-associated asthma (AFAA) refers to allergic sensiHzaHon to A. fumigatus in paHents with mild to moderate asthma. - Allergic bronchopulmonary aspergillosis/mycosis (ABPA/M) encompasses severe allergic reacHons to Aspergillus spp. or other fungi in paHents with severe asthma and bronchiectasis. ABPA is diagnosed based on a combinaHon of clinical, radiological, and immunological criteria. - Severe asthma with fungal sensiHzaHon (SAFS) is idenHfied in paHents with severe asthma and elevated fungus-specific IgE who do not meet the criteria for ABPA or ABPM. - Allergic fungal airway disease (AFAD) is an umbrella term that includes fungal asthma, fungal bronchiHs, AFAA, SAFS, ABPA, ABPM, and fungal allergies in paHents with chronic obstrucHve pulmonary disease (COPD) (2). According to the most recent ISHAM-ABPA guidelines (3), the diagnosHc algorithm incorporates radiological features and recommends subclassifying ABPA into: - Serological ABPA - ABPA with bronchiectasis - ABPA with mucus plugging - ABPA with high-a?enuaHon mucus - ABPA with chronic pleuropulmonary fibrosis CLINICAL EVIDENCE PaHents with IgE sensiHzaHon to Aspergillus fumigatus (AFS) are at risk of lung damage (4). Kurukulaaratchy et al. (5) reported that AFS in paHents with difficult-to-treat asthma is associated with a more severe disease phenotype, characterized by older age, male sex, longer disease duraHon, lung funcHon impairment, bronchiectasis, higher inflammatory markers, greater treatment needs, but fewer psychophysiological comorbidiHes. In a small, single-center Slovenian SHARP cohort, a higher prevalence of bronchiectasis in severe asthma paHents with AFS was observed, confirming previous findings. However, this associaHon was not seen with FEV1 decline or maintenance oral corHcosteroid use (6). DIRECTIONS FOR FUTURE RESEARCH Real-world clinical data on AFS remain limited, highlighHng the need for larger mulHnaHonal studies to be?er understand this under-recognized comorbidity. Early screening for AFS in asthma paHents may serve as a prevenHve measure against progression of airway damage. LITERATURE: 1. Del Giacco SR, Bakirtas A, Bel E, Custovic A, Diamant Z, Hamelmann E et al. Allergy in Severe Asthma. Allergy 2016. 2. Agarwal R, Muthu V, Sehgal IS. RelaAonship between Aspergillus and Asthma. Allergology InternaAonal 2023; 72 (4): 507– 20. h"ps://doi.org/10.1016/J.ALIT.2023.08.004. 3. Agarwal R, Sehgal IS, Muthu V, Denning DW, ChakrabarA A, Soundappan K, Garg M, Rudramurthy SM, Dhooria S, Armstrong-James D, Asano K, Gangneux JP, ChoArmall SH, Salzer HJF, Chalmers JD, Godet C, Joest M, Page I, Nair P, Arjun P, Dhar R, Jat KR, Joe G, Krishnaswamy UM, Mathew JL, Maturu VN, Mohan A, Nath A, Patel D, Savio J, Saxena P, Soman R, Thangakunam B, Baxter CG, Bongomin F, Calhoun WJ, Cornely OA, Douglass JA, Kosmidis C, Meis JF, Moss R, Pasqualoio AC, Seidel D, Sprute R, Prasad KT, Aggarwal AN. Revised ISHAM-ABPA working group clinical pracAce guidelines for diagnosing, classifying and treaAng allergic bronchopulmonary aspergillosis/mycoses. Eur Respir J. 2024 Apr 4;63(4):2400061. doi: 10.1183/13993003.00061-2024. PMID: 38423624; PMCID: PMC10991853. 4. Woolnough KF, Richardson M, C. Newby C et al. The relaAonship between biomarkers of fungal allergy and lung damage in asthma. Clinical & Experimental Allergy, 2017 (47) 48–56. doi: 10.1111/cea.12848. 5. Mistry H, Ajsivinac Soberanis HM, Kyyaly MA, Azim A, Barber C, Knight D, Newell C, Haitchi HM, Wilkinson T, Howarth P, Seumois G, Vijayanand P, Arshad SH, Kurukulaaratchy RJ. The Clinical ImplicaAons of Aspergillus Fumigatus SensiAzaAon in Difficult-To-Treat Asthma PaAents. J Allergy Clin Immunol Pract. 2021 Dec;9(12):4254-4267.e10. doi: 10.1016/j.jaip.2021.08.038. Epub 2021 Sep 14. PMID: 34534722. 6. Katarina Pelicon Slabanja, Matevž Harlander, Saša Rink, Simone Hashimoto, Jacob K. Sont, Elisabeth H. Bel, Sabina Skrgat. CharacterisAcs of Aspergillus sensiAzed severe asthma paAents in a single-center SHARP cohort. European Respiratory Journal 2023 62(suppl 67): PA976; DOI: hips://doi.org/10.1183/13993003.congress-2023.PA976 INVITED LECTURE WEIGHT-ADJUSTED BIOLOGIC THERAPY ARE THERE SOME BENEFITS? – Sanja Hromis. InsFtute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Serbia Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia ABSTRACT Weight-adjusted biologic therapy – are there some benefits? Severe asthma paHents with predominant eosinophilic inflammaHon require anH-IL-5 therapy due to key roles of IL-5 in the differenHaHon, maturaHon, recruitment, and acHvaHon of eosinophils. Among currently available anH-IL-5 biologics (mepolizumab, reslizumab and benralizumab), meta-analyses and real-world studies have shown comparable efficacy. Reslizumab is the only biologic administered in a weight-adjusted dose through intravenous infusion (IV) requiring more healthcare resources but potenHally offering advantages. A subopHmal response to biologics may be linked to dosing regiments and administraHon routes. Studies suggest that higher doses and IV administraHon of anH-IL-5 drugs are associated with be?er suppression of eosinophilic inflammaHon in the airways leading to greater clinical improvements. This may be especially relevant for paHents with late-onset, corHcosteroid dependent asthma. In certain cases, using a fixed dose of subcutaneous mepolizumab may result in insufficient neutralizaHon of IL-5, especially in paHents with higher local inflammaHon. Experimental studies suggest that this could lead to the formaHon of immune complexes (high molecular weight IL-5 bound complexes) and subsequently acHvaHon of the complement system contribuHng to increased inflammaHon. This risk appears to be significantly lower in paHents treated with weight-adjusted reslizumab. AddiHonally, auto-IgG anHbodies against eosinophil peroxidase (EPX) have been idenHfied in some paHents with an airway autoimmune response and their presence is associated with a reduced response to biologics. Notably, a reducHon in sputum anH-EPX IgG has been observed in reslizumab treated paHents in clinical studies. Furthermore, mepolizumab, as an IgG1 molecule may have the potenHal to acHvate complement and form hetero-immune complexes, although evidence supporHng these effects in clinical se|ngs is limited. In contrast, reslizumab and benralizumab, being IgG4 molecules, are unlikely to bind complement and instead inhibit complement-mediated lysis. Lastly, some reports suggest that benralizumab may carry a slightly higher risk of exacerbaHons due to viral or bacterial infecHons compared to mepolizumab or reslizumab, possibly related to a reducHon in NK cell number or funcHon, though further invesHgaHon is required. Therefore, weight-adjusted reslizumab may be a valuable therapeuHc opHon, parHcularly for paHents with late onset, corHcosteroid-dependent asthma, and uncontrolled airway inflammaHon as well as those with frequent infecHous exacerbaHons. Further research is needed to refine paHent selecHon criteria and opHmize individualized treatment strategies. REFERENCES 1. Salter B, Lacy P, Mukherjee M. Biologics in Asthma: A Molecular PerspecAve to Precision Medicine. Front Pharmacol. 2022; 12:793409. 2. Valverde-Monge M, Sánchez-Carrasco P, Betancor D, et al. Comparison of Long-term Response and Remission to Omalizumab and AnA-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma PaAents. Arch Bronconeumol. 2024;60(1):23-32. 3. Mukherjee M, Aleman Paramo F, et al. Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab. Am J Respir Crit Care Med. 2018;197(1):38-46. 4. 4Mukherjee M, Forero DF, Tran S, et al. SubopAmal treatment response to anA-IL-5 monoclonal anAbodies in severe eosinophilic asthmaAcs with airway autoimmune phenomena. Eur Respir J. 2020;56(4):2000117. 5. Poznanski SM, Mukherjee M, Zhao N, et al. Asthma exacerbaAons on benralizumab are largely non-eosinophilic. Allergy. 2021;76(1):375-379. INVITED LECTURE A NEW RHYTHM IN SEVERE ASTHMA MANAGEMENT: EXTENDING THE INTERVALS FOR BIOLOGICS? M. Vergles1 1 1 , G. Salai , I. Kovacevic 1 Department of Pulmonology, University Hospital Dubrava - Zagreb (CroaFa) BACKGROUND Severe eosinophilic asthma (SEA) remains a therapeuHc challenge despite advances in biologic treatments. Clinical remission has recently been recognized as a potenHal treatment goal in SEA management. Despite promising outcomes with biologics, key quesHons remain unanswered, parHcularly regarding the possibility of safely disconHnuing therapy in paHents who have a?ained remission. The randomized clinical study OPTIMAL, conducted in Denmark, addressed this quesHon by HtraHng anH-IL-5 therapy through prolonged dosing intervals. The study concluded that HtraHon of anH-IL-5 biologics is possible in paHents who have become stable on treatment. Further studies on the long-term prognosis of HtraHon and adjustments to the OPTIMAL HtraHon algorithm are warranted. METHODS A similar observaHonal study was conducted at University Hospital Dubrava on 31 SEA patients treated with anH-IL-5 biologics (mepolizumab and benralizumab) from January 2024. All paHents had to meet the criteria for a four-component clinical remission (CR) to be eligible for dose HtraHon. The dosing interval was increased by 25% over a period of six months. EvaluaHon at six months included spirometry (FEV1), fracHonal exhaled nitric oxide (FeNO), asthma control test (ACT), and blood eosinophil count (BEC). The loss of any remission component resulted in the paHent being reverted to the original dosing interval. RESULTS Among the 31 SEA paHents included, the majority were female. No significant differences were observed in age, sex, or comorbidity index. There were no recorded acute exacerbaHons or need for systemic corHcosteroids during the study period. FEV1, FeNO, ACT, and BEC showed no staHsHcally significant changes at six months compared with baseline. CONCLUSION Gradual HtraHon of anH-IL-5 biologics by extending dosing intervals at 25% increments every six months appears to be a safe and feasible strategy for SEA paHents in remission. The absence of acute exacerbaHons and stable clinical parameters during the study period indicates the potenHal for dose HtraHon in well-controlled SEA. Further long-term studies are warranted to confirm these findings and refine HtraHon protocols. INVITED LECTURE BIOLOGIC THERAPY IN EOSINOPHILIC COPD: INSIGHTS FROM OUR CLINICAL EXPERIENCE Irena Šarc. University Clinic of Respiratory and Allergic Diseases Golnik ABSTRACT INTRODUCTION Chronic obstrucHve pulmonary disease (COPD) with an eosinophilic phenotype is associated with frequent exacerbaHons and increased systemic corHcosteroid (CS) use. Mepolizumab, an anH-IL-5 monoclonal anHbody, has shown efficacy in reducing exacerbaHons in eosinophilic airway diseases. This study evaluated the effecHveness of mepolizumab in COPD paHents with eosinophilic inflammaHon and emphysema in a real-life se|ng. METHODS This monocentric study included 12 COPD paHents iniHated with mepolizumab (100 mg subcutaneously every four weeks) from 2020 to 2022 and followed for 2 years. PaHents required at least two exacerbaHons in the previous year requiring systemic CS treatment or maintenance oral corHcosteroids (OCS) and a blood eosinophil count >300 cells/µL. RESULTS Mepolizumab treatment led to a significant reducHon in exacerbaHon rates. The mean annualized rate of moderate or severe exacerbaHons decreased from 5.75 to 1.42 per year (rate raHo [RR] = 0.25, 95% confidence interval [CI] 0.14–0.42, p = 0.011). HospitalizaHon-related exacerbaHons were significantly reduced from 2.58 to 0.17 per year (RR = 0.06, 95% CI 0.02–0.27, p = 0.007). Moderate exacerbaHons requiring systemic CS decreased from 3.17 to 1.25 per year, but this reducHon was not staHsHcally significant (RR = 0.39, 95% CI 0.22–0.72, p = 0.138). Among seven paHents who conHnued treatment for the second year, the exacerbaHon rate showed a trend toward further reducHon (1.42 to 0.58 per year, RR = 0.47, 95% CI 0.19–1.14, p = 0.074). OCS maintenance therapy was disconHnued in two of four paHents (50%) a`er the first year (Fisher’s exact p = 0.640). CONCLUSIONS Mepolizumab significantly reduced exacerbaHon rates in this highly selected cohort of COPD paHents with an eosinophilic phenotype and frequent exacerbaHons, with 66% of paHents responding and an overall 75% reducHon in exacerbaHon rates. Among responders, the reducHon was sustained into the second year of treatment. These findings suggest that mepolizumab may be a valuable treatment opHon for a subset of COPD paHents, parHcularly those with a high exacerbaHon burden and corHcosteroid dependence. KEYWORDS: COPD, anH-IL-5, mepolizumab, eosinophilic COPD, exacerbaHons, biologic therapy, precision medicine INTRODUCTION Chronic obstrucHve pulmonary disease (COPD) is a progressive lung condiHon, primarily caused by long-term cigare?e smoking, characterized by persistent airflow limitaHon, chronic inflammaHon, and recurrent exacerbaHons (1). Acute exacerbaHons contribute to disease progression, increased healthcare uHlizaHon, and higher morbidity and mortality rates. While infecHons are a major trigger, some exacerbaHons are intrinsic and associated with elevated blood and sputum eosinophils (2,3). Current guidelines recommend triple inhaled therapy—combining inhaled corHcosteroids (ICS), long-acHng β2-agonists (LABAs), and long-acHng muscarinic antagonists (LAMAs) - for COPD paHents with frequent exacerbaHons and elevated blood eosinophils (4). However, despite this regimen, 30–40% of paHents conHnue to experience moderate to severe exacerbaHons. COPD is a heterogeneous disease with mulHple clinical phenotypes and inflammatory endotypes (5). Eosinophilic COPD, defined by blood eosinophil counts ≥150–200 cells/μL, is associated with a higher exacerbaHon risk but shows a be?er response to corHcosteroid therapy (3). Given its pathophysiological similariHes to eosinophilic asthma, targeted anH-IL-5 therapy has been invesHgated for COPD . Mepolizumab, a humanized monoclonal anHbody against interleukin-5 (IL-5), reduces blood and Hssue eosinophils by blocking IL-5 signaling. In severe eosinophilic asthma, it has significantly lowered exacerbaHon rates and improved quality of life (6). However, its role in COPD remains less clear. Two randomized controlled trials (METREX and METREO) assessed mepolizumab in COPD paHents with moderate-to-severe exacerbaHons. A significant reducHon in annual exacerbaHon rates was observed in METREX (p=0.04), parHcularly in paHents with higher baseline eosinophil counts (7). Similar findings were reported for benralizumab, another anH-IL-5 biologic, in the GALATHEA and TERRANOVA trials, although staHsHcal significance was not reached for overall exacerbaHon reducHon (8). Recent trials have explored dupilumab, a monoclonal anHbody targeHng interleukin-4 (IL-4) and interleukin-13 (IL-13), which are key drivers of Type 2 inflammaHon. The BOREAS trial demonstrated that dupilumab significantly reduced moderate-to-severe COPD exacerbaHons (rate raHo 0.70; p<0.001) in paHents with eosinophilic COPD (≥300 eosinophils/μL), alongside improvements in lung funcHon and quality of life. The NOTUS trial further confirmed these findings, showing a 34% reducHon in exacerbaHon risk (p<0.001), with sustained FEV1 improvements at weeks 12 and 52 (9). These findings reinforce the role of Type 2 inflammaHon in COPD pathophysiology. However, opHmal paHent selecHon criteria remain a challenge. This study aims to evaluate the efficacy of mepolizumab in a highly selected cohort of COPD paHents with eosinophilic inflammaHon and a high exacerbaHon burden, providing further insight into its role in exacerbaHon reducHon and overall clinical benefit. METHODS SUBJECTS This monocentric study was conducted at the University Clinic for Respiratory and Allergic Disease Golnik from 2020 to the end of 2022. During this period, thirteen COPD paHents were iniHated on mepolizumab. Eligibility for mepolizumab treatment was based on the following criteria: • Clinical instability: At least two exacerbaHons in the previous year requiring systemic corHcosteroid (CS) treatment or maintenance oral corHcosteroid (OCS) therapy for disease stability despite a high- dose inhaled corHcosteroid (ICS) regimen for at least six months. • Eosinophilic fenotype: A blood eosinophil count of >300 cells/μL in the last year. • Case review and approval by a mulHdisciplinary team (MDT) specializing in obstrucHve lung diseases before mepolizumab iniHaHon. Eligibility for study inclusion required addiHonal criteria: • A history of smoking ≥20 pack-years. • The presence of emphysema on high-resoluHon computed tomography (HRCT) of the lungs. STUDY PROTOCOL PaHents received mepolizumab (100 mg sc every four weeks) while conHnuing their standard COPD treatment, including inhaled bronchodilators and corHcosteroids, as indicated. PaHents were regularly followed up at each applicaHon visit and underwent addiHonal comprehensive assessments every six months. Clinical evaluaHons at one year and two years post-treatment iniHaHon included exacerbaHon frequency (number of moderate/severe exacerbaHons per year, focused on those requiring systemic corHcosteroids) and oral glucocorHcoid use (requirement for maintenance therapy). PaHents were classified as responders if their annual exacerbaHon frequency or OCS maintenance dose decreased by at least 50%. One paHent was excluded from the final analysis due to a short treatment duraHon and insufficient data. The study was approved by the NaHonal Medical Ethics Commi?ee. Data Analysis ConHnuous variables were expressed as medians and interquarHle ranges (IQRs), while categorical variables were summarized as percentages. ExacerbaHon rates before and a`er treatment were compared using the Wilcoxon signed-rank test for paired data. A two-tailed p-value <0.05 was considered staHsHcally significant. RESULTS Baseline patient characteristics The study included 12 paHents with a mean age of 67.8 ± 5.1 years, of whom 66.7% were female. The mean BMI was 27.0 ± 4.5 kg/m², and the mean smoking history was 41.7 ± 20.0 pack-years. All paHents were ex-smokers at baseline. Baseline blood eosinophil levels had a mean of 230.0 ± 194.4 cells/µL, with a historical maximum of 805.8 ± 335.7 cells/µL in the previous three years. On average, FeNO and total IgE levels were increased, with means of 78.6 ± 29.8 ppb and 214.0 ± 195.4 IU/mL, respecHvely. At six months, eosinophil counts had decreased to a mean of 55.8 ± 46.2 cells/µL (p = .002). Lung funcHon also showed a significant improvement, with an increase in FEV1% predicted (p=0.032). Detailed baseline characterisHcs are presented in Table 1. All paHents had HRCT performed within one year before treatment iniHaHon. Imaging revealed emphysema in all paHents. All paHents had varying degrees of mucus plugging. Bronchiectasis was present in at least a minimal form in 7 of 12 paHents, and excessive dynamic airway collapse (EDAC) was observed in 5 paHents. Table 1: Baseline paHent characterisHcs Characteris*c Value Number of pts. 12 Age (years) 67.8 ± 5.1 Gender, female 8 (66.7%) BMI (kg/m²) 27.0 ± 4.5 Smoking history (pack-years) 41.7 ± 20.0 BEC max (cells/µL) 805.8 ± 335.7 BEC baseline (cells/µL) 230.0 ± 194.4 BEC baseline (%) 2.0 ± 1.6 FVC (mL) 2681.7 ± 1123.2 FVC% (%) 84.2 ± 24.6 FEV1 (mL) 1018.3 ± 459.0 FEV1 % (%) 41.7 ± 15.4 Ti % 38.5 ± 9.3 FeNO (ppb) 78.6 ± 29.8 Total IgE (IU/mL) 214.0 ± 195.4 Atopy, n 1 (8.3%) ICS flu*casone equivalent 1110 ± 161 (µg/day) FVC at 6 M (mL) 2953.3 ± 1195.8 FVC at 6 M (%) 92.8 ± 24.6 FEV1 at 6 M (mL) 1114.2 ± 507.0 FEV1 % at 6 M (%) 45.8 ± 16.7 BEC at 6 M (cells/µL) 55.8 ± 46.2 BEC at 6 M (%) 0.55 ± 0.43 Data are number of parCcipants (%), mean ± SD; BMI – body mass index; BEC – blood eosinophil count; FVC – forced vital capacity; FEV1 – forced expiratory volume in 1 second; FeNO – fracConal exhaled nitric oxide; ICS – inhaled corCcosteroid; at 6 M – values measured at 6 months. EXACERBATIONS AND TREATMENT RESPONSE Based on predefined criteria of a 50% reducHon in exacerbaHons or a decrease in maintenance OCS dose within the first year of treatment, 8 paHents (66%) were classified as responders, while 4 paHents (33%) were classified as non-responders. Three paHents died in the first year of treatment: two non-responders due to COPD and one responder due to an unrelated cause. Furthermore, two paHents disconHnued treatment in the first year due to a lack of benefit. Treatment with mepolizumab led to a staHsHcally significant reducHon in exacerbaHon rates. In the analysis of moderate and severe AE, the mean annualized rate of moderate or severe exacerbaHons before treatment was 5.75 per year, as compared with 1.42 per year a`er one year of treatment (RR = 0.25, 95% CI [0.14, 0.42], p = 0.011). The reducHon in hospitalizaHon-related exacerbaHons was significant. The mean annual rate before treatment was 2.58 per year, as compared with 0.17 per year a`er one year of treatment (RR = 0.06, 95% CI [0.02, 0.27], p = 0.007). For moderate exacerbaHons requiring systemic corHcosteroids, the mean annualized rate was 3.17 per year before treatment, as compared with 1.25 per year a`er one year (RR = 0.39, 95% CI [0.22, 0.72], p = 0.138). Among paHents who remained on treatment for the second year (7 paHents), the annualized exacerbaHon rate was 1.42 per year in Year 1, as compared with 0.58 per year in Year 2 (RR = 0.47, 95% CI [0.19, 1.14], p = 0.074). The difference in OCS maintenance use between pre-treatment and post-treatment was also analyzed. Before treatment, 4 of 12 paHents (33%) were receiving chronic OCS maintenance therapy; a`er the first year, 2 of these paHents (50%) had disconHnued OCS maintenance (Fisher’s exact p = 0.640). Figure 1: Acute Exacerbation numbers over time. A: AE hospitalisation over time; B: CS treated moderate AE over time DISCUSSION Our study demonstrated a significant reducHon in moderate exacerbaHons and exacerbaHons requiring hospitalizaHon in a small cohort of paHents with severe eosinophilic COPD treated with mepolizumab in a real-world clinical se|ng, with 66% of paHents responding to treatment in the first year. These findings provide valuable insight into the effecHveness of mepolizumab in this high-risk populaHon, highlighHng its potenHal role in reducing the exacerbaHon burden in paHents with frequent, corHcosteroid-dependent exacerbaHons. Our study adds to the growing body of knowledge on the role of anH-IL-5 therapies in eosinophilic COPD. In the METREX trial, mepolizumab reduced the annualized exacerbaHon rate from 1.71 to 1.40 per year (RR = 0.82, 95% confidence interval [CI] 0.68–0.98, p = 0.04), while the METREO trial reported a decrease from 1.49 to 1.19 per year (RR = 0.80, 95% CI 0.65–0.98, p = 0.07) (7). The GALATHEA study of benralizumab reported an AE rate reducHon from 2.33 to 1.19 per year, but without staHsHcal significance (RR = 0.96, 95% CI 0.65–1.36, p = 0.65). Similarly, the TERRANOVA trial showed a decrease from 2.28 to 1.21 per year (RR = 0.85, 95% CI 0.06–1.37, p = 0.06) (8). While both mepolizumab and benralizumab were associated with numerical reducHons in exacerbaHons, only the METREX trial demonstrated a staHsHcally significant effect, highlighHng the complexity of anH-IL-5 therapy in COPD and the need for a more refined approach to paHent selecHon. Our study populaHon differed from those in these randomized trials in several important ways. In all studies, spirometric measures of disease severity, as assessed by FEV1, were similar and comparable to those in our cohort. However, our pre-treatment exacerbaHon rate was substanHally higher, with a baseline annualized rate of 5.75 per year, compared to 2.6 per year in METREX, 2.7 in METRO, and 2.3 in both GALATHEA and TERRANOVA, suggesHng that our cohort represented a more severe disease phenotype (7,8). A`er one year of mepolizumab treatment, exacerbaHons in our study were reduced to 1.42 per year, reflecHng an overall 75% reducHon. This magnitude of reducHon exceeds that observed in clinical trials, reinforcing the importance of paHent selecHon, parHcularly in those with a history of high eosinophil counts, and very frequent exacerbaHons requiring systemic corHcosteroid treatment. Furthermore, our study focused specifically on exacerbaHons requiring systemic corHcosteroids, whereas randomized trials o`en include exacerbaHons treated with anHbioHcs or increased inhaled therapy. This likely further improved the selecHon precision of paHents with the greatest benefit potenHal. A post hoc analysis of the METREX and METREO studies has already suggested that paHents with higher blood eosinophil counts and those with exacerbaHons requiring systemic corHcosteroids benefited the most from mepolizumab, which is consistent with our findings (7). In contrast to mepolizumab, the GALATHEA and TERRANOVA trials evaluaHng benralizumab in paHents with ≥220 eosinophils/µL failed to meet their primary endpoints for exacerbaHon reducHon, despite high baseline BEC levels (8). This raises quesHons about the reliability of BEC as a predicHve biomarker for anH-IL-5 response in COPD. Meanwhile, therapies targeHng a broader spectrum of type 2 inflammaHon, such as IL-4 and IL-13 inhibiHon with dupilumab, have shown promising results in COPD paHents with elevated eosinophils and/or FeNO. The BOREAS and NOTUS trials demonstrated both exacerbaHon reducHon and lung funcHon improvement in this broader inflammatory phenotype (9,10). In our study, paHents had very high historical BEC levels, which, combined with frequent exacerbaHons, may reflect transient eosinophil surges during exacerbaHons. This suggests that historical BEC, rather than stable-state BEC, could serve as a more refined biomarker for idenHfying paHents most likely to benefit from anH-IL-5 therapy. This concept is further supported by a recent study demonstraHng that benralizumab successfully reduced treatment failure in eosinophilic asthma and COPD exacerbaHons when administered at the Hme of an exacerbaHon (11). In our study, we also observed an improvement in lung funcHon, a finding not reported in previous trials, suggesHng that anH-IL-5 therapy may provide addiHonal benefits beyond exacerbaHon reducHon. This improvement may indicate that when anH-IL-5 treatment effecHvely reduces exacerbaHons, it can also posiHvely impact other disease parameters. The observed reducHon in BEC reflects a decrease in eosinophilic airway inflammaHon, a key pathophysiological mechanism in a subset of COPD paHents. This reducHon likely contributes not only to a lower exacerbaHon frequency but also to potenHal improvements in lung funcHon. A key strength of our study is the extended follow-up beyond one year, allowing for the assessment of longer-term treatment effects. The observed trend toward a further reducHon in exacerbaHon rates in the second year among paHents who conHnued with mepolizumab is an important finding. Although the small sample size limits the staHsHcal power of this observaHon, it suggests that the benefits of treatment may not only persist but potenHally increase over Hme in a carefully selected populaHon of paHents with severe eosinophilic COPD. Despite the limitaHons of a small sample size and the absence of a control group, our study provides valuable real-world evidence on the effecHveness of mepolizumab in a disHnct subgroup of eosinophilic COPD paHents with high exacerbaHon and corHcosteroid burden. It reinforces findings from larger clinical trials and contributes to a be?er understanding of paHent selecHon for mepolizumab treatment. Future larger prospecHve studies are needed to confirm our findings, further assess the long-term impact of mepolizumab in this populaHon, and compare its efficacy with other emerging biologic therapies targeHng type 2 inflammaHon. REFERENCES: 1. Stolz D, Mkorombindo T, Schumann DM, et al. Towards the eliminaAon of chronic obstrucAve pulmonary disease: a Lancet Commission. Lancet. 2022;400(10356):921-972. 2. Tu Y, Chen Y, Li X, et al. Advances in acute COPD exacerbaAon: clarifying specific immune mechanisms of infecAous and noninfecAous factors. Ther Adv Respir Dis. 2025;19:17534666241308408. 3. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbaAons of chronic obstrucAve pulmonary disease: idenAficaAon of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662-671. 4. Global IniAaAve for Chronic ObstrucAve Lung Disease. Global strategy for the diagnosis, management, and prevenAon of chronic obstrucAve pulmonary disease: 2025 report. [Internet]. 2024 [cited 2025 Mar 19]. Available from: hips://goldcopd.org/2025-gold-report/ 5. Ghebre MA, Pang PH, Diver S, et al. Biological exacerbaAon clusters demonstrate asthma and chronic obstrucAve pulmonary disease overlap with disAnct mediator and microbiome profiles. J Allergy Clin Immunol. 2018;141(6):2027-2036.e12. 6. Nopsopon T, Lassiter G, Chen ML, et al. ComparaAve efficacy of tezepelumab to mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: a Bayesian network meta-analysis. J Allergy Clin Immunol. 2023;151(3):747-755. 7. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eosinophilic chronic obstrucAve pulmonary disease. N Engl J Med. 2017;377(17):1613-1629. 8. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the prevenAon of COPD exacerbaAons. N Engl J Med. 2019;381(11):1023-1034. 9. Bhai SP, Rabe KF, Hanania NA, et al. Dupilumab for chronic obstrucAve pulmonary disease with type 2 inflammaAon: a pooled analysis of two phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2025;13(3):234-243. 10. Bhai SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with blood eosinophil evidence of type 2 inflammaAon. N Engl J Med. 2024;390(24):2274-2283. 11. Ramakrishnan S, Russell REK, Mahmood HR, et al. TreaAng eosinophilic exacerbaAons of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, acAve placebo-controlled randomised trial. Lancet Respir Med. 2025;13(1):59-68. INVITED LECTURE THE SIGNIFICANCE OF EOSINOPHIL LOCATION IN SEVERE ASTHMA: INSIGHTS FROM INDUCED SPUTUM Peter Kopač. University Clinic of Respiratory and Allergic Diseases Golnik Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia. Eosinophils, originaHng in the bone marrow, are regulated by cytokines such as IL-3, GM-CSF, and IL-5, which influence their expansion and migraHon. In asthma, elevated eosinophil counts are observed in both blood and sputum. The use of biologic therapies targeHng IL-5 and IL-13 has revoluHonized treatment for eosinophilic asthma, yet the opHmal biomarker for evaluaHng therapeuHc response remains unclear. While increased eosinophil levels in blood are o`en associated with asthma severity, they lack specificity, as other allergic condiHons can also elevate eosinophil counts. Furthermore, eosinophil levels may primarily reflect Th2-driven inflammaHon rather than direct airway pathology. Although eosinophil counts are commonly used to predict responses to anH-Th2 biologics, they may not reliably indicate airway inflammaHon. In contrast, induced sputum analysis provides a more direct assessment of airway eosinophilia and helps differenHate eosinophilic from non-eosinophilic exacerbaHons. However, sputum eosinophilia is not exclusive to airway diseases and exhibits variability, limiHng its reproducibility. In severe asthma, a baseline eosinophil count above 300/µL may predict a favorable response to anH-Th2 therapies. However, even low eosinophil counts in paHents on anH-IL-5 monoclonal anHbodies (mAbs) may correlate with poor asthma control and persistent sputum eosinophilia. Conversely, elevated eosinophil counts in paHents receiving anH-IL-4R mAbs may be associated with improved asthma control. Discrepancies between and sputum eosinophil levels, parHcularly in paHents on systemic corHcosteroids, suggest local eosinophilopoiesis driven by unneutralized IL-5 in the airways. Thus, eosinophil monitoring may not always reflect airway inflammaHon or treatment response. Despite the availability of mulHple biologic therapies, 10%-20% of paHents switch treatments due to subopHmal response. Persistent airway eosinophilia despite anH-IL-5 therapy indicates the necessity of targeHng local eosinophil producHon for be?er asthma control. Benralizumab has demonstrated superior efficacy in suppressing sputum eosinophilia compared to mepolizumab or reslizumab, making sputum eosinophils a key consideraHon in treatment adjustments. AddiHonally, factors such as sinus disease and mucus plugging may contribute to persistent symptoms. Severe asthma is a heterogeneous disease requiring individualized, targeted therapies for opHmal disease management. A comprehensive approach considering both systemic and local eosinophil acHvity is essenHal for improving clinical outcomes. REFERENCES: 1. Koenderman L, Hassani M, Mukherjee M, Nair P. Monitoring eosinophils to guide therapy with biologics in asthma: does the compartment maier? Allergy. 2021;76(4):1081-8. doi:10.1111/all.14700. 2. Pepper AN, Hanania NA, Humbert M, Casale TB. How to assess effecAveness of biologics for asthma and what steps to take when there is no benefit. J Allergy Clin Immunol Pract. 2021 Mar;9(3):1081-8. doi:10.1016/j.jaip.2020.10.048. 3. Mukherjee M, Forero DF, Tran S, Boulay ME, Bertrand M, Bhalla A, et al. SubopAmal treatment response to anA-IL-5 monoclonal anAbodies in severe eosinophilic asthmaAcs with airway autoimmune phenomena. Eur Respir J. 2020 Oct 8;56(4):2000117. doi:10.1183/13993003.00117-2020. 4. McDowell PJ, Diver S, Yang F, Borg C, Busby J, Brown V, et al. The inflammatory profile of exacerbaAons in paAents with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospecAve observaAonal study. Lancet Respir Med. 2021 Oct;9(10):1174-84. doi:10.1016/S2213-2600(21)00004-7. INVITED LECTURE IMMUNOLOGICAL PATHWAYS IN SEVERE T2 ASTHMA PATIENTS DURING DUPILUMAB TREATMENT Luka Kunej 1 2 2 2 3 1,3 , Peter Kopač , Peter Korošec , Urška Bidovec-Stojković , Saša Rink , Matevž Harlander, Sabina Škrgat1,3 1 Medical faculty, University of Ljubljana (Slovenia), 2University Clinic of Respiratory and Allergic Diseases Golnik, 3 Department of Pulmonary Diseases and Allergy, University Medical Centre Ljubljana (Slovenia) BACKGROUND PaHents with severe asthma (SA) may present with type 2 (T2) inflammatory disease as shown by elevated exhaled nitric oxide (FeNO), total circulaHng IgE (cIgE) and peripheral eosinophilia (1,2). Dupilumab is a human monoclonal anHbody targeHng IL-4 and IL-13, which both play an important role in promoHng T2 inflammaHon in SA. IMMUNOLOGICAL EVIDENCE By blocking IL-4 and IL-13 receptors dupilumab impacts several clinical and molecular pathways in SA. -IL-13 suppression miHgates bronchoconstricHon and mucus secreHon (1), thus resulHng in improved lung funcHon parameters, such as FEV 1 (%). -NO producHon takes place in airway epithelium and is sHmulated by IL-13. Reduced FeNO levels are a biomarker of less intense T2 inflammaHon and a predictor of lower exacerbaHon rates. (3) -IL-4 pathway promotes differenHaHon of Th2 cells, which are important mediators of T2 inflammaHon, and class switching of plasm cells into producHon of IgE (4). Reduced levels of cIgE have been observed in dupilumab treated paHents. -Eosinophils from peripheral blood are one of the main drivers of T2 airway inflammaHon in SA. IL- 4 and IL-13 both sHmulate recruitment of eosinophils through chemokine producHon and higher prevalence of adhesion molecules on the endothelium surface (5). Dupilumab treatment can lead to peripheral eosinophilia, if eosinophils cannot migrate to airway Hssue and remain in peripheral blood. -19 adult SA paHents treated at University Medical Centre Ljubljana from November 2021 to December 2023 were included in a prospecHve real-life study. Clinical, inflammatory and immunological parameters were measured at baseline before dupilumab introducHon and a`er 12 months of follow up. Dupilumab treatment significantly improved FEV 1 % (p=0,0085), reduced asthma oral corHcosteroids (OCS) related exacerbaHons (p=0,0051) and reduced levels of total IgE (p=0,0386). There was no significant difference in peripheral eosinophilia (p=0,1327) and FeNO (p=0,0555) (6). CONCLUSION AND FUTURE GOALS IntroducHon of dupilumab to severe T2 asthma paHents broadly supresses T2 inflammaHon biomarkers and concomitantly improves lung funcHon parameters. PaHents experience fewer OCS-related SA exacerbaHons and have reduced levels of cIge. Further research is needed to clarify whether IL-4 pathway blockage is associated with the reducHon of specific IgE in paHents with specific atopies and their clinical outcomes. LITERATURE: 1. Habib N, Pasha MA, Tang DD. Current Understanding of Asthma Pathogenesis and Biomarkers. Vol. 11, Cells. MDPI; 2022. 2. Brusselle GG, Koppelman GH. Biologic Therapies for Severe Asthma. New England Journal of Medicine. 2022 Jan 13;386(2):157–71. 3. Loewenthal L, Menzies-Gow A. FeNO in Asthma. Semin Respir Crit Care Med. 2022 Oct 1;43(5):635–45. 4. Le Floc’h A, Allinne J, Nagashima K, Scoi G, Birchard D, Asrat S, et al. Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα anAbody, is required to broadly inhibit type 2 inflammaAon. Allergy: European Journal of Allergy and Clinical Immunology. 2020 May 1;75(5):1188–204. 5. Rijavec M, Korošec P. Endotypes and Immune Cells in Severe Asthma. 6. Kunej L, Rink S, Korošec P, Bidovec-Stojković U, Harlander M, Škrgat S. Clinical and molecular response to treatment with dupilumab in paAents with severe type 2 asthma. European Respiratory Journal [Internet]. 64(suppl 68):PA3575. Available from: hips://publicaAons.ersnet.org//content/erj/64/suppl_68/PA3575.abstract PATIENT WITH SEVERE EOSINOPHILIC ASTHMA AND CRSWNP WHO DEVELOPED EGPA WHILE BEING TREATED WITH BENRALIZUMAB Gomerčić Palčić M 1,2, Padjen I2,3. Division of Pulmonology, Department for Internal Diseases, University Hospital Centre Sestre Milosrdnice, Zagreb, CroaFa School of Medicine, University of Zagreb, Zagreb, CroaFa Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University Hospital Centre Zagreb, CroaFa We report the case of a 58-year-old obese woman who developed EGPA during treatment with benralizumab for severe eosinophilic asthma. The paHent was diagnosed with eosinophilic asthma, CRSwNP, and AERD at the age of 35 and had undergone two surgeries for nasal polyps. In 2021, treatment was iniHated with mepolizumab, but she was a non-responder. Therefore, a`er six months, her treatment was switched to benralizumab. Following this change, her quality of life, number of exacerbaHons, ACT score, and lung funcHon improved. Occasionally, she required OCS due to nasal polyps (1-2 Hmes per year), without the need for surgery. Over a four-year period, she experienced two asthma exacerbaHons that required OCS due to viral infecHons. At the start of 2025, the paHent noHced a lump in the corner of her le` eye. A CT scan of the paranasal sinuses revealed a large dacryocyst. An extensive biopsy was performed, showing eosinophilic inflammaHon and raising suspicion for EGPA or IgG4-related disease. ANCA anHbodies were negaHve, and eosinophil levels in peripheral blood were zero. To confirm the diagnosis and address the paHent's symptoms, an ENT specialist and maxillofacial surgeon collaborated on a more extensive procedure. Pathology excluded IgG4-related disease, but EGPA could not be definiHvely ruled out. CT scans revealed bilateral ground-glass opaciHes (GGO) in the upper lung lobes, a few small mucoid impacHons, and slightly enlarged mediasHnal lymph nodes. The paHent declined a bronchoscopy at this Hme due to her recent surgery but planned to undergo the procedure a`er recovery. A rheumatologist was consulted, and based on all available data, a diagnosis of EGPA was made. It was decided to shorten the interval between benralizumab doses to 4 weeks, and a conHnuous dose of prednisone 0.5 mg/kg body weight was introduced with two 1 g/iv rituximab infusiones separated by two weeks as part of the treatment plan. Clinicians should remain vigilant for the development of EGPA in paHents with severe asthma and eosinophilia, despite benralizumab treatment, especially during the peroid of OCS withdrawal. ASTHMA AND PULMONARY EMBOLISM: CASE REPORT Jasmina Bošnjić. Department of Pulmonary Diseases, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina, jasmina.bosnjic@gmail.com ABSTRACT The associaHon between severe asthma and pulmonary embolism is sHll unclear. Pulmonary embolism is one of the most frequent cardiovascular diseases, with a high risk of adverse clinical outcomes. A significant number of paHents at increased risk of pulmonary embolism is sHll not recognized in rouHne clinical pracHce. Asthma is chronic inflammatory diseases associated with procoagulants and anHfibrinolyHc acHviHes in the airways. Here we present a case of severe asthma associated with pulmonary embolism, presented with shortness of breath and chest discomfort, complicated by submassive thrombosis on computed tomography angiography, successfully treated with convenHonal anHcoagulant therapy. This case report suggests that asthma and pulmonary embolism can present with overlapping symptoms, and disHnguishing between these two condiHons can be challenging in clinical pracHce. Physicians should keep in mind that paHents with asthma are at considerable risk of pulmonary embolism. Severe asthma can be associated with various comorbidiHes and complicaHons, and the right idenHficaHon of these risk factors is necessary to reduce the risk. KEYWORDS: severe asthma, pulmonary embolism, inflammaHon, coagulopathy THE IMPORTANCE OF DIAGNOSING AND TREATING OSA IN PATIENTS WITH SEVERE ASTHMA Špela Kosi1, Natalija Edelbaher1 1 University Medical Centre Maribor spela.kosi@ukc-mb.si KEY WORDS: severe asthma, obstructive sleep apnea, biological therapy, CPAP BACKGROUND Asthma and obstrucHve sleep apnea (OSA) are common respiratory diseases that frequently coexist and share common risk factors, such as rhiniHs, obesity, and gastroesophageal reflux disease. EsHmated prevalence of OSA in asthmaHc paHents ranges from 38% to 70%, with asthma severity associated with a higher risk of OSA (2, 3). Conversely, asthma itself may contribute to OSA development (4). We present three paHents with adult-onset severe eosinophilic asthma and clinically significant OSA. With conHnuous posiHve airway pressure (CPAP) and biologic therapy, one achieved remission, and all showed marked improvement. CASE REPORTS Case 1: A 59-year-old female with eosinophilic asthma and a strong psychological component experienced frequent exacerbaHons requiring systemic corHcosteroids. We confirmed moderate OSA and iniHated CPAP therapy. As inhaled corHcosteroids were insufficient, benralizumab was introduced, resulHng in disease remission and improved lung funcHon. Case 2: A 62-year-old male with asthma had six exacerbations in the past year. He had a prior diagnosis of severe OSA, for which CPAP therapy was initiated. The introduction of benralizumab led to less exacerbations. Case 3: A 75-year-old female with severe asthma-chronic obstructive pulmonary disease overlap syndrome features, obesity, and long-term home oxygen therapy was diagnosed with moderate OSA. CPAP therapy improved symptoms, but compliance remained an issue. Mepolizumab was introduced, eliminating further need for systemic corticosteroid therapy and hospitalization. CONCLUSION With increasing evidence of the connecHon between asthma and OSA, it is important for healthcare providers to consider OSA in paHents with severe or difficult-to-treat asthma. Early detecHon and the iniHaHon of CPAP therapy, combined with appropriate asthma management, improved outcomes of presented paHents. Further trials in this area are needed. LITERATURE 1. Prasad B, Nyenhuis SM, Imayama I, Siddiqi A, Teodorescu M. Asthma and ObstrucAve Sleep Apnea Overlap: What Has the Evidence Taught Us? American Journal of Respiratory and CriAcal Care Medicine. 2019. 201(11). 1345-1357. 2. Wang D, Zhou Y, Chen R, Zeng X, Zhang S, et al. The relaAonship between obstrucAve sleep apnea and asthma severity and vice versa: a systemaAc review and meta-analysis. Eur J Med Res. 2023;28:139. 3. Julien JY, MarAn JG, Ernst P, Olivenstein R, Hamid Q, Lemière C, et al. Prevalence of obstrucAve sleep apnea-hypopnea in severe versus moderate asthma. J Allergy Clin Immunol. 2009;124:371-376. 4. Teodorescu M, Polomis DA, Gangnon RE, Fedie JE, Consens FB, et al. Asthma control and its relaAonship with obstrucAve sleep apnea (OSA) in older adults. Sleep Disord. 2013;2013:251567. INVITED LECTURE ROLE OF OTORHINOLARYNGOLOGIST IN SEVERE ASTHMA PATIENT Jure Urbančič. UMC Ljubljana, Department of otorhinolaryngology and cervicofacial surgery, University of Ljubljana, Faculty of Medicine ABSTRACT Brief statement of the purpose of the study: Upper airways have a significant role in asthma management. Therefore, the collaboraHve role of the otorhinolaryngologist and pulmonologist provides comprehensive care and ensures accurate diagnosis and effecHve treatment plans(1). With the advent of progressive research in asthma, common airways, and chronic rhinosinusiHs, more overlapping molecular mechanisms have been found(2). The new knowledge has opened new opportuniHes for mutual collaboraHon to help otorhinolaryngologists overcome the legacy role in managing allergic rhiniHs, chronic rhinosinusiHs (CRS), and laryngopharyngeal reflux(3). The new role is to be an equal member of the mulHdisciplinary board for the common airways to help be?er diagnose and treat many illnesses of the upper and lower airways, including severe asthma. THE METHOD USED The Pulmonology and Department of Otorhinolaryngology and Cervicofacial Surgery at UMC Ljubljana founded a separate MulHdisciplinary board for common airways (MDBCA) in the autumn of 2024. Competencies and the overall field of experHse were set by trying to establish an insHtuHonal consulHng body for paHents with complex upper and lower airway disease. The expert commi?ee, frequency of sessions, and the hybrid type of meeHng were chosen. The main goals were the more elaborate presentaHon of cases and a crossecHonal transfer of knowledge and experHse. The measured outcome was a number of presented paHents, as well as diagnosHcs and treatment efficacy in terms of availability of definite care. THE RESULT OBSERVED From December 2024 to March 2025, MDBCA had four hybrid meeHngs using MS Teams. 15 paHents were presented from different insHtuHons. The mean length of sessions was 40.25 minutes. Most were for assessing the introducHon of the biologicals for CRS with asthma. Three were severe asthma paHents with leading lower airway disease. All but one with a posiHve result had therapy within three weeks of the board meeHng. THE CONCLUSIONS BASED UPON RESULTS CollaboraHon in pulmonology and otorhinolaryngology has been established priorly, including mutual work with University Clinic Golnik. However, at the MDBCA level, this joint effort is preferable since the main results are available in real-Hme. PaHents also benefit from a lack of delay in referring. REFERENCES 1. Mümmler C, Kemmerich B, Behr J, Kneidinger N, Milger K. Differen8al response to biologics in a pa8ent with severe asthma and ABPA: a role for dupilumab? Allergy Asthma Clin Immunol. december 2020;16(1):55. 2. Sutherland A, Keniston K, Wang V, Yusin J. Updates in the Role of Biologics in Asthma. Curr Treat Op8ons Allergy. 20. junij 2023;10(3):232–54. 3. Cingi C, Yorgancıoğlu A, Bayar Muluk N, Cruz AA, uredniki. Airway Diseases. 1st ed. 2023. Cham: Springer Interna8onal Publishing; 2023. 1 str. INVITED LECTURE EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS A – RHEUMATOLOGICAL PERSPECTIVE Alojzija Hočevar. Department of Rheumatology, UMC Ljubljana, Slovenia; Medical Faculty, University of Ljubljana, Slovenia BACKGROUND Eosinophilic granulomatosis with polyangiiHs (EGPA) is a rare small vessel vasculiHs, classified according to Chapel Hill Consensus Conference among ANCA vasculiHdes (1). The clinically heterogeneous disease is characterized by asthma, marked upper and lower respiratory tract involvement, and necroHsing vasculiHs of small to medium-sized vessels. Tissue and peripheral eosinophilia are addiHonal hallmarks of EGPA (2). Not infrequently clinical and laboratory features overlap with hypereosinophilic syndromes. Recently, the therapeuHc recommendaHons for EGPA have been updated (3). OBJECTIVE the aim of our observaHonal study was to analyse the cohort of EGPA paHents diagnosed and followed at Department of Rheumatology, UMC Ljubljana and to esHmate the incidence rate of EGPA in Ljubljana region. METHODS we prospecHvely collected paHents, diagnosed with EGPA for the first Hme in the period between January 2010 and December 2024. The diagnosis of EGPA was clinical, based on the combinaHon of clinical features, funcHonal tests, laboratory, imaging and histological findings. Disease manifestaHons at diagnosis and treatment were analysed. The disease acHvity and severity were assessed by five factor score (4), and Birmingham vasculiHs acHvity score (BVAS) (5). In addiHon, the fulfilment of ACR/EULAR 2022 EGPA classificaHon criteria (6) was determined. DescripHve staHsHc was used. Results were expressed as medians and interquarHle ranges (IQRs) for non-normally distributed variables, and as means with standard deviaHons (SD) for normally distributed metric variables. Categorical variables were expressed as absolute numbers and percentages. Finally, the incidence rate of EGPA was esHmated. RESULTS During the 15-year observaHon period we diagnosed 36 paHents with EGPA, 20 of them being residents of Ljubljana region. There were 18 males (50%), and the median (IQR) age at diagnosis was 60 (51; 70) years. Symptom duraHon Hme (excluding asthma) before diagnosis was 2 (2; 7) months. At diagnosis 31 (86%) of paHents had known asthma and 3 addiHonal paHents were diagnosed with asthma during follow up. The average (SD) duraHon of asthma was 9.6 (10.2) years. The inflammaHon of upper respiratory tract was present in 22 paHents (61%). The median (IQR) number of organ involvement was 4 (3; 4). Lungs were the most commonly affected organ (26 cases; 72%), followed by peripheral nervous system (20 cases; 56%) and skin (18 paHents; 51%). Cardiac and renal involvement were detected in 13 (36%) and 11 (31%) paHents, respecHvely. Median (IQR) BVAS score was 18 (15; 21). Five factor score of 0, 1 and 2 or more was found in 17 (47%), 12 (33%) and 7 (20%) paHents, respecHvely. ANCA were detected in 47% paHents. Thirty-four paHents (94.4%) fulfilled ACR/ELAR 2022 classificaHon criteria for EGPA. Regarding treatment, all paHents except one received systemic glucocorHcoids. Six paHents were treated only with glucocorHcoids. As an inducHon therapy 19 paHents (53%) received cyclophosphamide, 11 (31%) rituximab and 1 (3%) azathioprine. The esHmated average incidence rate (95% CI) of EGPA during the 15-year observaHon period was 2.4 (1.5; 3.8) per million inhabitants. CONCLUSION This study represents the first analysis of EGPA paHents managed in our centre. Compared to literature data, the proporHon of ANCA posiHve cases was higher in our cohort. In addiHon, for the first Hme ever, we have esHmated the incidence rate of EGPA in Ljubljana region. Since Slovenian populaHon is homogeneous, the numbers could be generalized for enHre country. REFERENCES 1. Jenneie JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised InternaAonal Chapel Hill Consensus Conference Nomenclature of VasculiAdes. ArthriAs Rheum 2013; 65:1-11. 2. Emmi G, Be}ol A, Gelain E, Bajema IM, BerA A, Burns S, et al. Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiiAs. Nat Rev Rheumatol 2023; 19:378-93. 3. Hellmich B, Sanchez-Alamo B, Schirmer JH, BerA A, Blockmans D, Cid MC, et al. EULAR recommendaAons for the management of ANCA-associated vasculiAs: 2022 update. Ann Rheum Dis 2024; 83:30-47. 4. Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al. PrognosAc factors in polyarteriAs nodosa and Churg-Strauss syndrome. A prospecAve study in 342 paAents. Medicine (BalAmore). 1996 Jan;75(1):17-28. 5. Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al. EULAR recommendaAons for the management of primary small and medium vessel vasculiAs. Ann Rheum Dis 2009; 68:310-7. 6. Grayson PC, Ponte C, Suppiah R, Robson JC, Craven A, Judge A, et al. 2022 American College of Rheumatology/European Alliance of AssociaAons for Rheumatology ClassificaAon Criteria for Eosinophilic Granulomatosis with PolyangiiAs. Ann Rheum Dis 2022; 81:309-14. INVITED LECTURE DIABETES/OBESITY/SEVERE ASTHMA Miodrag Janić. Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia Asthma is often related to allergies and non-allergic problems such as obesity, insulin resistance, and type 2 diabetes. These metabolic comorbidities lead more frequently to severe asthma with worse control, increased symptoms, increased use of medications, more emergency visits and hospitalisations, and poorer quality of life. Overweight or obese people have 1.5 to 2.5 times higher risk of developing asthma than lean individuals, while those with diabetes face a 2.2 times higher risk. The management of asthma, obesity, and insulin resistance/diabetes requires a comprehensive approach. Asthma treatments include inhaled glucocorHcoids, long-acHng beta agonists, leukotriene receptor antagonists, long-acHng anHmuscarinic agents, and biologic therapies, especially for high-T2-resistant asthma. There is sHll a treatment gap, as some paHents sHll have poorly controlled asthma despite advanced therapies. In those with asthma, along with obesity and insulin resistance/diabetes, the non-T helper cell 2 (Th2) phenotype is more common and generally resistant to therapies. GLP-1 and GIP/GLP-1 receptor agonists may help fill this void. Evidence suggests that GLP-1 and potenHally GIP/GLP-1 receptor agonists have the ability to improve asthma outcomes indirectly by effectuaHng weight reducHon and directly by decreasing airway inflammaHon and mucus producHon, a?enuaHng Th2 and non-Th2 inflammaHon signalling, reducing interleukins 4, 5, 13, 33, as well as 1b, 6 and 17 among other mediators, lowering mast cell acHvity, improving surfactant producHon, and smooth muscle relaxaHon. This phenomenon has been corroborated on a broader scale, as exemplified in a study in which asthma exacerbaHons decreased significantly in people with moderate to severe asthma who started therapy with the GLP-1 receptor agonist compared to other drug users, six months a`er starHng GLP-1 receptor therapy. The same trend was observed regarding asthma symptoms, and the findings remain consistent even a`er adjustment for variaHons in body mass index and glucose control, indicaHng that these associaHons and benefits are not solely dependent on weight or glucose management. However, prospective studies are still required to rigorously evaluate the effects of GLP-1 and GIP/GLP-1 receptor agonists on primary endpoints related to lung outcomes, especially within a subset of patients characterised by uncontrolled non-Th2 asthma among obese individuals. INVITED LECTURE BASIC PERSONALITY TRAITS OF SEVERE ASTHMA PATIENTS AND THEIR IMPACT ON TREATMENT OUTCOME Ana Komlenić. InsFtute for Pulmonary Diseases of Vojvodina okianna@gmail.com INDTRODUCTION The Five-Factor Personality Model has broad usage in describing the basic personality traits related to asthma. Model was designed with the goal of categorizing observed behaviors into constructs that are relatively stable over time, and in the Serbian population, it includes Neuroticism, Extraversion, Aggressiveness, Conscientiousness, Openness, Positive and Negative Valence. The aim of the research is to examine the impact of the basic personality traits of severe asthma patients and their influence on treatment outcome measured with asthma control. Previous studies link high neuroticism with the current diagnosis of asthma and duration of symptoms. Methods: The study was conducted in March at the Institute for Pulmonary Diseases of Vojvodina, with a total of 265 participants, including 106 individuals receiving treatment for severe asthma with biological therapy and 159 individuals not receiving treatment for severe asthma. Asthma control was measured using the Asthma Control Test and Asthma Control Questionnaire, while the basic personality dimensions were measured using the VP+2 questionnaire. The study had a correlational design, and the data were processed using SPSS 24. THE RESULTS Neuroticism (on entire sample) is significantly associated with poor asthma control (r = .222, n = 265, p = .000, p < .01). The correlation between neuroticism and asthma control is significant but effect is smaller in participants receiving biological therapy (r = .236, n = 106, p = .015, p < .05). We further found that neuroticism was significantly higher in participants with poorly controlled asthma in the overall sample (p < 0.05, F (2, 252) = 6.159, p = .002), which was not the case in patients receiving biological therapy, where such differences were marginal. A significant correlation was also found between low conscientiousness and poorer disease control in participants on biological therapy (r = –.213, n = 108, p = .028, p < .05), as well as in the overall sample, with the lowest conscientiousness observed in participants with poorly controlled asthma (F (2, 252) = 4.178, p = .02, p < 0.05). CONCLUSION Basic personality dimensions are associated with disease control, but the influence of neuroticism is neutralized by biological therapy and psychological treatments aimed at reducing neuroticism and increasing conscientiousness. INVITED PLENARY LECTURE THE CHALLENGE OF COMORBID OSA IN PATIENTS WITH DIFFICULT-TO-TREAT ASTHMA KrisFna Ziherl. University Clinic of Respiratory and Allergic Diseases Golnik ABSTRACT INTRODUCTION ObstrucHve sleep apnoea (OSA) and asthma are common chronic respiratory disorders with overlapping risk factors, including obesity, rhiniHs, and gastroesophageal reflux disease (GERD). Their bidirecHonal interacHon can worsen symptom control, parHcularly in difficult-to-treat asthma, where OSA prevalence remains unclear. Both condiHons contribute to sleep disturbances, fragmented sleep, and excessive dayHme sleepiness (EDS), making it challenging to differenHate symptoms. This study aimed to assess OSA prevalence in paHents with difficult-to-treat asthma, nigh|me symptoms, and their impact on asthma control. METHODS A prospecHve study was conducted at the University Clinic Golnik, enrolling 108 paHents with difficult-to-treat asthma between August 2022 and October 2023. PaHents underwent mulHdisciplinary evaluaHon, including polysomnography, asthma control assessments, and sleep quesHonnaires. RESULTS Polysomnography idenHfied sleep-disordered breathing (SDB) in 59 paHents (55%). OSA was diagnosed in 53 (49%) paHents (3 [3%] with mild OSA and Epworth Sleepiness Scale [ESS] >10, 25 [23%] with moderate OSA, and 25 [23%] with severe OSA), while six had central sleep apnoea. Polysomnography results revealed that 76 (70%) had prolonged sleep latency, 87 (81%) experienced prolonged wake a`er sleep onset, 82 (76%) had subopHmal sleep efficiency, 62 (58%) exhibited an arousal index >15/h, and 49 (46%) had a periodic leg movement index >15/h. PaHents reported a range of sleep problems, including snoring (32%), breathing pauses during sleep (28%), night awakenings (59%), night cough (42%), nocturia (70%), symptoms of restless leg syndrome (43%), restless sleep (36%), unrefreshed sleep (37%), and morning headaches (18%). Asthma control (Asthma Control Test [ACT] score <20) was significantly worse in paHents experiencing breathing pauses (39% vs. 16%, p=0.007), night awakenings (71% vs. 45%, p=0.007), night cough (60% vs. 23%, p<0.001), restless sleep (51% vs. 21%, p=0.002), and unrefreshed sleep (50% vs. 23%, p=0.005). CONCLUSIONS PaHents with difficult-to-treat asthma frequently exhibit symptoms of disrupted sleep and demonstrate poor sleep quality. Clinically significant OSA is present in half of these paHents. PaHents presenHng with breathing pauses, night awakenings, night cough, restless sleep, and unrefreshed sleep demonstrate poorer asthma control. KEY WORDS: obstrucHve sleep apnoea (OSA), difficult-to-treat asthma, polysomnography INTRODUCTION ObstrucHve sleep apnoea (OSA) and asthma are among the most common chronic respiratory disorders. The esHmated global prevalence of clinically significant OSA is 10%, affecHng approximately 425 million people aged 30–69 years worldwide (1). In contrast, asthma has an esHmated prevalence of 4.4% (2). OSA is characterized by repeHHve episodes of complete (apnoea) or parHal (hypopnoea) collapse of the upper airway during sleep, occurring at the level of the so` palate, tongue, and/or epiglo|s (3). Asthma, on the other hand, is defined by variable expiratory flow limitaHon, accompanied by symptoms such as wheezing, shortness of breath, chest Hghtness, and cough (4). OSA and asthma share common risk factors, including obesity, rhiniHs, and gastroesophageal reflux disease (GERD). There is a bidirecHonal interacHon between these diseases, where one condiHon can influence the severity of the other (5). Difficult-to-treat asthma is characterized by inadequate symptom control despite treatment with medium- or high-dose inhaled corHcosteroids combined with a second controller or maintenance oral corHcosteroids. It also includes cases requiring high-dose treatment to maintain good symptom control and minimize exacerbaHons. Approximately 17% of asthma paHents have difficult-to-treat asthma, and OSA is a potenHal contribuHng factor to poor symptom control in this group. Therefore, paHents with difficult-to-treat asthma should be evaluated for comorbid OSA (4), but the prevalence of OSA in this group of paHents is not known. Both OSA and asthma can lead to fragmented sleep, poorer sleep and excessive dayHme sleepiness (EDS). Recurrent coughing and dyspnoea during sleep contribute to EDS in asthma. Both condiHons involve frequent awakenings due to airflow limitaHon, increased respiratory effort, and oxygen desaturaHon during sleep. (6) It is o`en challenging to disHnguish which symptoms belong to which disease. The aim of this study was to evaluate the prevalence of OSA in paHents with difficult-to-treat asthma, the occurrence of nigh|me symptoms and their influence on asthma control. METHODS SUBJECTS This prospecHve monocentric study was conducted at the University Clinic for Respiratory and Allergic Disorders Golnik. PaHents were recruited from the outpaHent clinic using a mulHdisciplinary team (MDT) approach designed for the evaluaHon of difficult-to-treat asthma. All consecuHve paHents a?ending the clinic from August 2022 to October 2023 were invited to parHcipate. The study was approved by the NaHonal Medical Ethics Commi?ee. All patients had been referred to the MDT outpatient clinic by secondary care pulmonologists. Clinical history was obtained, and patients underwent chest X-rays, pulmonary function tests, skin prick testing for inhalant allergens, and a six-minute walk test (6MWT). Blood samples were collected for biochemical analysis. Additionally, a pharmacist evaluated each patient's medication regimen, adherence, and inhalation technique. STUDY PROTOCOL PaHents who consented to a sleep study were evaluated at the Laboratory for Sleep-Related Breathing Disorders. The study was conducted during a period of relaHve clinical stability. PaHents completed sleep-related symptom quesHonnaires and the Epworth Sleepiness Scale (ESS). Anthropometric measurements (height, weight, neck circumference, and waist circumference) were also recorded. Full a?ended diagnosHc polysomnography was performed using the Alice 5 (Philips Respironics, USA) or NoxA1 (Nox Medical, Iceland) device. The recordings were manually scored by a cerHfied European sleep expert, using American Academy of Sleep Medicine (AASM) second ediHon scoring rules (7). Sleep-disordered breathing was defined based on the apnoea-hypopnoea index (AHI): • No sleep-disordered breathing: AHI <5/h • Mild: AHI 5 to <15/h • Moderate: AHI 15 to <30/h • Severe: AHI >30/h OSA and central sleep apnoea (CSA) were classified based on the predominance of events (>50% obstructive events for OSA, >50% central events for CSA). Excessive daytime sleepiness was defined as an ESS score >10. Clinically relevant sleep-disordered breathing was defined as either AHI >15/h or AHI >5/h with ESS >10. DATA ANALYSIS Data were analysed using SPSS version 26.0. Results are presented as either the number of parHcipants (%) or mean (standard deviaHon, SD). Categorical variables were compared using Pearson’s chi-square test, while conHnuous variables were analyzed using an independent-sample t-test. RESULTS Between August 2022 and October 2023 108 paHents with difficult-to-treat asthma consent to undergo in laboratory diagnosHc polysomnography; 55 men (51%), 57.9 ±12.6 years old, 42 (39%) were classified as obese. Comparing men and women, men more o`en had comorbid arterial hypertension and coronary artery disease. Table 1 presents the basic demographical and clinical characterisHcs of paHents included. Overall Men (N=55) Women (N=53) p-value (N=108) Age (years) 57.9 ±12.6 57.1±12.6 58.8±12.6 0.486 BMI (kg/m2) 28.9 ± 5.5 29.2±5.1 29.7±5.9 0.640 VC (%predicted) 97.6 ± 15.4 95.1±15.5 100.3±15.0 0.077 FEV1 (% predicted) 78.4 ± 20.0 75.6±30.3 81.2±19.5 0.143 TI (% predicted) 62.8 ± 12.9 61.6±13.5 64.0±12.2 0.339 Allergic rhini[s 42 (39%) 18 (33%) 24 (45%) 0.181 Atopic status 52 (48%) 24 (44%) 28 (53%) 0.339 Arterial hypertension 43 (40%) 27 (49%) 16 (30%) 0.045 Coronary artery disease 4 (4%) 4 (7%) 0 (0%) 0.045 Diabetes mellitus II 15 (14%) 10 (18%) 5 (9%) 0.176 Hypothyroidism 9 (8%) 2(4%) 7(13%) 0.072 GERD 35 (32%) 16 (29%) 19 (36%) 0.453 Table 1: Basic characterisHcs of paHents included, divided by gender. Data are number of parHcipants (%), mean ± SD, BMI = body mass index, GERD = gastroesophageal reflux disease PaHents o`en complained of sleep problems – Table 2, most common symptoms were nocturia, night awakenings, night cough, and restless leg symptoms. Women more o`en experienced night cough, restless leg symptoms and unrefreshed sleep, while men more o`en had nocturia. Overall Men Women (N=53) p-value (N=108) (N=55) Snoring 34 (31%) 18 (33%) 16(30%) 0.727 Breathing pauses 30 (28%) 14 (25%) 16 (30%) 0.583 Night awakenings 63 (58%) 32 (58%) 31 (58%) 0.936 Night cough 45 (42%) 17 (31%) 28 (53%) 0.021 Nocturia 76 (70%) 45 (82%) 31 (58%) 0.008 Restless leg symptoms 46 (43%) 18 (33%) 28 (53%) 0.035 Unrefreshed sleep 40 (37%) 15 (27%) 25 (47%) 0.032 Table 2: Nigh|me symptoms in paHents with difficult-to-treat asthma Asthma control (Asthma Control Test [ACT] score <20) was significantly worse in paHents experiencing breathing pauses (39% vs. 16%, p=0.007), night awakenings (71% vs. 45%, p=0.007), night cough (60% vs. 23%, p<0.001), restless sleep (51% vs. 21%, p=0.002), and unrefreshed sleep (50% vs. 23%, p=0.005). Sleep-disordered breathing (SDB) was confirmed in 59 paHents (55%), including 3 paHents (3%) with mild sleep apnoea and an ESS >10, 29 (27%) with moderate sleep apnoea, and 27 (25%) with severe sleep apnoea. Among them, 53 were diagnosed with OSA, while 6 had central sleep apnoea, with none in the la?er group experiencing severe sleep apnoea. Polysomnography revealed disturbed sleep in most paHents, despite no reported difficulty falling asleep— 76 paHents (70%) had a sleep latency of less than 30 minutes. However, 87 paHents (81%) experienced wake a`er sleep onset (WASO) exceeding 30 minutes, and sleep efficiency (SE) was below 85% in 82 paHents (76%). AddiHonally, 23 paHents (21%) had an arousal index greater than 15/h. PaHents with SDB had higher BMI (30.5 +/- 5.5 vs. 27.0 +/- 4.9, p=0.001), more o`en had arterial hypertension (31 (52%) vs. 12 (25%), p=0.003), and more o`en reported breathing pauses (22 (37%) vs. 8 (16%), p=0.015). DISCUSSION The present study confirms high prevalence of clinically significant OSA in populaHon of paHents with difficult-to-treat asthma and underscores the significant comorbidity between asthma and OSA. It is well-established that OSA is more prevalent in individuals with asthma compared to the general populaHon, and this co-occurrence can have substanHal implicaHons for asthma management. (8) Our findings align with the noHon that clinicians should consider screening for OSA in asthma paHents, parHcularly those with poorly controlled symptoms, especially nocturnal manifestaHons. Two studies have examined the relaHonship between severe/difficult-to-treat asthma and OSA prevalence. Julien et al. found that OSA was present in 50% of paHents with severe asthma, 23% with moderate asthma, and 12% in the control group. The prevalence was significantly higher in severe asthma compared to both moderate asthma (p = 0.044) and controls (p = 0.003), but the difference between moderate asthma and controls was not staHsHcally significant (p = 0.303). (9) Similarly, Yigla et al. conducted a study on 22 paHents with difficult-to-treat asthma and reported an excepHonally high OSA prevalence of 95.5%. (10) It is important to acknowledge that not all studies have found a significant associaHon between asthma severity and OSA risk. (11) VariaHons in the reported prevalence of OSA in asthma may be a?ributed to the diagnosHc methods employed, with PSG generally yielding higher prevalence rates compared to validated quesHonnaires. The concept of a bidirecHonal relaHonship between asthma and OSA is supported by the literature. Shaker et al. suggested a bidirecHonal relaHonship where the frequency of OSA increased with increasing asthma severity. (12) This implies a complex interplay between the two condiHons, where each may influence the other. PotenHal pathophysiological mechanisms underlying this comorbidity likely involve both systemic and local airway inflammaHon. (13) In our study, paHents frequently reported sleep disturbances, which were confirmed by polysomnography. This aligns with the findings of Alanazi et al., where 66% of asthmaHc paHents experienced poor sleep quality, parHcularly those with subopHmal asthma control. (14) Several other studies corroborate the impact of OSA on asthma control. Teodorescu et al. reported that a high risk of OSA was linked to nearly three Hmes higher odds of poorly controlled asthma. (15) Tay et al. observed that asthmaHcs with OSA had worse Asthma Control Test (ACT) scores in univariate analysis. (16) In our cohort, paHents experiencing night symptoms had more o`en poorly control asthma. CONCLUSIONS PaHents with difficult-to-treat asthma frequently exhibit symptoms of disrupted sleep and demonstrate poor sleep quality. Clinically significant OSA is present in half of these paHents. PaHents presenHng with breathing pauses, night awakenings, night cough, restless sleep, and unrefreshed sleep demonstrate poorer asthma control. Our findings reinforce the clinical significance of recognizing and managing the co-occurrence of OSA in paHents with asthma, especially those with poorly controlled disease. REFERENCES 1. Benjafield A V., Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ, et al. Es8ma8on of the global prevalence and burden of obstruc8ve sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7(8):687–98. 2. Mor8mer K, Lesosky M, García-Marcos L, Asher MI, Pearce N, Ellwood E, et al. The burden of asthma, hay fever and eczema in adults in 17 countries: GAN Phase I study. Eur Respir J [Internet]. 2022;60(3). 3. McNicholas WT, Korkalainen H. Transla8on of obstruc8ve sleep apnea pathophysiology and phenotypes to personalized treatment: a narra8ve review. Vol. 14, Fron8ers in Neurology. 2023. 4. GINA. Gina 2023 Full Report. Global Ini8a8ve for Asthma. Global strategy for Asthma Management and Preven8on. 2023. 5. Prasad B, Nyenhuis SM, Imayama I, Siddiqi A, Teodorescu M. Asthma and obstruc8ve sleep apnea overlap: What has the evidence taught us? Am J Respir Crit Care Med. 2020;201(11):1345–57. 6. Salles C, Terse-Ramos R, Souza-Machado A, Cruz ÁA. Obstruc8ve sleep apnoea and asthma. J Bras Pneumol. 2013;39(5):604-612 7. Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM MC and VB. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifica8ons, Version 2.0. Darien, Illinois: American Academy of Sleep Medicine; 2012. 8. Sarah E Davies, Abigail Bishopp, Simon Wharton, Alice M Turner & Adel H Mansur (2018): The associa8on between asthma and obstruc8ve sleep apnea (OSA): A systema8c review, Journal of Asthma, DOI: 10.1080/02770903.2018.1444049 9. Julien JY, Mar8n JG, Ernst P, Olivenstein R, Hamid Q, Lemière C, et al. Prevalence of obstruc8ve sleep apnea-hypopnea in severe versus moderate asthma. J Allergy Clin Immunol. 2009;124(2):371–376. doi:10.1016/j.jaci.2009.05.016 10. Yigla M, Tov N, Solomonov A, Rubin AE, Harlev D. Difficult-to-Control Asthma and Obstruc8ve Sleep Apnea. 2003;40(8):865–71. 11. Karachaliou F, Kos8kas K, Pastaka C, Bagia8s V, Gourgoulianis KI. Prevalence of sleep-related symptoms in a primary care popula8on - their rela8on to asthma and COPD. Prim Care Respir J. 2007;16(4):222-228. doi:10.3132/pcrj.2007.00045 12. Shaker A. Study of obstruc8ve sleep apnea (OSA) in asthma8cs. Egypt J Chest Dis Tuberc. 2017;66(2):293–8 13. Saxena D, Imayama I, Adrish M. Revisi8ng Asthma Obstruc8ve Sleep Apnea Overlap: Current Knowledge and Future Needs. J Clin Med. 2023;12(20):6552. Published 2023 Oct 16. doi:10.3390/jcm12206552 14. Alanazi TM, Alghamdi HS, Alberreet MS, et al. The prevalence of sleep disturbance among asthma8c pa8ents in a ter8ary care center. Sci Rep. 2021;11(1):2457. Published 2021 Jan 28. doi:10.1038/s41598-020-79697-x 15. Teodorescu M, Polomis DA, Hall SV, et al. Associa8on of obstruc8ve sleep apnea risk with asthma control in adults. Chest. 2010;138(3):543-550. 16. Tay TR, Radhakrishna N, Hore-Lacy F, et al. Comorbidi8es in difficult asthma are independent risk factors for frequent exacerba8ons, poor control and diminished quality of life. Respirology. 2016;21(8):1384-1390. doi:10.1111/resp.12838 INVITED PLENARY LECTURE FUNCTIONAL ALGORITHM FOR SEVERE AIRWAY DISEASE: FROM DIAGNOSIS TO FOLLOW-UP AND PHENOTYPING Matjaž Fležar MD PhD; University Clinic for Pulmonary and Allergic Diseases Golnik, Slovenia Medical faculty, University of Ljubljana BACKGROUND Lung funcHon measurements are a cornerstone of asthma diagnosis and follow-up. Since in physiological terms, asthma is disease of airways with variable and reversible obstrucHon, tests of airway funcHon are used in regular follow up and treatment. This review focuses on airway development (trajectories of lung growth), respiratory infecHon burden in asthma development and effects of treatments of asthma on lung funcHon outcomes. METHODS We have used PubMed search for relevant topics described in background using the filters of systemaHc review and metanalysis. We presented samples of most prevalent lung funcHon trajectories for paHents on biologic therapy and pracHcal guidelines for lung funcHon tesHng in follow-up and in paHents with comorbidiHes. RESULTS 25 studies linked to asthma development, influence of infecHons and effects of asthma treatment were chosen for analysis. We have shown that there are at least three different lung growth trajectories from childhood Hll adult age with predictors such as childhood asthma, atopy, early childhood wheezing, lower respiratory tract infecHons, parHculate ma?er exposiHon, etc. There is a geneHc background of early onset childhood wheeze and predisposiHon to develop T2 response to rhinovirus infecHon. Effect of biologics in severe asthma is least seen on improvement of lung funcHon indexes, disease modifying potenHal of these drugs extends to remodelling reversibility and lung funcHon improvement that can be permanent. RelaHonship to success on treatment is related more to Pre BD FEV1 than Post BD FEV1. Overall, the response of lung funcHon to biologics is in general very unpredictable and the best parameter to access is the rate of variability of obstrucHon over subsequent visits. CONCLUSION We sHll have to monitor lung funcHon changes in asthma, since remodelling and development of fixed airway obstrucHon is sHll an unmet need for future treatments of asthma. CO-USE OF DUAL BIOLOGIC THERAPIES IN PATIENT WITH SEVERE ASTHMA AND ANKYLOSING SPONDYLITIS: SAFETY PROFILE Golubović Aleksa1. Belić Slobodan1,2. Đurđević Nataša1,. Biševac-Perić Gordana1. Stjepanović Mihailo1,2. 1 Clinic for pulmonology University Clinical Center of Serbia, Belgrade, Serbia 2 Faculty of Medicine University of Belgrade BACKGROUND Severe asthma and ankylosing spondyliHs are chronic inflammatory diseases that require different biologic therapies. Benralizumab, an IL-5 receptor antagonist, and infliximab, a TNF-α inhibitor, have been used independently for these condiHons, but limited data exist on their combined use in paHents with comorbidiHes. CASE PRESENTATION A 61-year-old female with a 10-year history of asthma and ankylosing spondyliHs presented to the pulmonology clinic for ongoing disease management. The paHent had a significant history of poorly controlled asthma, characterized by frequent exacerbaHons, reliance on oral corHcosteroids, and a high level of eosinophils in her blood (eosinophil count >500 cells/µL). Her asthma remained inadequately controlled despite high-dose inhaled corHcosteroids (ICS) and long-acHng beta-agonists (LABAs). AddiHonally, the paHent had ankylosing spondyliHs, iniHally treated with NSAIDs and physical therapy. Over Hme, she developed significant axial and peripheral joint involvement, anterior uveiHs, as well as frequent morning sHffness and pain, leading to decreased quality of life and funcHonal impairment. Benralizumab was iniHated two years ago a`er the paHent failed to achieve sufficient control with inhaled therapies and oral corHcosteroids. She reported significant improvement in asthma symptoms and a reducHon in exacerbaHons. Infliximab was introduced eight months ago a`er an inadequate response to NSAIDs and convenHonal therapy. METHODS The paHent was closely monitored with regular clinical assessments, including asthma control tests, lung funcHon tests, disease acHvity scores for ankylosing spondyliHs, and laboratory tests to evaluate inflammaHon markers and potenHal side effects of combined therapy. RESULTS A`er six months of dual therapy, the paHent demonstrated significant improvement in asthma control, with reduced exacerbaHons and improved lung funcHon. Disease acHvity in ankylosing spondyliHs also decreased, with reduced inflammatory markers and improved mobility. No major adverse events were noted, although mild injecHon site reacHons were observed. CONCLUSION This case suggests that dual biologic therapy with benralizumab and infliximab may be a feasible and effecHve opHon for paHents with both severe asthma and ankylosing spondyliHs, though careful monitoring for safety is essenHal. Further studies are needed to be?er understand the long-term safety of this treatment combinaHon. DROBNOCELI NI RAK PLJU : KJE SMO IN KAM GREMO? Č Č Dušanka Vidovič Oddelek za pljučne bolezni, Klinika za interno medicino, UKC Maribor UVOD Pljučni rak predstavlja resen zdravstveni problem, saj je najpogostejši vzrok za umrljivost in zbolevnost zaradi raka v svetu in pri nas. Razvrščamo ga v dve veliki skupini: drobnocelični rak pljuč (DRP) in nedrobnocelični rak pljuč (NDRP) DRP predstavlja približno 15 % vseh pljučnih rakov in je ena najbolj smrtonosnih malignih bolezni z izrazito slabim petletnim preživetjem, manj kot 7 %. Je najpogostejši nevroendokrini tumor v pljučih in z drugimi ( karcinoidi, velikocelični nevroendokrini tumorji) predstavlja 13% vse pljučnih tumorjev. Večina bolnikov z DRP so trenutni ali bivši težki kadilci. DRP je prvi opisal Bernard leta 1926. Terapevtske možnosH so bile v Hstem obdobju neznatne. Napredek pri zdravljenju je bilo zaznaH šele s pojavom kemoterapije (KT) in radioterapije (RT) v obdobju od šestdeseHh do osemdeseHh let prejšnjega stoletja. Kemoterapija (KT) na osnovi plaHne v kombinaciji z etopozidom in/ali radioterapijo (RT) ostaja osnovno zdravljenje DRP že zadnjih 40 let. V tem času se je petletno preživetje le malo izboljšalo iz 3,6% na slabih 7%. Zdravljenje z operacijo je zaradi hitrega podvojitvenega časa tumorja in nagnjenosH k zasevanju le redko možno. Poskusi zgodnjega odkrivanja DRP se niso obnesli niH v populaciji z visokim tveganjem. SIMPTOMI, DIAGNOSTIKA IN PROGNOZA Večina bolnikov je ob postavitvi diagnoze simptomatskih. Simptomi se običajno pojavijo manj kot 3 mesece pred postavitvijo diagnoze in približno 75% bolnikov potrebuje hospitalizacijo v prvih treh mesecih po postavitvi diagnoze. Ob odkritju je rak pri 70% bolnikov že razširjen. Do sedaj opravljene študije niso pokazale dobrobiH presejalnih programov za DRP. Z letnim spremljanjem z nizkodoznim CT se ni zmanjšal niH odstotek razširjene bolezni niH se ni izboljšalo preživetje. Simptomi kot so kašelj, sprememba značaja kašlja, hemopHza, monofoni piski, dispneja, hripavost, bolečina, sindrom zgornje vene kave in disfagija so posledica prizadetosH pljuč in drugih organov v prsnem košu zaradi priHska, vraščanja ali zasevanja v sosednje organe (mediasHnalne bezgavke, požiralnik, srce, perikard, plevro in prsno steno). Simptomi, ki so posledica oddaljenih zasevkov, so lahko splošni, kot so neješčnost, hujšanje, utrujenost in oslabelost, zasevki v kosteh, jetrih, nadledvičnih žlezah in drugih organih pa lahko povzročajo bolečine, krvavitve, zapore organov in patološke zlome kosH, nevrološka simptomaHka se pojavi ob zasevanju v CŽS. Več različnih simptomov in znakov je posledica sistemskih hormonskih učinkov tumorja, ki povzročajo različne paraneoplasHčne sindrome (sindrom neustreznega izločanja ADH, Cushingov sindrom, hiperparaHreodizem, hiponatriemija, hiperkalciemija, nefrotski sindrom, motnje v koagulaciji in presnovi glukoze). Ob sumu na pljučni rak opravimo najprej slikovno diagnosHko CT trojček (prsni koš, trebuh in glavo), pri omejeni bolezni tudi PET/CT in MR glave. Vzorce za patohistološko analizo in ev. sekvencioniranje naslednje generacije - NGS (pri nekadilcih z DRP) pridobimo iz najbolj dostopne spremembe bodisi iz primarnega tumorja v pljučih z bronhoskopijo bodisi s punkcijo najdostopnejšega zasevka. Slab izid zdravljenja in nizko stopnjo preživetja napovedujejo negaHvni prognosHčni dejavniki: obsežna bolezen, slabo splošno stanje, hujšanje, kaheksija, visok LDH v serumu. K ugodnejšemu poteku bolezni poleg omejene oblike pripomore dobro splošno stanje, ženski spol, starost pod 70 let, normalna LDH in kreaHnin v serumu, manjše število zasevkov pri obsežni bolezni in opusHtev kajenja. KJE SMO IN KAM GREMO? Zaradi vse boljšega razumevanja DRP in intenzivnega razvoja novih zdravil je v zadnjem času nekaj več upanja tudi za bolnike z DRP. Čeprav do danes še nimamo zanesljivih markerjev, ki bi napovedovali odziv na zaviralce imunskih kontrolnih točk (ZIKT) pri DRP, je odobritev atezolizumaba, pembrolizumaba in nivolumaba v kombinaciji s KT doprinesla k kliničnemu napredku pri zdravljenju. Zaradi genomske nestabilnost in skoraj popolne inakHvacije genov TP53 in RB1 je za DRP značilna dobra vaskularizacija tumorja, hitra rast in zgodnje zasevanje. Posledično ima večina bolnikov z DRP že ob postavitvi diagnoze zasevke tudi zunaj prsnega koša. Odzivnost na začetno zdravljenje je sicer dobro, vendar se bolezen pogosto ponovi. Po enem letu se rak ponovi pri več kot 88% bolnikov. Ko se rak ponovi, je bolj odporen na zdravljenje in popolna ozdravitev je izredno redka. V zadnjem desetletju pojavnost DRP upada, predvsem zaradi zmanjšane incidence pri moških. Zdi se da PET/CT izboljša natančnost zamejitve in načrtovanja zdravljenja. Omejeni stadij (limited disease - LD) je potencialno ozdravljiva bolezen, z dolgoročnim preživetjem približno 20 % pri zdravljenju s kemoterapijo na osnovi plaHne in sočasnim obsevanjem prsnega koša. Hiperfrakcionirano obsevanje prsnega koša in profilakHčno obsevanje glave (PCI) lahko znatno izboljšata splošno preživetje pri izbranih bolnikih z omejeno boleznijo. Pri bolnikih z obsežno boleznijo (extended disease - ED) se lahko preživetje poveča s kombinirano kemoterapijo, vendar bolezen ostaja neozdravljiva, dolgoročno preživetje je redko. Uporaba PCI lahko dodatno izboljša splošno preživetje pri razširjeni bolezni. Več novejših citotoksičnih učinkovin ima obetavno učinkovitost v zgodnjih kliničnih preskušanjih. Čeprav je bilo v predkliničnih študijah za DRP ugotovljenih veliko potencialnih molekularnih tarč, molekularno usmerjena terapija v kliničnih preskušanjih še ni pokazala bistvene učinkovitosH. Kljub temu bo prihodnji napredek pri tej bolezni nedvomno odvisen od izboljšav v našem razumevanju molekularnih mehanizmov, ki poganjajo proliferacijo in preživetje celic DRP. LITERATURA 1. Haddadin S, Perry MC. History of small-cell ling cancer. Clin. Lung Cancer 2011; 12:87-9. 2. Vrankar M, Boc N, Kern I, Rozman A, Stanič K, Štupnik T et al. Priporočila za obravnavo bolnikov s pljučnim rakom. Onkologija 2023; 30-88. 3. Raso MG, N Bota- Rabassesedas, Wistuba II. Pathology and classificaAon of SCLC. Cancer 2021; 13(4): 820. 4. Waqar SN, Morgensztern D. Treatment advances in small cell lung cancer (SCLC). Pharmacology & therapeuAcs 2017; 180: 16-23. 5. Poirier JT, George J, Owonikoko TK, Berns A. New approaches to SCLC therapy: from the laboratory to the clinic. Journal of thoracic oncology 2020; 15 (4): 520-540. INVITED LECTURE URGENTNA STANJA V DIAGNOSTIKI PLJU NEGA RAKA Č Katja Adamič, dr.med. spec., Univerzitetna klinika za pljučne bolezni in alergijo Golnik UVOD Bolniki s pljučnim rakom so pogosH obiskovalci urgentnih ambulant, že na začetku diagnosHke in kasneje v procesu zdravljenja ter paliaHvne oskrbe. Glavni razlogi za obiske v urgentnih ambulantah pri bolnikih, ki jim je bil kasneje ugotovljen pljučni rak, so bile nevrološke težave, plevralni izliv, pljučnice, perikardialni izliv, hemopHze in elektrolitske motnje. Zdravniki v urgentnih ambulantah bi morali biH pri kadilcih z omenjenimi težavami pozorni na možnost pojava pljučnega raka. Pravih urgentnih stanj, ki so zahtevala takojšnje ukrepanje ali ukrepanje v 24 urah, je bilo malo (< 5 %). V literaturi zasledimo dve stopnji nujnosH. Prva stopnja nujnosH se nanaša na stanja, ki bolnika neposredno ogrožajo z okvaro organa ali življenja. Druga stopnja nujnosH so stanja, kjer je potrebno hitro, vendar ne takojšnje ukrepanje. Določena manj urgentna stanja lahko že v nekaj urah preidejo v ogrožajoča. Za pravilno ukrepanje sta največkrat odločilna klinična presoja in opazovanje bolnika. PARANEOPLASTIČNI SINDROMI ParaneoplasHčni sindromi (PNS) so skupina nepravilnosH, ki se lahko pojavijo pri bolnikih z različnimi, običajno malignimi neoplazmami. So posledica izločanja hormonov ali funkcionalnih pepHdov (encimi, rastni dejavniki, citokini) iz tumorskih celic ali posledica navzkrižne imunske reakcije med tumorskim in gosHteljskim, to je bolnikovim tkivom. Ocenjujejo, da ima 10–20% bolnikov z maligno boleznijo tudi PNS. PNS so pri teh bolnikih drugi najpogostejši neposredni vzrok smrH, takoj za maligno boleznijo. Večino PNS razložita dva mehanizma: imunološki, ki je verjetno pogostejši, in neimunološki. Nosilci neimunološkega mehanizma so hormoni ali njim podobne snovi, funkcionalne beljakovine ali citokini, ki jih lahko izdelujejo nekatere tumorske celice. Ti lahko povzročajo elektrolitske in/ali presnovne nepravilnosH, npr. hiponatremijo zaradi prekomernega izločanja anHdiureHčnega hormona (ADH) ali hiperkalcemijo zaradi prekomernega izločanja paraHroidnemu hormonu podobnega pepHda. Nekateri PNS lahko resno ogrozijo bolnikovo življenje, so nujna stanja in zahtevajo prednostno ukrepanje. Ključno zdravljenje je učinkovito zdravljenje osnovne, maligne bolezni. Vse druge oblike zdravljenja so simptomatske, kar pomeni, da PNS ne zdravijo, ampak lahko le ublažijo njihove simptome in zmanjšajo ali preprečijo nastanek nepopravljivih okvar. Sem sodi imunosupresivno zdravljenje in plazmaferezo. Med imunosupresivnimi zdravili so prva izbira korHkosteroidi, redkeje imunoglobulini in ciklosporin. HIPERKALCEMIJA Hiperkalcemija je najpogostejša elektrolitska motnja pri bolnikih z malignimi boleznimi. Povezana je lahko s kostnim zasevki ali pa gre za paraneoplasHčno hiperkalcemijo, ki je lahko posledica ektopičnega izločanja PTH-rP, 1,25-dihidroksiholekalciferola (1,25-OHD; vitamin D) ali druge akHvne substance, ki se vpleta v presnovo kosH oz. homeostazo kalcija. PTH-rP po strukturi in delovanju posnema paraHroidni hormon (PTH). Spodbuja resorbcijo kosH in ledvično izgubo fosfata. To vodi v hiperkalcemijo in hipofosfatemijo, vrednosH intaktnega PTH (iPTH) je ob tem normalna ali znižana. V laboratorijskih izvidih izstopa visoka vrednost serumskega kalcija in ob tem zmanjšana kalciurija. Klinična slika bolnika je zelo odvisna od hitrosH nastanka hiperkalcemije in višine kalcija v serumu. Bolniki tožijo o slabosH, suhih usHh, žeji, poliuriji, zaprtju, splošni oslabelosH. Če H simptomi niso prepoznani, sledi dehidracija, ledvična okvara, nevrološki simptomi, kot je hipertonija, mišični krči, psihična spremenjenost, hipertenzija, življenjsko nevarne aritmije. Potrebna je izdatna hidracija bolnika z infuzijami fiziološke raztopine in sHmulacija kalciurije. Ključno simptomatsko zdravilo so bisfosfonaH. Zdravljenje s kalcitoninom ima manjši pomen. Vrednost serumskega kalcija po uporabi kalcitonina običajno hitro pade, vendar je učinek le kratkotrajen. HIPONATRIEMIJA KOT POSLEDICA SIADH SIADH (Sindrom neustreznega izločanja anHdiureHčnega hormona) je najpogostejši paraneoplasHčni endokrini sindrom povezan z drobnoceličnim rakom pljuč. Vzrok je neregulirana proizvodnja ADH, kar povzroči hiponatremijo, nizko osmolarnost, povečano izločanje natrija v urinu ter visoko osmolarnost urina v primerjavi s plazemsko osmolarnostjo. Zdravljenje SIADH, ki je posledica PNS, vključuje zdravljenje osnovnega malignoma. Hiponatremijo pa simptomastsko zdravimo z omejitvijo vnosa tekočin na 1 liter dnevno, dodajanjem soli v prehrano ali infuzijo 3% NaCl v primeru simptomatske hiponatremije. Druge možnosH zdravljenja so antagonisH receptorjev za vazopresin, ki jih je treba uporabljaH previdno, da se prepreči prekomerna korekcija hiponatremije. Hitrost korekcije natrija je pomembna, da se prepreči nevrološke poškodbe, kot je osmozna demielinizacija. Pri bolnikih z akutno hiponatremijo je korekcija 1–2 mmol/L/h varna in zadostna. Pri bolnikih s kronično hiponatremijo naj bi bila hitrost korekcije 0,5–1 mmol/L/h, brez preseganja 10–12 mEq natrija v prvih 24 urah. PARANEOPLASTIČNI NEVROLOŠKI SINDROMI Nevrološki PNS so redki. Natančna pojavnost ni poznana, ocenjujejo, da je 1–5-%,vendar je verjetno podcenjena, saj so zaradi redkosH in kompleksnosH številni PNS neprepoznani. Prizadet je lahko kateri koli del živčnega sistema: osrednje živčevje, živčno-mišični sHk, periferno živčevje ali več nivojev sočasno. Skladno s tem je klinična slika odvisna od nivoja, na katerem je patološko dogajanje. Patogeneza je verjetno raznolika in pogosto ni pojasnjena. Za nekatere je poznan imunsko posredovan mehanizem, to je navzkrižna reakcija med anHgeni tumorskih celic in njim podobnimi anHgeni živčnega sistema (onkonevralni anHgeni), ki jo izzovejo t. i. onkonevralna proHtelesa. Prisotnost nekaterih proHteles je povezana z različnimi nevrološkimi sindromi. Prav tako je pri nekem nevrološkem sindromu lahko prisotnih več različnih proHteles. Zelo pomembna je zgodnja prepoznava, saj onkonevralna proHtelesa lahko povzročijo trajno poškodbo živčnega sistema, ki vodi v trajno zmanjšano kakovost življenja bolnika. DiagnosHčni postopki so pogosto zahtevni in vključujejo klinični pregled, slikovne (MR, FDG-PET/CT), serološke, elektrofiziološke preiskave elektroencefalografija, elektromiografija, analizo likvorja in drugo. Pomembna preiskava je določanje onkonevralnih proHteles v likvorju in serumu. Slabost te diagnosHčne metode je nizka občutljivost in specifičnost. Do 30% bolnikov nima zaznavnih proHteles v serumu ali likvorju, zaznamo pa jih tudi pri posameznikih brez znakov in simptomov in brez znane maligne bolezni. Primer PNS na živčno mišičnem sHku je Lambert-Eatonov miastenični sindrom (LAMS). Klinična slika spominja na miastenijo gravis. Bolnik toži o šibkosH proksimalnih mišic, predvsem spodnjih okončin. Težave ima pri osnovnih dejavnosHh,kot so hoja po stopnicah in vstajanje s stola. Večkratna ponovitev določenega giba težave zmanjša. Zgodaj se lahko razvijejo tudi simptomi prizadetosH avtonomnega živčevja: suha usta, zmanjšano znojenje, zaprtje, erekHlna disfunkcija. Miastenija gravis je periferni nevropatski sindrom. Patološki proces je značilen in povzročen s prisotnostjo onkonevralnih proHteles, proHteles proH aceHlholinu (anH-Ach), ki delujejo na ravni nevromišične sinapse. Klinično se kaže z utrujenostjo in šibkostjo mišic, ki vključuje prostovoljne in neprostovoljne mišične skupine. Mišična šibkost se poslabša skozi dan in z ponovljenim naporom. Ta šibkost je še posebej izrazita v proksimalnih mišicah okončin. Očesna in bulbarna prizadetost sta prav tako pogostejši kot pri LEMS. Vključenost diafragmatskih mišic je prisotna pri hudih primerih miastenije gravis. Limbični encefaliHs se kaže kot akuten ali subakuten klinični sindrom. Bolniki imajo anterogradno amnezijo, spremembe razpoloženja, halucinacije in epilepHčne napade. Opsoklonus-mioklonus-ataxija je redka nevrološka motnja, ki združuje tri glavne simptome: opsoklonus: hitri, neprostovoljni in neurejeni gibi oči; mioklonus: kratki, neprostovoljni trzaji mišic ali skupin mišic; ataksija: motnje ravnotežja in koordinacije, kar lahko vodi v pogoste padce. ParaneoplasHčna cerebelarna degeneracija je redka nevrološka motnja, ki je povezana z različnimi vrstami tumorjev, vključno z rakom pljuč. Simptomi se pogosto začnejo nenadoma in lahko vključujejo težave z hojo, izgubo koordinacije okončin, težave z govorom (dizartrija), težave s požiranjem (disfagija), nistagmus (nenadzorovana gibanja oči) in omoHco. Včasih se lahko pojavijo tudi predhodni simptomi, kot so povišana telesna temperatura, slabo počutje, slabost in bruhanje. Subakutna senzorna nevropaHja je stanje, pri katerem pride do postopnega pojava senzoričnih motenj, kot so bolečine, parestezije ali zmanjšana občutljivost, običajno na rokah in nogah. Pogosto je povezana z avtoimunskimi ali paraneoplasHčnimi ganglionopaHjami zadnjega korena hrbteničnega živca. POVIŠANA TELESNA TEMPERATURA Bolnik toži o splošnem slabem počutju, ima zagone porasta telesne temperature, splošno propada, ima slab apeHt, izgublja telesno težo. Vzrok so verjetno pirogeni citokini ali njim podobne substance, ki jih proizvajajo tumorske celice, kot so interlevkin- 1 (IL-1), tumorje nekroHzirajoči dejavnik (angl. tumor necrosis factor, TNF), IL-6 itd. Najprej je treba izključiH vnetni (infekHvni) vzrok za povišano telesno temperaturo. Diagnoza paraneoplasHčne vročine je izključitvena. Spremlja lahko številne maligne bolezni, najpogostejša je pri limfoproliferaHvnih boleznih, pojavlja pa se tudi pri nekaterih solidnih rakih. Specifično zdravljenje je zdravljenje osnovne bolezni, simptomatsko vključuje nesteroidne anHrevmaHke. OBILNA KRVAVITEV IZ DIHAL Življenjsko nevarna ali masivna hemopHza je opredeljena kot večja količina krvi, medtem ko je klinična nestabilnost bolj ustrezna opredelitev. Količina krvi za masivno hemopHzo se giblje med 100 in 1000 mL v 24 h. Pomembnost krvavitve temelji na njenih kliničnih posledicah, ki lahko vključujejo: obstrukcijo dihalnih poH, hipoksemijo, intubacijo, hipotenzijo, potrebo po transfuziji, enostransko pljučno venHlacijo in smrt. Pri malignih obolenjih obstajajo številni mehanizmi hemopHze, ki vplivajo na količino in hitrost krvavitve. Vzroki za hemopHze so: neovaskularizacija znotraj tumorja in v njegovi okolici, razjedanje tumorske površine, vraščanje tumorja v dihalne poH okoliške žilne strukture ter iatrogene krvavitve po posegih na dihalnih poteh. Manjša hemopHza je veliko pogostejša kot masivna hemopHza, ki je razmeroma redka. Določanje klinične stabilnosH bolnika je na prvem mestu. Čas nastanka, ocenjena količina izkašljane krvi in hitrost krvavitve pomagajo pri oceni tveganja. Lokacija tumorja prav tako pripomore k opredelitvi tveganja za krvavitev. CT angiografija žilja v prsnem koša z omogoča podrobno oceno mesta krvavitve. Začetni pristop k masivni hemopHzi se mora vedno začeH z obvladovanjem dihalne poH in hemodinamske stabilizacije bolnika. Ko je bolnik stabiliziran, je ključnega pomena lokalizacija strani krvavitve, da zaščiHmo nekrvaveče pljučno krilo. Pri hemopHzi, povezani z maligno boleznijo, je poznavanje mesta primarnega tumorja bistveno, saj je to najverjetnejši vir krvavitve. Metastatska bolezen z obojestransko prizadetostjo pljuč pa lahko predstavlja večji izziv, saj je lahko več možnih mest krvavitve. Ko je določena stran krvavitve, je pomembno bolnika namesHH v lateralni dekubitus položaj s krvavečo stranjo navzdol. Ta položaj uporablja gravitacijo, da prepreči razlitje ali aspiracijo krvi v nepoškodovano pljučno krilo. Prisotnost obojestranskih intraalveolarnih infiltratov lahko nakazuje razlitje krvi v kontralateralno, nekrvaveče pljučno krilo in lahko pomeni bližajočo se respiratorno odpoved. Pomembna dispneja, nezmožnost obvladovanja količine krvi ali izločkov, slabša izmenjava plinov in/ali poslabšanje hipoksemije, hemodinamska nestabilnost ali hitro napredujoča hemopHza so vsi indikacije za intubacijo. Velikost tubusa naj bo ≥8 mm. Večji notranji premer omogoča uporabo terapevtskega bronhoskopa in drugih pripomočkov, kot so bronhialni blokatorji. Pri intubiranem bolniku se priporoča takojšnjo bronhoskopijo za odstranitev strdkov iz dihalnih poH. Terapevtski endobronhialni postopki so: bronhialni blokatorji, endobronhialna uporaba ledene fiziološke raztopine in vazokonstriktorjev, koagulacija z argon plazmo, z elektrokavterjem, laserjem, endobronhialno radioterapijo, vstavitev stentov. KonzervaHvno zdravljenje masivne hemopHze naj bi zagotavljalo le začasni terapevtski učinek, saj brez bolj definiHvnih ukrepov obstaja 50–100-odstotna stopnja ponovitve. Bronhialna arterijska embolizacija je danes široko uporabljena kot prva in učinkovita terapija za obvladovanje masive hemopHze. Postopek vključuje arteriogram, običajno izveden z kanulacijo femoralne arterije, in embolizacijo prizadete bronhialne arterije. S kirurško resekcijo dela pljuč odstranimo vzrok krvavitve. V akutni fazi jo napravimo takrat, kadar BAE ni bila uspešna in pri krvavitvah iz velikih žil. Z odloženimi resekcijami preprečimo ponovitev krvavitve po sicer uspešni BAE. Traneksamska kislina (TK) deluje kot anHfibrinoliHk. Njeno delovanje temelji na inhibiciji pretvorbe plazminogena v plazmin, kar zmanjšuje raztapljanje fibrinskih strdkov in s tem zmanjšuje krvavitve. V nekaterih primerih hemopHze je lahko peroralna ali nebulizirana uporaba TK učinkovita pri obvladovanju krvavitev. Čeprav večina raziskav obravnava hemopHzo, ki ni povezana z rakom, so nekatere manjše serije primerov pokazale pomemben učinek inhalirane in intravenske TK pri hemopHzi, povezani z malignimi obolenji. SINDROM ZGORNJE VOTLE VENE Tumorji zgornjega mediastinuma lahko pritisnejo na zgornjo votlo veno in posledično povzročijo moten odtok krvi v srce. Najpogostejši simptomi sindroma zgornje votle vene (SZVV) so otekanje obraza, vratu in rok. Čeprav sami po sebi niso nevarni, so lahko pokazatelj potencialno nevarnega edema drugje v telesu. Otekanje v grlo lahko povzroči dispnejo, stridor, kašelj ali disfagijo. Cerebralni edem lahko vodi do glavobola, zmedenosti in v najslabšem primeru do smrti zaradi cerebralne herniacije. Simptomi se pogosto poslabšajo pri ležanju ali sklanjanju naprej. Vidne so napolnjene vene vratu in zgornjega dela prsnega koša (kolateralni obtok). Najpogosteje vidimo SZVV pri drobnoceličnem raku pljuč. Pri tem podtipu raka je enako uspešno hitro specifično zdravljenje s kemoterapijo ali obsevanjem, pri ostalih vrstah je bolj uspešno obsevanje. V primerih akutnega SZVV s hudimi simptomi so začetni koraki zdravljenja ključni. Na srečo se v manj kot 15 % primerov SZVV pojavijo hudi simptomi. Dvig vzglavja postelje in dodatek kisika sta preprosta ukrepa za ublažitev simptomov. Intubacija je potrebna, če je prisoten znaten laringealni edem. Steroidi lahko zmanjšajo velikost tumorjev, odvisno od vrste. V literaturi ni podpore za uporabo diuretikov. Če bolnik potrebuje nujno zdravljenje venskih obstrukcij, kot so akutna obstrukcija osrednjih dihalnih poti, huda oteklina grla ali koma zaradi cerebralnega edema, je potrebno razmisliti o neposrednem odprtju ovire z endovaskularnim stentiranjem in angioplastiko s trombolizo. Takšen pristop lahko takoj lajša simptome, preden se uvedejo specifične terapije za raka, in je lahko primeren kot standardno zdravljenje za takojšnje simptomatsko obvladovanje. Endovaskularno stentiranje je prednostno v primerjavi z drugimi načini zdravljenja, saj hitreje olajša simptome SZVV v primerjavi s kemoterapijo in obsevanjem. Prav tako je stentiranje indicirano pri blagih simptomih, ki vztrajajo ali se ponovijo po sistemskem zdravljenju. OBSEŽEN MALIGNI PLEVRALNI IZLIV Maligni plevralni izliv je lahko prvi znak pljučnega raka ali pa nastane kot posledica zasevanja drugih malignomov. Bolnik dražeče kašlja, navaja dušenje in bolečino v prsnem košu. Pogosto potoži, da lahko leži oz. spi brez težav le na HsH strani, kjer je plevralni izliv. neslišno dihanje. Na rentgenski sliki pljuč obsežen izliv poHska mediasHnum in srce na zdravo stran. Pri kliničnem pregledu ugotavljamo tahipnejo, perkutorno zamolklino in oslabljeno dihanje. Priporočeno je odstraniH največjo možno varno količino izliva, saj s tem zagotovimo maksimalno olajšanje dispneje, pridobimo podatke o zmožnosH razpenjanja pljuč in čimbolj podaljšamo čas do ponovne razbremenilne punkcije. Večina priporočil priporoča odstranjevanje do 1500ml tekom ene torakocenteze, pomembna je prekinitev razbremenjevanja v primeru pojava bolečine ali Hščanja v prsnem košu. Ob sočasnem merjenju plevralnih tlakov, s katero tekom plevralne punkcije merimo plevralne tlake in njihovo dinamiko upada, lahko varno odstranimo tudi do 5000ml, poleg tega pa nam krivulje upada tlakov z odstranjenim volumnom razkrijejo ujeta pljuča. V primeru ustreznega razpenjana pljuč in dobrega kliničnega stanja bolnika izvedemo plevrodezo s talkom, ki jo izvajamo med torakoskopijo ali preko torakalnega drena. Če ima bolnik ujeta pljuča in se plevralni izliv hitro nabira ter so potrebne pogoste izpraznitvene punkcije, bolniku vstavimo trajni drenažni plevralni kateter. Na ta način velikokrat dosežemo mehansko plevrodezo in kateter kasneje odstranimo. MALIGNI PERIKARDIALNI IZLIV S TAMPONADO SRCA Pljučni rak je najpogostejši primarni tumor, ki prizadane perikard, s prevalenco do 50 %. Maligni perikardialni izliv s tamponado srca predstavlja nabiranje tekočine v perikardu. Nastane, ko sta zaradi zasevkov v perikardu ali razraščanja tumorja v mediasHnumu ovirani limfaHčna in venska drenaža. Bolniki z majhnim perikardialnim izlivom večinoma nimajo težav. Večji izlivi, ki povzročajo motnje diastolične polnitve srca in posledični padec utripnega volumna srca, pa vodijo v hipotenzijo in tamponado srca. Bolniki navajajo topo bolečino v prsnem košu, dušenje, hiter ali nereden srčni utrip, utrujenost in vrtoglavico. Pri bolniku ugotavljamo nabrekle vratne vene, tahikardijo, Hhe srčne tone, pri tamponadi pa tudi paradoksni utrip – zmanjšanje sistoličnega tlaka v inspiriju za več kot 10 mmHg. Za diagnozo je treba narediH ultrazvočno preiskavo srca in izmeriH velikost izliva. Pod ultrazvočno vodeno punkcijo v enoH intenzivne terapije, ob skrbnem monitoringu bolnika, izpraznimo perikardialni izliv preko katetra, ki ga vstavimo v perikardialni prostor. OBSTRUKCIJA DIHALNIH POTI Obstrukcijo zgornjih dihalnih poH pri raku pljuč zasledimo redko, do nje lahko pride zaradi zunanjega priHska tumorja ali zasevkov na sapnik ali primarnega tumorja traheje, ki pa je redek. Obstrukcija spodnjih dihal je pri bolnikih z rakom pogostejša, vendar večinoma ni življenjsko ogrožajoča. Bolniki se dušijo, kašljajo, lahko se pojavi stridor, hemopHze, avskultatorno slišimo piske. Obstrukcijo večjih dihalnih poH (pogosto že poobstrukcijski pnevmoniHs) pokaže rentgensko slikanje pljuč, manjše pa pogosto vidimo le na CT slikah. Za hitro lajšanje težav dajemo bolniku korHkosteroide in kisik ter bronhodilatatorje. Bolnik mora čim prej opraviH endoskopski pregled dihalnih poH, ki je istočasno lahko že terapevtski (mehanska odstranitev tumorja s kleščicami, krioterapijo, z laserjem ali endobronialna opornica pri priHsku od zunaj). KOMPRESIJA HRBTENJAČE Kompresija hrbtenjače ni življenjsko ogrožajoče stanje, lahko pa vodi v hudo invalidnost. Do nje pride, če zasevek pljučnega raka raste v spinalni kanal. Običajno gre za mehko tkivno tumorsko maso, ki raste paravertebralno in najde pot skozi intervertebralne foramne, ali pa zasevek povzroči destrukcijo in posledično sesedanje vretenca, ki nato priHsne navzad na hrbtenjačo. Običajno so bolnikove prve težave bolečine, ki jim sledijo nevrološki simptomi, kot so motnje senzibilitete, retenca urina in blata ter motnje motorike. Rentgenska preiskava lahko prikaže samo skeletne spremembe, ne pa tudi mehko tkivnih tumorskih mas. Pri razviH parezi je potrebno ukrepanje v 24 urah. Bolnika naj pregleda nevrolog, ki določi nivo okvare hrbtenjače. Na osnovi tega pregleda naredimo MR hrbtenice, v primeru kontraindikacij pa CT. MožnosH zdravljenja so: operacija (dekompresija in stabilizacija) in obsevanje ali samo obsevanje. Zasevke v skelet kot prvi znak pljučnega raka opisujejo v 2 % primerov. Če histološko rak še ni potrjen, je med operacijo nujno odvzeH tkivo za patološke preiskave. Bolnik naj miruje, predpišemo mu proHbolečinsko terapijo in anHedematozno terapijo s korHkosteroidi. ZVIŠAN INTRAKRANIALNI TLAK Možgani so pogosto mesto zasevkov pljučnega raka. Zaradi omejene možnosH širjenja struktur znotraj lobanje ob tumorski rasH in edemu nastanejo znaki zvišanega znotrajlobanjskega priHska. Pojavi se glavobol, slabost, bruhanje, zmedenost, vrtoglavica, v najhujših primerih otrplost Hlnika, edem papile, hipertenzija in bradikardija. Drugi znaki, ki so pogosteje znaki same lege zasevkov, pa so zanašanje pri hoji, afazija, hemiplegija, motnje vida. CT glave nam razkrije zasevke, njihovo število in velikost. Bolj natančna pa je preiskava z MR, ki je potrebna, če je na CT viden le en zasevek, saj je v primeru solitarnega zasevka najuspešnejša njegova operaHvna odstranitev. Če zasevek ni večji od 3 cm, se ga lahko enako uspešno stereotakHčno obseva. V primeru številnih zasevkov obsevamo celotne možgane. Pri obsežnem edemu uspešno blažimo simptome s korHkosteroidi v visokih odmerkih in z infuzijami manitola. V primeru epilepHčnih napadov uvedemo še anHepilepHke. ZAKLJUČEK Urgentna stanja pri bolniku, ki je v diagnosHki pljučnega raka, nastanejo kot posledica invazivne rasH tumorja, izločanja akHvnih substanc iz tumorja ali pa so posledica invazivne diagnosHke. Gre za raznolika klinična stanja, ki pogosto zahtevajo mulHdisciplinarno obravnavo. Ker gre pogosto za neposredno ogrožujoče življenjsko stanje, moramo ukrepaH hitro in je prav, da jih pozna vsak zdravnik, ki dela v urgentni ambulanH. LITERATURA 1. Matos E. ParaneoplasAčni sindromi, Med Razgl. 2023; 62 (3): 293–302 2. Soomro Z, Youssef M, Yust-Katz S, Jalali A, Patel AJ, Mandel J. ParaneoplasAc syndromes in small cell lung cancer. J Thorac Dis. 2020 Oct;12(10):6253-6263. 3. Pi J, Kang Y, Smith M, et al. A review in the treatment of oncologic emergencies. J Oncol Pharm PracAce 2015; 0: 1–14. 4. Sardina Gonzalez C, MarAnez Vivero C, Lopez Castro J. ParaneoplasAc syndromes review: The great forgoien ones. Crit Rev Oncol Hematol. 2022 Jun; 174. 5. Onyema MC, Drakou EE, Dimitriadis GK. Endocrine abnormality in paraneoplasAc syndrome. Best Pract Res Clin Endocrinol Metab. 2022; 36 (3): 101621. 6. Gilligan M, McGuigan C, McKeon A. ParaneoplasAc Neurologic Disorders. Curr Neurol Neurosci Rep. 2023; 23 (3): 67–82. 7. Kovač V, Stanič K. "Urgentna stanja pri pljučnem raku." Prva šola pljučnega raka (2015) Str. 27-40. 8. Stanič K. "Kdaj se mudi - urgentna stanja pri raku pljuč." Druga šola pljučnega raka (2016) Str. 32-37. 9. Marc Malovrh M et al: Zbornik prispevkov delavnice obravnave plevralnih bolezni, Golnik 2023 10. Gershman E, Guthrie R, Swiatek K, Shojaee S. Management of hemoptysis in paAents with lung cancer. Ann Transl Med. 2019 Aug;7(15):358. 11. Chow R, Simone BC, Rimner A. Management of malignant superior vena cava syndrome. Annals of PalliaAve Medicine.Vol 13, No 3, 2024, 2224-5839 12. Quencer KB. Superior Vena Cava Syndrome: EAologies, ManifestaAons, and Treatments. Semin Intervent Radiol. 2022 Aug 31;39(3):292-303. INVITED LECTURE VSTAVITEV OPORNICE V ZGORNJO VOTLO VENO Dimitrij Kuhelj, Klinični inšFtut za radiologijo UKCL, Ljubljana UVOD Sindrom zgornje votle vene (SZV) povzroči zožitev ali zapora zgornje votle vene in/ali njenih vej. Klinično se najpogosteje kaže kot zatekanje glave in vratu ter zgornjih okončin ter je lahko enostransko ali obojestransko. Lahko se kaže tudi z ortopnejo, vrtoglavico ali zamegljenim vidom, znaki so najbolj izraženi zjutraj. SZV lahko celo ogroža življenje bolnika, če nastane edem možgan ali dihalnih poH(1). Vzrokov za nastanek SZV je več, najpogostejši je maligen, ki ga povzročita drobnocelični rak pljuč ali limfom. Vse pogosteje srečujemo SZV tudi pri pacienHh z vstavljenimi različnimi katetri (bolniki na dializi, HsH s srčnimi spodbujevalci…). Diagnoza je klinična, s slikovnimi preiskavami le potrdimo vzrok za nastalo oteklino in/ali razširjene obvodne vene. Navadno uporabimo CT venografijo, redkeje MR venografijo. Kateterski prikaz zgornje votle vene je namenjen zdravljenju in se redko uporablja kot diagnosHčna metoda. Zdravimo izključno paciente, ki imajo simptome- prevenHvno zdravljenje slikovno odkriHh sprememb ni smiselno, saj lahko do klinične manifestacije SZV sploh ne pride. V primeru življenje-ogrožujočega SZV je potrebno čim prejšnje znotrajžilno zdravljenje. Pri bolnikih, ki so manj prizadeH, je oblika zdravljenja odvisna od eHologije- sama balonska širitev vene je navadno malo učinkovita, vstavitev opornice pa predstavlja trajen tujek v organizmu, zato znotrajžilno zdravljenje brez ustrezne opredelitve spremembe navadno ni smiselno. Pri drobnoceličnem raku pljuč in simptomatskem SZV je znotrajžilno zdravljenje navadno prvo zdravljenje, saj je radioterapevtsko in zdravljenje s kemoterapijo zdravljenje učinkovito v 3-30 dneh (2). Pogosto je znotrajžilno zdravljenje tudi prvo pri benignih vzrokih SZV, tako da ostaja kirurško zdravljenje omejeno le v primeru, ko znotrajžilno zdravljenje ni uspešno ali izvedljivo. IZVEDBA POSEGA Poseg je enostaven, pričakovanih zapletov je malo. Priprava bolnika zahteva, da je tešč ter da ima ustrezne vrednosH strjevanja krvi. Najpogosteje ga izvedemo v lokalni anesteziji, splošna anestezija je občasno potrebna zaradi bolnikovega splošnega stanja ali zaradi bolečin, ki nastanejo pri širjenju vene, predvsem v primeru benignih zožitev zaradi fibroze. Pristopimo skozi skupno femoralno veno, punkcijo izvedemo pod UZ kontrolo. Uvedemo žilno uvajalo ter poizkusimo preiH zožitev ali zaporo v zgornji votli veni. V primeru, da nam to ne uspe, navadno pristopimo še z druge strani, skozi kubitalno ali jugularno veno. Po prehodu zožitve ali zapore prikažemo njen obseg in premer pretočne zgornje votle vene. Apliciramo 5000 IE heparina. Glede na meritve izberemo ustrezno žilno opornico. Navadno uporabimo samoraztezne žilne opornice z visoko radialno silo. V zgornjo votlo veno postavimo navadno opornico premera od 20-40 mm. Če zajema sprememba tudi vene, ki se vlivajo v zgornjo votlo veno, moramo navadno dodaH opornice tudi tja (Y konfiguracija), ki so premera do 14-20 mm. V primeru, da je vena v celoH zaprta, jo lahko najprej razširimo z balonskim katetrom, saj brez tega ni možno uvesH opornice. Samo širjenje ven z balonskim katetrom navadno ni uspešno, saj se po širjenju vena najpogosteje zapre nazaj. Balonske katetre vedno uporabimo za širitev opornice po njeni postavitvi. Ker je širjenje boleče in se bojimo raztrganja vene, se navadno odločimo za postopno širjenje z balonskimi katetri naraščajočega premera. Cilj posega je doseči dober pretok ter navadno vsaj 50% normalnega premera vene. V primeru ponovnih simptomov je mogoče poseg tudi ponoviH. AlternaHva opornicam so pokrite žilne opornice. Njihova prednost je v tem, da zmanjšajo možnost raztrganja vene, vraščanja tumorja v opornico ter njeno ponovno zaporo. Pokrite žilne opornice so vsaj dva krat dražje od navadnih ter izključijo obvodnice, ki so lahko pomembne, če nastane ponovna zapora. Pri benignih spremembah navadno uporabljamo balonske katetre z zdravili, ki zavirajo hiperplazijo inHme in verjetno omogočajo dolgoročnejšo prehodnost vene. Občasno veno zaprejo strdki, ki jih je v veliki meri možno odstraniH z različnimi pripomočki, ki jih uporabljamo v intervencijski radiologiji. Ob tem ne moremo v celoH izključiH distalnih embolij, v tem primeru pljučne embolije, ki pa je najpogosteje subklinična ter jo pacient niH ne občuH. Po posegu izvršimo ročno kompresijo vbodnega mesta, zaradi nizkih takov v venskem sistemu ne pričakujemo večjih zapletov. Pacient lahko vstane čez 6-12 ur, glede na velikost žilnega uvajala. ZAPLETI V literaturi navajajo do 9% zapletov, resnih pa 1-2% (1). Najresnejši zaplet je verjetno raztrganje votle vene, ki pa navadno ni hemodinamsko pomembno in lahko poteka subklinično, posebno pri raztrganju z žico. Metaanaliza, ki je vključila več kot 2000 bolnikov z malignimi in benignimi vzroki je pokazala uspešnost metode okrog 90% in da povrnitev simptomov v manj kot 10% bolnikov v prvem letu (3). ZDRAVILA PO POSEGU Priporočajo oralne anHkoagulanse 3-6 mesecev po posegu za bolnike z malignimi vzroki SZV ter Hste z akutno ali subakutno trombozo. Na izbiro medikamentozne terapije bi verjetno moral vplivaH tudi pretok skozi zgornjo votlo veno, ki ga dosežemo s posegom. V primeru tehnično relaHvno slabega rezultata bi moralo biH medikamentozno zdravljenje bolj agresivno. ZAKLJUČEK Vstavitev opornice v zgornjo votlo veno je enostaven postopek, ki takoj Izboljša kakovost življenja bolnikov s simptomatskim sindromom zgornje votle vene. Pri malignih vzrokih sindroma je možna kombinacija tako s kemo kot radioterapijo, ki delujeta tudi sistemsko in odpravljata vzrok zapore. Izbira vrste zdravljenja je odvisna od bolnikovega stanja, pri edemu dihalnih poH in pri možganskem edemu je znotrajžilno zdravljenje prva izbira. LITERATURA 1. Sen I, Kalra M, Gloviczki P. IntervenAons for superior vena cava syndrome. J Cardiovasc Surg (Torino). 2022 Dec;63(6):674- 681. doi: 10.23736/S0021-9509.22.12448-1. PMID: 36469045. 2. Straka C, Ying J, Kong FM, Willey CD, Kaminski J, Kim DW. Review of evolving eAologies, implicaAons and treatment strategies for the superior vena cava syndrome. Springerplus. 2016 Feb 29;5:229. doi: 10.1186/s40064-016-1900-7. PMID: 27026923; PMCID: PMC4771672. 3. Aung EY, Khan M, Williams N, Raja U, Hamady M. Endovascular StenAng in Superior Vena Cava Syndrome: A SystemaAc Review and Meta-analysis. Cardiovasc Intervent Radiol. 2022 Sep;45(9):1236-1254. doi: 10.1007/s00270-022-03178-z. Epub 2022 Jul 12. PMID: 35821122; PMCID: PMC9458578. INVITED LECTURE ALI JE DROBNOCELI NI RAK PLJU LAHKO OZDRAVLJIVA BOLEZEN? Č Č Eva Ćirić UVOD Drobnocelični rak predstavlja okrog 15 odstotkov vseh rakov pljuč. Gre za biološko agresivno oblika raka, za katero je značilno hitro napredovanje in zgodnje zasevanje. Bolezen je tako pri več kot dveh tretjinah bolnikov odkrita v razširjenem stadiju, ki ni več ozdravljiv. Petletno preživetje bolnikov z drobnoceličnim rakom pljuč je manj kot 7%. Čeprav tudi pri drobnoceličnem raku pljuč (DRP) za določanje stadija uporabljamo TNM klasifikacijo, se v klinični praksi in raziskavah pogosteje uporablja delitev na omejeno in razširjeno obliko bolezni. Omejena oblika je definirana kot bolezen brez oddaljenih zasevkov omejena na prsni koš do obsega, ki ga je mogoče zajeH v radikalno obsevalno polje. Pri nekaterih od teh bolnikov lahko s kombinacijo kemo- in radioterapije ter profilakHčnega obsevanja možganov dosežemo ozdravitev. Petletno preživetje po tovrstnem zdravljenju je okrog 30 odstotkov. Nedavno objavljeni rezultaH raziskave ADRIATIC pa kažejo tudi na vlogo imunoterapije oz. zaviralcev imunskih kontrolnih točk pri zdravljenju omejene oblike drobnoceličnega raka. V pričujočem prispevku bom tako osvetlila osnovne principe radikalnega zdravljenja omejene oblike DRP, katerega primarni cilj je vedno ozdravitev. DIAGNOSTIČNE PREISKAVE ZA DOBRO ZAMEJITEV BOLEZNI Glede na visok metastatski potencial je poleg CT glave, prsnega koša in trebuha za zamejitev bolezni priporočena PET/CT preiskava, ki pri 19 odstotkih bolnikov z omejeno obliko po CT preiskavah stadij zviša v razširjenega, pri 8 odstotkih pa iz razširjene oblike zniža v omejeno. Ob diagnozi drobnoceličnega raka pljuč ima 10 do 15 odstotkov bolnikov možganske zasevke, zato je priporočena tudi MR glave. Ker DRP hitro napreduje, naj dodatne zamejitvene preiskave ne bi podaljšale časa do pričetka zdravljenja za več kot teden dni, zato je dobro načrtovanje diagnosHke brez nepotrebnega izgubljanja časa izjemno pomembno. Kadar bi dodatne diagnosHčne preiskave (PET/CT, MR glave) pomembno podaljšale čas do pričetka zdravljenja ali pa je bolnik močno simptomatski, zdravljenje pričnemo brez njih. ZDRAVLJENJE LOKALNO OMEJENE OBLIKE BOLEZNI (STADIJ I DO IIA) Bolniki, pri katerih je bolezen odkrita zelo zgodaj, to je preden zaseva v bezgavke (N0), so zelo redki. Takšnih je manj kot 5 odstotkov. Če so medicinsko operabilni in je mogoča operacija do obsega lobektomije, je to metoda, s katero začnemo zdravljenje. Po operaciji je ne glede na majhnost tumorja indicirana dopolnilna kemoterapija, v primeru pato-histološkega N2 stadija pa tudi pooperaHvno obsevanje. S takšnim pristopom poročajo o do 60 odstotnem 5-letnem preživetju, brez dopolnilne kemoterapije pa so preživetja precej slabša. Bolnike z N0 boleznijo, ki niso operabilni, zdravimo s sočasno kemoradioterapijo ali pa v zadnjem času, kadar je mogoče, s stereotakHčnim obsevanjem in dopolnilno kemoterapijo. RetrospekHvna analiza na veliki skupini bolnikov ni pokazala razlik v preživetju med obema pristopoma, brez kemoterapije pa je tudi pri tej skupini bolnikov preživetje bistveno slabše. Dobrobit profilakHčnega obsevanja možganov (PCI) je pri tako zgodnjih stadijih nejasna, zato odločitev sprejmemo po pogovoru z bolnikom. V kolikor se bolnik za PCI ne odloči, se priporoča redno sledenje z MR glave na 3 do 4 mesecev prvi dve leH po zdravljenju. ZDRAVLJENJE LOKALNO NAPREDOVALE OBLIKE BOLEZNI Večina bolnikov z omejeno obliko bolezni ima ob diagnozi močno lokoregionalno razširjeno bolezen s pogosto obsežnimi zasevki v hilusnih in mediasHnalnih bezgavkah. Zdravljenje izbora za to skupino predstavlja sočasna kemoradioterapija. Bolniki prejmejo šHri do šest krogov kemoterapije po shemi etopozid + cisplaHn oz. karboplaHn ter obsevanje z radikalno dozo 45 Gy v 30-ih frakcijah danih 2 krat dnevno oz. z dozo 60 do 66 Gy v 30 do 33-ih frakcijah danih 1 krat dnevno. Druga možnost je logisHčno precej lažje izvedljiva in se zato v našem prostoru uporablja bistveno pogosteje. RezultaH velike randomizirane raziskave CONVERT kažejo na podobno preživetje in toksičnost pri obeh režimih. Kar nekaj podatkov iz kliničnih raziskav kaže tudi na pomen čim prejšnjega pričetka z radioterapijo, saj je zgodnejši pričetek z obsevanjem in krajše celokupno trajanje zdravljenja povezano z boljšim izhodom. Obsevanje tako, če je le mogoče, priključimo že k prvemu oz. drugemu krogu kemoterapije. Kasnejši pričetek ali celo zaporedni režim, ko z obsevanjem pričnemo po zaključeni kemoterapiji, ki zmanjša obseg tumorskih sprememb v prsnem košu ter s tem obsevalno polje, pa je primeren za šibkejše bolnike in Hste z velikim obsegom bolezni. Najpogostejši neželeni učinki zdravljenja s kemoradioterapijo so poleg alopecije še hematološka toksičnost, radioezofagiHs in radiopnevmoniHs. Po zaključeni kemoradioterapiji je pri vseh bolnikih na mestu presoja glede profilakHčnega obsevanja možganov (več o tem spodaj). Opisani pristop je vrsto let predstavljal standardno zdravljenje omejene oblike DRP, ki se v zadnjih treh desetletjih pravzaprav ni bistveno spremenilo. Z njim smo dosegali 5 letno preživetje okrog 30 odstotkov. Šele lansko leto objavljeni rezultaH raziskave ADRIATIC končno kažejo tudi napredek pri zdravljenju teh bolnikov. Izkazalo se je, da, podobno kot pri nedrobnoceličnem raku pljuč, dopolnilno zdravljenje z zaviralcem imunskih kontrolnih točk, durvalumabom, ki ga bolniki prejemajo 2 leH po zaključeni kemoradioterapiji ± PCI, podaljša čas do progresa bolezni in celokupno preživetje teh bolnikov. Razlika v 2-letnem preživetju je bila 10% (68 % v roki z durvalumabom in 58 % v roki s placebom). Takšen pristop bo tako v kratkem predstavljal novo standardno zdravljenje. Tudi Sloveniji zato prvi bolniki z omejeno obliko DRP, ki so nedavno zaključili z radikalno kemoradioterapijo, že pričenjajo dopolnilno zdravljenje z durvalumabom. PROFILAKTIČNO OBSEVANJE MOŽGANOV Pri DRP se v poteku bolezni možganski zasevki (MZ) razvijejo kar pri 50 odstotkih bolnikov. Več starejših randomiziranih raziskav je pokazalo, da profilakHčno obsevanje celotnih možganov pomembno zmanjša incidenco MZ tako pri omejeni kot pri razširjeni obliki DRP. Metaanaliza randomiziranih raziskav na 987 bolnikih z omejeno ali razširjeno DRP objavljena že leta 1999 je potrdila pomembno znižanje incidence MZ (HR 0.45, p < 0,001) in pokazala za dobrih 5 odstotkov izboljšano 3-letno preživetje s PCI (HR 0.84, p = 0.01). V večini teh raziskav sicer CT ali MR slikanje možganov ni bilo zahtevano, zato ni povsem jasno, ali bi dobrobit v preživetju obstajala tudi ob dobri slikovni zamejitvi pred PCI. Randomizirana japonska raziskava na bolnikih z razširjenim DRP na primer, ki so pred PCI imeli negaHven MR glave, dobrobiH v preživetju s PCI ni pokazala, čeprav je bila incidenca MZ s PCI signifikantno manjša. So pa imeli vsi bolniki v tej raziskavi redno sledenje z MR glave na 3 mesece in je bil progres v možganih hitro razpoznan. Podobna randomizirana raziskava z MR sledenjem na bolnikih z omejeno obliko DRP je v teku in nam bo dala odgovor glede resnične dobrobiH PCI v preživetju tudi pri tej skupini. Zaenkrat PCI ponudimo vsem bolnikom z omejeno obliko DRP z odgovorom na kemoradioterapijo, ki so v dobrem stanju zmogljivosH. Ob tem podamo znane podatke glede dobrobiH in glede neželenih učinkov, ki lahko predvsem pri starejših bolnikih in HsHh z obstoječimi nevrološkimi okvarami pomembno vplivajo na kvaliteto življenja. Pri tej skupini bolnikov je namreč možnost kroničnih nevrokogniHvnih okvar po PCI relaHvno visoka. Ni še povsem jasno, ali obsevalna tehnika s ščitenjem hipokampalnih regij zmanjša stopnjo nevrokogniHvnh okvar, jo pa bolniku, ki se za PCI odloči, lahko ponudimo. Obsevalna doza, ki jo predpišemo za PCI, je nekoliko nižja kot pri paliaHvnem obsevanju celotnih možganov in je 25 Gy v 10-ih frakcijah. Kadar se bolnik za PCI ne odloči, opravljamo redno sledenje z MR glave prvi dve leH po zdravljenju. ZAKLJUČEK DRP je agresivna maligna bolezen, ki se pogosto, kljub dobrim začetnim odgovorom na zdravljenje, ponovi. Vseeno je ozdravitev pri nemajhnem deležu bolnikov z omejeno obliko DRP mogoča z uporabo mulHmodalnega pristopa, ki vključuje kemoterapijo, obsevanje, v zelo začetnih oblikah tudi operacijo in glede na podatke nedavno objavljene raziskave sedaj še imunoterapijo. Prav je, da bolniki ob prvem soočenju s to težko diagnozo slišijo takšno sporočilo. LITERATURA 1. Dingemans AC, Früh M, Ardizzoni A, et al. Small-cell lung cancer: ESMO Clinical PracAce Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol. 2021;32(7):839-853. doi:10.1016/j.annonc.2021.03.207 2. NaAonal Comprehensive Cancer Network. Small Celll Lung Cancer (Version 4.2025). hips://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462. Accessed March 20, 2025. INVITED LECTURE KAJ JE NOVEGA V SISTEMSKI TERAPIJI DROBNOCELI NEGA RAKA PLJU ? Č Č Avtorica: Loredana Mrak Drobnocelični rak pljuč (DRP), ki predstavlja približno 15 % vseh pljučnih rakov, že več desetleHj ni doživel pomembnih napredkov v zdravljenju. Osnova terapije pri omejeni in razširjeni obliki bolezni ostaja kemoterapija na osnovi plaHne, pri zgodnjih oblikah pa se uporablja tudi sočasno obsevanje ali, pri zelo zgodnjih oblikah, kirurško zdravljenje. Dolgoročni izhodi zdravljenja teh bolnikov zaenkrat ostajajo slabi (5 – letno preživetje napredovale oblike < 5%). Manjši napredek v preživetju bolnikov z metastatskim DRP je pred nekaj leH prinesla uvedba imunoterapije (atezolizumab ali durvalumab) v kombinaciji s standardno kemoterapijo na osnovi plaHne ter nadaljnje vzdrževalno zdravljenje z imunoterapijo z zaviralci imunskih nadzornih točk. Ta pristop je izboljšal srednje celokupno preživetje za približno dva meseca (iz 10 na 12 mesecev), vendar večini bolnikov ni prinesel pričakovanih korisH imunoterapije. Kljub temu ta terapija glede na podatke iz raziskave omogoča približno 12-odstotno 5-letno preživetje. Leta 2024 so bili objavljeni še obetavnejši podatki o uporabi imunoterapije z zaviralci imunskih nadzornih točk po zaključku kemoradioterapije pri zgodnjem DRP. Vzdrževalno zdravljenje z durvalumabom je v primerjavi s placebom izboljšalo celokupno preživetje za 22,5 meseca (55,9 proH 33,4 meseca), kar pomeni pomemben napredek v dolgoročnih izidih zdravljenja za te bolnike. Večina DRP slabo odgovori na zdravljenje z imunoterapijo, saj gre za t. i. »imunsko-hladne« tumorje z motnjo v predstavitvi anHgenov imunskemu sistemu. Zato se je razvoj terapije pri DRP usmeril v bispecifične T-celične povezovalce. Ti se na eni strani vežejo na T-limfocit, na drugi pa na rakavo celico, s čimer vzpostavijo citoliHčno sinapso, ki omogoča uničenje rakave celice neodvisno od predstavitve anHgena preko molekule glavnega kompleksa histokompaHbilnosH I (MHC I). Eno izmed najdlje preizkušanih zdravil iz te skupine je tarlatamab, ki je že pridobilo odobritev ameriškega Urada za hrano in zdravila (FDA) za uporabo v drugi liniji zdravljenja napredovalega DRP. Tarlatamab je bispecifični T-celični povezovalec (monoklonsko proHtelo), ki se veže na molekulo CD3 na citotoksičnih T-limfociHh in na DLL3 (delta-like ligand 3) na rakavih celicah DRP. DLL3 je protein vključen v NOTCH signalno pot, ki je pri DRP spremenjena. Pri zdravih celicah se DLL3 nahaja znotrajcelično, medtem ko se pri DRP v približno 85–94 % primerih nepravilno izraža na površini rakavih celic in predstavlja tarčo za ciljano zdravljenje. Zdravilo tarlatamab je bilo v ZDA odobreno na podlagi študije faze II DeLLphi-301, ki je preučevala njegovo učinkovitost pri bolnikih z napredovalim DRP v drugi ali naslednji liniji zdravljenja. TesHrana sta bila dva odmerka zdravila, in sicer 10 mg in 100 mg, pri čemer je bila za nadaljnje raziskave izbrana doza 10 mg zaradi primerljive učinkovitosH in boljšega varnostnega profila. Podatki podaljšanega spremljanja bolnikov, zdravljenih s tarlatamabom v odmerku 10 mg, kažejo 40-odstotno stopnjo odgovora na zdravljenje, srednji čas do napredovanja bolezni 4,3 meseca in srednje celokupno preživetje 15,2 meseca. Še posebej spodbudno je dejstvo, da je pri večini bolnikov, ki so se odzvali na zdravljenje (31 od 40), ta odziv trajal več kot 6 mesecev. Učinkovitost tarlatamaba se sedaj preučuje v študiji faze III (DeLLphi-304), kjer ga primerjajo s standardno kemoterapijo v drugi liniji zdravljenja napredovalega DRP. Zdravljenje z bispecifičnimi T-celičnimi povezovalci prinaša tudi specifične neželene učinke, predvsem sindrom sproščanja citokinov (CRS) in nevrotoksičnost (ICANS, ki je kraHca za immune effector cell-associated neurotoxicity syndrome, ki sta bila doslej bolj poznana pri CAR-T terapijah. CRS se pojavi pri približno polovici bolnikov, najpogosteje po prvi (43 %) ali drugi dozi (29 %) zdravila, običajno v blagi do zmerni obliki s srednjim časom do nastopa simptomov 13,5 ur po aplikaciji tarlatamaba. Najpogostejši simptomi s katerimi se CRS kaže so: vročina ≥ 38 stopinj C, hipotenzija in hipoksija. Blagi primeri se obvladujejo simptomatsko z npr. paracetamolom za zbijanje vročine, občasno je potrebna tudi uporaba intravenske hidracije in aplikacija korHkosteroida. Pri zmernih in hujših primerih pa je potrebno že navedenim ukrepom pridružiH še zdravljenje s kisikom, vazopresorji in tocilizumabom. Patofiziologija ICANS še ni dobro poznana. Povečana produkcija vnetnih citokinov lahko povzroči akHvacijo endotelijskih celic, povečano prepustnost krvno-možganske pregrade in zvišane ravni citokinov v likvorju. ICANS se pojavi pri okoli 10% bolnikov zdravljenih s tarlatamabom v odmerku 10 mg, večinoma v blagi do zmerni obliki, redkeje v težji obliki. Simptomi vključujejo zmedenost, motnje pozornosH, afazijo, tremor in mišično oslabelost. Pojavi se povprečno 30 dni po začetku zdravljenja. Gre za izključitveno diagnozo, saj so simptomi lahko podobni hudim okužbam ali sepsi, možganski kapi, elektrolitskim motnjam (hiponatremija), neželenim učinkom ob uporabi analgeHkov ali napredovanju bolezni v osrednjem živčevju. V terapiji se pri blažjih primerih uporablja podporna terapija in korHkosteroidi, pri hujših pa je lahko potrebna dihalna podpora in zdravljenje epilepHčnega statusa. Zaradi teh tveganj je pri prvih dveh odmerkih zdravljenja s tarlatamabom priporočeno 24 urno bolnišnično spremljanje, pričetek zdravljenja z znižanim začetnim odmerkom ter premedikacija s korHkosteroidi in intravensko hidracijo. Zaenkrat ni zanesljivih markerjev, ki bi napovedali, kdo bo razvil CRS ali ICANS, bolj pa naj bi bili ogroženi bolniki z visokim tumorskim bremenom, številnimi predhodnimi zdravljenji in pomembnimi pridruženimi boleznimi. V prihodnjih leHh lahko poleg bispecifičnih T-celičnih povezovalcev pričakujemo tudi razvoj konjugatov proHtelo-zdravilo pri zdravljenju DRP. Gre za ciljno usmerjeno terapijo, in sicer monoklonsko proHtelo z vezanim s citotoksičnim zdravilom (kemoterapevHkom) prek posebne povezovalne molekule. ProHtelo prepozna specifične tarčne beljakovine na površini rakavih celic in se nanje veže. Po vezavi se kompleks vnese v celico, kjer se povezovalni element razgradi in sprosH kemoterapevHk, ki nato uniči celico. Celice DRP izražajo več potencialnih tarčnih beljakovin, ki so v središču razvoja teh zdravil, med drugim B7-H3 [CD276], SEZ6 90 [seizure-related homolog 6], TROP2 [tumor-associated calcium signal transducer 2] in nenazadnje tudi DLL3. Prve klinične raziskave so pokazale obetavne rezultate, saj so ta zdravila pri bolnikih s ponovitvijo DRP bolezni dosegla visoke stopnje odgovora na zdravljenje (42–73 %). Čeprav DRP trenutno obravnavamo kot enotno bolezen, se to v prihodnosH morda spremeni. Na podlagi ekspresije specifičnih transkripcijskih faktorjev se namreč pojavljajo delitve DRP na šHri podHpe, odvisno od prevladujočega transkripcijskega faktorja. Ta razvrsHtev bi lahko v prihodnje omogočila bolj personaliziran pristop k zdravljenju in izboljšala terapevtske možnosH za bolnike. LITERATURA 1. Poročilo bolnišničnega registra tumorjev prsnega koša Klinike Golnik, 2010 – 2022 [internet]. Golnik: Klinika Golnik; 2022 [ciArano 26.03.2025]. Dosegljivo na hips://www.klinika-golnik.si/ 2. Shields MD, Chiang AC, Byers LA. Top advances of the year: small cell lung cancer. Cancer. 2025;e35770. 3. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for PaAents with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. 4. Sands J, et al. DeLLphi 301 – Slides presented at World Conference on Lung Cancer (WCLC) 2024 Annual MeeAng. September 7-10, 2024; San Diego, CA. 5. Sands JM, Champiat S, Hummel HD, et al. PracAcal management of adverse events in paAents receiving tarlatamab, a delta-like ligand 3-targeted bispecific T-cell engager immunotherapy, for previously treated small cell lung cancer. Cancer. 2025;131(3):e35738. 6. Peng YL, Guo Z, Zhou Q. The Distance Toward Precision Medicine in SCLC. J Thorac Oncol. 2025;20(2):132-135. BIOLOGIC TREATMENT WITH RESLIZUMAB IN SEVERE ASTHMA WITH FUNGAL SENSITIZATION: A CASE REPORT OF CLINICAL RESPONSE M. Terzić1 1,2 1,2 1,2 ,I. Oštrić-Pavlović , S. Rašković ,V. Tomić-Spirić 1 Clinic of Allergology and Immunology,University Clinical Centre of Serbia 2 Faculty of Medicine, University of Belgrade, Serbia INTRODUCTION Severe asthma with fungal sensiHzaHon (SAFS) is an allergic, immune-mediated disorder that lies between nonsensiHzed asthma and allergic bronchopulmonary aspergillosis (ABPA). Both thermotolerant and non-thermotolerant fungi can trigger allergic sensiHzaHon in humans. AIM To present the case of poorly controlled asthma, despite guideline-based (GINA step 4) treatment. The patient was found to be sensitized to both thermotolerant and non-thermotolerant fungi, which led to the initiation of biologic therapy. CASE PRESENTATION A 47-year-old male with a 20-year history of asthma presented with worsening symptoms. He reported increased symptoms indoors, in the presence of mold. Despite treatment with inhaled corHcosteroids, long-acHng β-2 agonists, theophylline, and anHleukotrienes, his asthma remained poorly controlled, with an Asthma Control Test (ACT) score of 10/25 and an Asthma Control QuesHonnaire (ACQ) score of 3.33. The paHent had frequent exacerbaHons, requiring systemic corHcosteroids more than five Hmes in the past year. Spirometry showed moderately severe obstrucHon (FEV1 52%, FEV1/FVC 0.55). Although skin prick tests for Aspergillus and mold mixtures were negaHve, specific IgE levels for A. alternata (3.34 IU/ml) and P. notatum (12.96 IU/ml) were elevated. Total IgE was also elevated (128 IU/ml), as well as blood eosinophils (670 cells/μl). A. fumigatus-specific IgG was increased (83.75 U/ml), IgM was borderline (52.84 U/ml), but Aspergillus galactomannan Ag was negaHve. Sputum culture was also negaHve. Chest radiography was normal. Based on clinical evaluaHon, the paHent met the criteria for SAFS—uncontrolled severe asthma despite convenHonal treatment and fungal sensiHzaHon in the absence of ABPA. As a result, biologic treatment was iniHated. Commonly used biologics include omalizumab. Given the paHent's eosinophilia, anH-IL5 biologics were also considered. Reslizumab was administered. A`er one year of treatment, the paHent showed clinical and subjecHve improvement. Over the year, he experienced only two exacerbaHons, which required short-term corHcosteroid use. The ACT improved to 19, and the ACQ score reduced to 2.5. Spirometry revealed improved lung funcHon (FEV1 70%, FEV1/FVC 0.63). The eosinophil count reduced to 0 cells/μl. CONCLUSION The treatment approach for SAFS should be similar to other forms of severe asthma. In this case, biologics, specifically reslizumab, were effecHve in improving asthma control and reducing exacerbaHons. SEVERE ASTHMA FORUM 7TH INTERNATIONAL SOUTHEAST MEETING ON SEVERE ASTHMA SPOMLADANSKO STROKOVNO SREČANJE ZDRUŽENJA PNEVMOLOGOV SLOVENIJE 4. – 5. April 2025, Hotel Rikli Balance Bled Electronic edition Organizer: Slovenian Respiratory Society Organising committee: Mitja Košnik, Robert Marčun, Sabina Škrgat Scientific Committee: Sabina Škrgat, Peter Korošec, Ramesh Kurukulaaratchy, Stefano Del Giacco, Marina Lampalo, Sanja Hromiš, Peter Kopač, Natalija Edelbaher, Katja Mohorčič Editors and reviewers: Mitja Košnik, Sabina Škrgat Published by: Združenje pnevmologov Slovenije Place and year of publishing: Golnik, 2025 Design: LEPPA Kataložni zapis o publikaciji (CIP) pripravili v Narodni in univerzitetni knjižnici v Ljubljani COBISS.SI-ID 234270467 ISBN 978-961-96963-1-6 (PDF)