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Значительная доля людей, столкнувшихся с коронавирусной инфекцией имеют осложнение в виде COVID-19-ассоциированной пневмонии и нуждаются в доступной и квалифицированной реабилитации. Цель работы - оценить влияние программы физической реабилитации на толерантность к физическим нагрузкам и функциональное состояние кардио-респираторной системы пациентов, перенесших COVID-19-ассоциированную пневмонию. В исследовании приняли 20 пациентов, перенесших COVID-19-ассоциированную пневмонию. В работе использовались следующие методы исследования: оценка толерантности к физической нагрузке оценивалась с помощью теста шестиминутной ходьбы, для оценки степени одышки после нагрузки использовалась шкала Борга, определяли сатурацию в покое и после проведения теста шестиминутной ходьбы, оценивалась частота сердечных сокращений до и после тестирования, а также выраженность одышки при повседневной деятельности оценивалась по шкале mMRC. Согласно полученным результатам, разработанная программа реабилитации повлияла на повышение толерантности к физическим нагрузкам, улучшение функционального состояния кардио-респираторной системы и субъективной переносимости физической нагрузки у пациентов, перенесших COVID-19-ассоциированную пневмонию. / A significant proportion of people who have experienced coronavirus infection have a complication in the form of COVID-19-associated pneumonia and need affordable and qualified rehabilitation. The aim of the work was to evaluate the impact of the physical rehabilitation program on exercise tolerance and the functional state of the cardio-respiratory system in patients who had undergone COVID-19-associated pneumonia. The study included 20 patients with COVID-19-associated pneumonia. Research methods were used in the work: assessment of exercise tolerance was assessed using a six-minute walk test, the Borg scale was used to assess the degree of dyspnea after exercise, saturation was determined at rest and after a six-minute walk test, heart rate was assessed before and after testing, as well as the severity of dyspnea during daily activities was assessed using the mMRC scale. According to the results obtained, the developed rehabilitation program influenced the increase in exercise tolerance, the improvement of the functional state of the cardio-respiratory system and the subjective exercise tolerance in patients who underwent COVID-19-associated pneumonia.

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Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in the intensive care unit, resulting in a high burden of illness, mortality and increased cost. The literature around the cost-effectiveness of probiotics in prevention of health-care associated infections has not been previously well-described, and a definitive health economic evaluation alongside a well-designed randomized control trial assessing probiotic prophylaxis has not been previously performed. This thesis consists of 3 separate manuscripts (with 2 published in peer-reviewed journals and 1 pending). The theme of this thesis was to: (1) describe the literature about the cost-effectiveness of probiotics in hospitalized patients in preventing healthcare-associated infections; (2) design a protocol for an economic evaluation alongside a randomized control trial (RCT) examining probiotic prophylaxis of VAP; and then (3) perform and analyze the health economic evaluation presented in the protocol. The first component of this thesis is a systematic review of probiotic prophylaxis of healthcare-associated infections in hospitalized patients. We performed an extensive search including multiple databases which found 7 studies. Probiotics demonstrated favourable cost-effectiveness in 6 of 7 (86%) economic evaluations, with 3 studies being manufacturer-supported, all suggesting cost-effectiveness. Certainty of cost-effectiveness evidence was very low due to risk of bias, imprecision and inconsistency using the GRADE approach. Hence further RCTs with economic evaluations were stated as a solution. The second component of this thesis is a study protocol for an economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT), which assessed the efficacy of probiotic prophylaxis in the prevention of healthcare-associated infections (specifically VAP). The third component of this thesis is the cost-effectiveness analysis performed utilizing the individual patient data from PROSPECT to produce the economic evaluation (E-PROSPECT). As of the date of thesis submission, PROSPECT is still pending publication, and hence E-PROSPECT is also pending analysis and publication. However, I have prepared a draft manuscript (along with figures and tables) that will be produced at the conclusion of E-PROSPECT for thesis committee review. / Thesis / Master of Health Sciences (MSc) / Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in the intensive care unit, resulting in a high burden of illness, mortality and increased cost. The literature around the cost-effectiveness of probiotics in prevention of health-care associated infections has not been previously well-described, and a definitive health economic evaluation alongside a well-designed randomized control trial assessing probiotic prophylaxis has not been previously performed. This thesis consists of 3 separate manuscripts (with 2 published in peer-reviewed journals and 1 pending). The theme of this thesis was to: (1) describe the literature about the cost-effectiveness of probiotics in hospitalized patients in preventing healthcare-associated infections; (2) design a protocol for an economic evaluation alongside a randomized control trial (RCT) examining probiotic prophylaxis of VAP; and then (3) perform and analyze the health economic evaluation presented in the protocol. The first component of this thesis is a systematic review of probiotic prophylaxis of healthcare-associated infections in hospitalized patients. We performed an extensive search including multiple databases which found 7 studies. Probiotics demonstrated favourable cost-effectiveness in 6 of 7 (86%) economic evaluations, with 3 studies being manufacturer-supported, all suggesting cost-effectiveness. Certainty of cost-effectiveness evidence was very low due to risk of bias, imprecision and inconsistency using the GRADE approach. Hence further RCTs with economic evaluations were stated as a solution. The second component of this thesis is a study protocol for an economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT), which assessed the efficacy of probiotic prophylaxis in the prevention of healthcare-associated infections (specifically VAP). The third component of this thesis is the cost-effectiveness analysis performed utilizing the individual patient data from PROSPECT to produce the economic evaluation (E-PROSPECT). As of the date of thesis submission, PROSPECT is still pending publication, and hence E-PROSPECT is also pending analysis and publication. However, I have prepared a draft manuscript (along with figures and tables) that will be produced at the conclusion of E-PROSPECT for thesis committee review.

There are few data on mortality after discharge with community-acquired pneumonia (CAP). Therefore, we evaluated risk factors for 30-day post-discharge mortality after CAP. We included all patients of the prospective multi-national CAPNETZ study between 2002 and 2018 with (1) hospitalized CAP, (2) survival until discharge, and (3) complete follow-up data. The study endpoint was death within 30 days after discharge. We evaluated risk factors including demographics, comorbidities, admission CAP severity, and laboratory values and treatment-related factors in uni- and multivariable analyses. A total of 126 (1.6%) of 7882 included patients died until day 30 after discharge, corresponding to 26% of all 476 deaths. After multivariable analysis, we identified 10 independent risk factors: higher age, lower BMI, presence of diabetes mellitus, chronic renal or chronic neurological disease (other than cerebrovascular diseases), low body temperature or higher thrombocytes on admission, extended length of hospitalization, oxygen therapy during hospitalization, and post-obstructive pneumonia. By addition these factors, we calculated a risk score with an AUC of 0.831 (95%CI 0.822–0.839, p < 0.001) for prediction of post-discharge mortality. Early post-discharge deaths account for ¼ of all CAP-associated deaths and are associated with patient- and CAP-severity-related risk factors. Additional studies are necessary to replicate our findings in independent cohorts. Study registration: NCT 02139163.

The COVID-19 pandemic elucidated geographical disparities in COVID-19 burden on a globalscale. Geographical disparities in adverse COVID-19 outcomes may suggest population-level drivers of disease, such as environmental exposures. Epidemiological literature provides strong evidence that greater exposure to ambient air pollution, an environmental exposure, is associated with a greater risk of COVID-19 hospitalization and fatality. The pathways by which ambient air pollution exposure influences adverse COVID-19 outcomes are currently unknown. I propose that cardiovascular morbidity is relevant in this pathway, given that cardiovascular morbidity is a predominant risk factor of adverse COVID-19 outcomes, and there are strong and consistent associations between air pollution and cardiovascular morbidity. I suggest that the role of cardiovascular morbidity will be different for historical air pollution (period > 30 days) and short-term air pollution (period < 30 days). By proposing clear causal structures for the relationship between air pollution and adverse COVID-19 outcomes, we can explicate how air pollution leads to greater COVID-19 burden and address the larger goal of reducing geographic disparities in adverse COVID-19 outcomes. This dissertation is comprised of three specific aims. For the first aim, I performed a systematic review of the literature that examined the relationship between ambient air pollution and individual-level adverse COVID-19 outcomes. I identified if and how researchers conceptualized the causal role of comorbidities, specifically cardiovascular morbidities, in the relationship between air pollution and adverse COVID-19 outcomes. For the second aim, I examined if cardiovascular morbidity mediates the relationship between historical air pollution and adverse COVID-19 outcomes. For the third aim, I examined if there was evidence of synergistic interaction between short-term air pollution and cardiovascular morbidity in influencing the risk of adverse COVID-19 outcomes, suggesting that the effect of both short-term air pollution and cardiovascular morbidity on adverse COVID-19 is greater than the sum of the individual effects. In conducting the first aim, I used Covidence, a software used to manage systematic reviewstudies, to identify studies that examined the relationship between ambient air pollution exposure and individual-level adverse COVID-19, using the Embase, MEDLINE, and Web of Science databases. In conducting the empirical aims, I used a retrospective cohort study design using INSIGHT-Clinical Research Network (CRN) data, a harmonized repository of inpatient electronic health records in New York City (NYC) across metropolitan healthcare systems (3/1/2020-2/28/2021). INSIGHT-CRN included data pertaining to sociodemographics, diagnoses, outcomes, and residential ZIP Code to link air pollution exposure. For the second aim, I used the New York City Community Air Survey (NYCCAS) to estimate historical air pollution exposure to particulate matter (PM2.5), black carbon (BC), nitrogen dioxide (NO₂), and ozone (O₃) on a ZIP Code level (2009-2019). For the third aim, I used the 2020 Environmental Protection Agency (EPA) Community Multiscale Air Quality (CMAQ) downscaler modeled data, which estimated 2020 daily exposure to PM2.5 and O3 on a census tract level. I aggregated the census tract data to ZIP Code using a spatial weighting approach and estimated short-term air pollution as a 7-day average of daily PM2.5 and O3 exposure prior to patient hospitalization. For the first aim, the systematic review included 42 studies that examined the relationship between ambient air pollution, such as exposures to PM2.5, NO₂, and O₃, and individual-level adverse COVID-19, such as hospitalization, intensive care unit (ICU) admission, intensive respiratory support (IRS), and fatality. The studies were primarily retrospective cohort study designs, and were conducted in the United States and Europe (2020 to 2021). The majority of studies adjusted for cardiovascular morbidity without causal role specification, whereas some studies identified cardiovascular morbidity as a mediator or an effect modifier. For the second aim, I found evidence of cardiovascular morbidity mediating the relationship between historical air pollution and risk of acute respiratory distress syndrome (ARDS), dialysis use, ventilation use, and COVID-19 fatality, but not risk of pneumonia from March to June 2020, within areas of greater hospital catchment. Indirect effects suggest that historical air pollution increases the risk of atrial fibrillation and myocardial infarction, which increases risk of adverse COVID-19. For the third aim, I found evidence of synergistic interaction between short-term PM2.5 and presence of cardiovascular morbidities for only risk of COVID-19 pneumonia, in the latter half of 2020. Overall, there was evidence that cardiovascular morbidity mediates the relationship betweenhistorical air pollution and more severe COVID-19 outcomes, while cardiovascular morbidity synergistically interacts with short-term air pollution for risk of acute respiratory infections, such as pneumonia. This dissertation assesses the pathways by which air pollution may influence risk of adverse COVID-19, in better examining the causal role of cardiovascular morbidity. Knowledge gained could be used to mitigate population-level vulnerabilities to air pollution, and encourage population-level pandemic preparedness in the future.

Sekundäre bakterielle Infektionen im Verlauf oder in Folge einer Infektion mit Influenza A Viren (IAV) steigern oftmals die Schwere des Krankheitsverlaufes, was besonders während der IAV Pandemien von 1918, 1968 und 2009 deutlich wurde. Genaue mechanistische Ursachen, welche dieser gesteigerten Kopathogenität zugrunde liegen wurden überwiegend in Tierversuchsmodellen adressiert und sind immunologisch unvollständig. Aufgrund organstruktureller und immunfunktioneller Speziesunterschiede ist ungewiss, inwieweit eine Übertragbarkeit der Daten zwischen Mensch und Maus besteht. Fokus der Arbeit bildete die Analyse potentieller IAV assoziierter Änderungen der angeborenen Immunität, welche sekundäre Pneumokokkeninfektionen in humanem ex vivo Lungengewebe begünstigen. Dafür wurden zentrale Zyto - bzw. Chemokine als Reaktion auf Einzelinfektionen mit dem saisonalen IAV Pan/99(H3N2) sowie Streptococcus pneumoniae D39 mit denen subsequenter viral-bakteriellen Koinfektion verglichen. Ausgelöst durch die antivirale Interferonantwort erfolgte die Reduktion der pneumokokkeninduzierten Bildung von IL-1β und GM-CSF auf translationaler und transkriptioneller Ebene. Vermutlich beeinflussen Typ I und II Interferone die IL-1β Bildung, welches über parakrine Wechselwirkungen an der GM-CSF Regulation beteiligt ist. Auf zellulärer Ebene verursachte IAV die Freisetzung von Typ I, II und III Interferonen aus primären humanen Alveolarepithelzellen vom Typ II. In humanen Alveolarmakrophagen unterdrückten Typ I und II Interferone die pneumokokkeninduzierte IL-1β Freisetzung. Folglich unterblieb die IL-1β-regulierte GM-CSF Sekretion aus Alveolarepithelzellen vom Typ II. Die Ergebnisse zeigen, dass influenzainduzierte Interferone durch die Unterdrückung der IL-1β regulierten Bildung von GM-CSF in humanem Lungengewebe beitragen. Damit unterstützt sie das Verständnis immunologischer Faktoren, welche diesem Krankheitsbild im Menschen pathophysiologisch zugrunde liegen können. / Secondary bacterial infections, which occur during or following an IAV infection, exaggerate the severity of the course of disease up to a lethal outcome, clearly recognizable during the fatal IAV pandemics from 1918, 1968 or 2009. Particular mechanisms underlying this exaggerated viral-bacterial copathogenity were almost solely addressed using animal models and are immunologically incomplete. Due to structural and immunofunctional interspecies differences the transferability of data between human and mice remains indeterminate. The study mainly purposed to investigate IAV associated modulations of innate immunity, which potentially facilitates secondary pneumococcal pneumonia in primary human ex vivo lung tissue. Hence secretion of central cyto- and chemokines initiated by single infection with the seasonal IAV Pan/99(H3N2) or the bacterium Streptococcus pneumoniae D39 were compared to subsequent viral-bacterial coinfection. In context of an antiviral interferon response the pneumococcal induced translation and transcription of IL-1β and GM-CSF were reduced. Probably type I and type II interferons affect generation of IL-1β, which participates in the regulation of GM-CSF by paracrine interactions. On a cellular basis the infection of primary human alveolar epithelial cells type II (AECII) with IAV triggered the release of interferon type I, II and III. In human alveolar macrophages type I and II interferons suppressed the pneumococcal induced release of IL-1β. Consequently, the IL-1β regulated generation of GM-CSF in AECII was impeded. The present study indicates, that influenza related induction of interferons suppresses the IL-1β related release of GM-CSF in human lung tissue. Thereby it takes part in contributing to pathophysiological comprehension of immunological factors underlying this copathogenity.

Anlass dieser Studie war die Erfassung und Beurteilung radiologischer Genauigkeit in Thoraxübersichtsaufnahmen bei der Diagnostik von ARDS und Pneumonie. Dazu wurden von 84 Patienten (35 mit ARDS, 46 Patienten mit zusätzlicher Pneumonie) drei aufeinander folgende Aufnahmen befundet und hinsichtlich verschiedener radiomorphologischer Merkmale qualitativ, quantitativ und statistisch analysiert. Es konnte nachgewiesen werden, daß es für eine sichere Befundung von Röntgenthoraces keine statistisches Korrelat gibt (p > 0.6). Die Irrtumswahrscheinlichkeit für falsch positive und falsch negative Ergebnisse lag bei 78% und entsprach dabei den Angaben in der Literatur. Die Ergebnisse unterstreichen zudem die Feststellung, daß auch Serienaufnahmen nicht zur Verbesserung der diagnostischen Sicherheit führen, die Wertigkeit von Röntgenthoraxaufnahmen beim ARDS daher nur im Rahmen einer allgemeinen Verlaufsbeurteilung zu sehen ist. / In addition to general clinical factors involved in the course of ARDS, the aspect of pneumonia superimposed on ARDS, its incidence, the predisposing factors and the underlying sources of infection were to be analysed and the reasons for the different radiological interpretation of this disease reported in literature and practice were to be established. Three consecutive radiographic chest views of 84 patients (35 with ARDS, 49 with ARDS and primary or secondary pneumonia) which were optically and statistically comparable as regards their radiological features were reviewed and evaluated comparatively by discriminance analysis. The study showed that no statistical correlate exists (p > 0.6) for a reliable interpretation of adiographic chest views with regard to ARDS and/or ARDS with additional pneumonia. Furthermore, the results underline the fact that even a series of films obtained within a 24-hour interval cannot help to improve the diagnostic safety and that, consequently, radiographic chest views are of value only for a general assessment of the course of ARDS, whether with or without accompanying pneumonia.

Influenzavirus (IV)-Infektionen der unteren Atemwege induzieren virale Pneumonien, die häufig in akutem Lungenversagen resultieren. Merkmale einer IV-induzierten Pneumonie sind Schädigungen des Alveolarepithels und eine Ansammlung von Ödemflüssigkeit im Alveolarraum, wodurch der Gasaustausch beeinträchtigt wird. In Abhängigkeit eines Natriumgradienten, aufgebaut durch die basolaterale Na,K-ATPase (NKA) und den apikalen epithelialen Natriumkanal (ENaC), wird unter normalen Bedingungen die Ödemflüssigkeit aus dem Alveolarraum entfernt. In Folge einer IV-Infektion werden verschiedene Membranionenkanäle dysreguliert und eine verringerte alveoläre Flüssigkeitsresorption (AFC) beobachtet. Eine IV-Infektion führt u.a. zu einer reduzierten NKA-Expression in nicht-infizierten Nachbarzellen, sowie zu einer Dislokation der NKA zur apikalen Zellmembran in infizierten Zellen. Co-Immunopräzipitationsstudien identifizierten das virale M2-Protein als NKA-Bindepartner. Mittels Mutationsanalyse konnten drei Aminosäuren im zytoplasmatischen Teil von M2 als kritisch für die NKA-Bindung identifiziert werden. Rekombinante IV mit gestörter NKA Bindung zeigten im Vergleich zu IV WT in polarisierten Calu 3 Zellen in vitro sowie in Mäusen in vivo eine verbesserte AFC. Eine mutationsbedingte Glykosylierung des M2-Proteins führte jedoch unerwartet zu einer verstärkten Immunantwort in vivo, die trotz verbesserter AFC zu einem schwereren Krankheitsverlauf führte. Grund dafür könnte eine Aktivierung der Unfolded Protein Response aufgrund der Glykosylierung sein. Die Erkenntnis, dass M2 ein wichtiger Modulator in der Regulation der alveolären Flüssigkeitshomöostase ist, könnte dennoch helfen, neue therapeutische Ansätze für IV-induzierte Pneumonien zu definieren. Darüber hinaus unterstreicht es die Relevanz einer in der vorliegenden Arbeit durchgeführten Surfactome-Analyse zur Identifizierung neuer potentieller Angriffspunkte an der Zelloberfläche IV-infizierter Zellen, die in der antiviralen Therapie von Bedeutung sein könnten. / Influenza Virus (IV) infections of the lower respiratory tract can induce viral pneumonia resulting in acute lung injury (ALI/ARDS) with fatal outcome. Characteristics of an IV-induced pneumonia are alveolar epithelial cell (AEC) damage and accumulation of protein-rich edema fluid in the alveolar compartment impairing gas exchange. Depending on a sodium gradient established by the basolateral Na,K-ATPase (NKA) and the apical epithelial sodium channel (ENaC) edema fluid is removed from the alveolar space under normal conditions. However, after IV-infection various ion channels are dysregulated and reduced alveolar fluid clearance (AFC) is observed. An IV-infection leads to a reduced NKA expression in the non-infected neighbouring cells and to a mistargeting of the NKA to the apical cell membrane in IV-infected cells. Co immunoprecipitation (co-IP) studies identified the viral M2 protein as NKA binding partner and mutational analysis presented three amino acids in the cytoplasmic tail of M2 directly abutting the transmembrane domain as critical for NKA binding. A recombinant IV mutant with disrupted NKA binding showed in comparison to IV WT an increased fluid transport in polarized Calu 3 cells in vitro as well as in mice in vivo. However, mutation-induced glycosylation of the M2 protein unexpectedly led to an enhanced immune response in vivo, resulting in a more severe disease course despite improved AFC. The reason for this could be an activation of the unfolded protein response by the glycosylation of M2. Nevertheless, the finding that M2 appears to be an important modulator in the regulation of alveolar fluid homeostasis might provide new potential approaches for therapeutics of an IV induced pneumonia. Moreover, it highlights the relevance of a surfactome analysis performed in the present work to identify novel potential targets on the cell surface of IV-infected cells which could play an important role in antiviral therapy.

Ultrasound is a widely used imaging modality to evaluate various anatomical structures in the human body, such as the lungs and heart, due to its non-invasive nature and real-time imaging capabilities. However, the effectiveness of these evaluations is highly dependent on the manual annotation/segmentation of visual patterns. In lung assessments, patterns such as hyper-echoic horizontal and vertical artifacts and hypo-echoic consolidations are crucial for diagnosing both adult and neonatal respiratory conditions. Similarly, in cardiac evaluations, ultrasound imaging facilitates the visualization of anatomical structures, including the endocardium, myocardium, and atrium of the left ventricle, which are essential for the measurement of clinical indices such as ejection fraction (EF). Despite the advancements in ultrasound technology, manual annotation remains the standard practice in clinical routines due to the lack of fully automated AI solutions. However, manual annotation/segmentation of ultrasound patterns is not only time-consuming but also prone to inter-observer variability (IOV). Given with these challenges, evaluating inter-rater reliability across multiple operators, medical centers, and diverse patient populations is crucial for advancing lung ultrasound (LUS) diagnostics and improving patient outcomes. Additionally, the integration of AI to reduce the impact of IOV in ultrasound pattern interpretations has not been fully explored in the literature. Moving forward, many stateof- the-art studies have primarily focused on the interpretation of LUS patterns in adults, resulting in a notable gap in research concerning neonates. This thesis addresses this gap by introducing an advanced methodology aimed at standardizing and automating the interpretation of LUS patterns in neonates. To achieve this, various deep learning approaches, including classical neural networks and advanced transformer-based models, are employed. Additionally, domain adaptation techniques are introduced to facilitate the transfer of knowledge from adult LUS assessments to neonates. Furthermore, IOV also contributes to inconsistencies in data distribution, leading to an unequal representation of different classes within the dataset. To address these challenges, this thesis explores the application of generative AI, emphasizing the techniques that could effectively balance the data distributions. Building on this foundation, this thesis examines the use of generative AI models for the automated segmentation of left ventricle (LV ) regions to mitigate the effects of IOV. The proposed segmentation method was rigorously evaluated through qualitative and quantitative analyses, setting a new benchmark for future studies by demonstrating improved performance of EF estimation over state-of-the-art techniques. Lastly, this thesis introduces a novel approach that leverages generative AI models for automated labeling of LV regions using adjacent anatomical structures, such as utilizing the myocardium to segment the endocardium region or vice versa. This novel approach significantly reduces the need for manual labeling, ultimately minimizing IOV and saving time in clinical practice.