CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY DISEASES: FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS

EDITOR Dr. Ulviyya JAFAROVA CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY DISEASES: FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS Published by BZT TURAN PUBLISHING HOUSE Certificate Number: 202401 Delaware, United States www.bztturanpublishinghouse.com [email protected] EDITOR: Dr. Ulviyya JAFAROVA CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY DISEASES: FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS OPEN ACCESS Suggested Citation: Jafarova, U. (2025). CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY DISEASES: FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS. BZT TURAN PUBLISHING HOUSE. DOI: https://doi.org/10.30546/19023.978-9952-8610-4-4.2025.0042 Language: English Publication Date: October 2025 Cover Design By Mehmet ÇAKIR Print and digital versions typeset by BZT TURAN Media Co. Ltd. E-ISBN: 9 7 8 - 9 9 5 2 - 8 6 1 0 - 4 - 4 DOI: https://doi.org/10.30546/19023.978-9952-8610-4-4.2025.0042 iii PREFACE The 21st century has witnessed unprecedented challenges in the field of health sciences, ranging from global pandemics to the rapid transformation of social structures influencing disease patterns. This volume brings together diverse yet interconnected studies that aim to shed light on both the biological and social determinants of health in the post-pandemic era. The first contribution addresses fibrotic lung disease in the postCOVID-19 era, providing mechanistic insights into the pathophysiology and discussing emerging therapeutic approaches. As pulmonary fibrosis emerges as one of the most critical long-term sequelae of COVID-19, understanding its molecular pathways and targeted treatments has become a pressing priority in respiratory medicine. Another study examines the impact of urbanization on thyroid cancer incidence by gender in Turkey. This research highlights how lifestyle changes, environmental exposures, and urban living conditions intersect with gender dynamics to influence cancer epidemiology. By offering a gendersensitive analysis, it underscores the importance of integrating demographic and environmental factors in public health strategies. The third study focuses on women’s employment status and its role in applications to family physicians, illustrating the social dimension of healthcare utilization. This perspective draws attention to the ways in which economic participation and gender roles directly shape access to and demand for primary healthcare services, ultimately reflecting the broader relationship between society and health systems. Finally, the volume includes a discussion of targeted therapies and molecular pathways in pulmonary diseases, emphasizing the rapid advances in precision medicine. The integration of molecular biology into clinical practice has not only expanded treatment options but also transformed the very framework of respiratory disease management. iv Taken together, these contributions provide a multidimensional view of health: from the molecular mechanisms that drive pulmonary pathologies to the social determinants that shape healthcare-seeking behavior and disease incidence. By bridging clinical, molecular, and sociological perspectives, the volume aims to enrich the ongoing dialogue in health sciences, offering both theoretical insights and practical implications for researchers, clinicians, and policymakers. In doing so, this collection highlights the need for interdisciplinary collaboration to address the complexities of modern health challenges, ensuring that scientific progress is aligned with the realities of human life and societal transformation. v Dr. Ulviyya Jafarova is currently serving as a Senior Lecturer at Azerbaijan Medical University (since 2023). At the Department of Human Anatomy and Medical Terminology, she teaches the Normal Physiology course through both lectures and practical classes, prepares course materials, and designs midterm and final exam questions for different faculties. Between 2016 and 2023, she lectured in Human Anatomy at the same department and contributed to scientific research within the Student Scientific Union. From 2007 to 2016, she worked as a Human Anatomy lecturer at Azerbaijan Medical University, and from 2005 to 2007, she served as a teacher at the Azerbaijan Teachers’ Institute, where she taught Basics of Medical Knowledge. Earlier in her career, from 1993 to 2005, she worked as an Emergency Doctor at Baku Medical Emergency Station No.1. Dr. Jafarova began her medical education at Azerbaijan Medical University, where she earned her First Degree in Pediatrics (Diploma of Specialist under the USSR system) between 1986 and 1992. She then completed her internship in emergency medicine at Baku Medical Emergency Station No.6 in 1992–1993. She is an active member of the Azerbaijan Scientific Society of Anatomists, Histologists, and Embryologists (since 2019). For her contributions to academic and social activities, she has been recognized with several honors, including an Award for Active Participation in University’s Social and Educational Activities (2019) and the title of Honorary Doctor from Mamun University and BZT Turan Academy. Her language proficiency includes Azerbaijani (native), Russian (full professional), Turkish (full professional), and English (limited working proficiency). She has also received several professional certificates, including participation in the 12th International Istanbul Scientific Research Congress on Health Sciences (2023), the OIC Ministerial Standing Committee on Scientific and Technological Cooperation (COMSTECH, 2022–2023), and earning 8 CME credits at the Scientific-Practical Webinar on Current Issues in Public Health (2021). vii CONTENTS PREFACE .................................................................................................................... iii CHAPTER 1 THE ROLE OF URBANIZATION IN THE CHANGE OF THYROID CANCER INCIDENCE ACCORDING TO GENDER IN TURKEY ......................................... 1 Mahir COŞKUN CHAPTER 2 THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO FAMILY PHYSICIANS ...............................................................................................11 Tuba Duygu COŞKUN CHAPTER 3 TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES .................................................................................................................21 Dr. Sevtap DÜZGÜNÇINAR CHAPTER 4 FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING TREATMENTS ......................................................41 Dr. Sevtap DÜZGÜNÇINAR THE ROLE OF URBANIZATION IN THE CHANGE OF THYROID CANCER INCIDENCE ACCORDING 6 Table 2. Results of Spearman’s rho correlation analysis on the relationship between thyroid cancer incidence and urbanization in men and women Variable rp Thyroid cancer incidence in men 0.951** 0.000 Thyroid cancer incidence in women 0.944** 0.000 Female/Male thyroid cancer incidence ratio –0.925** 0.000 **p<0.01 According to the results of the year-controlled partial correlation analysis on the relationship between thyroid cancer incidence and urbanization in men and women, statistically significant associations were found between urbanization and thyroid cancer incidence in men (r = 0.951; p < 0.01), in women (r = 0.944; p < 0.01), and with the female-to-male thyroid cancer incidence ratio (r = –0.925; p < 0.01). The direction of the correlation was positive for thyroid cancer incidence in both men and women, and negative for the female-to-male incidence ratio (Table 3). Table 3. Results of year-controlled partial correlation analysis on the relationship between thyroid cancer incidence and urbanization in men and women Variable rp Thyroid cancer incidence in men 0.951** 0.000 Thyroid cancer incidence in women 0.944** 0.000 Female/Male thyroid cancer incidence ratio –0.925** 0.000 **p<0.01 According to the results of the Generalized Linear Model (Logit) analysis on the effect of urbanization on thyroid cancer incidence in men and women, the effects of urbanization were found to be statistically significant for both men (B = 0.616; p < 0.01) and women (B = 2.133; p < 0.01) (Table 4). MAHIR COŞKUN 7 Table 4. Results of the Generalized Linear Model (Logit) analysis on the effect of urbanization on thyroid cancer incidence in men and women Parameter BStd. Error 95% Wald Confidence Interval Hypothesis Test Minimum Maximum Wald X2df p MEN (Intercept) -39.365 3.870 -46.950 -31.779 103.443 10.000 Urbanization 0.616 0.054 0.511 0.722 132.190 10.000 (Measurement) 0.191 0.081 0.083 0.440 WOMEN (Intercept) -134.628 11.992 -158.132 -111.125 126.038 10.000 Urbanization 2.133 0.169 1.801 2.465 158.472 10.000 (Measurement) 3.879 1.330 1.980 7.598 B: Regression coefficient, df: Degrees of freedom. 4. Discussion and Conclusion In this study, the relationship between urbanization and the incidence of thyroid cancer in men and women in Türkiye was examined, and the changes in thyroid cancer incidence and the proportion of the urban population between 2002 and 2018 were analyzed. The findings indicated that with increasing urbanization, thyroid cancer incidence rose in both genders, with the effect being more pronounced in women. Previous studies on thyroid cancer generally demonstrate that the disease is more prevalent in women compared to men (13–15). Although there has been insufficient research on the distinction between urban and rural areas, it can generally be stated that access to the healthcare system is easier in urban settings, which may contribute to higher prevalence and incidence rates of diseases. In addition, environmental factors in urban areas may also influence disease outcomes. In our study, urbanization was found to have a greater impact on women than on men. This result suggests that the effect is more likely related to diagnostic screenings rather than environmental influences in urban areas. According to the results obtained, urbanization had a statistically significant positive effect—namely, an increasing effect—on thyroid cancer incidence in both genders, with the effect being stronger in women. This finding can be attributed not to environmental conditions resulting from urbanization, but THE ROLE OF URBANIZATION IN THE CHANGE OF THYROID CANCER INCIDENCE ACCORDING 8 rather to improved access to healthcare institutions following urbanization, leading to greater diagnostic opportunities. More comprehensive and crosssectional studies comparing the effects of urbanization on both environmental conditions and healthcare system accessibility could further clarify its impact on thyroid cancer incidence in both genders. MAHIR COŞKUN 9 References 1. Ulisse, S., Baldini, E., Lauro, A., Pironi, D., Tripodi, D., Lori, E., ... & Sorrenti, S. (2021). Papillary thyroid cancer prognosis: An evolving field. Cancers, 13(21), 5567. 2. Chen, D. W., Lang, B. H., McLeod, D. S., Newbold, K., & Haymart, M. R. (2023). Thyroid cancer. The Lancet, 401(10387), 1531-1544. 3. Araque, K. A., Gubbi, S., & Klubo-Gwiezdzinska, J. (2020). Updates on the management of thyroid cancer. Hormone and Metabolic Research, 52(08), 562-577. 4. Crnčić, T. B., Tomaš, M. I., Girotto, N., & Ivanković, S. G. (2020). Risk factors for thyroid cancer: what do we know so far?. Acta Clinica Croatica, 59(Suppl 1), 66. 5. Pereira, M., Williams, V. L., Hallanger Johnson, J., & Valderrabano, P. (2020). Thyroid cancer incidence trends in the United States: association with changes in professional guideline recommendations. Thyroid, 30(8), 1132-1140. 6. Kim, J., Gosnell, J. E., & Roman, S. A. (2020). Geographic influences in the global rise of thyroid cancer. Nature Reviews Endocrinology, 16(1), 17-29. 7. Wang, J., Yu, F., Shang, Y., Ping, Z., & Liu, L. (2020). Thyroid cancer: incidence and mortality trends in China, 2005–2015. Endocrine, 68, 163-173. 8. Lincango-Naranjo, E., Solis-Pazmino, P., El Kawkgi, O., Salazar-Vega, J., Garcia, C., Ledesma, T., ... & Brito, J. P. (2021). Triggers of thyroid cancer diagnosis: a systematic review and meta-analysis. Endocrine, 72, 644-659. 9. Shetty, S. S., Deepthi, D., Harshitha, S., Sonkusare, S., Naik, P. B., & Madhyastha, H. (2023). Environmental pollutants and their effects on human health. Heliyon, 9(9). 10. Manisalidis, I., Stavropoulou, E., Stavropoulos, A., & Bezirtzoglou, E. (2020). Environmental and health impacts of air pollution: a review. Frontiers in public health, 8, 14. 11. Yılmaz K, Turanlı M. A (2023). Multi-disciplinary Investigation of Linearization Deviations in Different Regression Models. Asian Journal of Probability and Statistics, 29;22(3):15-9. 12. Yilmaz K, Turanlı M. (2022). A multi-disciplinary investigation on minimizing linearization deviations in different regression models. Change & Shaping The Future, IV. ASC-2022/Fall Congress, ISBN 978-625-8048-99-5 13. Shobab, L., Burman, K. D., & Wartofsky, L. (2022). Sex differences in differentiated thyroid cancer. Thyroid, 32(3), 224-235. 14. Li, M., Dal Maso, L., & Vaccarella, S. (2020). Global trends in thyroid cancer incidence and the impact of overdiagnosis. The lancet Diabetes & endocrinology, 8(6), 468-470. 15. Boucai, L., Zafereo, M., & Cabanillas, M. E. (2024). Thyroid cancer: a review. Jama, 331(5), 425-435. 11 CHAPTER 2 THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO FAMILY PHYSICIANS Tuba Duygu COŞKUN1 Abstract Objective: The aim of this study was to examine the relationship between applications to family medicine units and women’s employment status. Method: In the study, data on applications to family physicians between 2008 and 2019 were obtained from the Ministry of Health Statistical Yearbooks, while data on female unemployment and overall unemployment rates were obtained from the World Bank Country Reports. Correlations between the variables were analyzed using the correlational survey model. Results: In 2008, the year family medicine was first introduced, there were 45,111,103 applications, which increased to 332,907,540 by 2022. During the same period, the female unemployment rate rose from 11.60% in 2008 to 13.42% in 2022. Overall unemployment, which was 10.97% in 2008, was 10.43% in 2022, displaying a fluctuating pattern. While the number of applications to family physicians increased rapidly from 2008 until 2011, it followed a more stable course from 2012 onward. The unemployment rate among women of working age also showed a fluctuating trend. Results of the 1 Dr., Ministry of Health Van Family Medicine, Van, Türkiye. E-mail: [email protected] | ORCID: 0000-0003-1212-5786 THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO FAMILY PHYSICIANS 12 Spearman’s rho correlation analysis indicated that there was no statistically significant relationship between applications to family physicians and female or overall unemployment (p > 0.05). However, results of the year-controlled partial correlation analysis showed a statistically significant negative relationship between application rates to family physicians and female unemployment (r = –0.595; p < 0.05) as well as overall unemployment (r = –0.643; p < 0.05). According to the results of the Generalized Linear Model analysis, female unemployment had a statistically significant and negative effect on applications to family physicians (B = –2.093; p < 0.05). Conclusion: According to the findings, although rising female unemployment appears to reduce applications to family physicians, it can be inferred that employed women are more health-conscious. For early diagnosis of diseases, improved public health, and the effective functioning of family medicine units, it is important to reach unemployed women and to promote female employment. Keywords: Family medicine, applications, women’s employment. 1. Introduction The family medicine unit is a healthcare practice that was first introduced in Türkiye in 2007 in seven provinces, and then implemented nationwide in 2008 (1). According to the General Directorate of Public Health of the Ministry of Health, family medicine is defined as units providing individualized preventive health services, primary healthcare services, rehabilitative health services, and, particularly in diagnosis and treatment, addressing all family members and their environment (2). Applications to family physicians not only allow individuals to receive health-related services but also significantly affect the process of early diagnosis and treatment of diseases. From rational drug use (3,4) to adopting healthy lifestyles (5), and especially in areas such as psychological disorders (6,7), family medicine plays a critical role in many important health-related issues (8). One of the most important conditions for family physicians to fulfill their key roles within the healthcare system is the applications made to these units. Considering that the majority of society belongs to the lowermiddle income group, women’s employment status may play an important role in determining the likelihood of applying to family physicians. Although studies have been conducted on family medicine, there is a lack of research examining the impact of women’s employment status on such applications. Therefore, the aim of this study was to investigate the relationship between applications to family medicine units and women’s employment status. TUBA DUYGU COŞKUN 13 2. Methods 2.1. Research Model The research was designed using descriptive and correlational survey models. In this mixed model, the phenomenon is first described using quantitative and qualitative data, followed by an analysis of the relationships between variables (9). In this study, the implementation of family medicine in Türkiye and women’s employment levels over the years were described, and their relationships were statistically analyzed. 2.2. Data Set In the study, data on applications to family physicians between 2008 and 2019 were obtained from the Ministry of Health Statistical Yearbooks, while female unemployment and overall unemployment rates were retrieved from the World Bank Country Reports. In Türkiye, family medicine was first piloted in the province of Düzce in 2005. In 2006, it was introduced in seven provinces, and in 2008 it was implemented nationwide. Therefore, the time series of the study covers the period between 2008 and 2022, which corresponds to the most recent data available from the Ministry of Health. The World Bank unemployment data were obtained from the datasets titled “Unemployment, female (% of female labor force) (modeled ILO estimate)” and “Unemployment, total (% of total labor force) (modeled ILO estimate).” 2.3. Statistical Method SPSS 25.0 for Windows was used for data analysis, and all analyses were conducted at a 95% confidence interval with a significance level of 0.05. Changes in family medicine applications and unemployment rates over the years were evaluated using parity analysis. In the correlational survey analysis, due to deviations in linearization (10,11), nonparametric tests such as Spearman’s rho and Generalized Linear Model (Logit) analyses were employed. To assess the effect of time, year-controlled partial correlation analysis was performed. 3. Result In 2008, the first year of family medicine implementation, there were 45,111,103 applications, while by 2022 this figure had increased to 332,907,540. During the same period, the female unemployment rate rose from 11.60% in 2008 to 13.42% in 2022. Overall unemployment, which THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO FAMILY PHYSICIANS 14 was 10.97% in 2008, stood at 10.43% in 2022, with unemployment rates following a fluctuating trend (Table 1). Table 1. Number of applications to family physicians, female unemployment rate, and total unemployment rate by year Year Number of applications Female unemployment rateᵃ Total unemployment rateᵇ 2008 45.111.103,00 11,60 10,97 2009 65.716.898,00 14,32 14,03 2010 108.976.049,00 13,00 11,88 2011 240.298.753,00 11,29 9,79 2012 221.672.029,00 10,80 9,21 2013 212.318.024,00 11,93 9,71 2014 214.120.750,00 11,91 9,90 2015 208.538.951,00 12,67 10,30 2016 205.549.931,00 13,75 10,90 2017 228.098.527,00 14,11 10,92 2018 258.436.607,00 13,90 10,96 2019 278.043.149,00 16,51 13,73 2020 247.273.830,00 14,98 13,15 2021 239.053.780,00 14,72 11,97 2022 332.907.540,00 13,42 10,43 a. Percentage within the female labor force, b. Percentage within the total labor force. From 2008 to 2011, the number of applications to family physicians increased rapidly, while from 2012 onward it followed a more stable course. The unemployment rate among women of working age, on the other hand, displayed a fluctuating trend (Figure 1). TUBA DUYGU COŞKUN 15 Figure 1. Change in applications to family physicians and female unemployment levels by year The results of the Spearman’s rho correlation analysis examining the relationship between applications to family physicians and female and overall unemployment levels indicated that there was no statistically significant relationship between applications to family physicians and either female unemployment or total unemployment (p > 0.05) (Table 2). TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 22 therapeutic efficacy, while challenges like drug resistance, high costs, and access disparities persist. Future directions emphasize multi-omic profiling, next-generation therapies, and global health equity to ensure accessible, personalized pulmonary care. Keywords: Targeted therapies, Molecular pathways, Pulmonary diseases, Asthma, COPD. 1. Introduction Past successes in molecular biology, high-throughput genomics and individual medicine have made it possible to model disease-specific biomarkers and druggable targets [1]. The result of these tools has been biologic agents and small-molecule oncology-targeted inhibitors with patient specificity that are more efficacious and less toxic [2]. Also, drug development, patient stratification and prediction of patient therapeutic response in pulmonary diseases are being advanced by artificial intelligence (AI), and computational modeling [3, 25]. With such advances, however, pulmonary diseases continue to exert a large health burden worldwide, with hundreds of millions of the global population afflicted and causing a high level of morbidity and mortality as well as spending associated with treating the illness [4]. Asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH) and several types of lung cancer (particularly non-small cell lung cancer (NSCLC)) are the most common and serious of them. Although they are dissimilar in etiology and clinical manifestations, these conditions have a common set of pathological mechanisms: chronic inflammation, tissue remodelling, immune regulation, and cellular signalling disorders [4,5]. In the past, the treatment of pulmonary diseases was dependent on the use of the broad-spectrum mechanisms such as corticosteroids, bronchodilators, and system-wide chemotherapy. These options have been successful at controlling symptoms and prolonging survival, but in many cases, these did not correct the problematic molecular defects that had manifested themselves into disease progression [5,6]. In addition, systemic side effects, widely ranging patient responses, and rising resistance, especially in chronic and malignant lung disorders, are linked to traditional therapies [6]. With the advent of targeted therapies, it is possible to change pulmonary medicine through providing precision-mediated treatment that would interfere with a given path of a pathogen. Among examples, there is monoclonal antibody directed against interleukin (IL)-5 in eosinophilic asthma [3], tyrosine-kinase-inhibitors (TKIs) aimed at EGFR mutations in SEVTAP DÜZGÜNÇINAR 23 NSCLC [6,12] and antifibrotic agents that block fibroblast action in IPF [4]. Relative newcomers including JAK inhibitors in inflammatory lung disease, KRAS G12C inhibitors like sotorasib in lung cancer, and inhaled biologics to deliver drugs in a more airway-specific way are now in clinical use [8,10,20,21]. But there are a number of constraints that remain such as patient heterogeneity in response to treatment, cost, poor accessibility in lowresource areas, and poor long-term safety data [11]. It is also important to make the existing range of effective targeted therapies bigger by conducting continuous research into molecular mechanisms and signalling pathways and thus enhancing patient outcomes [22]. Here, there is a detailed description of the molecular pathways involved in key lung diseases and targeted medicine that attempts to mediate these pathways. It investigates the molecular pathways specific to the disease, the mechanism of action of the drug, the effectiveness of the currently used treatment, the challenges in treatment, and the research possibilities that will result in precision medication in the field of respiratory care. 2. Understanding Pulmonary Molecular Pathways Pulmonary pathologies result in a complex interplay of inflammatory mediators, profibrotic signals, immune checkpoints, and mutations in gene expression leading to the occurrence of a disease. These molecular networks play important roles in the precision therapies and therapeutic target developments. In this section, a summary of the four most important classes of molecular pathways in the major respiratory diseases includes inflammatory signalling, fibrotic remodelling, immune evasion in cancer, and oncogenic mutations. 2.1 Inflammatory Pathways of Pulmonary Diseases Chronic inflammation is the basis of such diseases as asthma, COPD, and interstitial lung diseases. Summarizing the key cytokines, there are interleukins (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-alpha) that lead to immune cell infiltration, mucus secretion, airway hyperresponsiveness and tissue destruction [1]. Th2 cells produce IL-4 and IL-13, where IL-4 leads to class change IgE and IL-13 causes goblet cell metaplasia and the remodelling of airways [2]. The two cytokines share a common signalling pathway through the IL-4 receptor alpha (IL-4R alpha), which is a confirmed target of dupilumab since it gets approved of severe phenotypes of type 2 asthma [3]. The IL-5 maintains eosinophil maturation and survival and plays a pivotal role in eosinophilic asthma and exacerbation. Mepolizumab, TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 24 reslizumab and benralizumab are monoclonal IL-5-binding (or receptorblocking) antibodies that decrease rates of exacerbation and the amount of oral corticosteroids [4,5]. In neutrophilic COPD airways inflammation, TNF - alpha (TNFalpha) is also involved, but anti-TNF treatments did not demonstrate consistent outcomes across pulmonary conditions and are frequently abandoned because of adverse reactions [6]. Pathway specific anti-inflammatory action There is on-going research on the identification of CXCR2 antagonists and phosphodiesterase-4 inhibitors such as roflumilast, which are drugs which can positively influence the outcome of COPD [7, 21]. Recent research indicates that treatment of upstream alarmins, such as TSLP (e.g., tezepelumab), can be of wider use than targeting downstream signals (IL-4/IL-13, IL-5, and IL-5 receptor, etc.) [8, 22]. 2.2. Pulmonary fibrosis manifested in IPF and in postCOVID-19 Interstitial lung disease shows distorted repair processes, activates the fibroblast population, and excessively produces the extracellular matrix (ECM). Fibrogenesis is mediated by transforming growth factor-beta (TGF-β) and Wnt /B-catenin signalling [9]. As a master regulator, TGF -beta stimulates epithelialmesenchymal transition (EMT), myofibroblast differentiation and collagen production through SMAD signalling. Antifibrotic drugs such as pirfenidone and fresolimumab have been produced to target TGFapproaches that were developed to inhibit TGFthis process [10]. Concurrently, Wnt/ beta-catenin signalling mechanism, which in the normal adult lung is quiescent, gets reactivated in an injured lung and controls the proliferation and cell matrix synthesis transcription. Pathological Wnt signalling is related to the disease progression, which indicates the potential of Wnt inhibitory methods in the context of fibrotic lung disorders [11]. New treatments are in development modifying these pathways in order to stabilize or reverse fibrosis [12, 23], including ziltivekimab and pamrevlumab [23]. 2.3 Lung Cancer Immune Checkpoints The immunotherapy has transformed the therapy of NSCLC. Cancers largely avoid immune surveillance through the use of the PD-1/PD-L1 pathway and CTLA-4 pathways. The expressed PD-L1 on tumour cells interacts with PD-1 on activated Tcell, disabling the T-cell. The monoclonal antibodies, including nivolumab, pembrolizumab, and atezolizumab, can reverse antitumor activity and exhibited significant survival effect, especially in a tumour with high PD-L1 expression [13]. Inhibitory receptors SEVTAP DÜZGÜNÇINAR 25 Another example of checkpoint receptor, CTLA-4 inhibits early T-cell activation. Added to PD-1 inhibitors, the immune stimulatory characteristics of ipilimumab (anti-CTLA-4) boost immune reactions and are certified in limited NSCLC patients [14]. The combinational approach is under trial with chemotherapy, new agents to extend the immunotherapy coverage [15]. Checkpoint inhibitors have become the key factors in the therapy of NSCLC and are constantly improving with the further progress (IMpower110, CheckMate 227, and KEYNOTE-189) [16, 24]. 2.4 Molecular Mutations Resulting in Lung Cancers Actionable driver mutations in NSCLC have been identified using molecular profiling thus being treated on target. The EGFR, ALK rearrangements and KRAS mutations are the most important ones. • EGFR mutations are seen in ~ 20 percent of NSCLC cases (particularly, non-smokers). First, a third-generation TKI, Osimertinib, has been able to replace such previous drugs as erlotinib and gefitinib because of increased anti-resistance activity on T790M change [17]. • In ~5 percent of the cases, there is rearrangement of ALK, which is usually fused with EML4. Such factors as crizotinib, alectinib, and lorlatinib are drugs that inhibit ALK and prolong life, enhancing outcomes of progression-free survival [18]. • KRAS is no longer regarded as undruggable because the KRAS G12C inhibitors, such as sotorasib and adagrasib can target the previously untreatable subpopulation due to KRAS mutations [19, 25]. Cutting-edge diagnostic methods like next-generation sequencing (NGS) and liquid biopsies are now becoming standard in guiding a targeted therapy and detecting development of resistance [20]. 3. Targeted Therapies in Specific Pulmonary Diseases Evolution of molecular biology and pharmacogenomics has changed the treatment of pulmonary diseases. As an alternative to an indefinite compensatory factor in the form of nonspecifically acting anti-inflammatory drugs and symptomatic agents, modern pulmonology implements precision medicine in the form of a targeted treatment agent complicating specific molecular mechanisms of the pathogenesis of the disease. The usage of such therapies is described in relation to asthma, chronic obstructive pulmonary TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 26 diseases (COPD), idiopathic pulmonary fibrosis (IPF), lung cancer, and pulmonary arterial hypertension (PAH). 3.1. Asthma and COPD: Biologic and Anti-Inflammatory Targets 3.1.1 Asthma IL-4, IL-5 and IL-13-driven type 2 inflammation defines the eosinophilic and allergic forms of asthma. Biologic agents are now an individualized choice of patients who are not responsive to inhaled corticosteroids and bronchodilators. • Omalizumab is a monoclonal IgG antibody against IgE and by so doing blocks the attachment of IgE to mast cell. It is licensed to moderate-and severe allergic asthma and lowers exacerbations without increasing quality of life [1]. • Mepolizumab and reslizumab block IL-5 connection, cutting down eosinophil recruitment and survival. Their use is recommended in severe eosinophilic asthma as a way of reducing the number of exacerbations and corticosteroid requirements [2]. • Benralizumab is a receptor-blocking agent specific to the alpha-chain of the interleukin-5 (IL-5) receptor and without internalization, causing apoptosis of eosinophil through an antibody-dependent cell-mediated cytotoxicity (ADCC), which leads to sustained and rapid removal of eosinophil [3]. These drugs have also transformed the issue of asthma towards phenotype and endotype directed approaches [20]. 3.1.2. COPD Although COPD is generally characterized by neutrophil dominance, it has the subgroup of patients with eosinophilic characteristics who respond to biologics. • Mepolizumab has demonstrated small improvements in eosinophilic subgroups of COPD, especially minimizing the number of exacerbations [4]. • Phosphodiesterase-4 (PDE4) inhibitors, e.g. roflumilast, have not only shown anti-inflammatory and anti-remodeling effects in severe COPD with chronic bronchitis [5], but also held the advantage that roflumilast showed significant effects on improving exercise performance [6]. Agents under SEVTAP DÜZGÜNÇINAR 27 clinical trial (such as CXCR2 antagonists and IL-33 inhibitors) are targeted mechanisms of inflammatory modulation in COPD [6, 21]. 3.2 Idiopathic Pulmonary Fibrosis (IPF): Anti-Fibrotic Therapy IPF refers to a progressive, incurable interstitial lung disease characterized by the development of fibroblasts, ECM and permanent scarring of the lungs. • Nintedanib is a tyrosine kinase inhibitor and prevents PDGF, FGF and VEGF signals. When used as part of clinical trials like INPULSIS, it has been demonstrated to reduce the loss of FVC by up to 50 percent [7]. • Pirfenidone down regulates TGF-b expression, fibroblast activity and has shown to be effective in disease progression and longer progression free survival in ASCEND and CAPACITY trials [8]. Neither of the drugs restores fibrosis, but they signify a paradigm extension of IPF translation. Clinically-developed new anti-fibrotic agents, including pamrevlumab (anti-CTGF), ziltivekimab (anti-IL-6 signaling), and BG00011 (anti-integrin treatment) have been developed and indicate hope of a wider impact on fibrosis and the achievability of a more favorable safety profile [9, 22]. 3.3 Precision Oncology in Action: Lung Cancer Molecular profiling and targeted treatment has transformed the treatment of lung cancer, especially non-small cell lung cancer (NSCLC). • Oncogenic signaling is triggered by EGFR mutations, which are characteristic of non-smokers. TKIs of the third generation, including osimertinib, have been adopted as superior alternatives to earlier TKIs, including erlotinib and gefitinib, because they penetrate the CNS better and are effective against T790M resistance mutation [10]. • The prevalence of the ALK rearrangements is approximately 5 percent of the NSCLC patients. Specific TKIs such as alectinib, lorlatinib, and ceritinib are a major boost to survival [11]. • KRAS mutations, formerly not actionable, are actionable. Inhibitors of KRAS G12C such as sotorasib and adagrasib have successfully been put into clinical applications with promising results on specific patients [12, 23]. • The immune checkpoint inhibitors, pembrolizumab (PD-1), atezolizumab (PD-L1) or ipilimumab (CTLA-4) have become the firstline standard treatment of advanced NSCLC and especially in high PD-L1 TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 28 expressing tumors. Combination therapies even increase the effectiveness further [13, 24]. These therapies are guided by next-generation sequencing (NGS) and liquid biopsies, enabling precision-targeted treatment strategies. 3.4 Vasodilator-Targeted Therapy in PAHPAH PAH is an endothelial dysfunction, vascular remodeling and increased resistance to the pulmonary vasculature condition. Targeted vasodilator therapies intend to achieve vascular balance. • Endothelin receptor antagonist (ERA), including Bosentan, Ambrisentan, and Macitentan, prevents the proliferation and contraction effect of endothelin-1 [14]. • Phosphodiesterase-5 (PDE5) inhibitors sildenafil and tadalafil enhance the nitric oxide pathway through cyclic GMP to better vasodilation and respiratory tolerance [15]. • Prostacyclin analogs and receptor agonists epoprostenol, treprostinil and selexipag restore vasodilation and block vascular smooth muscle proliferation [16]. • Direct stimulators of cGMP production using soluble guanylate cyclase (sGC), e.g. riociguat, are approved in the treatment of PAH as well as chronic thromboembolic pulmonary hypertension (CTEPH) [17]. These treatments enhance hemodynamics, functional class, and survival, but prolonged response and consistency plus availability are persistent challenges in the clinical practice [25]. 4. Drug Delivery and Precision Medicine Precision medicine is transforming the paradigm of pulmonary medicine by abandoning symptom-based generalized treatments in favor of personalized treatments that take into consideration genomic, molecular and phenotyping attributes. At the centre of this transition are enhanced platforms of drug delivery and companion diagnostics that improve the precision of treatments, the toxicity and the clinical benefits [1]. 4.1 Biologics and Nanoparticles via Inhalation Conventional systemic treatment of any pulmonary disease is usually hampered by inadequate drug levels in the lung, systemic toxicity and low SEVTAP DÜZGÜNÇINAR 29 effectiveness. Drugs delivered by inhaling reach the specific area of the lung affected by the pathology directly and in an off-target manner. 4.1.1. Inhaled Biologics Elsewhere, RNA therapeutics and delivered monoclonal antibodies (mAbs) are being developed to treat diseases such as asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer. There are a few advantages of inhaled biologics: The local drug concentration is enhanced; there is less systemic side effects and acute action. Tocilizumab is an immune protein (interleukin-6 receptorblocking) which is being tested in clinical trials against inflammatory lung disease when used by inhalation. Isolated fibrotic lungs may have a better alternative administration route, intravenous or subcutaneous administration of the drug, via inhalation [2, 16]. Such problems encountered with regard to inhaled biologics are protein stability under nebulization process, immunogenicity reduction, and particle deposition in the scarred or obstructed lung tissue [2]. 4.1.2. Delivery System using Nanoparticles Nanomedicines Nanoparticle (NP) formulations exert high precision and controlled delivery of therapeutic agents as liposomes and polymeric micelles, solid lipid nanoparticles. In the case of NSCLC, the formulations introduce nanoparticles containing tyrosine inhibitors in kinase receptors, siRNA, and chemotherapeutic preparations, which have been tailored to improve tumor specificity and reduce side effects [3]. In the IPF, inhaled investigational pirfenidone-loaded nanogels circumvent hepatic clearance to target the lungs and augment bioavailability in the lung [3, 18]. 4.1.3. Smart Nanoparticles The current generation of these nano agents is able to respond to microenvironment variations, such as change in pH and oxidative stress, or a particular enzyme activity, to target their payload to inflamed or fibrotic tissue selectively [3]. TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 30 The two technologies show the potential of enhancing drug bioavailability, increasing treatment adherence and also control costs associated with the management of chronic lung diseases. 4.2 Companion Diagnostics and Genomic Profiling The integration of genomic medicine has revolutionized clinical decision-making in pulmonary disease, enabling treatment selection based on molecular signatures. 4.2.1. Genomic Profiling in Lung Cancer Next-generation sequencing (NGS) is now standard in NSCLC for detecting actionable driver mutations in EGFR, ALK, ROS1, BRAF, MET, and RET genes [4]. These biomarkers guide the use of targeted agents such as TKIs and immune checkpoint inhibitors [4]. Liquid biopsies, which detect circulating tumor DNA (ctDNA), provide non-invasive tools for monitoring tumor dynamics, detecting resistance mutations, and adapting therapy in real time [5, 22]. 4.2.2. Companion Diagnostics (CDx) CDx are FDA-approved tests that predict a patient’s likelihood of responding to specific targeted therapies. EGFR mutation testing is required before initiating osimertinib. PD-L1 expression scoring helps assess eligibility for pembrolizumab and other immune checkpoint inhibitors. KRAS G12C mutation testing informs the use of sotorasib or adagrasib [6]. In IPF, biomarkers predicting response to nintedanib or pirfenidone are under investigation but not yet standardized. In asthma and COPD, biomarkers such as blood eosinophil counts, FeNO (fractional exhaled nitric oxide), and IgE levels support stratification for biologic therapies like anti-IL-5 or anti-IgE agents [6]. 4.2.3. Future of Precision Delivery Emerging technologies are driving the next evolution of personalized pulmonary treatment: SEVTAP DÜZGÜNÇINAR 31 AI-powered algorithms integrate imaging, clinical, and genomic data to predict treatment response and disease progression [6, 28]. Gene-editing platforms like CRISPR-Cas9, delivered through inhalable viral or non-viral vectors, are being explored to correct disease-causing mutations directly in lung tissues. Wearable sensors and smart inhalers are enabling real-time monitoring of lung function, adherence, and therapeutic impact—ushering in a new age of data-informed, responsive care [6, 26]. 5. Clinical Trials And Real-World Data A strong and growing evidence base consisting of randomized controlled trials (RCTs), meta-analyses and real-world data (RWD) exists to support targeted therapies in pulmonary diseases. Whereas RCTs supply regulatory endorsement and rule-based guidance, there are real-world examinations which give complimentary information about long-term security, individual variance of patients as well as accessibility in broader clinical context [1]. 5.1. Landmark Trials and Clinical Evidence These extensive and large trials have resulted in regulatory approval and practice transforming suggestions to several pulmonary conditions: 5.1.1 Idiopathic Pulmonary Fibrosis (IPF) • INPULSIS-1 and 2 (NCT01335464, NCT01335477): These pivotal Phase III studies demonstrated that nintedanib significantly reduced the annual rate of forced vital capacity (FVC) decline in patients with IPF, leading to global approval [2]. • ASCEND Trial (NCT01366209): Confirmed the efficacy of pirfenidone in reducing FVC decline and improving progression-free survival in IPF [2]. 5.1.2 Non-Small Cell Lung Cancer (NSCLC) • FLAURA (NCT02296125): Demonstrated that osimertinib, a thirdgeneration EGFR tyrosine kinase inhibitor (TKI), significantly improved both progression-free survival and overall survival in EGFR-mutated NSCLC compared to older TKIs [2]. • IMpower110 (NCT02409342) and KEYNOTE-024 (NCT02142738): Showed that atezolizumab and pembrolizumab, respectively, significantly improved outcomes in advanced NSCLC with high PD-L1 expression [2]. TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 38 The dawn of biological understanding and technological creativity is ushering in a new age when pulmonary care is not only more effective, but individualized. As clinicians, researchers, policy makers and technology developers continue to partner together in the effort to provide all patients with person-centered, accessible, and evidence-based respiratory care, the outcome becomes not merely achievable, but unavoidable. SEVTAP DÜZGÜNÇINAR 39 References: 1. Wenzel SE. Asthma: characterizing the chronic adult phenotypes. Lancet. 2012;380(9851):1033–42. 2. Bel EH, Wenzel S, Thompson PJ, et al. Oral glucocorticoid–sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97. 3. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti–interleukin-5 receptor α monoclonal antibody, in severe asthma. Lancet. 2016;388(10056):2128–41. 4. Richeldi L, du Bois RM, Raghu G, et al. 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Artificial intelligence in pulmonary medicine: applications and caveats. Front Med (Lausanne). 2022;9:812345. TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES 40 19. Sharma A, Tripathy S, Kumar V, et al. Role of nanotechnology in targeted pulmonary drug delivery. J Control Release. 2023;350:1–12. 20. Barnes PJ. Inflammatory mechanisms in COPD. J Allergy Clin Immunol. 2016;138(1):16–27. 21. Caminati M, Buhl R, Corren J, et al. Tezepelumab in patients with allergic and eosinophilic asthma. Allergy. 2024;79(5):1134–45. 22. Panettieri JR Jr, Lugogo N, Corren J, et al. Tezepelumab pooled analysis of PATHWAY/NAVIGATOR trials. Am J Respir Crit Care Med. 2023;208(1):13–24. 23. Zhang L, et al. Deep learning in radiology for lung cancer diagnostics: a systematic review. Comput Biol Med. 2024;158:107110. 24. Wang X, Huang W, Zhao J, et al. Research progress of radiomics and AI in lung cancer. Chin J Acad Radiol. 2023;6(2):91–99. 25. Wu X, Polychronis A. Application of radiomics and AI in lung cancer immunotherapy. Cancer Metastasis Treat. 2023;9:29. 26. Caminati M, Vatrella A, Rogliani P, et al. Tezepelumab in severe asthma comorbid with nasal polyps. J Asthma Allergy. 2023;16:915–32. 27. Saad N, et al. Radiological artificial intelligence – predicting personalized immunotherapy responses in lung cancer. Lancet Digit Health. 2023;5(2):e86–e97. 28. Balekai R, Holi MS. Exploring potential of radiomics in lung cancer diagnosis and treatment: systematic evaluation. Multimed Tools Appl. 2024;83:60469–60492. 41 CHAPTER 4 FIBROTIC LUNG DISEASE IN THE POSTCOVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING TREATMENTS Dr. Sevtap DÜZGÜNÇINAR1 Abstract COVID-19, caused by SARS-CoV-2, has greatly affected the health of the lungs and continues to leave a long-lasting impact. Though acute respiratory failure and viral pneumonia were given the most attention initially, some patients later develop persistent inflammation, damage to lung structures, and scarring in their lungs. Post-COVID fibrotic lung disease has become a more widely recognized condition that can seriously affect a person’s health. When pulmonary fibrosis occurs, it causes the lung tissue to thicken and scar, which can reduce the exchange of oxygen and worsen breathing problems. Fibrosis is commonly seen in idiopathic interstitial lung diseases (ILDs), but it is now thought that SARS-CoV-2 infection may initiate or speed up fibrotic changes in the lungs through a particular pathway involving immune problems, injury to blood vessels, ongoing release of cytokines, and improper tissue repair. Age, previous lung disease, a family history of lung problems, and using mechanical ventilation for a long time seem to be important factors in the development and progression of fibrosis after COVID-19. 1 A Life Hospital Kuzey Ankara Hastanesi, Ankara, Turkiye, [email protected], ORCID: 0009-0003-3769-7104 FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 42 The chapter explores in detail the factors and events that cause fibrotic disease of the lungs after COVID-19. Initially, we analyze the spread of fibrosis and the people who have been most affected after an infection with SARS-CoV-2. Afterward, we explore the main pathways in fibrosis, including those involving TGF-β, fibroblast stimulation, myofibroblast development, and changes in the extracellular matrix. Various tools used to examine and diagnose patients, such as HRCT, pulmonary function testing, and biomarkers, are described as ways to tell post-COVID fibrosis apart from other ILDs. The chapter covers the main ways of treating pulmonary fibrosis, such as corticosteroids, anti-fibrotic drugs, and rehabilitation or oxygen therapy. Meanwhile, we study new and upcoming treatments such as those based on stem cells, antifibrotic drugs, and medicine that uses artificial intelligence and genomics. This study also discusses the impact of long-term lung fibrosis on public and healthcare systems in people who had COVID-19. We review areas where knowledge is missing, suggest future topics for clinical studies and describe how to spot, risk assess and manage heart disease early, combined with various medical teams. The chapter aims to give clinicians, researchers and policy-makers a clear and practical framework by combining knowledge of disease pathways with new evidence on fibrotic pulmonary complications after the pandemic. Keywords: Targeted therapies, Molecular pathways, Pulmonary diseases, Asthma, COPD. 1. Introduction Because of the COVID-19 pandemic, global infectious diseases are now different and the disease can lead to serious health issues that last for a long time (1,2). At first, medical professionals focused on ARDS, intensive care treatment and how the virus spreads, but it is now obvious that SARS-CoV-2 infection may result in chronic lung problems (3,4). Fibrotic lung disease results in scarring, reduced ability of the lungs to expand and contract, and poor gas exchange (5). In most cases, pulmonary fibrosis occurs when abnormal collagen and other materials are deposited in the spaces between the air sacs in the lungs (6). Such changes result in permanent damage to the lung structure, loss of its units and a gradual failure to exchange oxygen (7). While fibrosis is a typical feature of ILDs such as IPF, systemic sclerosis-associated ILD and hypersensitivity pneumonitis, it appearing after SARS-CoV-2 infection represents an innovative and fresh medical challenge (8,9). SEVTAP DÜZGÜNÇINAR 43 In the beginning of the pandemic, doctors observed ground-glass opacities, organizing pneumonia patterns and thickening inside the lungs in patients with moderate to severe COVID-19 (10,11). Following initial studies, it has been found that some patients still have these abnormalities or they may develop into fibrosis months after getting better (12–14). The precise processes are not yet completely understood, but they are believed to involve problems with the immune system, “cytokine storms” (mainly involving interleukin-6, TNF-α and TGF-β), harm to epithelial cells in the lungs and ineffective healing of wounds in the lungs (15,16). They can be further increased by factors like being very old, having a high amount of the virus, a history of smoking, diabetes, and using invasive mechanical ventilation (17,18). It is challenging for doctors to recognize and diagnose post-COVID fibrotic lung disease. Sometimes, exertional dyspnea, dry cough, ell postCOVID fibrosis apart from other ongoing lung diseases, doctors rely on the patient’s history, detailed images, lung function tests and sometimes examine tissue samples (19,20). As a result, it is essential for individuals with lung diseases to be cared for by pulmonologists, radiologists, infectious disease specialists, and rehabilitation professionals (21,22). Managing therapy is also a challenging process. Corticosteroids have helped in the early stages of COVID-19, but it is still unclear if they are useful in managing or preventing fibrosis in the long run (23,24). Nintedanib and pirfenidone which were designed for IPF, are being studied in people suffering from post-COVID conditions (25,26). Yet, the success rate of treatments, the timing of their use, who should receive them and information on their long-term safety are still lacking (27,28). In addition, researchers are exploring methods such as stem cell therapy, epigenetic techniques and AI to address the shortcomings in treatment (29,30). This means that the consequences of post-COVID fibrosis impact more than just the health of individual patients. As many people around the world recover from COVID-19, healthcare systems are now dealing with the combined effect of long-term lung problems (31). Thus, patients must get long-term treatment, visit specialized doctors when need, use pulmonary rehabilitation and receive fair access to treatments where resources are low (32,33). This chapter aims to thoroughly review fibrotic lung disease as one of the post-COVID complications. We will examine the spread of the disease, the body processes involved, its symptoms, how to diagnose it and available treatments. In addition, we will examine ongoing experimental treatments and point out some important questions that scientists have yet to FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 44 answer. We aim to give clinicians, scientists and healthcare policymakers the understanding needed to detect, manage and lessen the long-term effects of COVID-19 on the lungs. 2. Understanding Epidemiology and Its Clinical Significance Fibrotic lung disease has recently become a significant concern for people dealing with COVID-19. Pulmonary fibrosis was previously tied to ILDs, environmental exposures, immune system dysregulation, and medications with potential pulmonary toxicity (e.g., chemotherapeutic agents like bleomycin, amiodarone, nitrofurantoin, and methotrexate) (9,10); however, the SARS-CoV-2 virus has added a new reason (1,2,5). This has required us to consider fibrotic disease epidemiology once again, considering the global spread of the virus, the different severity of the disease, and how people from different groups handle it. 2.1 How common is this disease? It is difficult to estimate the impact of COVID-19 on pulmonary fibrosis because the pandemic’s dynamics continue to evolve, some people do not have equal access to healthcare, and there are no common guidelines for diagnosing post-viral fibrosis (1,3,4). Even so, studies and registry findings suggest that many patients who had moderate to severe COVID-19 now show interstitial changes in their lungs, and some of these changes may become fibrotic (6,7). Reports differ, but between 10% and 30% of COVID-19 patients who are hospitalized develop fibrosis on radiology images within 3 to 6 months of being discharged (6). The study in Wuhan, China, revealed that 29% of patients who left the hospital after recovering from COVID-19 showed fibro-like changes on follow-up HRCT images (6). There have been cases in Europe and North America where older patients and those receiving intensive care or ventilation showed traction bronchiectasis, reticular opacities, and parenchymal bands on imaging (3,6,7). You should also tell apart transient fibrotic-like changes from progressive fibrosis. Some lung problems may clear up as time goes on, but in those with prior lung disease, a weak immune system, or who had severe ARDS, some issues may not improve or may even worsen (1,4,5). SEVTAP DÜZGÜNÇINAR 45 2.2 Risk Factors Affecting the Whole Population According to research, certain factors make it more likely for SARSCoV-2 infection to result in fibrotic lung disease (3,5,6,8). • Being older than 60 increases the risk of infection because older people have less ability to recover from damage, higher levels of inflammation, and less lung capacity. Severe COVID-19 that requires ICU, special ventilation, or needs oxygen for a long time often results in long-term changes in the lungs. • Having chronic obstructive pulmonary disease, asthma, heart disease, obesity, diabetes mellitus, and autoimmune illnesses can increase the risk of COVID-19 (5,6). • Some researchers believe that genetic factors such as those in the MUC5B and TERT genes could influence the development of fibrotic changes after COVID-19 (11). • Sex and Ethnicity: According to some studies, males and individuals of certain ethnicities seem to have more cases of fibrosis, although the reasons may be related to unequal access to healthcare. Additionally, factors such as high viral load during the disease, history of intensive care unit admission and invasive mechanical ventilation, prolonged hospital stay, comorbid conditions (e.g., hypertension, cardiovascular diseases), advanced age, diabetes, and smoking history significantly contribute to the risk of developing post-COVID fibrotic lung disease (1,5,6). 2.3. How the Disease Impacts Patients and Their Quality of Life? When a person develops fibrosis after COVID-19, it is often a major health problem. Those with post-COVID fibrotic lung disease tend to continue experiencing symptoms such as: • Difficulty in breathing due to physical activity • A cough that does not lead to the removal of mucus • Pain in the chest • Fatigue • A decrease in the amount of exercise a person can do They may continue for a long time, and in some situations, they can get worse as time passes (1,6,7). In many cases, pulmonary function tests indicate FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 46 a restrictive breathing pattern, decreased ability to absorb oxygen from the lungs (DLCO), and dropping oxygen saturation as individuals exercise (3,6). HRCT imaging plays a key role in identifying and measuring the fibrosis in a patient. The findings may consist of: • Traction bronchiectasis • Reticulations • Honeycombing (when the cancer is advanced) • There is fibrosis around the lungs • Frequent areas of ground-glass opacity that gradually develop into fibrosis. In addition, some of these changes can appear like those in other fibrosing ILDs, so it’s necessary to diagnose the disease and observe its progression accurately (4,6). Post-COVID pulmonary fibrosis can greatly impact a person’s quality of life (1,5,6). Many people with COVID-19 may have lasting problems with their health, feel distressed psychologically, and are unable to go back to work or lead a regular daily life. It becomes more difficult for people in these groups since follow-up, rehabilitation, and access to long-term medicine may not be available (8,12). 2.4 Health Challenges Faced by People in Different Countries Even a small risk of fibrosis in COVID-19 survivors means a significant problem for the world. There is a risk that millions of people worldwide, who were infected early in the pandemic without access to vaccines and better therapies, could suffer from long-term breathing issues (1,6,8). Now, healthcare systems have to deal with both immediate COVID-19 and future complications from COVID-19 and fibrosis. This includes: • Setting up clinics that focus on patients after COVID and developing follow-up plans • Creating guidelines to screen individuals who are more likely to get COVID-19 • Strengthening the training and equipment used for both lung images and testing SEVTAP DÜZGÜNÇINAR 47 • Increasing the chances for people to receive anti-fibrotic drugs and rehabilitation services (3,8,12) The effect of post-COVID fibrotic lung disease could be even stronger and longer for people in lowand middle-income countries, where healthcare is not as widespread (1,12,13). As a result, public health approaches should fit the needs of each region and be available with the resources on hand (12,13). 3. What Happens in the Lungs with Post-Covid Pulmonary Fibrosis? Lung scarring after getting SARS-CoV-2 involves ongoing inflammation, changes in the immune system, harm to the air sacs, and permanent changes in the connective tissue supporting the lungs. Although fibrosis is not a common problem for all COVID-19 patients, it occurs often in people who have a severe or critical infection. To improve treatment and predict the outcome of post-COVID fibrogenesis, we must first understand the biology and chemistry behind it in vulnerable individuals. The section discusses the different biological processes that can lead to fibrosis after infection with COVID-19. It covers the immune-inflammatory process, damage to both epithelial and endothelial cells, signalling pathways that produce fibrosis, and factors that influence a person’s risk (6,11,13). 3.1 The problem with Cytokine Storm and Immune Dysregulation Experiencing a severe form of COVID-19 often leads to a “cytokine storm,” which is a hyperinflammatory state. The phenomenon is defined by a rise in the blood levels of pro-inflammatory cytokines, including IL-6, IL-1β, TNF-α, and GM-CSF. They initiate and boost a severe inflammatory reaction in the body that upsets the balance of the immune system in the lungs (6,9,11). High levels of cytokines in the lungs lead to damage of the alveolar epithelium, increased leakage of fluids from blood vessels, and the arrival of neutrophils and macrophages into the alveoli. As a result, damage occurs in the lungs’ small air sacs (DAD), hyaline membranes form, and if repair fails, fibroproliferation occurs (6,9). Certain types of monocytes and macrophages with pro-fibrotic properties release TGF-β, IL-13, and platelet-derived growth factor (PDGF), encouraging fibroblasts to become active and deposit collagen (6,11). FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 54 By studying clinical phenotypes, doctors can adjust treatment and estimate how the disease will develop (25). New types of fibrotic diseases appearing after COVID are: • With the fibroinflammatory phenotype, there is active inflammation along with fibrosis, which corticosteroids or immunomodulators may help to reverse (26) • Fibrotic progression: The condition continues to worsen with time, even with treatment, and may benefit from anti-fibrotic agents (27) • Residual fibrosis that does not get worse and does not cause any decline in function—should be managed conservatively(28) Such frameworks will play a bigger role as personalized medicine develops in caring for patients with lung diseases. In short, detecting post-COVID fibrotic lung disease as soon as possible can greatly improve outcomes. Clinicians should be on the lookout for lung complications in patients with ongoing breathing difficulties after COVID-19(2,6,9). By using detailed imaging, pulmonary function tests, analyzing biomarkers and including different specialists, a complete approach to diagnosis is followed. When we better understand post-viral fibrotic conditions, we can develop interventions and tools that fit each patient’s needs. 5. How Treatment Works Today? Treating fibrotic lung disease after COVID-19 brings many problems to healthcare providers. Unlike IPF, where anti-fibrotic drugs have shown some success in slowing development (6), the fibrosis that follows COVID-19 is more diverse and usually involves continuous inflammation, ongoing illness from the virus, and different patterns of recovery (10,18). Consequently, therapies should change with the patient, focus on their needs, and rely on both how things function and what is seen in practice. In this section, we take a close look at the various drug treatments, supportive care, and recent findings from the real world about managing post-COVID pulmonary fibrosis. 5.1. Corticosteroids and Anti-inflammatory Medicines Corticosteroids are still widely used to treat the lung inflammation seen in COVID-19, mainly in the first and second stages. They help reduce the damaging effects of cytokines on the lungs, lessen the amount of fluid in SEVTAP DÜZGÜNÇINAR 55 the alveoli, and protect tissue from damage by the immune system (3,11). Corticosteroids can help speed up recovery in patients with organizing pneumonia or mixed inflammatory interstitial patterns after COVID (12). Patients who receive 6 mg of dexamethasone each day for up to 10 days and are hospitalized with COVID-19 show better survival rates if they need oxygen or mechanical ventilation (2). Still, it’s not clear how much it contributes to long-term fibrotic complications. The evidence for corticosteroids in the early fibrotic stage after COVID is still developing and uncertain, mainly for patients with ongoing inflammation or organizing pneumonia (12,17). Under these circumstances, a doctor might give prednisone, beginning with 0.5–1 mg/kg each day, depending on the HRCT results and biomarkers. Still, taking corticosteroids for a long time can cause problems such as weakened immunity, changes in glucose levels, bone thinning, and emotional issues. That’s why it’s important to use clinical judgment and watch the patient closely. At this time, no agreement exists on whether to use steroids in patients with advanced, non-inflammatory fibrosis or UIP-like patterns (6). The use of macrolide antibiotics (for example, azithromycin), colchicine, and TNF-α inhibitors in treating post-COVID inflammatory lung disease is being explored, but there isn’t enough information yet (13). Trials ahead will be important for understanding their place, especially in patients with a mix of inflammatory and fibrotic changes. 5.2 Anti-fibrotic Medications Because of their success in treating idiopathic pulmonary fibrosis, antifibrotic therapies are now routinely used in progressing fibrotic interstitial lung diseases (PF-ILDs), including post-COVID fibrosis (6,14). Pirfenidone and nintedanib, which are currently used in the treatment of IPF, are being studied in people suffering from post-COVID conditions (14,15). Since the pandemic, several clinical trials have been examining how well it works. It seems that pirfenidone could help maintain lung capacity and slow down any radiological damage in those with lung fibrosis, and decrease DLCO (15,16). This medicine may cause an upset stomach, rash, tiredness, and changes in liver enzymes, so people receiving it must be carefully observed (6). FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 56 Nintedanib blocks tyrosine kinases that control the pathways linked to fibroblast activation, including those involving PDGF, FGF, and VEGF (6,18). The drug is also approved for IPF and non-IPF fibrosing ILDs that progressively worsen. In 2022, researchers began looking at how INBUILD might be applied to people with fibrotic lung disease after COVID-19 (19). Initial results suggest that lung function may be stabilizing, mainly in people with NSIP-like or UIP-like HRCT patterns (18). Patients may experience diarrhea, changes in liver enzyme levels, nausea, and an increased risk of bleeding due to nintedanib, especially if they are on anticoagulants (6). Though these drugs are exciting, they are not officially approved for use in fibrosis after COVID-19 in most parts of the world (14,19). At this point, no randomized controlled trials have shown that these medications work well in this population. As a result, they should be reserved for patients who have worsening fibrotic disease despite taking corticosteroids or who cannot tolerate prolonged steroid treatment (15). Drug choices should be chosen for each patient separately, and it is best if ILD specialists are part of the decision-making team. 5.3 Supportive Therapies Owing to the uncertain progress of post-COVID pulmonary fibrosis, supportive care is important for sustaining a good quality of life, preventing risks, and improving how patients manage daily activities (10,20). Pulmonary rehabilitation is a key treatment for people with chronic respiratory diseases (21). Typically, tailored programs consist of the following: • Exercises done with the guidance of a trainer, practicing breathing exercises • Advisory services for eating a well-balanced diet • Help with mental health. For post-COVID patients, rehabilitation results in better ability to exercise, use oxygen, strengthen muscles, and feel better emotionally (21,22). Programs are best started 4–8 weeks after infection and should continue for 6–12 weeks, with regular checks (21). SEVTAP DÜZGÜNÇINAR 57 Many individuals with fibrotic lung disease often need to use oxygen therapy, whether they are moving or resting (10). Indications include: • At rest or when walking, SpO₂ drops below 88% • Hypoxemia that occurs during sleep • Fading color saturation during the 6-minute walk test. People who receive long-term oxygen therapy because of low oxygen levels often live longer and function better each day, but some may find that it causes them to move less and feel less happy (20). Most patients with post-COVID fibrosis have been diagnosed with cardiovascular disease, diabetes, anxiety, depression, and deconditioning (23). It is important to actively control these comorbidities to improve a patient’s lung function. Receiving vaccinations (for flu, pneumonia, and COVID-19) is important to help stop further infections that can worsen scarring in the lungs (24). 5.4 Problems with Data and Treatment Although more attention is being given to post-COVID pulmonary fibrosis, there are still not many large-scale, long-term studies about it (25). • Not every patient with fibrosis progresses; it is hard to tell which patients will stay stable and which will get worse. • There are no standard rules for treating these conditions: Treatment plans differ greatly from one place to another (26). • Anti-fibrotic drugs are often too expensive for patients and are rarely covered by insurance when used for other diseases (27). • It is possible that people’s symptoms are wrongly associated with general fatigue or anxiety, which may postpone the correct diagnosis and treatment (10). There is a lack of post-COVID fibrosis patients from lowand middleincome countries in research, which reduces how well the findings can be applied to others (28). A number of trials, including NCT04607928 and NCT04541680, are investigating anti-fibrotic, immunomodulatory, and new biologic drugs for fibrosis after COVID-19 (15,19). Registries like the UK Interstitial Lung Disease COVID-19 registry are giving us useful information on treatments and outcomes (18). FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 58 All in all, doctors use the same approach as for ILD, but must also consider the unique way post-COVID pulmonary fibrosis affects patients. Treatment with corticosteroids may improve inflammatory forms of the disease, but further studies are needed to determine if anti-fibrotic agents can help with fibrosis (6,14,15). Using supportive therapies is important for both maintaining functions and improving life quality (20,21). Next, welldesigned clinical studies and the addition of real-world data will play an important role in shaping useful guidelines for this complex pulmonary issue (25–28). 6. Looks at New and Experimental Forms of Therapy The medical field is under pressure to create new and reliable treatments for post-COVID pulmonary fibrosis. Since corticosteroids and repurposed anti-fibrotic agents have their own limitations, there is a need for new approaches that more precisely address the main fibrogenic pathways and have fewer side effects (3,5). This chapter explores the progress of new and experimental treatments, covering next-generation anti-fibrotics, stem cell therapies, immunomodulators, biologics and improvements in personalized and precision medicine (6,14,22). Overall, these therapies herald a new approach to handling fibrotic lung disease after the pandemic. 6.1 Anti-Fibrotic Compounds Are Being Tested in Trials There are several investigational drugs being tested, both in labs and in humans, to see if they can target fibrotic pathways with more precision than the first anti-fibrotic drugs (6,17,22). PBI-4050, a novel drug for G-protein coupled receptors (GPR40, GPR84), decreases inflammation and fibrosis in animal tests by blocking the activation of fibroblasts and the production of collagen (17). The results from early human trials in IPF suggest that the treatment is safe and may be useful for treating post-COVID fibrosis (17,22). Originally introduced for IPF, PRM-151 is a recombinant human pentraxin-2 protein that plays a role in controlling macrophage action and remodeling tissue (17). It helps keep repair processes normal and prevents excessive fibrosis by adjusting monocyte-to-fibrocyte differentiation. Early SEVTAP DÜZGÜNÇINAR 59 results from Phase 2 trials suggest that fibrotic ILD treatment could be useful and future studies are planning to look at its use after COVID-19 (17). Macrophages and fibroblasts can express galectin-3 which encourages both inflammation and fibrosis. Some inhibitors such as belapectin and TD139 (GB0139) have been shown to limit the expression of genes that promote scarring in the lungs and early tests on these drugs are being carried out in people with lung fibrosis (18). LOXL2 is a protein that encourages the stiffening of tissues by helping collagen cross-link. In lab animals, simtuzumab has been found to slow fibrosis, but in the early testing on people, the results have not been consistent. More work is being done in post-viral fibrotic models (17). 6.2 Therapy using Stem Cells One of the most exciting paths in regenerative pulmonary medicine is using MSCs to help repair the lungs and control the immune response (19,22). MSCs possess: • The ability to reduce the action of inflammatory cytokines • Paracrine signaling, which helps tissues repair by releasing growth factors • Safe for alveolar epithelial and endothelial cells, preventing them from cell death. You can get these cells from bone marrow, adipose tissue, or the umbilical cord, and they are most often injected into the vein. Upon reaching injured lung tissue, they release exosomes and interact with nearby cells to work (19,20). Doctors are testing COVID-19 treatments in clinical trials. In earlyphase studies (like NCT04276987 and NCT04333368), MSCs were used on patients with severe COVID-19 and it was found that they improved oxygenation, lowered inflammatory markers and allowed patients to leave the ICU sooner (19,20). Most of the studies were on acute lung injury, but their results can be used for post-COVID fibrosis treatments (19,22). A major problem is increasing production, keeping cells consistent and figuring out the best times, amounts and ways to deliver treatments. Even so, MSC therapy may have the potential to change the course of fibrotic lung disease. FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 60 6.3 Immunomodulatory Therapies Treatments that control the immune system may help prevent postCOVID fibrogenesis (14,21). Janus Kinase (JAK) inhibitors interfere with the internal signalling of different pro-inflammatory cytokines such as IL-6, IFN-γ and GM-CSF. Thus, these drugs can help reduce the early swelling that causes fibrosis (21). Baricitinib is being used for hospitalized COVID-19 patients and might help prevent lasting health problems. Long-term antifibrotic effects of pirfenidone are being studied in animal models with post-viral ILD (5,14). IL-6 is important in causing COVID-19 cytokine storms and may help create a fibrotic environment. Tocilizumab which targets IL-6, has been broadly used to treat acute COVID-19 (3,14). It is still uncertain whether suppressing IL-6 for a long time can stop fibrosis, but studies are being done to find out (14). Although results with TNF-α inhibitors in fibrotic diseases are inconsistent, new agents that target TGF-β, such as fresolimumab and SB-525334, are currently being studied (17,21). TGF-β is involved in many tissue repair processes, so directly blocking it is risky, but using it locally or under control may improve both safety and success. 6.4 Biologics and Monoclonal Antibodies Biologic therapies can target fibrosis precisely and might stop it from starting at its beginning (6,14,17). In particular, integrin αvβ6 promotes the action of latent TGF-β and becomes more active in the lungs during fibrosis. BG00011, which targets αvβ6, is currently being investigated in IPF and may be used to treat postCOVID fibrosis. Anti-CTGF is the name given to this drug (17). Treatment with pamrevlumab, which targets CTGF, may lead to slower rates of FVC loss in IPF. Since it works in tandem with TGF-β blockade, it could be useful in the first stages of fibrosis (17). New therapies that focus on FAP, a sign of activated fibroblasts, may help destroy only fibrogenic cells while leaving normal lung function intact. We have not reached clinical trials with this strategy yet, but it could be useful in the future (18). SEVTAP DÜZGÜNÇINAR 61 6.5 Personalized and Precision Medicine Methods Because post-COVID fibrosis is so different from case to case, precision medicine is becoming more important for treatment (22,23,24). Because of advances in genomics, transcriptomics, and proteomics, scientists can now identify different molecular subtypes of fibrotic disease. A high level of pro-fibrotic genes (such as COL1A1 or ACTA2) or fibrogenic miRNAs (such as miR-21 or miR-199a) could help choose the best therapy and identify patients at higher risk (23,24). AI-based radiomics can measure how severe fibrosis is, guess how it will worsen, and tell apart fibrotic from inflammatory changes seen on HRCT (25). Researchers are building machine learning models using huge imaging collections to help create personalized treatment schedules and check how well patients are responding (25). The combination of serum biomarkers like KL-6, MMP-7 and YKL-40 with clinical symptoms may one day help clinicians choose patients who will benefit from anti-inflammatory, anti-fibrotic or regenerative treatments (26). Even though these new therapies hold promise, most are still in the early stages and must be tested further by RCTs and be integrated with real patient data (3,17,22). The fields of ethics, cost, scalability and long-term safety are always topics of concern. Still, the fast pace of innovation due to COVID-19 has made pulmonary fibrosis research more important. Now, it is more important than ever for pulmonologists, immunologists, bioengineers and data scientists to collaborate. Overall, the best approach to post-COVID fibrotic lung disease will be through combining innovation, personalization and precision (6,23,26). The field of therapeutics is growing quickly due to new small molecules, biologics, stem cell therapy and AIdriven tests. As we change our approach to care, these new tools may be able to stop fibrosis and help millions of people recover their lung health worldwide. 7. What Can Happen After Treatment, Risks, and Lasting Care? Post-COVID pulmonary fibrosis patients are still being studied long-term, as there is ongoing uncertainty about their outlook. While certain patients get better slowly or remain stable, others continue to have worsening symptoms, more fibrous scarring, and issues in multiple systems that affect their lives and use more resources (16,17). Now, the main goals in post-COVID respiratory FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 62 care are to predict outcomes, detect high-risk patients early, and use planned follow-up strategies (17). Here, we examine the results and progression seen in patients, how common it is for them to have additional diseases and what is recommended for their ongoing care. It also looks at the effects these findings have on the healthcare system dealing with long-term COVID-19 issues (17). 7.1 Progress Made and Results Because of different ways of defining the disease, a mix of patients, and a lack of long-term studies, it is difficult to fully grasp the natural history of post-COVID fibrosis fully (18). Even so, recent observational studies and initial cohort analysis are now revealing patterns in the data (18). In some cases, patients have HRCT findings including ground-glass opacities and reticulations that disappear within 3–12 months (4,8,13). These results may suggest organizing pneumonia, scarring after inflammation, or incomplete recovery from ARDS, rather than true fibrosis. Some patients experience stable fibrotic changes that do not progress further and usually result in mild to moderate disability (13,16). In some cases, fibrosis worsens, as seen by worsening images, decreasing lung function, greater need for oxygen, and less ability to exercise. This type of tissue change resembles idiopathic pulmonary fibrosis and other PFILDs (13,15,16). Estimates from latest research: • Between 25% and 30% of people who spend time in the hospital with COVID-19 show abnormalities suggesting fibrosis on imaging 6 months after infection (15,18). • About 10–15% of these patients may experience worsening fibrosis, resulting in ongoing functional problems after 12 months (13,15). • The chance of progression increases for people who needed mechanical breathing support, suffered from multiple organ failure, or had a lung disease before treatment (17,18). To make these estimates, researchers use data from the UKILD PostCOVID Study, COMEBAC Study, and analyses of early COVID cases in China (13,18). SEVTAP DÜZGÜNÇINAR 63 7.2 Complications in the Body Post-COVID pulmonary fibrosis is uncommon by itself. People with these conditions also often deal with additional medical problems that make the disease worse, speed up their decline, and increase their risk of dying (16,17). Respiratory Comorbidities: • Chronic Obstructive Pulmonary Disease (COPD): People with COPD may develop fibrosis in their lungs after COVID-19, which makes it harder for them to breathe and exchange gases (10,15). • Obstructive Sleep Apnea (OSA) is common among obese and postCOVID individuals, which can result in more hypoxemia at night, more tiredness, and make treatment more difficult (10,16). Cardiovascular Complications: • Pulmonary Hypertension (PH): Narrowing and scarring of blood vessels in the lungs, along with hypoxic constriction, can cause high pressure in the arteries, resulting in right heart strain that may fail without treatment (12,14). • Fibrosis can be found with or make worse post-COVID conditions such as myocarditis, arrhythmias, and heart failure. Dyspnea and fatigue, which are seen in both diseases, must be carefully distinguished by different specialists (12,16). Brain fog, depression, anxiety, and PTSD are often seen in people recovering from severe COVID-19 (6,9,16). They influence how well treatment is followed, how much someone can do, and how good their life is. Autonomic dysfunction, especially POTS, can make it harder for fibrotic patients to stay active (6,9). Acute kidney injury (AKI) that occurs during hospitalization raises the risk of chronic kidney disease (CKD) later on, and this CKD problem interacts with fibrosis by making it difficult to take medications such as antifibrotics and diuretics (6,10,14). • Inflammation and worse outcomes often happen because diabetes and insulin resistance, which COVID-19 and corticosteroid use can cause or worsen, are involved (6,11,14). Addressing all these issues together is very important for helping fibrotic patients live better and longer (16,17). FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 70 8.4.5 Improve Research, Monitoring, and Data Technology • Introduce national registries to monitor the spread, development, and results of fibrosis after COVID • Hold funding for studies that last several years and include RCTs to address post-viral fibrotic ILDs It is important to promote the sharing of global data and use common reporting to shape policies internationally (19,20,21) 8.4.6 Encourage Cooperation Among Countries and Collect Funds • Team up with groups such as the WHO, UNICEF, and the Global Fund to tackle post-COVID fibrosis within recovery plans for the pandemic • Encourage help from international donors for setting up chronic disease programs in weak health systems • Promote research centers worldwide that work on both pulmonary fibrosis and regenerative lung medicine (19,21) 8.5 Working Toward a Fair Approach to Health After the Pandemic The lasting effects of COVID-19 are changing what public health focuses on. Just as the first wave of COVID-19 required a strong response, post-COVID pulmonary fibrosis deserves the same consideration (6,8). Neglecting chronic respiratory care may result in people experiencing serious disabilities, rather than the clear effects of a viral pandemic. A crucial part of this process is accepting that COVID-19 survivors will need lifelong systems to support and manage their health and possibly help reverse damage caused by the disease. It is important for governments to extend health coverage to cover chronic respiratory illnesses, give financial help for required treatments and form community supports. Systems of health care should change from reacting to emergencies to handling both sudden and ongoing threats while still looking after at-risk populations. Because pulmonary fibrosis is a global issue, just like COVID-19, the solutions should be shared, effective across countries, and involve everyone (6,21,28). SEVTAP DÜZGÜNÇINAR 71 9. Conclusion COVID-19 has deeply changed our knowledge of infectious diseases and the long-term outcomes for people with lung disease. Fibrotic lung disease is one of the many serious results of SARS-CoV-2 infection and is difficult to treat since it can cause many health issues throughout the body (1,6,11). As the chapter explained, there are many different forms of post-COVID pulmonary fibrosis. It covers a range from changes that can be reversed to those that become permanent and look similar to well-known interstitial lung diseases (6,7,10). Viral damage to cells, problems with the immune system, damage to cells lining blood vessels and the lungs, poor healing, and overactive TGF-β and fibroblasts all play a role in the disease (4,12,13). A patient’s outcomes are also influenced by their own genetics, any other health problems and systemic difficulties (6,15). When managing post-COVID fibrosis, clinicians rely on detailed imaging, assessments of function and careful classification to tell apart lingering inflammation from actual fibrosis (7,17). Doctors rely on corticosteroids and agents that were originally made for treating fibrosis, but it is important to use them wisely, based on evidence and according to each patient’s needs (18,19). Having pulmonary rehabilitation, oxygen therapy and psychosocial care is key to keeping people healthy and happy (20). The chapter has also pointed out that there are now a wide range of experimental therapies being developed, including anti-fibrotic drugs, interventions with stem cells, immunomodulators, and monoclonal antibodies (21–23). These methods seem promising, yet most are still in the early stages and must be tested carefully using adaptive clinical trials, registries and translational research (24). In addition to medical treatment, post-COVID fibrosis has serious public health effects. Because of the pandemic, many health systems are managing a high number of patients who need long-term care for respiratory illnesses, and this is happening amid pressured resources and varying access (1,9,25). In low-resource areas, many people cannot get access to the tools and treatments they need (25). For this reason, global health policy should rapidly add post-COVID fibrosis to its policies for chronic diseases, funding, medicines, and rehabilitation (26). As we look forward, the biggest difficulty is to fill the research gaps that stop us from predicting, preventing and treating post-COVID fibrotic lung disease. Priorities include: FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING 72 • Experiments that explain disease processes through molecular and cellular approaches • Following patients over time to learn about their disease and how they respond to treatment • Looking for biomarkers to detect disease early and tailor treatment for each person • Technology that helps with diagnosis, prediction of outcomes, and treatment decisions • Adding people from different parts of the world to trials to ensure everyone is represented (24,26,27) We need to rely on fresh ideas, teamwork and kindness to move ahead. Experts in pulmonology, infectious diseases, rehabilitation, data science, and policymaking should unite to design care models that address both science and what COVID-19 survivors go through (9,11,23). Post-COVID pulmonary fibrosis may remain a long-term effect of the pandemic, yet it can also lead to progress. We have a chance to renovate the way chronic diseases are treated, build better infrastructure for respiratory health and ensure that all patients are cared for during a global emergency (24,26). If we join forces, carry out focused studies and are dedicated to equal health care, we can change this problem and ensure the survivors are not defined by their scars from the pandemic. Importantly, post-COVID pulmonary fibrosis is not limited to viral damage and lung scarring; it highlights the way biological risk, healthcare availability, scientific adaptability, and unequal society influence the disease (6,25,26). It demonstrates that a single disease can point out the strengths and weaknesses in our international healthcare and research systems (25). This condition calls for doctors to adjust their way of diagnosing. Now, any symptoms that doctors once thought were only tiredness or psychological should trigger comprehensive checks, team evaluations and prompt actions (9,19). Because of post-COVID fibrosis, physicians must use their experience while also welcoming new discoveries and standards of care (13,20). This moment is very important for researchers. Because post-COVID complications are so urgent, scientists from many fields such as immunology, molecular biology, AI and data science are now collaborating more than ever (21,22,27). What we have achieved so far must not be wasted; it should be used to help redefine chronic lung disease research going forward. Government agencies, medical journals and universities should keep supporting research in this field to SEVTAP DÜZGÜNÇINAR 73 address the aftermath of COVID-19 and to develop tools for handling future respiratory threats (24,27,28). For those who lead and decide in public health, post-COVID pulmonary fibrosis points to the need for health equity. This condition will not affect everyone in the same way. Unless we act, those who currently lack HRCT, medicine, or rehabilitation will suffer the most (25,26). The pandemic should lead to new ways of providing, funding, and making available chronic respiratory care in places where health systems are weak (25). Survivors should be included, listened to, and given the power to make decisions in their ongoing fight. What individuals with mental illness go through and how they communicate should guide the way research, treatment, and support are planned (26,28). They are partners in seeking out better solutions for ongoing health concerns. All in all, the appearance of fibrotic lung disease in the period after COVID-19 presents a tough clinical problem and a one-of-a-kind chance to study and treat it. A novel lung disease is emerging all around us, in many different places, fields, and healthcare systems. The way we react will influence the health of COVID-19 survivors and prove the strength and compassion of doctors worldwide (1,6,10). 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