The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified in China in 2019, rapidly spread globally, causing the COVID-19 pandemic. The disease presents with a wide spectrum of severity, ranging from asymptomatic cases to severe forms characterized by pneumonia, respiratory failure, shock, and multi-organ dysfunction. The normal immune response plays a crucial role in recovery, but in some cases, an exaggerated inflammatory response, known as a "cytokine storm" or cytokine release syndrome (CRS), leads to severe complications and increased mortality. Secondary bacterial infections, often opportunistic, represent another significant challenge, particularly in critically ill patients. While treatments like corticosteroids and antibiotics are used, they are insufficient for managing complex cases. Therefore, this review focuses on the immunopathology and pathophysiological mechanisms of COVID-19, particularly the roles of cytokine storm and bacterial co-infection, and explores the potential therapeutic applications of mesenchymal stem cells (MSCs), a promising area in regenerative medicine.

The literature review examines existing knowledge regarding the immunopathology of COVID-19, highlighting the interplay between innate and adaptive immune responses. Studies show that early SARS-CoV-2 infection involves rapid viral multiplication through suppression of the innate immune system. Later stages, however, can lead to overwhelming inflammatory responses, manifesting as CRS. The review also delves into secondary bacterial infections in COVID-19 patients, examining their prevalence, associated risk factors (such as pre-existing conditions, prolonged hospitalization, and mechanical ventilation), and the challenges posed by antibiotic resistance. Existing treatments for COVID-19 and its complications are discussed, noting their limitations, which underscores the need for novel therapeutic approaches.

This is a review article, not an empirical study. Therefore, there is no original methodology section. The authors systematically reviewed existing literature on COVID-19 immunopathology, focusing on the roles of cytokine storm and bacterial co-infection. They searched databases (specific databases should be mentioned if provided in the paper) for relevant publications, applying inclusion and exclusion criteria (criteria not specified here, but should be mentioned in the actual paper) to select studies for inclusion in the review. Data extraction and analysis were conducted to summarize findings from these studies. The review incorporates evidence from various studies on the pathogenesis of COVID-19, highlighting the activation of signaling pathways (JAK/STAT, NF-κB, NLRP3, MAPK, Notch) and their implications for disease severity. The roles of different immune cells and the mechanisms of bacterial infections in exacerbating COVID-19 are also examined.

The review highlights that SARS-CoV-2 infection triggers an immune response that may become dysregulated, leading to a cytokine storm characterized by elevated levels of pro-inflammatory cytokines such as IL-6, IL-7, IL-10, GM-CSF, and TNF-α. The activation of signaling pathways, including JAK/STAT, NF-κB, NLRP3, MAPK, and Notch, contributes to the pathogenesis of severe COVID-19. Secondary bacterial infections frequently complicate COVID-19, particularly in critically ill patients, with gram-negative bacteria often associated with higher mortality. Risk factors for bacterial co-infection include pre-existing respiratory conditions, prolonged hospitalization, mechanical ventilation, and immunosuppressive therapies. The review emphasizes the therapeutic potential of MSCs, focusing on their immunomodulatory, regenerative, and antimicrobial properties. MSCs can suppress excessive inflammation, promote tissue repair, and potentially enhance bacterial clearance. Several clinical trials exploring MSC-based therapies for COVID-19 are discussed, and the advantages and limitations of MSC-based versus cell-free strategies are compared.

This review underscores the critical roles of cytokine storm and bacterial co-infection in the pathogenesis and severity of COVID-19. The dysregulation of immune responses and signaling pathways contribute significantly to disease outcomes. The findings emphasize the urgent need for novel therapeutic strategies to effectively manage these complications. The discussion highlights mesenchymal stem cells (MSCs) as a promising therapeutic approach. The immunomodulatory, regenerative, and antimicrobial properties of MSCs make them well-suited to addressing the challenges posed by both cytokine storm and bacterial co-infection. The review analyzes clinical trials employing MSCs in COVID-19, noting the potential for both cell-based and cell-free therapies. The advantages and limitations of these approaches are critically evaluated, providing a framework for future research and development.

This review highlights the significant roles of cytokine storm and secondary bacterial infections in COVID-19 severity, emphasizing the need for innovative treatment strategies. Mesenchymal stem cell (MSC)-based therapies, including cell-based and cell-free approaches, demonstrate promising potential in mitigating these challenges. Future research should focus on optimizing MSC sourcing, standardization of MSC products, enhancing delivery systems, and conducting larger, well-designed clinical trials to validate the efficacy and safety of MSC therapies for COVID-19. Further investigation into the intricate interplay between viral infection, immune dysregulation, and bacterial co-infection will refine targeted therapeutic interventions.

As a review article, this study is limited by the scope and quality of the included literature. The authors' selection of studies might introduce bias, and the conclusions are based on existing research, not original data collection. The lack of detail on the search strategy and inclusion/exclusion criteria limits the reproducibility of the review. The discussion of clinical trials is limited by the availability of published data; ongoing trials may yield further insights. The heterogeneity of MSC sources and therapeutic approaches across studies poses a challenge for generalizing the findings.