PATHOPHYSIOLOGICAL ASPECTS OF RESPIRATORY SYSTEM DAMAGE AND FEATURES OF PNEUMONIA COURSE AFTER THE NEW CORONAVIRUS INFECTION Текст научной статьи по специальности «Клиническая медицина»

PATHOPHYSIOLOGICAL ASPECTS OF RESPIRATORY SYSTEM DAMAGE AND FEATURES OF PNEUMONIA COURSE AFTER THE NEW CORONAVIRUS INFECTION

1Urazova G.B., 2Jiemuratova G.K.

!Karakalpak Branch of the Republican Scientific Center for Emergency Medical Aid 2Nukus Branch of the Institute of Human Immunology and Genomics, Academy of Sciences of

Uzbekistan https://doi.org/10.5281/zenodo.13123853

Abstract. COVID-19 is an acute infection, and changes in the structure of respiratory organs are the most common. Damage to the respiratory tract is caused by virus-dependent mechanisms (including SARS-CoV-2 affecting alveolar epithelial cells and endothelial cells) and virus-independent mechanisms (such as immunological damage, including perivascular inflammation), which together contribute to the destruction of the endothelial-epithelial barrier and the extravasation of protein-rich exudate into the alveolar space.

This article presents the features of the viral landscape of the respiratory tract in children with acute respiratory viral infections (ARVI). It details the clinical and radiological manifestations of lung damage in children with COVID-19.

Keywords: children, respiratory system, lung pathohistology, long-term manifestations of COVID-19.

Relevance. The new coronavirus infection (COVID-19) has become a serious challenge and a major trial for humanity [1]. In addition to often life-threatening acute courses, COVID-19 can lead to the development of symptoms that persist for a long time. Common respiratory symptoms include persistent and incessant cough, shortness of breath, discomfort, and chest pain, with some cases requiring rehospitalization due to radiologically persistent signs of interstitial lung damage and symptoms of respiratory failure [2,21]. The clinical, radiological, and histopathological picture of post-coronavirus pneumonia shares common features with secondary organizing pneumonia [3].

Several mechanisms influence the development of post-COVID syndrome, including immune dysregulation and autoimmune mechanisms, systemic inflammatory response syndrome, hemostasis disorders and vasculopathy; direct cytotoxic effects of the virus on cells and prolonged viral persistence; autonomic, nervous, endocrine, and metabolic dysfunction; imbalance in the functioning of peptides resulting from the action of ACE1 and ACE2 receptors; and the consequences of the patient's critical condition [10,23].

This disease is characterized by a high level of respiratory tract involvement, frequent development of pneumonia in these patients, severe respiratory failure, and a high mortality rate, especially among those hospitalized in intensive care units [1,7].

Initially, it was assumed that COVID-19 is an acute infection with complete resolution of mild to moderate forms within 2-3 weeks. However, over time, more data have emerged showing that clinical manifestations can persist for more than 6 months [13].

The aim of the study is to review current information on the epidemiology, clinical features, and possible pathogenetic mechanisms of long-term consequences of coronavirus infection.

The analysis included literature reviews, meta-analyses, systematic reviews, and clinical studies. The most informative and relevant articles were selected. The search depth was not limited, as the vast majority of the works found were published in the last two years.

Respiratory tract damage is caused by virus-dependent mechanisms (including SARS-CoV-2 affecting alveolar epithelial cells and endothelial cells) and virus-independent mechanisms (such as immunological damage, including perivascular inflammation), which together contribute to the destruction of the endothelial-epithelial barrier and the extravasation of protein-rich exudate into the alveolar space [15].

This process can be triggered by pro-inflammatory cytokines such as interleukin-6 (IL-6) [17], which can further predispose patients to bacterial colonization and subsequent secondary infection [18]. Microthrombosis and macrothrombosis of pulmonary vessels, endothelial dysfunction, and thrombotic microangiopathy, observed in 20-30% of COVID-19 patients amid hypoxia, hyperinflammation, hypercoagulation, complement activation, platelet activation, platelet-leukocyte interaction, and the release of pro-inflammatory cytokines, also contribute to lung damage in post-COVID syndrome [19, 20]. The risk of thrombotic complications during the post-COVID syndrome is likely due to the duration and severity of the hyperinflammatory state [2].

It should be noted that radiological signs of pneumonia are observed in approximately 67% of recovered individuals [14]. Although the disease resolves spontaneously in 25% of cases [11] and is easily treated in most others, fibrosis can develop in 5-8% of cases, accompanied by symptoms of respiratory failure [5]. Considering the scale of the SARS-CoV-2 epidemic, a large number of patients experiencing respiratory system issues and requiring rehospitalization can be expected.

To date, several studies have demonstrated the possibility of prolonged persistence of SARS-CoV-2 in the human body, which may be a cause of various immune reactions contributing to the development of long COVID.

Given that a significant number of studies have shown the possibility of prolonged SARS-CoV-2 persistence in the human body, there is a hypothesis regarding the potential role of immune system activation in the pathogenesis of long COVID. In particular, a review has been published indicating that T-cell dysfunction may contribute to the development of long COVID, the pathophysiology of which closely resembles autoimmune diseases [22]. This is supported by autopsy results of patients who died from COVID-19, where high concentrations of CD8+ T-lymphocytes, which are key mediators of autoimmune reactions, were found in the lungs and other organs [17].

B-lymphocytes may also play a role in the immunopathogenesis of long COVID. For instance, anti-phospholipid antibodies were detected in 52% of blood samples from patients hospitalized with COVID-19. Further research confirmed the role of these antibodies in neutrophil hyperactivation and more severe disease progression [6,24]. Additionally, other studies have identified autoantibodies against interferons, neutrophils, connective tissue, and others in 10-50% of COVID-19 patients [8,16]. Furthermore, it is now evident that severe COVID-19 is associated with lymphopenia (i.e., a decrease in B- and T-lymphocytes), leading to excessive inflammatory responses [9,12]. This is because lymphocytes, particularly T-lymphocytes, play a crucial role in resolving inflammation associated with infection [7, 14]. Meta-analysis results also support this,

showing that lymphopenia and elevated levels of pro-inflammatory neutrophils are independent risk factors for severe COVID-19 and mortality [18,24].

The evolution of the radiological picture over time was described for 21 recovered patients who had previously had COVID-19 [19]. In the early stages of the disease (0-4 days after symptom onset), 24 CT scans did not show focal or multifocal lung opacities or ground-glass opacities (42%). About 50% of patients had peripheral lung opacities predominating. CT scans performed between 5-13 days showed disease progression. In the most severe cases, there was progressive consolidation of lung tissue (21%) and a high frequency of bilateral and multi-lobar involvement (86%). Late-stage CT scans (14 days and beyond) showed improvement in the radiological picture, but complete resolution required at least 26 days. CT scans of patients with COVID-19 exhibited patterns typical of pneumonia. These complications peaked approximately 9-13 days after onset and then gradually resolved.

In a study by F. Fu et al. [4,20], 56 patients with confirmed new coronavirus infection underwent CT. Of these, 40 (83.6%) had two or more lung opacities. Ground-glass opacities were observed in 18 (32.7%); 29 (52.7%) had both ground-glass opacities and consolidation; and 8 (14.5%) had only consolidation. In total, 43 (78.2%) patients had involvement of two lung lobes. Initial follow-up CT scans showed that 12 (30%) patients experienced improvement, 26 (65%) had mild/moderate progression, and 2 (5%) had severe progression with "white lung" findings. According to the second follow-up CT scans, 22 (71%) patients showed improvement compared to the first follow-up CT, 4 (12.9%) had worsening, and 5 (16.1%) had no change in the radiological picture [14,25].

Li N. et al. analyzed data from 22 patients with laboratory-confirmed COVID-19. All patients showed clinical recovery, positive changes on chest CT scans, and no need for continued therapy. However, in all cases, SARS-CoV-2 RNA was detected in upper respiratory tract swabs for more than 50 days after recovery. The average virus shedding period was 76 days, with a maximum of 112 days [9]. Other studies have reported cases of prolonged detection of SARS-CoV-2 in upper respiratory tract samples by quantitative PCR for up to 4 months [10]. In Salmon-Ceron D. et al.'s study, PCR tests of nasopharyngeal swabs for SARS-CoV-2 RT-PCR were positive in 11 of 43 patients two months after the onset of illness, and three patients remained positive three months after the onset [11]. Although SARS-CoV-2 is primarily transmitted via airborne droplets and clinically manifests with respiratory organ involvement, it is important to remember that due to the widespread presence of ACE-2 receptors in the body, COVID-19 is a systemic infection.

In the study by Y. Li et al. (2021), changes resembling nonspecific interstitial pneumonia were demonstrated in the late phase of diffuse alveolar damage [4,17]. Some of these changes may persist in the long term. Focal fibrosis of the visceral pleura is a consequence of previous inflammation. In COVID-19, some patients have been described with lymphoid infiltration of the pleura [18]. Small areas of fibrosis, generally not exceeding a few millimeters, have apparently formed in areas of organizing pneumonia. Several authors believe that extensive lung damage from COVID-19 may lead to the development of interstitial lung fibrosis in the future [16].

Thus, unresolved excessive inflammatory response may play a significant role in the development of long COVID. It has also been shown that low levels of T- and B-lymphocytes create conditions favorable for the persistence of SARS-CoV-2, which in turn may sustain immune system activation in long COVID [12]. Furthermore, a substantial number of cases of multisystem

inflammatory syndrome (MIS), developing in children and adults 2-6 weeks after the acute phase of infection, have been described. Interestingly, these patients may have had a relatively mild or even asymptomatic course during the acute phase, but subsequently experienced increased levels of inflammatory markers (CRP, IL-6, ferritin, D-dimer), lymphopenia, and severe disturbances in the cardiovascular, nervous, and gastrointestinal systems [23,25]. The delayed development of multisystem inflammatory syndrome underscores the significance of adaptive immune dysregulation [18].

Conclusion. This article reviewed possible long-term consequences of COVID-19 and the pathogenetic mechanisms associated with their development. Changes in the respiratory system are manifested by diffuse alveolar damage, damage to the microcirculatory system with blood coagulation abnormalities, which is synonymous with the clinical concept of "acute respiratory distress syndrome" (ARDS). The destruction of the endothelial-epithelial barrier with neutrophil invasion and the extravasation of protein-rich exudate into the alveolar space is facilitated by both virus-dependent and virus-independent immunological damage.

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