[Pulmonary fibrosis in patients with COVID-19: A review].

The viral infectious disease pandemic caused by SARS-CoV-2 has affected over 500 million people and killed over 6 million. This is the official data provided by the WHO as of the end of May 2022. Among people who have recovered from COVID-19, post-COVID syndrome is quite common. Scattered epidemiological studies on post-COVID syndrome, however, indicate its high relevance. One of the manifestations of post-COVID syndrome is the development of pulmonary fibrosis (PF). This article is devoted to the analysis of literature data on epidemiology, immunomorphology, as well as X-ray morphological and functional characteristics of PF in patients with post-COVID syndrome. Attention is drawn to the various phenotypes of the post-COVID syndrome and the incidence of PF, which, as clinical practice shows, is most common in people who have had severe COVID-19. This article discusses in detail the molecular biological and immunological mechanisms of PF development. The fibrotic process of the lung parenchyma is not an early manifestation of the disease; as a rule, radiomorphological signs of this pathological process develop after four weeks from the onset of acute manifestations of a viral infection. The characteristic signs of PF include those that indicate the process of remodulation of the lung tissue: volumetric decrease in the lungs, "cellular" degeneration of the lung parenchyma, bronchiectasis and traction bronchiolectasis. The process of remodulating the lung tissue, in the process of fibrosis, is accompanied by a violation of the lung function; a particularly sensitive test of functional disorders is a decrease in the diffusion capacity of the lung tissue. Therefore, in the process of monitoring patients with post-COVID syndrome, a dynamic study of the ventilation function of the lungs is recommended. The main clinical manifestation of PF is dyspnea that occurs with minimal exertion. Shortness of breath also reflects another important aspect of fibrous remodulation of the lung parenchyma - oxygen dissociation is disturbed, which reflects a violation of the gas exchange function of the lungs. There are no generally accepted treatments for PF in post-COVID syndrome. The literature considers such approaches as the possibility of prescribing antifibrotic therapy, hyaluronidase, and medical gases: thermal helium, nitric oxide, and atomic hydrogen. The article draws attention to the unresolved issues of post-covid PF in people who have had COVID-19.

Innate immune cell activation causes lung fibrosis in a humanized model of long COVID.

COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing "COVID lung fibrosis." Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients.

Middle East Respiratory Syndrome-Coronavirus Infection into Established hDPP4-Transgenic Mice Accelerates Lung Damage Via Activation of the Pro-Inflammatory Response and Pulmonary Fibrosis.

Middle East respiratory syndrome coronavirus (MERS-CoV) infects the lower respiratory airway of humans, leading to severe acute respiratory failure. Unlike human dipeptidyl peptidase 4 (hDPP4), a receptor for MERS-CoV, mouse DPP4 (mDPP4) failed to support MERS-CoV infection. Consequently, diverse transgenic mouse models expressing hDPP4 have been developed using diverse methods, although some models show no mortality and/or only transient and mild-to-moderate clinical signs following MERS-CoV infection. Additionally, overexpressed hDPP4 is associated with neurological complications and breeding difficulties in some transgenic mice, resulting in impeding further studies. Here, we generated stable hDPP4-transgenic mice that were sufficiently susceptible to MERS-CoV infection. The transgenic mice showed weight loss, decreased pulmonary function, and increased mortality with minimal perturbation of overexpressed hDPP4 after MERS-CoV infection. In addition, we observed histopathological signs indicative of progressive pulmonary fibrosis, including thickened alveolar septa, infiltration of inflammatory monocytes, and macrophage polarization as well as elevated expression of profibrotic molecules and acute inflammatory response in the lung of MERS-CoV-infected hDPP4-transgenic mice. Collectively, we suggest that this hDPP4-transgenic mouse is useful in understanding the pathogenesis of MERS-CoV infection and for antiviral research and vaccine development against the virus.

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches.

Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.

New grading system for post-COVID-19 pulmonary fibrosis based on computed tomography findings.

BACKGROUND: There is currently no objective computed tomography (CT)-defined grading system for coronavirus disease (COVID-19)-related pulmonary fibrosis. We propose a CT-based radiological scale that adapts the histological fibrosis scale to pulmonary fibrosis CT findings, to evaluate possible predictive factors for the degree of fibrosis in these patients. METHODS: A new radiological fibrosis grading system was created based on existing histological fibrosis scales. One hundred forty-seven COVID-19 patients with any degree of fibrosis on CT were evaluated. Smoking status, the presence of hypertension, the duration of hospital stays, the presence of comorbid diseases, and the levels of prognostic and predictive factors for COVID-19 were evaluated, and how these parameters affected the fibrosis scores was examined. RESULTS: Of 147 patients, 17.7% had grade 1, 17% had grade 2, 51.7% had grade 3, and 13.6% had grade 4 fibrosis. ANOVA revealed statistically significant relationships between the fibrosis scores and lactate dehydrogenase values, lymphocyte count, C-reactive protein level, and length of hospital stay. Smoking, advanced age, hypertension, and male sex showed significantly higher scores for fibrosis. CONCLUSIONS: Using our CT-defined lung fibrosis grading system, we could predict the severity of fibrosis as well as the resultant lung pathology in COVID-19 patients. Thus, disease exacerbation and development of permanent severe fibrosis can be prevented using the appropriate treatment methods in high-risk patients.

VEGF, IL-17 and IgG4 levels of patients with lung sequelae in post-COVID-19 period.

Introduction: Although the epidemiological and clinical characteristics of COVID-19 patients have been described; the pathogenesis of the disease and its long-term consequences are still unclear. Pulmonary fibrosis is one of these late outcomes. In this study we evaluated Interleukin-17 (IL-17), vascular endothelial growth factor (VEGF), and immunoglobulin G4 (IgG4) levels of COVID-19 infected patients with different clinical course and their effect on pulmonary fibrosis in post-COVID period. Materials and Methods: In total, 90 patients were evaluated. Among the patients who presented for a control visit between 3-12 weeks after acute infection; patients with signs of pulmonary sequelae radiologically (traction bronchiectasis, interseptal thickening, disorders in parenchyma architecture) were classified as Group I (n= 32), patients who recovered without sequelae radiologically as Group II (n= 32). The Control group included healthy individuals who did not have COVID-19, and was classified as Group III (n= 26). Result: The mean age in Group I was significantly higher than Group II and III (p<0.001). There was a statistically significant difference between the VEGF and IL-17 values based on the patient group they are in (p<0.05). Vascular endothelial growth factor values of Group I and III were significantly lower than the patients in Group II (p<0.001). IL-17 values of Group I and II were found to be significantly lower than Group III (p= 0.005). There was no statistically significant relationship between groups in terms of IgG4 values. Conclusions: In our study, it was observed that the profibrotic effects of VEGF, IL-17, and IgG4 were not dominant in patients who recovered with pulmonary sequelae after COVID; therefore, it is thought that different mechanisms mentioned or not yet revealed may cause this outcome.

Bioavailability Enhancement of Cepharanthine via Pulmonary Administration in Rats and Its Therapeutic Potential for Pulmonary Fibrosis Associated with COVID-19 Infection.

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-ß1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.

Pulmonary Function and Chest Computed Tomography (CT) Scan Findings After Antifibrotic Treatment for COVID-19-Related Pulmonary Fibrosis.

BACKGROUND Physicians worldwide have been reporting many cases of COVID-19-induced pulmonary fibrosis. We report the case of a 51-year-old Filipino asthmatic woman who developed post-COVID-19 pulmonary fibrosis subsequently treated with Nintedanib. CASE REPORT The patient presented with a 4-day history of flu-like symptoms in September 2020 and was eventually diagnosed with severe COVID-19 pneumonia. Despite receiving Dexamethasone, Tocilizumab, Remdesivir, and multiple antibiotics, there was increasing oxygen requirement, necessitating ICU admission and high-flow nasal cannula (HFNC). An additional course of hydrocortisone was given due to asthma exacerbation, gradually liberating her from the HFNC. A chest CT scan showed extensive parenchymal changes, for which she received methylprednisolone and physical rehabilitation with persistence of respiratory symptoms. After 40 days of hospitalization, she was sent home on oxygen support and Nintedanib. The patient initially had severe dyspnea (Borg Scale 7) with 6-minute walk distance (6MWD) of 295 meters. Pulmonary function showed moderately severe restrictive lung defect at 52% predicted total lung capacity (TLC) and severely reduced DLCO (28% predicted). Chest CT scoring indicated severe lung involvement. One month after Nintedanib treatment, her Borg Scale improved to 4. Her 6MWD, TLC, and DLCO increased to 434 meters, 64% predicted, and 36% predicted, respectively. A chest CT scan showed regressing fibrosis. After 6 months of treatment, her pulmonary function normalized. DLCO remained moderately reduced (59% predicted) but her 6MWD (457 meters) and CT scan results continued to improve. CONCLUSIONS Nintedanib, along with other interventions, may have potentially improved pulmonary function and CT scan findings in a COVID-19 survivor with pulmonary fibrosis 6 months after treatment.

Clinical characteristics and outcomes of post-COVID-19 pulmonary fibrosis: A case-control study.

ABSTRACT: The development of pulmonary fibrosis is a rare complication of the novel coronavirus disease 2019 (COVID-19). Limited information is available in the literature about that, and the present study aimed to address this gap.This case-control study included 64 patients with post-COVID-19 pulmonary fibrosis who were hospitalized for COVID-19.The percentage of patients aged ≥65 years (44%) who demised was higher than those who survived (25%). Male patients (62%) had higher mortality than female patients (37%). The most frequently reported clinical symptoms were shortness of breath (98%), cough (91%), and fever (70%). Most COVID-19 patients with pulmonary fibrosis (81%) were admitted to an intensive care unit (ICU), and 63% required mechanical ventilation. Bilateral lung infiltrates (94%), "ground glass" opacity (91%), "honeycomb" lung (25%), and pulmonary consolidation (9%) were commonly identified in COVID-19 patients with pulmonary fibrosis who survived. The findings for computed tomography and dyspnea scale were significantly higher in severe cases admitted to the ICU who required mechanical ventilation. A higher computerized tomography score also correlated significantly with a longer duration of stay in hospital and a higher degree of dyspnea. Half of the COVID-19 patients with pulmonary fibrosis (50%) who survived required oxygen therapy, and those with "honeycomb" lung required long-term oxygen therapy to a far greater extent than others. Cox regression revealed that smoking and asthma were significantly associated with ICU admission and the risk of mortality.Post-COVID-19 pulmonary fibrosis is a severe complication that leads to permanent lung damage or death.

Exercise-based pulmonary rehabilitation for a post-COVID-19 pulmonary fibrosis patient: A case report.

RATIONALE: Pulmonary fibrosis is an infamous sequela of coronavirus disease 2019 (COVID-19) pneumonia leading to long-lasting respiratory problems and activity limitations. Pulmonary rehabilitation is beneficial to improve the symptoms of lung fibrosis. We experienced a post-COVID-19 pulmonary fibrosis patient who received a structured exercise-based pulmonary rehabilitation program. PATIENT CONCERNS: This article presents a case of successful pulmonary rehabilitation of a patient with post-COVID-19 pulmonary fibrosis. The patient could not cut off the oxygen supplement even after a successful recovery from COVID-19. DIAGNOSIS: Diagnosis of COVID-19 was based on the reverse transcription-polymerase chain reaction (RT-PCR). Pulmonary fibrosis was diagnosed by patient's complaint, clinical appearance, and computed tomography (CT) on chest. INTERVENTION: The patient underwent ten sessions of exercise-based rehabilitation program according to Consensus Document on Pulmonary Rehabilitation in Korea, 2015. OUTCOME: On the 8th day, he could cut off the oxygen supplementation and complete the one-hour exercise without oxygen. He was discharged after completing the 10-session program without any activity limitations. LESSONS: Exercise-based pulmonary rehabilitation will help the post-COVID-19 pulmonary fibrosis patients. This case suggested the importance of pulmonary rehabilitation program to the post-COVID-19 pulmonary fibrosis patient.

Increasing incidence of lung transplantation in patients with post-COVID-19 pulmonary fibrosis.

Twenty months into the COVID-19 pandemic, we are still learning about the various long-term consequences of COVID-19 infection. While many patients do recover with minimal long-term consequences, some patients develop irreversible parenchymal and interstitial lung damage leading to diffuse pulmonary fibrosis. Unfortunately, these are some of the consequences of post-SARS-CoV-2 infection which thousands more people around the world will experience and which will outlast the pandemic for a long time to come. It is now being observed at various leading medical centres around the world that lung transplantation may be the only meaningful treatment available to a select group of patients experiencing serious lung damage and non-resolving COVID-19-associated respiratory failure, resulting from the triad of coronavirus infection, a hyper-inflammatory immune response to it and the inability of the human body to repair that injury.

Virus infection induced pulmonary fibrosis.

Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.

Progressive Pulmonary Fibrosis After Non-Critical COVID-19: A Case Report.

BACKGROUND The COVID-19 global pandemic is ongoing, and despite vaccination efforts, SARS-CoV-2 continues to circulate worldwide. The spectrum of COVID-19 illness is broad, from asymptomatic infection to respiratory failure and acute respiratory distress syndrome (ARDS), and the long-term sequelae of infection are unclear. COVID-19-related pulmonary fibrosis has been previously described in the setting of critical illness and ARDS but has not been well described in cases requiring minimal supplemental oxygen. CASE REPORT We present the case of a 42-year-old man hospitalized with coronavirus disease 2019 (COVID-19) who initially required minimal supplemental oxygen but weeks later developed progressive pulmonary fibrosis requiring high-flow nasal cannula and ICU admission. Using novel computed tomography (CT) imaging processing techniques, we demonstrate progression from initial ground-glass opacities to pulmonary fibrosis and traction bronchiectasis over several months. Additionally, we describe clinical responsiveness to an extended course of corticosteroids. CONCLUSIONS Although pulmonary fibrosis is a known complication of severe COVID-19-related ARDS requiring mechanical ventilation, our report suggests that patients with milder forms of COVID-19 infection may develop post-acute pulmonary fibrosis.

Sequelae of COVID-19 pneumonia: Is it correct to label everything as post-COVID lung fibrosis?

One of the common long-term consequences observed in survivors of COVID-19 pneumonia is the persistence of respiratory symptoms and/or radiological lung abnormalities. The exact prevalence of these post-COVID pulmonary changes is yet unclear. Few authors, based on their early observations, have labeled these persistent computed tomography (CT) abnormalities as post-COVID lung fibrosis, which appears to be an overstatement. Lately, it is being observed that many of the changes seen in post-COVID lungs are temporary and tend to show resolution on follow-up, with only a few developing into lung fibrosis. Thus, based on the presumptive diagnosis of lung fibrosis, these patients should not be blindly started on anti-fibrotic drugs. One must not forget that these drugs can do more harm than good, if used injudiciously. It is better to use the term "post-COVID interstitial lung changes", which covers a broader spectrum of pulmonary changes seen in patients who have recovered from COVID-19 pneumonia. At the same time, it is essential to identify the sub-set of COVID-19 survivors who are at an increased risk of developing lung fibrosis and to carefully chalk out management strategies so as to modify the course of the disease and prevent irreversible damage. Meticulous and systematic longitudinal follow-up studies consisting of clinical, laboratory, imaging, and pulmonary function tests are needed for the exact estimation of the burden of lung fibrosis, to understand the nature of residual pulmonary changes, and to predict the likelihood of development of lung fibrosis in COVID-19 survivors.