Elastin-targeted nanoparticles delivering doxycycline mitigate cytokine storm and reduce immune cell infiltration in LPS-mediated lung inflammation.

BACKGROUND AND PURPOSE: Cytokine storm invoked during acute and chronic lung injury promotes alveolar damage and remodeling. The current study shows that degraded elastin-targeted nanoparticles releasing doxycycline (Doxy NPs) are potent in mitigating cytokines storm, migration of immune cells in the lungs, and inhibiting inflammasome pathways in the LPS mouse model. EXPERIMENTAL APPROACH: Cytokine storm and lung injury were induced using LPS and elastase in C57BL/6 mice (rodent model for emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or Doxy a day before LPS administration. Cytokine levels, immune cell population, and MMP activity were analyzed in broncheo-alveolar lavage fluid (BALF) 4 hours after LPS administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1, NLRP3, Caspase 1 and MMPs were investigated in alveolar cells on day 3 after LPS administration. KEY RESULTS: Doxycycline NPs but not Doxycycline significantly decreased IL-6, TNF-α, IL-23 and were significantly more effective in decreasing the percentage of immune cells in the BALF. This is the first in-vivo study to demonstrate that Doxycycline can effectively inhibit inflammasome pathways in the lungs. CONCLUSION AND IMPLICATIONS: IV administration of elastin antibody conjugated Doxycycline-loaded albumin NPs can effectively modulate the local immune environment in the lungs, which is not achieved by IV Doxycycline even at 100-fold higher dose. This novel method of drug delivery can effectively lead to the repurposing of traditional Doxycycline as a potential adjunct treatment for managing the cytokine storm in the lungs in COPD and viral infections.

Brave New Lungs: Aging in the Shadow of COVID-19.

As the COVID-19 pandemic continues to affect communities worldwide, this novel disease is leaving many survivors with severe lung damage. Among older patients, advanced lung damage is more likely. Survivors of all ages who have extensive lung impacts are likely to be new to managing those issues. Supporting healthy aging for these patients will require both gathering data about their unique experiences and using the existing evidence basis about adapting to managing obstructive lung disease. This article outlines key priorities for research with COVID-19 survivors aging with permanent lung damage and highlights unique considerations for people older at age of onset. It also outlines the relevance of findings from this research for clinical care supporting people newly aging with advanced lung disease from COVID-19. In the process, it summarizes lessons from established patient populations aging with progressive lung disease-using cystic fibrosis as a prominent example from the author's lived experience-that may enhance the experiences of older COVID-19 survivors.

A 43-Year-Old Brazilian Man with Acute Impairment of Lung Function and Pulmonary Nodules with Features of Electronic Cigarette or Vaping Product Use-Associated Lung Injury (EVALI).

BACKGROUND Electronic smoking devices were created, and their production industrialized, recently. Since their creation, their use has spread widely. This increase in users led to the appearance of a new lung condition. In 2019, the CDC established the criteria for the diagnosis of electronic cigarette or vaping product use-associated lung injury (EVALI) and the eponym EVALI is now widely recognized. The condition results from the inhalation of heated vapor, which damages the large and small airways and alveoli. CASE REPORT This report presents the case of a 43-year-old Brazilian man with acute impairment of lung function, pulmonary nodules on chest computed tomography (CT) and features of EVALI. He was hospitalized after 9 days of respiratory symptoms due to worsening dyspnea, and underwent a bronchoscopy on the same day. His condition evolved into severe hypercapnic respiratory failure that took 3 weeks to improve, and he underwent a surgical lung biopsy that showed an organizing pneumonia pattern. He was discharged after 50 days of hospitalization. Infectious diseases and other lung conditions were ruled out on clinical, laboratory, radiological, epidemiological, and histopathological grounds. CONCLUSIONS In conclusion, we report the unusual presentation of EVALI on chest CT showing nodules instead of a ground-glass pattern, as stated in the CDC definitions of a confirmed case. We also report the progression to a critical clinical state and, after treatment, the evolution to complete recovery. We also draw attention to the difficulties in diagnosing and managing the disease, especially at a time when COVID-19 has emerged.

Development and Validation of an Acute Respiratory Distress Syndrome Prediction Model in Coronavirus Disease 2019: Updated Lung Injury Prediction Score.

OBJECTIVE: To develop and validate an updated lung injury prediction score for coronavirus disease 2019 (COVID-19) (c-LIPS) tailored for predicting acute respiratory distress syndrome (ARDS) in COVID-19. PATIENTS AND METHODS: This was a registry-based cohort study using the Viral Infection and Respiratory Illness Universal Study. Hospitalized adult patients between January 2020 and January 2022 were screened. Patients who qualified for ARDS within the first day of admission were excluded. Development cohort consisted of patients enrolled from participating Mayo Clinic sites. The validation analyses were performed on remaining patients enrolled from more than 120 hospitals in 15 countries. The original lung injury prediction score (LIPS) was calculated and enhanced using reported COVID-19-specific laboratory risk factors, constituting c-LIPS. The main outcome was ARDS development and secondary outcomes included hospital mortality, invasive mechanical ventilation, and progression in WHO ordinal scale. RESULTS: The derivation cohort consisted of 3710 patients, of whom 1041 (28.1%) developed ARDS. The c-LIPS discriminated COVID-19 patients who developed ARDS with an area under the curve (AUC) of 0.79 compared with original LIPS (AUC, 0.74; P<.001) with good calibration accuracy (Hosmer-Lemeshow P=.50). Despite different characteristics of the two cohorts, the c-LIPS's performance was comparable in the validation cohort of 5426 patients (15.9% ARDS), with an AUC of 0.74; and its discriminatory performance was significantly higher than the LIPS (AUC, 0.68; P<.001). The c-LIPS's performance in predicting the requirement for invasive mechanical ventilation in derivation and validation cohorts had an AUC of 0.74 and 0.72, respectively. CONCLUSION: In this large patient sample c-LIPS was successfully tailored to predict ARDS in COVID-19 patients.

A Specific Pattern and Dynamics of Circulating Cytokines Are Associated with the Extension of Lung Injury and Mortality in Colombian Adults with Coronavirus Disease-19.

Increased systemic levels of inflammatory cytokines have been associated with the development of pathophysiologic events during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To further explore differences in the pattern and dynamics of plasma cytokines in individuals with coronavirus disease-19 (COVID-19), and the relationship with disease mortality, here we evaluated the plasma levels of proinflammatory and regulatory cytokines in Colombian patient survivors and nonsurvivors of SARS-CoV-2 infection. Individuals with confirmed COVID-19, with other respiratory diseases requiring hospitalization, and healthy controls, were included. Plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-γ, IL-10, soluble tumor necrosis factor receptor I (sTNFRI), and transforming growth factor-ß1 were measured by a bead-based assay or enzyme-linked immunosorbent assay and clinical, laboratory, and tomographic parameters were registered during hospitalization. The levels of most of the evaluated cytokines were increased in COVID-19 individuals relative to healthy controls. The levels of IL-6, IL-10, and sTNFRI were directly associated with the development of respiratory failure, immune dysregulation, and coagulopathy, as well as with COVID-19 mortality. Particularly, the early, robust, and persistent increase of circulating IL-6 characterized COVID-19 nonsurvivors, while survivors were able to counteract the inflammatory cytokine response. In addition, IL-6 systemic levels positively correlated with the tomographic extension of lung damage in individuals with COVID-19. Thus, an exacerbated inflammatory cytokine response, particularly mediated by IL-6 added to the inefficiency of regulatory cytokines, distinguishes COVID-19-associated tissue disturbances, severity, and mortality in Colombian adults.

Selected Phytochemicals to Combat Lungs Injury: Natural Care.

The human has two lungs responsible for respiration and drug metabolism. Severe lung infection caused by bacteria, mycobacteria, viruses, fungi, and parasites may lead to lungs injury. Smoking and tobacco consumption may also produce lungs injury. Inflammatory and pain mediators are secreted by alveolar macrophages. The inflammatory mediators, such as cytokines, interleukin (IL)-1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α, neutrophils, and fibroblasts are accumulated in the alveoli sac, which becomes infected. It may lead to hypoxia followed by severe pulmonary congestion and the death of the patient. There is an urgent need for the treatment of artificial respiration and ventilation. However, the situation may be the worst for patients suffering from lung cancer, pulmonary tuberculosis, and acute pneumonia caused by acute respiratory distress syndrome (ARDS). Re-urgency has been happening in the case of coronavirus disease of 2019 (COVID-19) patients. Therefore, it is needed to protect the lungs with the intake of natural phytomedicines. In the present review, several selected phyto components having the potential role in lung injury therapy have been discussed. Regular intake of natural vegetables and fruits bearing these constituents may save the lungs even in the dangerous attack of SARS-CoV-2 in lung cancer, pulmonary TB, and pneumatic patients.

CD73: Friend or Foe in Lung Injury.

Ecto-5'-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to limit an excessive immune response in many pathophysiological events, such as lung injury induced by a variety of contributing factors. Multiple lines of evidence suggest that the location of CD73, in proximity to adenosine receptor subtypes, indirectly determines its positive or negative effect in a variety of organs and tissues and that its action is affected by the transfer of nucleoside to subtype-specific adenosine receptors. Nonetheless, the bidirectional nature of CD73 as an emerging immune checkpoint in the pathogenesis of lung injury is still unknown. In this review, we explore the relationship between CD73 and the onset and progression of lung injury, highlighting the potential value of this molecule as a drug target for the treatment of pulmonary disease.

Impact of inactivated COVID-19 vaccines on lung injury in B.1.617.2 (Delta) variant-infected patients.

BACKGROUND: Chest computerized tomography (CT) scan is an important strategy that quantifies the severity of COVID-19 pneumonia. To what extent inactivated COVID-19 vaccines could impact the COVID-19 pneumonia on chest CT is not clear. METHODS: This study recruited 357 SARS-COV-2 B.1.617.2 (Delta) variant-infected patients admitted to the Second Hospital of Nanjing from July to August 2021. An artificial intelligence-assisted CT imaging system was used to quantify the severity of COVID-19 pneumonia. We compared the volume of infection (VOI), percentage of infection (POI) and chest CT scores among patients with different vaccination statuses. RESULTS: Of the 357 Delta variant-infected patients included for analysis, 105 were unvaccinated, 72 were partially vaccinated and 180 were fully vaccinated. Fully vaccination had the least lung injuries when quantified by VOI (median VOI of 222.4 cm3, 126.6 cm3 and 39.9 cm3 in unvaccinated, partially vaccinated and fully vaccinated, respectively; p < 0.001), POI (median POI of 7.60%, 3.55% and 1.20% in unvaccinated, partially vaccinated and fully vaccinated, respectively; p < 0.001) and chest CT scores (median CT score of 8.00, 6.00 and 4.00 in unvaccinated, partially vaccinated and fully vaccinated, respectively; p < 0.001). After adjustment for age, sex, comorbidity, time from illness onset to hospitalization and viral load, fully vaccination but not partial vaccination was significantly associated with less lung injuries quantified by VOI {adjust coefficient[95%CI] for "full vaccination": - 106.10(- 167.30,44.89); p < 0.001}, POI {adjust coefficient[95%CI] for "full vaccination": - 3.88(- 5.96, - 1.79); p = 0.001} and chest CT scores {adjust coefficient[95%CI] for "full vaccination": - 1.81(- 2.72, - 0.91); p < 0.001}. The extent of reduction of pulmonary injuries was more profound in fully vaccinated patients with older age, having underlying diseases, and being female sex, as demonstrated by relatively larger absolute values of adjusted coefficients. Finally, even within the non-severe COVID-19 population, fully vaccinated patients were found to have less lung injuries. CONCLUSION: Fully vaccination but not partially vaccination could significantly protect lung injury manifested on chest CT. Our study provides additional evidence to encourage a full course of vaccination.

Pathogenesis of E-Cigarette Vaping Product Use-Associated Lung Injury (EVALI).

EVALI is an acute inflammatory disease in response to lung cell injury induced by electronic cigarettes and vaping devices (EV) frequently containing Vitamin E Acetate or tetrahydrocannabinol additives, in the context of risk factors such as microbial exposure. EVALI resembles a respiratory viral illness that may progress to acute respiratory failure and acute respiratory distress syndrome (ARDS) but can also affect extra pulmonary organs. Manifestations may be severe, leading to death or long-term morbidity and current treatments are largely supportive. While COVID-19 has demanded public and research attention, EVALI continues to affect young individuals and its better understanding via research remains a priority. Although clinical research led to improved recognition of triggers, clinical and pathological manifestations, and natural course of EVALI, important questions remain that require a better understanding of disease pathogenesis. Preclinical models utilizing laboratory animals and cell or tissue culture platforms provide insight into the physiologic and mechanistic consequences of acute and chronic EV exposure, including the characteristics of the respiratory dysfunction and inflammatory response. However, a key limitation in the field is the absence of an established animal model of EVALI. Important areas of research emphasis include identifying triggers and risk factors to understand why only certain vapers develop EVALI, the role of specific lung immune and structural cells in the pathogenesis of EVALI, and the most important molecular mediators and therapeutic targets in EVALI. © 2023 American Physiological Society. Compr Physiol 13:4617-4630, 2023.

The Macklin effect closely correlates with pneumomediastinum in acutely ill intubated patients with COVID-19 infection.

PURPOSE: Patients with COVID-19 infection are frequently found to have pulmonary barotrauma. Recent work has identified the Macklin effect as a radiographic sign that often occurs in patients with COVID-19 and may correlate with barotrauma. METHODS: We evaluated chest CT scans in COVID-19 positive mechanically ventilated patients for the Macklin effect and any type of pulmonary barotrauma. Patient charts were reviewed to identify demographic and clinical characteristics. RESULTS: The Macklin effect on chest CT scan was identified in a total of 10/75 (13.3%) COVID-19 positive mechanically ventilated patients; 9 developed barotrauma. Patients with the Macklin effect on chest CT scan had a 90% rate of pneumomediastinum (p < 0.001) and a trend toward a higher rate of pneumothorax (60%, p = 0.09). Pneumothorax was most frequently omolateral to the site of the Macklin effect (83.3%). CONCLUSION: The Macklin effect may be a strong radiographic biomarker for pulmonary barotrauma, most strongly correlating with pneumomediastinum. Studies in ARDS patients without COVID-19 are needed to validate this sign in a broader population. If validated in a broad population, future critical care treatment algorithms may include the Macklin sign for clinical decision making and prognostication.

[Dead space fraction for treatment guidance and prognosis evaluation of acute respiratory distress syndrome].

Acute respiratory distress syndrome (ARDS) is a common cause of critical illness and high mortality from respiratory failure. Increased dead space fraction (VD/VT) was independently associated with lung injury and mortality of ARDS. VD/VT is readily obtained by bedside measurements of arterial blood gas and end-tidal carbon dioxide. Early attention and application of VD/VT as an indicator will help to better understand the pathophysiological of ARDS, guide clinical treatment, and better assess the severity and clinical prognosis of the disease.

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID.

BACKGROUND: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). METHODS: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. RESULTS: Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. CONCLUSIONS: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Mortality and Deep Vein Thrombosis in the Gamma Variant of Covid 19 and Lung Injury.

Purpose: The SARS-CoV-2 disease predisposes infected individuals to thrombosis, the underlying mechanisms of which are not fully understood. The balance between pro-coagulant factors and natural coagulation inhibitors in critically ill patients with Covid-19 is fundamental to the prevention and treatment of complications. The aim of the present study was to investigate the pulmonary injury patterns in Covid-19 having higher mortality in the presence of deep vein thrombosis in comparison to patients without venous thrombosis and determine the Gamma variant. Methods: A retrospective study was conducted involving the evaluation of 200 medical records of patients with Covid-19 and a clinical suspicion of deep vein thrombosis (DVT) at the intensive care unit of a public hospital. The sample was divided into two groups of patients were formed - those positive and those negative for DVT. Statistical analysis involved the use of Fisher's exact test, the paired t-test and chi-square test. Results: Patients with DVT had more severe lung injuries (greater than 70%) compared to those without DVT (p = 0.003). Lesions affecting 50% to 70% of the lung area occurred in little more half of the group with DVT and just under half in the group without DVT (p = 0.5). Pulmonary lesions affecting less than 50% of the lung occurred more in patients without DVT (p = 0.0001). The Gamma variant increased prevalence of the both DVT and mortality (p=0.0001). Conclusion: Deep vein thrombosis is an aggravating factor of mortality in patients with SARS-CoV-2, and the Gamma variant is an aggravating factor of both thrombotic events and mortality.

E-cigarette or Vaping product use Associated Lung Injury (EVALI) in a 15 year old female patient - case report.

BACKGROUND: E-cigarettes are devices which allow to aerosolize liquids containing nicotine or other substances. Ever since they were released on the market in 2006, the number of users have been constantly increasing, especially among adolescents, ranging from 7,6% to 9,3% in the age group 18-24 years old from 2014 to 2019. Hand in hand with the spread of E-cigarettes many have been the efforts to understand their impact on health. EVALI (E-cigarette or Vaping product use Associated Lung Injury) is an emerging condition with a heterogeneous presentation with several reported cases worldwide. We mean to report a case of EVALI in a 15-year-old female Caucasian patient, who's currently attending her clinic follow-up at Bambino Gesù Pediatric Hospital in Rome. CASE PRESENTATION: The patient was admitted to the Emergency Room due to acute respiratory failure in November 2020. At admittance, she was severely dyspneic (HR 120 bpm, SatO2 75%). As she was hospitalized amid the COVID-19 pandemics, she underwent a nasopharyngeal swab for SARS-CoV2, which turned out negative, and a chest CT scan. Chest CT scan showed a central ground grass pattern with peripheral sparing. At the anamnestic recall, it was disclosed she was an e-cigarette smoker and occasional marijuana user. The microbiological work-up proved only positive for Rhinovirus. Her clinical and radiological case was discussed with our radiologist who suspected EVALI. She was assisted through HFNC, antibiotical therapy and corticosteroids with a dramatic recovery within the first 48 h. CONCLUSIONS: EVALI started being recognized a specifically nosological entity in summer 2019, with increasing cases being reported. No diagnostic criteria have been agreed upon yet, but its usual presentation includes respiratory, gastrointestinal and systemic symptoms of different degree and the diagnosis can be hypothesised in case the patient has an evocative clinical and radiological presentation and has been an E-cigarette smoker in previous 90 days. Due to the novelty of the condition and its heterogeneous presentation it is of interest to report the cases in which EVALI is identified to raise awareness about this emerging new-age disease.

Discrepancy between biomarkers of lung injury and 1-year mortality in COVID-19.

BACKGROUND: COVID-19 global pandemic started in late 2019 with the first wave. In this cross-sectional and observational study, we evaluated the associations between the biomarkers, COVID-19 pneumonia severity and 1-year mortality. METHODS: A sample of 276 polymerase chain reaction (PCR)-positive patients for SARS-CoV-2 was included. Computerized tomography severity score (CT-SS) was used to assess the severity of COVID-19 pneumonia in 222 cases. Multivariate analyses were performed to find the predictors of CT-SS, severe CT-SS (≥20) and 1-year mortality. Biomarkers of ferritin, high-sensitive C-reactive protein (CRP), lactate dehydrogenase (LDH), cardiac troponin (cTn), neutrophil-to-lymphocyte ratio (NLR), uric acid (UA) and d-dimer were routinely measured. RESULTS: Severe CT-SS (>20) was observed in 86 (31.2%) cases. Mortality was observed in 75 (27.2%) patients at 1 year. LDH displayed the highest predictive accuracy for severe CT-SS (AUC 0.741, sensitivity = 81% and specificity = 68%, cut-off value: 360 mg/dl). Linear regression analysis displayed that LDH predicted CT-SS [B = 11 (95% CI for B = 5-17, p < .001)]. Age was the most significant parameter that was associated with severe CT-SS (OR 0.96, 95% CI 0.92-0.99, p = .015). d-dimer was the only biomarker that predicted with 1-year mortality (OR 1.62, 95% CI 1.08-2.42, p = .020). CONCLUSION: LDH is a sensitive and specific biomarker to determine patients with severe lung injury in COVID-19. d-dimer is the only biomarker that predicts 1-year mortality. Neither LDH nor CT-SS is associated with 1-year mortality.

Clinical manifestations of EVALI in adolescents before and during the COVID-19 pandemic.

INTRODUCTION: E-cigarette, or vaping, product use-associated lung injury (EVALI) results from inhaling the aerosol of e-cigarettes and has similar clinical features to coronavirus disease 2019 (COVID-19). EVALI case counts since the declaration of the COVID-19 pandemic is unknown. METHODS: A retrospective electronic health record chart review of adolescents hospitalized at one institution with EVALI was conducted. Clinical characteristics and hospital course of patients hospitalized during the pandemic were compared to those prepandemic. RESULTS: The clinical presentation of adolescents hospitalized prior-to (n = 19) and during the COVID-19 pandemic (n = 22) were similar with respect to constitutional, respiratory, and gastrointestinal symptoms. All patients hospitalized during the pandemic were tested for COVID-19 at least once. Only one patient had a positive SARS-CoV-2 RT-PCR test result. Thirty-one out of 39 patients treated with corticosteroids had clinical improvement within 24 h (79%). Patients hospitalized during the pandemic had a shorter median length of stay (5 vs. 7 days, p < 0.01), and were less often discharged with home oxygen (1 vs. 6 patients, p = 0.04). Pulmonary function tests improved pre- to postcorticosteroid treatment and postcorticosteroid to follow-up. CONCLUSIONS: Eliciting a history of vaping in adolescents presenting with constitutional, respiratory, and gastrointestinal symptoms is important to identify EVALI cases, which have continued throughout the COVID-19 pandemic. A shorter length of stay with less need for mechanical ventilation and home oxygen in adolescents hospitalized during the pandemic may reflect increased familiarity with EVALI characteristics. Corticosteroids led to clinical and pulmonary function improvement.

Pulmonary sequelae at six months in children with SARS-CoV-2 infection: A Single-Centre Study (preprint)

Objective: Pulmonary sequelae post SARS - CoV-2 infection have been reported in adults; however, there is scant literature regarding pulmonary dysfunction following SARS-CoV-2 infection in children. We studied the long term pulmonary sequelae in children who had SARS-CoV-2 infection. Methods: This single center descriptive study conducted in a public sector tertiary care hospital in Northern India, from June, 2020 to October, 2021. We enrolled children aged 7-18 years admitted with SARS-CoV-2 infection and followed them up for 6 months. A detailed interval history was taken and pulmonary function tests were performed after 6 months, using a spirometer. A convenience sample of 40 children was enrolled. There were 21 males and the median (IQR) age was 13 (10.75, 17) years. Results: Thirty percent of children (n=12) had pulmonary function abnormalities, which was of restrictive pattern in all. Children who were underweight had higher odds of developing pulmonary dysfunction following SARS-CoV-2 infection [OR (95% CI) 5.13 (1.19, 22.11); P=0.028]. There were no significant association with age, sex, severity of initial infection and oxygen requirement during the initial infection. Three children had persistence of dyspnea during follow up. Conclusion: This study is the one of the first Indian studies regarding the pulmonary sequelae in children. A possibility of long term sequelae should be considered in children with history of SARS-CoV-2, presenting with suggestive complaints.

What do we know about pathological mechanism and pattern of lung injury related to SARS-CoV-2 Omicron variant?

Pulmonary damage in SARS-CoV-2 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis. In addition, nosocomial bacterial superinfections and ventilator-induced lung injury (VILI) are likely to occur. The SARS-CoV-2 Omicron variant have manifested itself as a more diffusive virus which mainly affects the upper airways, such as the nose and pharynx. The mechanism leading to a lung injury with a complex clinical course for the Omicron SARS-CoV-2 variant remains unclear. A key question is whether the organ damage is due to direct organ targeting of the virus or downstream effects such as an altered immune response. An immune escape process of Omicron variant is being studied, which could lead to prolonged viral shedding and increase hospitalization times in patients with comorbidities, with an increased risk of pulmonary co-infections/superinfections and organ damage. This brief commentary reports the current knowledge on the Omicron variant and provides some useful suggestions to the scientific community.

Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19.

Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in Plau-/- and Plaur-/- mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in Plaur-/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial-mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in Plaur-/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation.

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury.

Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.