Severe Acute Respiratory Distress Syndrome Coronavirus 2 Research Articles

CircRNA: a rising therapeutic strategy for lung injury induced by pulmonary toxicants.

Lung injury has been a serious medical problem that requires new therapeutic approaches and biomarkers. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) that exist widely in eukaryotes. CircRNAs are single-stranded RNAs that form covalently closed loops. CircRNAs are significant gene regulators that have a role in the development, progression, and therapy of lung injury by controlling transcription, translating into protein, and sponging microRNAs (miRNAs) and proteins. Although the study of circRNAs in lung injury caused by pulmonary toxicants is just beginning, several studies have revealed their expression patterns. The function that circRNAs perform in relation to pulmonary toxicants (severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2), drug abuse, PM2.5, and cigarette smoke) is the main topic of this review. A variety of circRNAs can serve as potential biomarkers of lung injury. In this review, the biogenesis, properties, and biological functions of circRNAs were concluded, and the relationship between circRNAs and pulmonary toxicants was discussed. It is expected that the new ideas and potential treatment targets that circRNAs provide would be beneficial to research into the molecular mechanisms behind lung injury.

SARS-CoV-2 Accessory Protein Orf7b Induces Lung Injury via c-Myc Mediated Apoptosis and Ferroptosis.

The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. The airway is the primary target in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks of exposure. The viral factors that contribute to cell death and lung injury remain incompletely understood. Thus, this study investigated the role of open reading frame 7b (Orf7b), an accessory protein of the virus, in causing lung injury. In screening viral proteins, we identified Orf7b as one of the major viral factors that mediates lung epithelial cell death. Overexpression of Orf7b leads to apoptosis and ferroptosis in lung epithelial cells, and inhibitors of apoptosis and ferroptosis ablate Orf7b-induced cell death. Orf7b upregulates the transcription regulator, c-Myc, which is integral in the activation of lung cell death pathways. Depletion of c-Myc alleviates both apoptotic and ferroptotic cell deaths and lung injury in mouse models. Our study suggests a major role of Orf7b in the cell death and lung injury attributable to COVID-19 exposure, supporting it as a potential therapeutic target.

Intention to vaccinate chronic disease children against COVID-19; a multicenter survey

BackgroundVaccination against severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) has gained recognition as a crucial strategy to prevent and reduce the risk of infection, including emerging variants, due to its proven safety, immunogenicity, and effectiveness. This study aimed to evaluate the vaccination hesitancy (VH) among Egyptian parents towards SARS-CoV-2 vaccination, specifically focusing on parents with chronically ill children.MethodA multicentered cross-sectional survey was conducted at outpatient clinics of El-Raml Pediatric Hospital, Ministry of Health and Population (MOHP) in Alexandria, Alexandria Main University Hospital for Maternity and Children (AMUH), Al-Galaa Teaching Hospital, General Organization for Teaching Hospitals and Institutes (GOTHI) Cairo, and Pediatric Department, Menoufia University Hospital from May 1st till December 15th, 2022. Parents of children with chronic diseases were recruited using a simple random sampling technique to respond to the validated Arabic version of parental attitudes about childhood vaccination (PACV).ResultsIn this study, we enrolled 527 caregivers, 55.4% of them were aged 30–39 years old, 85.2% were females, and 46.9% had chronic diseases. Commonly mentioned information sources included television and radio (69.8%), and social media (35.3%). Among the parents studied, 59.6% refused vaccination. The predictors of the PACV score were governorate, Menoufia (β = 11.30, 95%CI [5.32, 17.27], p < 0.001), study setting, Menoufia University Hospital (β = -20.07, 95%CI [-25.40, -14.75] and El-Raml Hospital (β = -10.74, 95%CI [-14.50, -6.98], p < 0.001), income; not enough and loans repaid (β = 3.18, 95%CI [0.54, 5.82], p = 0.018) and not enough and loans not repaid (β = 3.57,95%CI [0.08, 7.07], p = 0.045).ConclusionsThe study reveals geographic and economic factors as predictors of PACV, and emphasizes the need for region-specific interventions and financial barriers to improve vaccine acceptance and child well-being.

Bioactive Components of Myracrodruon urundeuva against SARS-CoV-2: A Computational Study

SARS-CoV-2 (severe acute respiratory distress syndrome coronavirus 2) is the causative agent for the novel coronavirus disease 2019 (COVID-19). It raises serious biosecurity questions due to its high contagious potential, thereby triggering rapid and efficient responses by the scientific community to take necessary actions against viral infections. Cumulative scientific evidence suggests that natural products remain one of the main sources for pharmaceutical consumption. It is due to their wide chemical diversity that they are able to fight against almost all kinds of diseases and disorders in humans and other animals. Knowing the overall facts, this study was carried out to investigate the chemical interactions between the active constituents of a promising medicinal plant, Myracrodruon urundeuva, and some specific proteins of SARS-CoV-2. For this, we used molecular docking to predict the most appropriate orientation by binding a molecule (a ligand) to its receptor (a protein). The best results were evaluated by screening their pharmacokinetic properties using the online tool pkCSM. Findings suggest that among 44 chemical compounds of M. urundeuva, agathisflavone, which is abundantly present in its leaf, exhibited excellent molecular affinity (−9.3 to −9.7 kcal.mol−1) with three functional proteins, namely, Spike, MPro, and RBD of SARS-CoV-2. In conclusion, M. urundeuva might be a good source of antiviral agents. Further studies are required to elucidate the exact mechanism of action of the bioactive compounds of M. urundeuva acting against SARS-CoV-2.

Clinical and epidemiological factors causing longer SARS-CoV 2 viral shedding: the results from the CoviCamp cohort

IntroductionThe aim of this study was to investigate how long hospitalized patients stayed positive to the nasopharyngeal swab, and what demographic and clinical factors influence the time-to-negative swab.MethodsWe enrolled in a multicenter, observational, retrospective study involving 17 COVID-19 units in eight cities of the Campania, southern Italy all patients hospitalized from March 2020 to May 2021 diagnosed with Severe Acute Respiratory Distress Syndrome-Coronavirus-2 (SARS-CoV-2) infection for whom time-to-negative swab was available.Results963 patients were enrolled. We defined three groups considering time-to-negative swab: the first including patients with time-to-negative swab before the 26th day, the second including patients with time-to-negative swab from day 26 to day 39, and the third including patients with time-to-negative swab > 39 days. 721 (74.9%) patients belonged to the first group, 194 (20.1%) to the second, and 52 (5.4%) belonged to the third group. Belonging to group 2 and 3 seemed to be influenced by age (p value < 0.001), Charlson comorbidity index (p = 0.009), arterial hypertension (p = 0.02), cardiovascular disease (p = 0.017), or chronic kidney disease (CKD) (p = 0.001). The multivariable analysis confers a leading role to CKD, with an odds ratio of 2.3 as factor influencing belonging to the groups showing a longer time-to-negative swab. Patients with CKD and diabetes were more frequently in the third group.DiscussionOur analysis showed that CKD is a factor related to longer time-to-negative swab, probably because of immunosuppression related to this condition.

Guillain-Barre Syndrome linked to SARS-CoV-2 infection – meta-analysis and literature review

Background&#x0D; The novel coronavirus disease-2019 (COVID-19), which is caused by Severe Acute Respiratory Distress Syndrome coronavirus 2 (SARS-CoV2), was originally detected in Wuhan, China in December 2019. In this meta-analysis and literature review, we compared and summarized the clinical presentation, cerebrospinal fluid (CSF) and electromyography (EMG) findings and outcomes in SARS-CoV-2 patients with Guillain-Barre Syndrome (GBS) and its variants.&#x0D; Methods&#x0D; We conducted a literature review in February 2023 searching for terms “Guillain-Barre Syndrome and COVID-19", “SARS neurology”, “COVID-19 complications”. We used PubMed and Google Scholar databases inquiring case reports or series of cases published between April 1, 2020, and September 14, 2023.&#x0D; Results&#x0D; Of the 52 GBS cases 61,5% (n=32) were male and 39,5% (n=20) were female. The mean age was 57 years old. A total of 75% (n=33) patients presented acute inflammatory demyelinating polyneuropathy (AIDP) variant, 6,8% (n=3) presented acute motor axonal neuropathy (AMAN) variant, 15,9% (n=7) presented acute motor-sensory axonal neuropathy (AMSAN) variant. A total of 85,7% (n=42) of patients were diagnosed with albuminocytological dissociation. During the hospitalization, a total of 30,8% (n=16) required mechanical ventilation. A total of 61,5% (n=32) of patients were treated with a 5-day regimen of intravenous immunoglobulin (IVIG) in dose 0.4 g/kg/day. There were 46,1% (n=24) complete recoveries from GBS, 32,7% (n=17) partial recoveries and 9,6% (n=5) of patients did not respond to treatment. A total of 11,5% (n=6) of patients died.&#x0D; Conclusion&#x0D; It is crucial to follow patients with COVID-19 and GBS over time to estimate properly the efficacy of treatment and evaluate the real percentage of recovery and complications.

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

Severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) has infected over 650 million people and claimed the lives of nearly 7 million since the start of the pandemic. While SARS-CoV-2 is becoming endemic with several preventative therapies, an effective treatment against severe disease remains unavailable. Immunocompromised patients remain vulnerable given the limited efficacy of vaccinations and are at risk of respiratory failure, organ failure, and septic shock if infected.1Stawicki S.P. Jeanmonod R. Miller A.C. Paladino L. Gaieski D.F. Yaffee A.Q. De Wulf A. Grover J. Papadimos T.J. Bloem C. et al.The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: a joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper.J. Glob. Infect. Dis. 2020; 12: 47-93https://doi.org/10.4103/jgid.jgid_86_20Crossref PubMed Scopus (197) Google Scholar The development of therapeutics to combat the progression and severity of SARS-CoV-2 infection presents an opportunity to explore innovative approaches to treating viral diseases. Novel therapeutic strategies aim to target the host response to hyper-inflammation and prevent the cytokine storm that is often associated with severe COVID-19 cases.2Dorward D.A. Russell C.D. Um I.H. Elshani M. Armstrong S.D. Penrice-Randal R. Millar T. Lerpiniere C.E.B. Tagliavini G. Hartley C.S. et al.Tissue-specific immunopathology in fatal COVID-19.Am. J. Respir. Crit. Care Med. 2021; 203: 192-201https://doi.org/10.1164/rccm.202008-3265OCCrossref PubMed Scopus (160) Google Scholar In recent years, researchers have focused on intracellular secreted factors, such as extracellular vesicles (EVs), to improve and build upon the knowledge gained from cell-based research and spearhead the use as potential therapeutic agents for various diseases, including SARS-CoV-2. EVs are small membranous structures secreted by the cell membrane or the cell’s internal recycling pathways and have emerged as a promising therapeutic strategy due to their involvement in a range of biological processes, including cell signaling, immune response, and disease progression. The objective of this analysis is to examine the potential efficacy of EV-based therapies in the treatment of SARS-CoV-2 severity, with a particular emphasis on their common mechanisms and suitability for future therapeutic use in human patients. Severe SARS-CoV-2 acts via direct and indirect pathways to cause local and systemic injury. In the direct pathway, severe SARS-CoV-2 utilizes its spike protein to bind to angiotensin-converting enzyme 2 (ACE-2), allowing entry into cells. Cells in the nasopharyngeal tract and lungs are most prone to damage by SARS-CoV-2 due to higher cell surface expression of the ACE-2 receptor.3Yan R. Zhang Y. Li Y. Xia L. Guo Y. Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.Science. 2020; 367: 1444-1448https://doi.org/10.1126/science.abb2762Crossref PubMed Scopus (3130) Google Scholar,4Sungnak W. Huang N. Bécavin C. Bécavin C. Queen R. Litvinukova M. Talavera-López C. Talavera-López C. Reichart D. Sampaziotis F. et al.SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.Nat. Med. 2020; 26: 681-687https://doi.org/10.1038/s41591-020-0868-6Crossref PubMed Scopus (1598) Google Scholar After direct cellular entry, SARS-CoV-2 replicates using host machinery, and viral-mediated damage results in the secretion of pro-inflammatory cytokine interleukin-6 (IL-6).5Narazaki M. Kishimoto T. The two-faced cytokine IL-6 in host defense and diseases.Int. J. Mol. Sci. 2018; 19: 3528https://doi.org/10.3390/ijms19113528Crossref PubMed Scopus (122) Google Scholar Clinically, this presents with anosmia and ageusia with rapid progression to dyspnea and respiratory failure, ultimately resulting in multi-organ damage.6Renieris G. Katrini K. Damoulari C. Akinosoglou K. Psarrakis C. Kyriakopoulou M. Dimopoulos G. Lada M. Koufargyris P. Giamarellos-Bourboulis E.J. Serum hydrogen sulfide and outcome association in pneumonia by the SARS-CoV-2 coronavirus.Shock. 2020; 54: 633-637https://doi.org/10.1097/SHK.0000000000001562Crossref Scopus (58) Google Scholar The virus also acts via an indirect pathway to induce systemic injury. SARS-CoV-2-infected cells can undergo pyroptosis, which leads to the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs).7Wang M. Chang W. Zhang L. Zhang Y. Pyroptotic cell death in SARS-CoV-2 infection: revealing its roles during the immunopathogenesis of COVID-19.Int. J. Biol. Sci. 2022; 18: 5827-5848https://doi.org/10.7150/ijbs.77561Crossref Scopus (4) Google Scholar This mobilizes antigen-presenting cells (APCs)—including dendritic cells and pulmonary macrophages—that recognize PAMPs and DAMPs and release pro-inflammatory cytokines and chemokines, including interferon (IFN)-γ, IL-6, IP-10, and IL-1β. IL-1β further drives the activation of pro-inflammatory pathways, resulting in the recruitment of neutrophils and cytotoxic T cells and the upregulation of cytokines—mainly IL-6. Hypoxia induced by SARS-CoV-2 triggers further IL-6 secretion.8Farahani M. Niknam Z. Mohammadi Amirabad L. Amiri-Dashatan N. Koushki M. Nemati M. Danesh Pouya F. Rezaei-Tavirani M. Rasmi Y. Tayebi L. Molecular pathways involved in COVID-19 and potential pathway-based therapeutic targets.Biomed. Pharmacother. 2022; 145: 112420https://doi.org/10.1016/j.biopha.2021.112420Crossref Scopus (47) Google Scholar IL-6 also modulates its own expression by upregulating the production of IL-10 (anti-inflammatory). However, in the presence of SARS-CoV-2, there is significantly greater IL-6 production, resulting in a net pro-inflammatory state. Dysregulation of the innate immune response leads to increased inflammation and end-organ damage.9Gubernatorova E.O. Gorshkova E.A. Polinova A.I. Drutskaya M.S. IL-6: relevance for immunopathology of SARS-CoV-2.Cytokine Growth Factor. Rev. 2020; 53: 13-24https://doi.org/10.1016/j.cytogfr.2020.05.009Crossref PubMed Scopus (184) Google Scholar,10Islam H. Chamberlain T.C. Mui A.L. Little J.P. Elevated interleukin-10 levels in COVID-19: potentiation of pro-inflammatory responses or impaired anti-inflammatory action?.Front. Immunol. 2021; 12: 677008https://doi.org/10.3389/fimmu.2021.677008Crossref Scopus (62) Google Scholar One promising treatment modality for severe SARS-CoV-2 infection is EVs. EVs can secrete proteins and anti-inflammatory molecules that can modulate the host immune response. Additionally, EVs may act as a negative regulatory element in the transmission of viral infection.11Dogrammatzis C. Waisner H. Kalamvoki M. Cloaked viruses and viral factors in cutting edge exosome-based therapies.Front. Cell Dev. Biol. 2020; 8: 376https://doi.org/10.3389/fcell.2020.00376Crossref Scopus (21) Google Scholar Given these properties, EVs act at multiple points within the direct and indirect pathways to inhibit the inflammatory cascade (Figure 1). EVs can inhibit viral replication and thereby decrease direct viral injury.12Caobi A. Nair M. Raymond A.D. Extracellular vesicles in the pathogenesis of viral infections in humans.Viruses. 2020; 12: 1200https://doi.org/10.3390/v12101200Crossref Scopus (40) Google Scholar Their ability to block IL-6, IL-6 precursors (IL-1β), and inflammatory cytokines (tumor necrosis factor α [TNF-α], IL-8, and MIP-2) at multiple points within the pathway13Moon H.-G. Cao Y. Yang J. Lee J.H. Choi H.S. Jin Y. Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway.Cell Death Dis. 2015; 6: e2016https://doi.org/10.1038/cddis.2015.282Crossref PubMed Scopus (115) Google Scholar,14Weber B. Henrich D. Hildebrand F. Marzi I. Leppik L. The roles of extracellular vesicles in sepsis and systemic inflammatory response syndrome.Shock. 2023; 59: 161-172https://doi.org/10.1097/SHK.0000000000002010Crossref Scopus (1) Google Scholar while upregulating IL-10 results in downregulation of cytokine production and reduction in systemic injury. Given their ability to act on multiple pathways, EVs can provide a more comprehensive and effective approach to treating complex diseases.15Lener T. Gimona M. Aigner L. Börger V. Buzas E. Camussi G. Chaput N. Chatterjee D. Court F.A. Del Portillo H.A. et al.Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper.J. Extracell. Vesicles. 2015; 4: 30087https://doi.org/10.3402/jev.v4.30087Crossref PubMed Scopus (844) Google Scholar To highlight the therapeutic properties of EVs, we conducted a review of 9 studies reporting the effects of EV therapy on lung injury models (Table 1). The reported outcomes of the reviewed EV therapies in experimental models (Table 1) indicate lung injury recovery, improved respiratory function, and overall survival. This was achieved by (1) reducing pro-inflammatory cytokines, (2) enhancing anti-inflammatory cytokines, (3) decreasing neutrophil infiltration, and (4) increasing macrophage polarization to the anti-inflammatory M2 phenotype. EV administration also resulted in downregulation of IL-1β, TNF-α, IL-6,16Wang X. Liu D. Zhang X. Yang L. Xia Z. Zhang Q. Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages.Cell Death Discov. 2022; 8: 18https://doi.org/10.1038/s41420-021-00785-6Crossref PubMed Scopus (11) Google Scholar,17Wang J. Huang R. Xu Q. Zheng G. Qiu G. Ge M. Shu Q. Xu J. Mesenchymal stem cell–derived extracellular vesicles alleviate acute lung injury via transfer of miR-27a-3p.Crit. Care Med. 2020; 48: e599-e610https://doi.org/10.1097/CCM.0000000000004315Crossref PubMed Scopus (72) Google Scholar,18Zhou Y. Li P. Goodwin A.J. Cook J.A. Halushka P.V. Chang E. Zingarelli B. Fan H. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury.Crit. Care. 2019; 23: 44https://doi.org/10.1186/s13054-019-2339-3Crossref PubMed Scopus (134) Google Scholar MIP-1,18Zhou Y. Li P. Goodwin A.J. Cook J.A. Halushka P.V. Chang E. Zingarelli B. Fan H. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury.Crit. Care. 2019; 23: 44https://doi.org/10.1186/s13054-019-2339-3Crossref PubMed Scopus (134) Google Scholar,19Bellio M.A. Young K.C. Milberg J. Santos I. Abdullah Z. Stewart D. Arango A. Chen P. Huang J. Williams K. et al.Amniotic fluid-derived extracellular vesicles: characterization and therapeutic efficacy in an experimental model of bronchopulmonary dysplasia.Cytotherapy. 2021; 23: 1097-1107https://doi.org/10.1016/j.jcyt.2021.07.011Abstract Full Text Full Text PDF Scopus (12) Google Scholar MIP-2, and CXCL2,18Zhou Y. Li P. Goodwin A.J. Cook J.A. Halushka P.V. Chang E. Zingarelli B. Fan H. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury.Crit. Care. 2019; 23: 44https://doi.org/10.1186/s13054-019-2339-3Crossref PubMed Scopus (134) Google Scholar,20Hao Q. Gudapati V. Monsel A. Park J.H. Hu S. Kato H. Lee J.H. Zhou L. He H. Lee J.W. Mesenchymal stem cell–derived extracellular vesicles decrease lung injury in mice.J. Immunol. 2019; 203: 1961-1972https://doi.org/10.4049/jimmunol.1801534Crossref PubMed Scopus (68) Google Scholar in addition to upregulation of IL-10.16Wang X. Liu D. Zhang X. Yang L. Xia Z. Zhang Q. Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages.Cell Death Discov. 2022; 8: 18https://doi.org/10.1038/s41420-021-00785-6Crossref PubMed Scopus (11) Google Scholar,21Huang R. Qin C. Wang J. Hu Y. Zheng G. Qiu G. Ge M. Tao H. Shu Q. Xu J. Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.Aging. 2019; 11: 7996-8014https://doi.org/10.18632/aging.102314Crossref PubMed Scopus (74) Google Scholar,22Khatri M. Richardson L.A. Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.Stem Cell Res. Ther. 2018; 9: 17https://doi.org/10.1186/s13287-018-0774-8Crossref PubMed Scopus (209) Google Scholar Moreover, EVs reportedly preserved alveolar structure,19Bellio M.A. Young K.C. Milberg J. Santos I. Abdullah Z. Stewart D. Arango A. Chen P. Huang J. Williams K. et al.Amniotic fluid-derived extracellular vesicles: characterization and therapeutic efficacy in an experimental model of bronchopulmonary dysplasia.Cytotherapy. 2021; 23: 1097-1107https://doi.org/10.1016/j.jcyt.2021.07.011Abstract Full Text Full Text PDF Scopus (12) Google Scholar reduced alveolar wall thickness,18Zhou Y. Li P. Goodwin A.J. Cook J.A. Halushka P.V. Chang E. Zingarelli B. Fan H. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury.Crit. Care. 2019; 23: 44https://doi.org/10.1186/s13054-019-2339-3Crossref PubMed Scopus (134) Google Scholar,21Huang R. Qin C. Wang J. Hu Y. Zheng G. Qiu G. Ge M. Tao H. Shu Q. Xu J. Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.Aging. 2019; 11: 7996-8014https://doi.org/10.18632/aging.102314Crossref PubMed Scopus (74) Google Scholar,23Sun A. Lai Z. Zhao M. Mu L. Hu X. Native nanodiscs from blood inhibit pulmonary fibrosis.Biomaterials. 2019; 192: 51-61https://doi.org/10.1016/j.biomaterials.2018.10.045Crossref Scopus (7) Google Scholar and inhibited virus-induced apoptosis in lung epithelial cells.22Khatri M. Richardson L.A. Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.Stem Cell Res. Ther. 2018; 9: 17https://doi.org/10.1186/s13287-018-0774-8Crossref PubMed Scopus (209) Google Scholar Finally, the ability of mesenchymal stem cell (MSC)-EVs to transfer cargo, such as miR-27a-3p, increased M2 macrophage polarization, effectively reducing TNF-α17Wang J. Huang R. Xu Q. Zheng G. Qiu G. Ge M. Shu Q. Xu J. Mesenchymal stem cell–derived extracellular vesicles alleviate acute lung injury via transfer of miR-27a-3p.Crit. Care Med. 2020; 48: e599-e610https://doi.org/10.1097/CCM.0000000000004315Crossref PubMed Scopus (72) Google Scholar and inhibiting lung fibrosis.24Cui H. Banerjee S. Xie N. Ge J. Liu R.-M. Matalon S. Thannickal V.J. Liu G. MicroRNA-27a-3p is a negative regulator of lung fibrosis by targeting myofibroblast differentiation.Am. J. Respir. Cell Mol. Biol. 2016; 54: 843-852https://doi.org/10.1165/rcmb.2015-0205OCCrossref PubMed Scopus (61) Google ScholarTable 1Articles reporting the effects of EV therapy on lung injury modelsSource of EVsModelSampleEV effects on cytokines and inflammatory moleculesPathological outcomesSourceAdipose MSCssepsis-induced ALI: in vivo mouselung tissueblood↓IL-6, ↓TNF-⍺, ↓IL-1β, ↑EBI3-protein, ↑P28-protein↓IL-27reduction in pulmonary inflammation and lung tissue injury (↓macrophage infiltration), increased survival rateWang et al.16Wang X. Liu D. Zhang X. Yang L. Xia Z. Zhang Q. Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages.Cell Death Discov. 2022; 8: 18https://doi.org/10.1038/s41420-021-00785-6Crossref PubMed Scopus (11) Google ScholarAmniotic fluidBPD: in vivo ratlung tissue↓IL-1⍺, ↓IL-1β, ↓MCP-1, ↓MIP-1⍺significant decrease of pulmonary hypertension, preservation of alveolar structure, reduction in vascular remodeling, suppression of lung inflammation, reduction of macrophage infiltrationBellio et al.19Bellio M.A. Young K.C. Milberg J. Santos I. Abdullah Z. Stewart D. Arango A. Chen P. Huang J. Williams K. et al.Amniotic fluid-derived extracellular vesicles: characterization and therapeutic efficacy in an experimental model of bronchopulmonary dysplasia.Cytotherapy. 2021; 23: 1097-1107https://doi.org/10.1016/j.jcyt.2021.07.011Abstract Full Text Full Text PDF Scopus (12) Google ScholarAdipose MSCsALI: in vivo mouseALI: in vitro mouselung tissueBALBMDMs↓TNF-⍺, ↓IL-1β, ↓IL-6, ↑IL-10, ↓iNOS, ↓NF-κB↓TNF-⍺, ↓IL-1β, ↓iNOS, ↑ YM-1, ↑MRC-1, ↑mi-27-a-3preduction of pulmonary endothelial barrier, inflammation (↓ pro-inflammatory cytokines, ↑ anti-inflammatory cytokines, ↓ neutrophils), and alveolar septal thickeningWang et al.17Wang J. Huang R. Xu Q. Zheng G. Qiu G. Ge M. Shu Q. Xu J. Mesenchymal stem cell–derived extracellular vesicles alleviate acute lung injury via transfer of miR-27a-3p.Crit. Care Med. 2020; 48: e599-e610https://doi.org/10.1097/CCM.0000000000004315Crossref PubMed Scopus (72) Google ScholarAdipose MSCsALI: in vivo mouseALI: in vitro mouselung tissueBALBMDMs↓IL-1β, ↑IL-10↓IL-6, ↑↓IL-1β, ↓TNF-⍺, ↓iNOS, ↑TGF-β1, ↑YM-1reduction in inflammation (↓ neutrophils, ↓macrophage recruitment) and alveolar wall thicknessHuang et al.21Huang R. Qin C. Wang J. Hu Y. Zheng G. Qiu G. Ge M. Tao H. Shu Q. Xu J. Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.Aging. 2019; 11: 7996-8014https://doi.org/10.18632/aging.102314Crossref PubMed Scopus (74) Google ScholarBone marrow MSCsALI: in vivo mouseALI: in vitro mouseBALRAW267.4↓MIP-2, ↓TNF-⍺, ↑LTB4↓MRP1-protein, ↑miR-145antimicrobial effect (↑ monocyte phagocytosis, ↓bacterial levels), reduction of inflammation (↓leukocytes, ↓neutrophils)Hao et al.20Hao Q. Gudapati V. Monsel A. Park J.H. Hu S. Kato H. Lee J.H. Zhou L. He H. Lee J.W. Mesenchymal stem cell–derived extracellular vesicles decrease lung injury in mice.J. Immunol. 2019; 203: 1961-1972https://doi.org/10.4049/jimmunol.1801534Crossref PubMed Scopus (68) Google ScholarUmbilical cord jelly MSCsinfluenza-induced ALI: in vitro humanAECno particular mechanism studiedrestoration of alveolar fluid clearance, reduction alveolar protein permeability29Umbilical cord EPC (rich in miR-126)ALI: in vivo mouseALI: in vitro humanlung tissueBALAEC↓TNF-⍺, ↓IL-1β, ↓IL-6, ↓IFN-γ, ↓MIP-1↓MIP-2, ↓MIG, ↓IP-10, ↓MPO↑Claudin1, ↑Claudin4, ↑Occludinreduction of inflammation (↓ pro-inflammatory cytokines, ↑ anti-inflammatory cytokines, ↓ neutrophils), alveolar wall thickness, and hyaline membrane formationZhou et al.18Zhou Y. Li P. Goodwin A.J. Cook J.A. Halushka P.V. Chang E. Zingarelli B. Fan H. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury.Crit. Care. 2019; 23: 44https://doi.org/10.1186/s13054-019-2339-3Crossref PubMed Scopus (134) Google ScholarWhole bloodfibrosis: in vivo mouselung tissue↓hydroxyprolinereduction of immune cell recruitment, alveolar wall thickness, and collagen depositionSun et al.23Sun A. Lai Z. Zhao M. Mu L. Hu X. Native nanodiscs from blood inhibit pulmonary fibrosis.Biomaterials. 2019; 192: 51-61https://doi.org/10.1016/j.biomaterials.2018.10.045Crossref Scopus (7) Google ScholarBone marrow MSCsinfluenza-induced ALI: in vivo piginfluenza-induced ALI: in vitro pigslung tissueLECs↓TNF-⍺, ↓CXCL10, ↑IL-10↓apoptosisinhibition of viral replication, reduction of inflammation, decrease in virus-induced lung lesions, inhibited virus-induced apoptosis in lung epithelial cellsKhatri et al.22Khatri M. Richardson L.A. Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model.Stem Cell Res. Ther. 2018; 9: 17https://doi.org/10.1186/s13287-018-0774-8Crossref PubMed Scopus (209) Google ScholarAECs, alveolar epithelial cells; ALI, acute lung injury; BAL, bronchioalveolar lavage; BMDMs, bone marrow-derived macrophages; BPD, bronchopulmonary dysplasia; CXCL, chemokine (C-X-C motif) ligand; EPC, endothelial progenitor cell; EVs, extracellular vesicles; IFN, interferon; IL, interleukin; LECs, lymphatic endothelial cells; LTB4, leukotriene B4; MCP, monocyte chemotactic protein; MIG, monokine induced by gamma interferon; MIP, macrophage induced protein; MIR, microRNA; MPO, myeloperoxidase; MRC-1, mannose receptor C-type 1; MRP1, multidrug resistance associated protein 1; MSC, mesenchymal stem/stromal cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS, nitric oxide synthase (iNOS, inducible; eNOS, endothelial); RAW267.4, monocyte/macrophage lineage; TGF, transforming growth factor; TNF, tumor necrosis factor; YM-1, Chitinase 3-like 3, a macrophage protein. Open table in a new tab AECs, alveolar epithelial cells; ALI, acute lung injury; BAL, bronchioalveolar lavage; BMDMs, bone marrow-derived macrophages; BPD, bronchopulmonary dysplasia; CXCL, chemokine (C-X-C motif) ligand; EPC, endothelial progenitor cell; EVs, extracellular vesicles; IFN, interferon; IL, interleukin; LECs, lymphatic endothelial cells; LTB4, leukotriene B4; MCP, monocyte chemotactic protein; MIG, monokine induced by gamma interferon; MIP, macrophage induced protein; MIR, microRNA; MPO, myeloperoxidase; MRC-1, mannose receptor C-type 1; MRP1, multidrug resistance associated protein 1; MSC, mesenchymal stem/stromal cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS, nitric oxide synthase (iNOS, inducible; eNOS, endothelial); RAW267.4, monocyte/macrophage lineage; TGF, transforming growth factor; TNF, tumor necrosis factor; YM-1, Chitinase 3-like 3, a macrophage protein. The translation of EV-based therapies from acute lung injury models to human clinical studies have significant potential for the treatment of SARS-CoV-2-induced acute respiratory distress syndrome (ARDs). Preclinical models of lung injury have shown upregulated inflammatory responses and migration of neutrophils and macrophages to pulmonary tissues (Table 1). This was verified pathologically and shown to be due to an upregulation of IL-6. In preclinical models, EVs have demonstrated an ability to dampen inflammation and reduce T cell proliferation caused by SARS-CoV-2, establishing the rationale for present clinical trials.25del Rivero T. Milberg J. Bennett C. Mitrani M.I. Bellio M.A. Human amniotic fluid derived extracellular vesicles attenuate T cell immune response.Front. Immunol. 2022; 13: 977809https://doi.org/10.3389/fimmu.2022.977809Crossref Scopus (2) Google Scholar Several EV-based therapies have entered clinical trials with the aim of assessing safety, efficacy, administration route, and optimal dosing in various respiratory conditions. A complete list of ongoing clinical trials on the use of EV-based therapeutics in COVID-19 treatment is shown in Table 2. Due to the rapid spread of COVID-19 and lack of effective therapies, several studies were approved on an emergency basis by ethical committees. In a study where amniotic fluid-derived EVs were administered to high-risk patients with mild-to-moderate COVID-19, results showed a significant decrease in CRP, IL-6, and TNF-α, as well as stabilized absolute lymphocyte count (ALC).26Bellio M.A. Bennett C. Arango A. Khan A. Xu X. Barrera C. Friedewald V. Mitrani M.I. Proof-of-concept trial of an amniotic fluid-derived extracellular vesicle biologic for treating high risk patients with mild-to-moderate acute COVID-19 infection.Biomater. Biosyst. 2021; 4: 100031https://doi.org/10.1016/j.bbiosy.2021.100031Crossref Scopus (7) Google Scholar Additional clinical testing performed on three severely ill patients with COVID-19 revealed a decrease in inflammatory biomarkers and improvements in patient clinical status and respiratory function.27Mitrani M.I. Bellio M.A. Sagel A. Saylor M. Kapp W. VanOsdol K. Haskell G. Stewart D. Abdullah Z. Santos I. et al.Case report: administration of amniotic fluid-derived nanoparticles in three severely ill COVID-19 patients.Front. Med. 2021; 8: 583842https://doi.org/10.3389/fmed.2021.583842Crossref PubMed Scopus (25) Google Scholar Both studies were completed without any adverse events or safety concerns.Table 2List of clinical trials on the use of EV-based therapeutics in COVID-19 managementReferenceaObtained from clinicaltrials.gov using “extracellular vesicles” or “exosomes” as search strings, with results restricted to COVID-19.Official titleStatusNCT04493242Extracellular Vesicle Infusion Treatment for COVID-19 Associated ARDS (EXIT-COVID19)completedNCT05787288A Clinical Study on Safety and Effectiveness of Mesenchymal Stem Cell Exosomes for the Treatment of COVID-19recruitingNCT04657458Expanded Access for Use of bmMSC-Derived Extracellular Vesicles in Patients With COVID-19 Associated ARDSavailableNCT05116761ExoFlo™ Infusion for Post-Acute COVID-19 and Chronic Post-COVID-19 Syndromenot yet recruitingNCT05354141Bone Marrow Mesenchymal Stem Cell Derived EVs for COVID-19 Moderate-to-Severe Acute Respiratory Distress Syndrome (ARDS): A Phase III Clinical TrialrecruitingNCT05228899Zofin to Treat COVID-19 Long HaulersrecruitingNCT04902183Safety and Efficacy of Exosomes Overexpressing CD24 in Two Doses for Patients With Moderate or Severe COVID-19recruitingNCT05216562Efficacy and Safety of EXOSOME-MSC Therapy to Reduce Hyper-inflammation In Moderate COVID-19 Patients (EXOMSC-COV19)recruitingNCT04798716The Use of Exosomes for the Treatment of Acute Respiratory Distress Syndrome or Novel Coronavirus Pneumonia Caused by COVID-19 (ARDOXSO)not yet recruitingNCT05387278Safety and Effectiveness of Placental Derived Exosomes and Umbilical Cord Mesenchymal Stem Cells in Moderate to Severe Acute Respiratory Distress Syndrome (ARDS) Associated With the Novel Corona Virus Infection (COVID-19)recruitingNCT04491240Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Pneumonia. (COVID-19EXO)completedNCT04384445Zofin (Organicell Flow) for Patients With COVID-19active, not recruitingNCT04657406Expanded Access to Zofin for Patients With COVID-19availablea Obtained from clinicaltrials.gov using “extracellular vesicles” or “exosomes” as search strings, with results restricted to COVID-19. Open table in a new tab The ongoing COVID-19 pandemic caused by SARS-CoV-2 highlights the critical need for effective therapies to mitigate disease progression and reduce severity. EV-based therapeutics have shown the capacity to attenuate the hyper-inflammatory response caused by SARS-CoV-2 and promote repair of damaged lung tissue in preclinical models, with similar results when translated into SARS-CoV-2 patients. In addition, EVs may harbor therapeutic applications to tackle the prolonged symptoms of infection (long COVID) that are associated with prolonged overactivation and exhaustion of immune cells.28Phetsouphanh C. Darley D.R. Wilson D.B. Howe A. Munier C.M.L. Patel S.K. Juno J.A. Burrell L.M. Kent S.J. Dore G.J. et al.Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.Nat. Immunol. 2022; 23: 210-216https://doi.org/10.1038/s41590-021-01113-xCrossref PubMed Scopus (202) Google Scholar The overview presented in this work highlights the innovative use of EVs as a promising approach to address severe SARS-CoV-2 infections. Recent progress in clinical trials has also laid the groundwork for the development of effective EV-based therapies for a broad range of viral infections. Y.L. would like to acknowledge the mentors who have played a profound role in their career development and to the patients who inspire them to strive for greatness daily. Y.L. also wants to acknowledge MSSN for its support of scholarly endeavors. Funding: Funding information is not applicable. Y.L., idea conception; primary author for design, framework, and refinement of severe SARS-CoV-2 model, EVs as a therapeutic agent against severe SARS-CoV-2; review of literature; summarizing and organizing of data; main manuscript writing contribution; participation in post-peer review manuscript revisions. G.G., primary author for introduction, extracellular vesicle therapy, and future direction and conclusion. M.J., main manuscript writing; literature review; addition of substantial, clinically oriented written content. G.P.M., main manuscript writing; literature review; addition of substantial, clinically oriented written content. A.V.d.K., main manuscript writing; literature review; addition of substantial, clinically oriented written content. M.I.M., editing and revision of manuscript. M.A.B., editing and revision of manuscript. T.d.R., editing and revision of manuscript. All authors read, reviewed, and approved the final manuscript. G.G., M.I.M., T.d.R., and M.A.B. are employees of Organicell Regenerative Medicine. M.I.M. is the Chief Science Officer, serves on the Organicell Regenerative Medicine Board of Directors, and holds equity in the company.

SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups.

Liver is unlikely the key organ driving mortality in coronavirus disease 2019 (COVID-19) however, liver function tests (LFTs) abnormalities are widely observed mostly in moderate and severe cases. According to this review, the overall prevalence of abnormal LFTs in COVID-19 patients ranges from 2.5% to 96.8% worldwide. The geographical variability in the prevalence of underlying diseases is the determinant for the observed discrepancies between East and West. Multifactorial mechanisms are implicated in COVID-19-induced liver injury. Among them, hypercytokinemia with "bystander hepatitis", cytokine storm syndrome with subsequent oxidative stress and endotheliopathy, hypercoagulable state and immuno-thromboinflammation are the most determinant mechanisms leading to tissue injury. Liver hypoxia may also contribute under specific conditions, while direct hepatocyte injury is an emerging mechanism. Except for initially observed severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) tropism for cholangiocytes, more recent cumulative data show SARS-CoV-2 virions within hepatocytes and sinusoidal endothelial cells using electron microscopy (EM). The best evidence for hepatocellular invasion by the virus is the identification of replicating SARS-CoV-2 RNA, S protein RNA and viral nucleocapsid protein within hepatocytes using in-situ hybridization and immunostaining with observed intrahepatic presence of SARS-CoV-2 by EM and by in-situ hybridization. New data mostly derived from imaging findings indicate possible long-term sequelae for the liver months after recovery, suggesting a post-COVID-19 persistent live injury.

Wuhan 3years after the outbreak of the pandemic-cardiological insights and perspectives.

In November 2019, Wuhan, acity in Central China, became the center of an outbreak of pneumonia of unknown cause, which was later named "coronavirus disease 2019" (COVID-19). COVID-19 is caused by the novel severe acute respiratory distress syndrome coronavirus2 (SARS-CoV-2) infection. The emergence of novel SARS-CoV‑2 strains and mutations exerted aserious global public health threat. Although various vaccines have been developed, specific anti-SARS-CoV‑2 drugs are limited. As cardiologists, we believe that because SARS-CoV‑2 can bind to the angiotensin2 receptor on the surface of cardiomyocytes, it may also lead to cardiac injury. COVID-19-associated cardiac injury is not rare in clinical practice, and most of these cases are mild, while afew might progress to fulminant myocarditis (FM). Overactivated immune response and inflammatory storm represent the core pathogenesis of COVID-19-associated FM. Early identification and diagnosis of COVID-19-associated FM are critical for its treatment. Recently, Wuhan was hit by the Omicron variant again. We proposed managing COVID-19-associated cardiac injury according to the severity, which has had asignificant effect on outcome.

Clinical application of SARS-CoV-2 antibody detection and monoclonal antibody therapies against COVID-19.

The purpose of this study was to investigate the clinical application of severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) specific antibody detection and anti-SARS-CoV-2 specific monoclonal antibodies (mAbs) in the treatment of coronavirus infectious disease 2019 (COVID-19). The dynamic changes of SARS-CoV-2 specific antibodies during COVID-19 were studied. Immunoglobulin M (IgM) appeared earlier and lasted for a short time, while immunoglobulin G (IgG) appeared later and lasted longer. IgM tests can be used for early diagnosis of COVID-19, and IgG tests can be used for late diagnosis of COVID-19 and identification of asymptomatic infected persons. The combination of antibody testing and nucleic acid testing, which complement each other, can improve the diagnosis rate of COVID-19. Monoclonal anti-SARS-CoV-2 specific antibodies can be used to treat hospitalized severe and critically ill patients and non-hospitalized mild to moderate COVID-19 patients. COVID-19 convalescent plasma, highly concentrated immunoglobulin, and anti-SARS-CoV-2 specific mAbs are examples of anti-SARS-CoV-2 antibody products. Due to the continuous emergence of mutated strains of the novel coronavirus, especially omicron, its immune escape ability and infectivity are enhanced, making the effects of authorized products reduced or invalid. Therefore, the optimal application of anti-SARS-CoV-2 antibody products (especially anti-SARS-CoV-2 specific mAbs) is more effective in the treatment of COVID-19 and more conducive to patient recovery.

Impact of COVID-19 on Cardiovascular Disease.

Coronavirus disease 2019 (COVID-19) is a viral infection with the novel severe acute respiratory distress syndrome corona virus 2 (SARS-CoV-2). Until now, more than 670 million people have suffered from COVID-19 worldwide, and roughly 7 million death cases were attributed to COVID-19. Recent evidence suggests an interplay between COVID-19 and cardiovascular disease (CVD). COVID-19 may serve as a yet underappreciated CVD risk modifier, including risk factors such as diabetes mellitus or arterial hypertension. In addition, recent data suggest that previous COVID-19 may increase the risk for many entities of CVD to an extent similarly observed for traditional cardiovascular (CV) risk factors. Furthermore, increased CVD incidence and worse clinical outcomes in individuals with preexisting CVD have been observed for myocarditis, acute coronary syndrome, heart failure (HF), thromboembolic complications, and arrhythmias. Direct and indirect mechanisms have been proposed by which COVID-19 may impact CVD and CV risk, including viral entry into CV tissue or by the induction of a massive systemic inflammatory response. In the current review, we provide an overview of the literature reporting an interaction between COVID-19 and CVD, review potential mechanisms underlying this interaction, and discuss preventive and treatment strategies and their interference with CVD that were evaluated since the onset of the COVID-19 pandemic.

Intranasal COVID-19 vaccine: a modern vaccination approach.

Dear Editor, The emergence of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) which was originally reported to WHO in December 2019 resulted in the coronavirus illness and it was subsequently declared a global coronavirus disease 2019 (COVID-19) pandemic in March 2020. Recurring disease outbreaks repeatedly overloaded the public health sector, infecting over 613 million people and killing more than 6.5 million as of September 20221. As new strains emerge and natural immunity wanes, the population, particularly immunocompromised individuals, stand an increased risk of severe sickness and death due to this disease. Various research advances paved the way for developing multiple COVID-19 vaccines which have been approved to treat and prevent COVID-19. Currently, available COVID-19 vaccines including mRNA vaccines, recombinant adenovirus vaccines, and recombinant protein vaccines that have received Emergency Use Authorization (EUA) and have been subsequently used to immunize millions of people are all administered through intramuscular injection2. Intramuscular vaccines have been designed to induce antibody-mediated and cell-mediated immune responses and minimal to no detectable mucosal immunity at the site of infection. Since the nose and upper respiratory tract are the primary routes for inhalation pathogens like SARS-CoV-2 and are more susceptible to infection,3 the vaccine response generated after intramuscular immunization can leave the upper respiratory tract vulnerable to viral replication and dissemination because these vaccines are inefficient in stimulating immunoglobulin A secretion in mucosal cells2. Alternatively, it has been found recently that the intranasal (IN) vaccines for COVID-19 have shown a promising ability to induce sterilizing mucosal immunity against mucosal pathogens apart from inducing an antibody-mediated immune response and a robust cell-mediated immunity2. A single dose of effective SARS-CoV-2 vaccine via IN route boosts mucosal immunoglobulin A and T-cell responses in both upper and lower respiratory tract, providing almost complete prevention against viral infection, multiplication, and reducing virus shedding via nasal mucosa that acts as a first-line barrier to the virus entrance before spreading into the lungs2. This immediate protection at the site of infection by restricting the viral replication and clearance of SARS-CoV-2 infection reflects the potency of IN COVID-19 vaccines in the alleviation of seeding new cases of COVID-19 amidst the pandemic; hence, preventing even mild cases of illness and inhibiting the virus transmission to other people. In addition, these vaccines are minimally invasive, have a needle-free mode of administration, and are usually in the form of a nasal spray2. Owing to the easy transportation and storage, these vaccines are also more convenient to use2. However, an essential consideration for IN COVID-19 vaccine is its safety. An extremely rare risk of reversion of live attenuated virus into replicating state, regaining its ability to cause disease in the individual has been observed4. With that, the effectiveness of the vaccine is determined by the immunization type chosen and the addition of essential adjuvants. Phase I, II, and III clinical trials were performed to assess the efficacy of IN COVID-19 immunization by two companies; CanSino Biologics, a Chinese pharmaceutical company, and Bharat Biotech International, a biotechnology company headquartered in India, which received approval in their respective countries for its use after gaining successful results5. These companies have created ‘viral vector’ vaccines that use a harmless adenovirus to deliver the genetic material of the SARS-CoV-2 into host cells. Given the severity of the situation where the healthcare systems are challenged globally due to increased COVID-19-related hospitalizations, it is critical to continue developing effective and reliable COVID-19 vaccines in present times. In the context of respiratory pathogens like SARS-CoV-2, IN vaccines’ pros conceivably outweigh their cons, along with offering both localized protection at the site of infection and activating systemic responses as compared with intramuscular vaccines eliciting only systemic responses. Large-scale clinical studies and trials should be conducted to gather further evidence to prove its effectiveness so that the availability of IN COVID-19 vaccines may be made feasible. This vaccine might also serve as an alternative to limited and inadequate vaccine supplies as well as a booster to intramuscular vaccines. Immunization with IN COVID-19 vaccines will hopefully help deal with the persistent COVID-19 pandemic and potential viral contagious diseases that might arise in the future. Ethics approval Not applicable. Sources of funding None. Authors’ contribution All authors contributed equally. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration Unique Identifying number (UIN) None. Guarantor Govinda Khatri.

Post COVID-19 Infection with Staphylococcus Aureus Bacteraemia: A Case Series

Staphylococcus aureus (S.aureus) is a leading bacterial pathogen, that causes deadly infections such as bacteraemia, Toxic Shock Syndrome (TSS) and endocarditis. It has been the main contributor to secondary bacterial infections during viral pandemics, greatly raising patient morbidity and fatality rates. It is unknown how this secondary bacteraemia would affect people who have Severe Acute Respiratory Distress Syndrome Coronavirus 2 (SARS-CoV2). Herein, the authors present a series of case studies of 8 patients, (4 males and 4 females) infected with Coronavirus Disease-2019 (COVID-19) at tertiary hospital, Hyderabad, India, who eventually developed S.aureus bacteraemia with widespread seeding of secondary infections including cellulitis and abscess formation. Adult patients aged 20-60 years of age who were infected with COVID-19 from June’2022-August’2022 and had positive bacterial cultures for S.aureus during admission were included in the study. A total of eight patients hospitalised for COVID-19 with secondary bacteraemia were identified. Of these patients admitted with severe limb infections, three patients expired after a week of ongoing treatment from their blood cultures. Multivariate analysis identified the onset of bacteraemia (&gt;4 days from date of admission) and age as significant predictors of mortality in admitted patients. Systemic Inflammatory Response Syndrome (SIRS) scoring and blood cultures were used to identify the mortality risk with p-value=0.05 statistical significance. The patients were subsequently treated with antibiotics and given conservative management, some of the patients admitted to Intensive Care Unit (ICU) who had critical co-morbidities, expired within a week of ongoing treatment. The final outcome of the present case series was that bacteraemia caused by S.aureus is associated with a high mortality rate in COVID-19 patients. More research is needed to understand the relationship between COVID-19 and secondary S.aureus bacteraemia.

Codivir suppresses SARS-Cov-2 viral replication and stabilizes clinical outcome: In vitro and Phase I clinical trial results.

Treatment of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) remains a significant challenge in the face of increased worldwide morbidity and mortality. The acute illness caused by SARS-CoV-2 is initiated by a viral phase, followed by an inflammatory phase. Numerous anti-inflammatory and anti-viral therapies, with a relatively minor clinical effect, have been applied. Developing a safe and efficient direct anti-viral treatment is essential as it can block disease progression before significant complications ensue and potentially prevent transmission. The present phase 1 study aimed to determine the safety of Codivir, a newly developed anti-viral agent, and to preliminarily assess its anti-viral activity in patients infected by COVID-19. In vitro studies were conducted to determine the direct anti-viral effect of Codivir using an immunofluorescence-based assay and to assess its cytotoxic effect by tetrazolium assay (MTT). In a phase I clinical trial, Codivir was administered for ten days in 12 patients who were followed for its safety. Patients were followed for clinical manifestations during administration. Sequential nasal viral PCR titers (Cycle Threshold, CT) were determined preceding and during treatment. In vitro, Codivir showed activity against SARS-CoV-2 with 90% viral replication suppression and minimal cytotoxicity. The anti-viral activity was demonstrated at the early stages of infection, post-entry of the virus in the cell. Codivir was safe in all 12 patients in phase I clinical trial and significantly suppressed viral replication in 5/7 fully assessed patients, with an anti-viral effect noted as early as three days. The present study's data support the safety of Codivir administration in humans and suggest its significant anti-COVID-19 effect. These results support the testing of the drug in more extensive controlled trials in patients with SARS-CoV-2.

Rare Adverse Events Associated with BNT162b2 mRNA Vaccine (Pfizer-BioNTech): A Review of Large-Scale, Controlled Surveillance Studies.

Given the increasing anti-vaccine movements erroneously touting vaccine danger, this review has investigated the rare adverse events potentially associated with BNT162b2 (Pfizer-BioNTech), an mRNA vaccine against the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). Only real-world surveillance studies with at least 0.1 million BNT162b2-vaccinated participants and one unvaccinated control group were selected for review. A total of 21 studies examining the potential association of BNT162b2 with cardiovascular, herpetic, thrombotic or thrombocytopenic, neurological, mortality, and other miscellaneous rare adverse events were described in this review. Only myocarditis is consistently associated with BNT162b2. An unclear direction of association was seen with stroke (hemorrhagic and ischemic), herpes zoster, and paresthesia from BNT162b2, which may require more studies to resolve. Fortunately, most surveillance studies detected no increased risks of the remaining rare adverse events reviewed herein, further reassuring the safety of BNT162b2. In conclusion, this review has concisely summarized the current rare adverse events related and unrelated to BNT162b2, arguably for the first time in sufficient depth, to better communicate vaccine safety to the public.

A Pilot Study on COVID-19 Positive Subjects: An Excerpt of Post-Infection-Pro-Diabetic Disposition & Related Consequences in Correlation to Hepato-Pancreatic Bio-Markers, Pro-Inflammatory Cytokines and Other Risk Factors.

COVID-19, a global pandemic that led to increased morbidity and mortality worldwide since its outcome at the end of the year 2019. A newly discovered variant of severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) was the arbitrator for spreading the syndrome by droplet transmission causing multi-organ failure in many occasions. A post-infection-pro-diabetic disposition was found evident in this study with the persistence of hepato-pancreatic aberrations in respect of reference range of tissue specific bio-markers in hospital admitted COVID-19 cases. The results of this study show that hyperglycemia is a risk factor in precipitating disease oriented complications to the patients with COVID-19 disease. A post-infection follow- up on glycemic-index and related complexities is a vital need to the COVID-19 infected convalescent subjects. Implementation of guidelines on social measure and awareness of anti-viral interventions may be the only way to prevent COVID-19 transmission.

Neurosurgery Practice During the COVID-19 Pandemic

Background and Aim: The viral agent in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19). It was first identified in December 2019 in the city of Wuhan, Hubei, China, and the World Health Organization declared it as an outbreak and a Public Health Emergency of International Concern on 30 January 2020, and a pandemic on 11 March 2020. Neurosurgeons are not prime in COVID-19 management but they continue for caring, visiting, and operating neurosurgical patients. In neurosurgical cases that need non-urgent operation, systematic SARS-CoV-2 testing of low-risk patients should be considered. In cases with positive SRAS-COV-2 testing, the procedures should be delayed until they are cured. The high-risk settings in the neurosurgical operation room are endotracheal intubation and extubation, operations in the vicinity of sinuses and/or mastoids, operations with accidental injury to respiratory or digestive tracts, and usage of aerosol-generating instruments on virioncontaminated tissues. The risk of SARS-COV-2 infection is decreased by delaying all nonemergent cases, replacing general anesthesia with other anesthesia methods, replacing neurosurgical approaches with alternative approaches that bypass the respiratory tract, and decreasing the usage of aerosol-generating instruments. Methods and Materials/Patients: This is a narrative study about COVID-19 infection in neurosurgery. Using the keywords SARS-COV2, neurosurgery, and COVID-19, all the relevant articles (about 52) were retrieved from Google Scholar, Medline, and PubMed and reviewed and critically analyzed. Results: Neurosurgeons can change neurosurgical routines in COVID-19 patients such as delaying all nonemergent cases, replacing general anesthesia with other anesthesia methods, replacing neurosurgical approaches with alternative approaches that bypass the respiratory tract, decreasing the usage of aerosol-generating instruments, and doing preoperative SRAS-COV-2 testing. Conclusion: For decreasing the risk of COVID-19 transmission in neurosurgery, we can change routine neurosurgical protocols. Without the prevention of COVID-19 transmission, all neurosurgeons, personnel, and patients will contract COVID-19.

Age-adjusted mortality and predictive value of liver chemistries in a Viennese cohort of COVID-19 patients.

Background and AimsThe coronavirus disease of 2019 (COVID‐19) causes considerable mortality worldwide. We aimed to investigate the frequency and predictive role of abnormal liver chemistries in different age groups.MethodsPatients with positive severe acute respiratory distress syndrome‐coronavirus‐2 (SARS‐CoV‐2) polymerase chain reaction (PCR) test between 03/2020‐07/2021 at the Vienna General Hospital were included. Patients were stratified for age: 18–39 vs. 40–69 vs. ≥70 years (y). Aspartate aminotransferase (AST), alanine‐aminotransferase (ALT), alkaline phosphatase (ALP), gamma‐glutamyl transferase (GGT) and total bilirubin (BIL) were recorded.Results900 patients (18–39 years: 32.2%, 40–69 years: 39.7%, ≥70 years: 28.1%) were included. Number of comorbidities, median D‐dimer and C‐reactive protein increased with age. During COVID‐19, AST/ALT and ALP/GGT levels significantly increased. Elevated hepatocellular transaminases (AST/ALT) and cholestasis parameters (ALP/GGT/BIL) were observed in 40.3% (n  = 262/650) and 45.0% (n  = 287/638) of patients respectively. Liver‐related mortality was highest among patients with pre‐existing decompensated liver disease (28.6%, p < .001). 1.7% of patients without pre‐existing liver disease died of liver‐related causes, that is consequences of hepatic dysfunction or acute liver failure. Importantly, COVID‐19‐associated liver injury (16.0%, p < .001), abnormal liver chemistries and liver‐related mortality (6.5%, p < .001) were most frequent among 40–69 years old patients. Elevated AST and BIL after the first positive SARS‐CoV‐2 PCR independently predicted mortality in the overall cohort and in 40–69 years old patients.ConclusionsAlmost half of the COVID‐19 patients exhibit abnormal hepatocellular and cholestasis‐related liver chemistries with 40–69 years old patients being at particularly high risk for COVID‐19‐related liver injury and liver‐related mortality. Elevated AST and BIL after SARS‐CoV‐2 infection are independent predictors of mortality, especially in patients aged 40–69 years.

Stress Hyperglycemia, Diabetes Mellitus and COVID-19 Infection: Risk Factors, Clinical Outcomes and Post-Discharge Implications.

The novel severe acute respiratory distress syndrome-coronavirus 2 (SARS-CoV-2) has caused one of the most substantial pandemics that has affected humanity in the last century. At the time of the preparation of this review, it has caused the death of around 5 million people around the globe. There is ample evidence linking higher mortality risk rates from Coronavirus disease-19 (COVID-19) with male gender, advancing age and comorbidities, such as obesity, arterial hypertension, cardiovascular disease, chronic obstructive pulmonary disease, diabetes mellitus, and cancer. Hyperglycemia has been found to be accompanying COVID-19 not only in individuals with overt diabetes. Many authors claim that blood glucose levels should also be monitored in non-diabetic patients; moreover, it has been confirmed that hyperglycemia worsens the prognosis even without pre-existing diabetes. The pathophysiological mechanisms behind this phenomenon are complex, remain controversial, and are poorly understood. Hyperglycemia in the setting of COVID-19 could be a consequence of deterioration in pre-existing diabetes, new-onset diabetes, stress-induced or iatrogenic due to substantial usage of corticosteroids within the context of a severe COVID-19 infection. It is also plausible that it might be a result of adipose tissue dysfunction and insulin resistance. Last but not least, SARS-CoV-2 is also claimed to trigger sporadically direct β-cell destruction and β-cell autoimmunity. Pending further validations with longitudinal data are needed to legitimize COVID-19 as a potential risk factor for the development of diabetes. Hereby, we present an emphasized critical review of the available clinical data in an attempt to unravel the complex mechanisms behind hyperglycemia in COVID-19 infection. The secondary endpoint was to evaluate the bidirectional relationship between COVID-19 and diabetes mellitus. As the worldwide pandemic is still expanding, demand for answering these questions is arising. It will be of immense help for the management of COVID-19 patients, as well as for the implementation of post-discharge policies for patients with a high risk of developing diabetes.

Nitric Oxide in the Management of Respiratory Consequences in COVID-19: A Scoping Review of a Different Treatment Approach.

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) virus causing COVID-19 significantly affects the respiratory functions of infected individuals by massively disrupting the pulmonary oxygenation and activating the synthesis of proinflammatory cytokines, inducing severe oxidative stress, enhanced vascular permeability, and endothelial dysfunction which have rendered researchers and clinicians to depend on prophylactic treatment due to the unavailability of proper disease management approaches. Previous studies have indicated that nitric oxide (NO) application appears to be significant concerning the antiviral activities, antioxidant, and anti-inflammatory properties in relieving disease-related symptoms. To identify, explore, and map the literature on the role of nitric oxide in the management of respiratory consequences in COVID-19 through this scoping review, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed during the search to answer the focal question: "What are the potential uses of nitric oxide in the management of respiratory failure in COVID-19?" Administering exogenous NO in the form of inhaled gas or stimulating the system to produce NO appears to be a suitable option to manage COVID-19-induced pneumonia and respiratory illness. This treatment modality seems to attenuate respiratory distress among patients suffering from severe infections or patients with comorbidities. Exogenous NO at different doses effectively reduces systemic hyperinflammation and oxidative stress, improves arterial oxygenation, and restores pulmonary alveolar cellular integrity to prevent the lungs and other organs from further damage. This therapy could pave the way for better management of COVID-19 before the onset of disease-related complications.