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1.
Profilakticheskaya Meditsina ; 24(12):79-83, 2021.
Article in Russian | EMBASE | ID: covidwho-1818838

ABSTRACT

The article describes a clinical case of death of a 57-year-old patient from idiopathic AL-amyloidosis after infection with SARS-CoV-2. Histological examination revealed signs of pneumonia with symptoms of pneumosclerosis, histologically determined di-apedesic hemorrhages, necrosis and desquamation of the alveolar epithelium, along the contours of the alveolar passages, al-veolar sacs — hyaline membranes. In many areas, the histoarchitectonics of the pulmonary parenchyma was sharply disturbed, connective tissue was determined in the alveolar passages, in the lumens of the alveoli. The interalveolar septa were thickened due to the proliferation of connective tissue. Positive Congo red staining was visualized mainly in the perivascular and interalveo-lar septa, along the vessels;in the heart — between cardiomyocytes, in the kidneys — in the capillary loops of the glomeruli, base-ment membranes of individual tubules of the cortical layer, in the walls of blood vessels. Thus, the cause of death of the patient was the severe course of infection with SARS-CoV-2;the presence of a concomitant disease in the form of idiopathic AL-amyloi-dosis of internal organs and chronic diseases, obviously, aggravated the patient’s condition and contributed to the onset of death.

2.
American Journal of Physiology - Lung Cellular and Molecular Physiology ; 322(3):L503-L506, 2022.
Article in English | EMBASE | ID: covidwho-1816806
3.
Journal of Aerosol Medicine and Pulmonary Drug Delivery ; 35(2):A7, 2022.
Article in English | EMBASE | ID: covidwho-1815947

ABSTRACT

The work led to the formulation of a powder of calcium phosphate coated liposomes containing cyclosporine A (CsA). The formulation was designed to reduce the dose of CsA to be administered following lung transplantation. Potentially this formulation can be used also to contain the inflammatory process due to SARS-CoV-2. Calcium phosphate (CaP) is a material found in bones and teeth and considered non-toxic and biocompatible and this coating could reduce the recognition by alveolar macrophages and increase the cell uptake. Moreover, CaP is insoluble at physiological pH (7.4), while it solubilizes easily at pH below 5. This could favor drug release in the cell after pinocytosis and in inflamed tissues, while reducing drug release at physiological pH [1]. The liposomes produced were evaluated in terms of size, surface charge and drug loading. The presence of the CaP coating was verified by calcium titration, variation of the zeta potential and by cryogenic transmission electron microscopy (cryo-TEM). The highest loading was obtained in the formulation containing CsA at 7% (w/w). Cholesterol was added to liposomes at two different concentrations in order to improve the stability of the nanostructure and reduce the drug leakage. However, cholesterol did not bring any improvement to the formulation. The inhalation powder produced by spray drying with the best aerosolization performance (fine particle fraction of coated liposomes powder 33.69 - 1.6% and 50.50- 0.6% for the uncoated liposomes powder) was obtained using a 1:3 weight ratio between liposomes and excipients using mannitol as bulking agent and 15% L-leucine. Key Message: This work aimed to develop a respirable dry powder for inhalation containing CsA for the local treatment of lung immune diseases. CsA was efficiently loaded into CaP-coated liposomes and transformed into a respirable powder by spray-drying. The inhaled immunosuppressive product would offer multiple advantages related to drug deposition at the target site. Furthermore, the coating of the liposomes governs the release of the drug which will occur only at only at biological acidic conditions.

4.
Egyptian Journal of Radiology and Nuclear Medicine ; 53(1), 2022.
Article in English | EMBASE | ID: covidwho-1779685

ABSTRACT

Background: One of the largest outbreaks of rhinosinocerebral mucormycosis (RSCM) occurred in India close to the second wave of the SARS-CoV-2 infection. RSCM is a rare infection caused by several fungal species occurring in immunocompromised subjects. Mucor shows a high propensity to invade the central nervous system. There have been limited studies, mostly isolated case reports, on the neurological manifestations of RSCM. The outbreak of mucormycosis infection was thus the most opportune to study the neurological manifestations and cranial nerve involvement in mucormycosis in greater depths. Aim of the study: The purpose of the study was to investigate and review the involvement of cranial nerves in a series of cases of rhinosinocerebral mucormycosis associated with the novel coronavirus disease caused by SARS-CoV-2. Results: It was a retrospective cross-sectional study of seven patients who were undergoing treatment of RSCM with a recent history of coronavirus disease caused by SARS-CoV-2 infection within the last 3 months. Patients with cranial nerve involvement were identified by magnetic resonance imaging (MRI) at a single institution. Demographic details of the patients, clinical presentation, imaging, microbiological and pathological findings were recorded. All subjects had two or more cranial nerves affected by fungal infection. The most commonly involved cranial nerve was found to be the optic nerve followed by the trigeminal nerve and its branches. We document three cases with extensive involvement of the inferior alveolar branch of the mandibular division of the trigeminal nerve (V3), a previously unreported finding. In one case, in addition to the second and fifth cranial nerves, the third, fourth, sixth, seventh, eighth, and twelfth cranial nerves were involved without any sensory or motor long tract involvement, suggestive of Garcin syndrome secondary to intracranial abscesses and skull base osteomyelitis due to invasive fungal infection. This case is of rare occurrence in the literature, and our study provides one such example. Conclusion: Cranial nerve involvement in patients of mucormycosis tends to have a poor prognosis, both cosmetic and functional. Radical surgeries and aggressive medical management is needed in such cases to improve the outcome.

5.
Meng, B.; Ferreira, I. A. T. M.; Abdullahi, A.; Goonawardane, N.; Saito, A.; Kimura, I.; Yamasoba, D.; Gerba, P. P.; Fatihi, S.; Rathore, S.; Zepeda, S. K.; Papa, G.; Kemp, S. A.; Ikeda, T.; Toyoda, M.; Tan, T. S.; Kuramochi, J.; Mitsunaga, S.; Ueno, T.; Shirakawa, K.; Takaori-Kondo, A.; Brevini, T.; Mallery, D. L.; Charles, O. J.; Bowen, J. E.; Joshi, A.; Walls, A. C.; Jackson, L.; Cele, S.; Martin, D.; Smith, K. G. C.; Bradley, J.; Briggs, J. A. G.; Choi, J.; Madissoon, E.; Meyer, K.; Mlcochova, P.; Ceron-Gutierrez, L.; Doffinger, R.; Teichmann, S.; Pizzuto, M.; de Marco, A.; Corti, D.; Sigal, A.; James, L.; Veesler, D.; Hosmillo, M.; Lee, J. H.; Sampaziotis, F.; Goodfellow, I. G.; Matheson, N. J.; Thukral, L.; Sato, K.; Gupta, R. K.; Kawabata, R.; Morizako, N.; Sadamasu, K.; Asakura, H.; Nagashima, M.; Yoshimura, K.; Ito, J.; Kimura, I.; Uriu, K.; Kosugi, Y.; Suganami, M.; Oide, A.; Yokoyama, M.; Chiba, M.; Saito, A.; Butlertanaka, E. P.; Tanaka, Y. L.; Ikeda, T.; Motozono, C.; Nasser, H.; Shimizu, R.; Yuan, Y.; Kitazato, K.; Hasebe, H.; Nakagawa, S.; Wu, J.; Takahashi, M.; Fukuhara, T.; Shimizu, K.; Tsushima, K.; Kubo, H.; Kazuma, Y.; Nomura, R.; Horisawa, Y.; Nagata, K.; Kawai, Y.; Yanagida, Y.; Tashiro, Y.; Tokunaga, K.; Ozono, S.; Baker, S.; Dougan, G.; Hess, C.; Kingston, N.; Lehner, P. J.; Lyons, P. A.; Matheson, N. J.; Owehand, W. H.; Saunders, C.; Summers, C.; Thaventhiran, J. E. D.; Toshner, M.; Weekes, M. P.; Maxwell, P.; Shaw, A.; Bucke, A.; Calder, J.; Canna, L.; Domingo, J.; Elmer, A.; Fuller, S.; Harris, J.; Hewitt, S.; Kennet, J.; Jose, S.; Kourampa, J.; Meadows, A.; O’Brien, C.; Price, J.; Publico, C.; Rastall, R.; Ribeiro, C.; Rowlands, J.; Ruffolo, V.; Tordesillas, H.; Bullman, B.; Dunmore, B. J.; Fawke, S.; Gräf, S.; Hodgson, J.; Huang, C.; Hunter, K.; Jones, E.; Legchenko, E.; Matara, C.; Martin, J.; Mescia, F.; O’Donnell, C.; Pointon, L.; Pond, N.; Shih, J.; Sutcliffe, R.; Tilly, T.; Treacy, C.; Tong, Z.; Wood, J.; Wylot, M.; Bergamaschi, L.; Betancourt, A.; Bower, G.; Cossetti, C.; de Sa, A.; Epping, M.; Fawke, S.; Gleadall, N.; Grenfell, R.; Hinch, A.; Huhn, O.; Jackson, S.; Jarvis, I.; Krishna, B.; Lewis, D.; Marsden, J.; Nice, F.; Okecha, G.; Omarjee, O.; Perera, M.; Potts, M.; Richoz, N.; Romashova, V.; Yarkoni, N. S.; Sharma, R.; Stefanucci, L.; Stephens, J.; Strezlecki, M.; Turner, L.; de Bie, E. M. D. D.; Bunclark, K.; Josipovic, M.; Mackay, M.; Mescia, F.; Michael, A.; Rossi, S.; Selvan, M.; Spencer, S.; Yong, C.; Allison, J.; Butcher, H.; Caputo, D.; Clapham-Riley, D.; Dewhurst, E.; Furlong, A.; Graves, B.; Gray, J.; Ivers, T.; Kasanicki, M.; Le Gresley, E.; Linger, R.; Meloy, S.; Muldoon, F.; Ovington, N.; Papadia, S.; Phelan, I.; Stark, H.; Stirrups, K. E.; Townsend, P.; Walker, N.; Webster, J.; Scholtes, I.; Hein, S.; King, R.; Márquez, S.; Prado-Vivar, B.; Becerra-Wong, M.; Caravajal, M.; Trueba, G.; Rojas-Silva, P.; Grunauer, M.; Gutierrez, B.; Guadalupe, J. J.; Fernández-Cadena, J. C.; Andrade-Molina, D.; Baldeon, M.; Pinos, A..
Web of Science; 2021.
Preprint in English | Web of Science | ID: ppcovidwho-331154

ABSTRACT

The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.

6.
European Journal of Molecular and Clinical Medicine ; 9(3):442-450, 2022.
Article in English | EMBASE | ID: covidwho-1766812

ABSTRACT

BACKGROUND: COVID19 outbreak has become a pandemic worldwide. There has been a fairly high rate of clinical recovery among Covid patients but complete resolution or sequelae in terms of radiological findings need to be studied. AIM OF THE STUDY: 1. To understand the common pulmonary sequalae, time taken for complete resolution and factors affecting the resolution process in covid-19 patients who have been discharged after recovery, with Chest HRCT follow up. MATERIAL AND METHODS: This is an observational study which included a total of 100 discharged patients diagnosed with covid-19 by RTPCR at Index Medical College, Hospital & Research Centre, Indore-MP-India, from March 15 to June 30-2021.All the patients underwent an initial chest CT scan done 3-5 days after the onset of symptoms,followed by serial CT scans done at discharge and at 1st, 2nd and 3rd weeks after discharge. The radiological characteristics and patterns on CT chest were studied and a CT severity scoring was done for all the scans. RESULTS: GGO were the most common pattern seen (88%) on chest CT at discharge followed by fibrotic bands (61%) with the right lower lung (85%) most commonly involved.61% of patients showed complete resolution at the end of 3rd week after discharge indicating that COVID 19 induced pulmonary damage is reversible in majority of cases with no long term sequalae. However 39 patients demonstrated residual abnormalities. Older patients are at high risk for residual pulmonary lesions and there is no gender predilection. Patients having comorbidities like hypertension, diabetes or bronchial asthma were not at a higher risk of developing pulmonary sequalae. CONCLUSION: The resolution of most lesions by 3 weeks after discharge implies gradual resolution of inflammation with re-expansion of alveoli and perhaps the reversible nature of the lesions of Covid-19.

7.
Open Forum Infectious Diseases ; 8(SUPPL 1):S71-S72, 2021.
Article in English | EMBASE | ID: covidwho-1746785

ABSTRACT

Background. Despite antifungal therapy and surgical debridement, overall mortality of invasive mucormycosis is >40%. Currently the world is witnessing an explosion in mucormycosis in India among COVID-19 patients with an official count of 28,252 cases as of 06/07/2021. Thus, novel therapeutic modalities are needed. We previously reported on a mouse monoclonal antibody (C2) targeting CotH invasins being protective against mucormycosis. Here, we humanized C2 MAb and assessed its efficacy in vitro and in vivo. Methods. The C2 (IgG1) paratopes of the heavy chain and light chain were grafted on the most suitable human IgG1 with back mutations in the paratopes needed to restore binding of humanized clones to CotH3 (by biolayer interferometry using Gator). Clones were compared to C2 in their ability to prevent Rhizopus delemar-induced injury to A549 alveolar epithelial and primary human endothelial cells and for enhancing human neutrophil killing of the fungus in vitro. C2 and the humanized clones were also compared for their ability to protect neutropenic mice from mucormycosis induced by R. delemar or Mucor cicrinelloides with and without antifungal therapy. Results. Three humanized clones showed 10-fold enhanced binding affinity to CotH3 protein (~5 nM for humanized vs. ~50 nM for C2). One humanized clone (VX01) doubled the ability of neutrophils to kill R. delemar and resulted in ~50% reduction in host cell damage. A single low dose of VX01 (30 μg) given 24 h post infection resulted in comparable survival of 60-70% in mice infected intratracheally with either R. delemar or M. cicrinelloides vs. placebo mice (0% survival, P < 0.02). Importantly, VX01 acted synergistically in protecting mice when combined with liposomal amphotericin B or posaconazole in a severe model of mucormycosis with treatment starting 48 h post infection (~70% survival for combination vs. 0-20% survival for monotherapy and reduced lung fungal burden by 1.5 log, P< 0.001). GLP-tissue cross reactivity studies of VX01 showed favorable safety profiles. Conclusion. VX01 shows enhanced binding to CotH3 protein and maintained the protective features of C2 MAb against murine mucormycosis. Clinical testing of combination therapy of VX01 + antifungals is warranted. VX01 is currently in manufacturing.

8.
Open Forum Infectious Diseases ; 8(SUPPL 1):S634-S635, 2021.
Article in English | EMBASE | ID: covidwho-1746329

ABSTRACT

Background. ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and additional SARS-like CoVs with pandemic potential and an extended half-life. A QSP/PBPK model was constructed using ADG20-specific physiochemical properties and published non-human primate (NHP) and human PK data for other antibodies;it was used to a priori predict and confirm NHP and human PK. Methods. An existing QSP/PBPK model was modified to include 3 distinct lung sub-compartments: upper airway, lower airway, and alveolar tissue (Figure A). Each sub-compartment (Figure B) contained an epithelial lining fluid (ELF) space (Figure B). The model was fit separately to digitized NHP and human serum PK data for 7 extended half-life antibodies to estimate the apparent neonatal Fc receptor (FcRn) binding affinity (KD,FcRn) and bioavailability by drug. Nasopharyngeal swab (upper airway) and lung (lower airway) ELF PK data from 4 additional antibodies were used to optimize a single rate constant for transcytosis in lung. Patches of positive charge was a covariate on the rate of pinocytosis of antibody entry and exit from the endosomal space (Figure B). Observed NHP (ADG20 10 mg/kg IM) and human (ADG20 300 mg IM) PK data collected over the initial 21 days post dose were compared with model forecasts from a 1000-iteration simulation. Results. The distribution of fitted NHP KD,FcRn provided accurate predictions of NHP serum PK data (Figure C). NHP ADG20 KD,FcRn was optimized to be 35.7 nM and human ADG20 KD,FcRn (9.55 nM) was derived using a mean NHP:human KD,FcRn ratio of 3.74 across antibodies. Model-based simulated human serum PK data using inter-subject variability from NHP and actual weight distribution from an ongoing Phase 1 study aligned with initial 21-day data (Figure D). Using an adult CDC weight distribution (45-150 kg), the simulated median exceeded 74 days. Conclusion. The QSP/PBPK model a priori predicted NHP and human ADG20 PK. This innovative QSP-based modeling and simulation approach enabled the evaluation of candidate dose regimens prior to the availability of PK data, supporting the rapid advancement of the ADG20 clinical program during the COVID-19 pandemic.

9.
Degenhardt, F.; Ellinghaus, D.; Juzenas, S.; Lerga-Jaso, J.; Wendorff, M.; Maya-Miles, D.; Uellendahl-Werth, F.; ElAbd, H.; Rühlemann, M. C.; Arora, J.; Özer, O.; Lenning, O. B.; Myhre, R.; Vadla, M. S.; Wacker, E. M.; Wienbrandt, L.; Ortiz, A. B.; de Salazar, A.; Chercoles, A. G.; Palom, A.; Ruiz, A.; Garcia-Fernandez, A. E.; Blanco-Grau, A.; Mantovani, A.; Zanella, A.; Holten, A. R.; Mayer, A.; Bandera, A.; Cherubini, A.; Protti, A.; Aghemo, A.; Gerussi, A.; Ramirez, A.; Braun, A.; Nebel, A.; Barreira, A.; Lleo, A.; Teles, A.; Kildal, A. B.; Biondi, A.; Caballero-Garralda, A.; Ganna, A.; Gori, A.; Glück, A.; Lind, A.; Tanck, A.; Hinney, A.; Nolla, A. C.; Fracanzani, A. L.; Peschuck, A.; Cavallero, A.; Dyrhol-Riise, A. M.; Ruello, A.; Julià, A.; Muscatello, A.; Pesenti, A.; Voza, A.; Rando-Segura, A.; Solier, A.; Schmidt, A.; Cortes, B.; Mateos, B.; Nafria-Jimenez, B.; Schaefer, B.; Jensen, B.; Bellinghausen, C.; Maj, C.; Ferrando, C.; de la Horra, C.; Quereda, C.; Skurk, C.; Thibeault, C.; Scollo, C.; Herr, C.; Spinner, C. D.; Gassner, C.; Lange, C.; Hu, C.; Paccapelo, C.; Lehmann, C.; Angelini, C.; Cappadona, C.; Azuure, C.; Bianco, C.; Cea, C.; Sancho, C.; Hoff, D. A. L.; Galimberti, D.; Prati, D.; Haschka, D.; Jiménez, D.; Pestaña, D.; Toapanta, D.; Muñiz-Diaz, E.; Azzolini, E.; Sandoval, E.; Binatti, E.; Scarpini, E.; Helbig, E. T.; Casalone, E.; Urrechaga, E.; Paraboschi, E. M.; Pontali, E.; Reverter, E.; Calderón, E. J.; Navas, E.; Solligård, E.; Contro, E.; Arana-Arri, E.; Aziz, F.; Garcia, F.; Sánchez, F. G.; Ceriotti, F.; Martinelli-Boneschi, F.; Peyvandi, F.; Kurth, F.; Blasi, F.; Malvestiti, F.; Medrano, F. J.; Mesonero, F.; Rodriguez-Frias, F.; Hanses, F.; Müller, F.; Hemmrich-Stanisak, G.; Bellani, G.; Grasselli, G.; Pezzoli, G.; Costantino, G.; Albano, G.; Cardamone, G.; Bellelli, G.; Citerio, G.; Foti, G.; Lamorte, G.; Matullo, G.; Baselli, G.; Kurihara, H.; Neb, H.; My, I.; Kurth, I.; Hernández, I.; Pink, I.; de Rojas, I.; Galván-Femenia, I.; Holter, J. C.; Afset, J. E.; Heyckendorf, J.; Kässens, J.; Damås, J. K.; Rybniker, J.; Altmüller, J.; Ampuero, J.; Martín, J.; Erdmann, J.; Banales, J. M.; Badia, J. R.; Dopazo, J.; Schneider, J.; Bergan, J.; Barretina, J.; Walter, J.; Quero, J. H.; Goikoetxea, J.; Delgado, J.; Guerrero, J. M.; Fazaal, J.; Kraft, J.; Schröder, J.; Risnes, K.; Banasik, K.; Müller, K. E.; Gaede, K. I.; Garcia-Etxebarria, K.; Tonby, K.; Heggelund, L.; Izquierdo-Sanchez, L.; Bettini, L. R.; Sumoy, L.; Sander, L. E.; Lippert, L. J.; Terranova, L.; Nkambule, L.; Knopp, L.; Gustad, L. T.; Garbarino, L.; Santoro, L.; Téllez, L.; Roade, L.; Ostadreza, M.; Intxausti, M.; Kogevinas, M.; Riveiro-Barciela, M.; Berger, M. M.; Schaefer, M.; Niemi, M. E. K.; Gutiérrez-Stampa, M. A.; Carrabba, M.; Figuera Basso, M. E.; Valsecchi, M. G.; Hernandez-Tejero, M.; Vehreschild, M. J. G. T.; Manunta, M.; Acosta-Herrera, M.; D'Angiò, M.; Baldini, M.; Cazzaniga, M.; Grimsrud, M. M.; Cornberg, M.; Nöthen, M. M.; Marquié, M.; Castoldi, M.; Cordioli, M.; Cecconi, M.; D'Amato, M.; Augustin, M.; Tomasi, M.; Boada, M.; Dreher, M.; Seilmaier, M. J.; Joannidis, M.; Wittig, M.; Mazzocco, M.; Ciccarelli, M.; Rodríguez-Gandía, M.; Bocciolone, M.; Miozzo, M.; Ayo, N. I.; Blay, N.; Chueca, N.; Montano, N.; Braun, N.; Ludwig, N.; Marx, N.; Martínez, N.; Cornely, O. A.; Witzke, O.; Palmieri, O.; Faverio, P.; Preatoni, P.; Bonfanti, P.; Omodei, P.; Tentorio, P.; Castro, P.; Rodrigues, P. M.; España, P. P.; Hoffmann, P.; Rosenstiel, P.; Schommers, P.; Suwalski, P.; de Pablo, R.; Ferrer, R.; Bals, R.; Gualtierotti, R.; Gallego-Durán, R.; Nieto, R.; Carpani, R.; Morilla, R.; Badalamenti, S.; Haider, S.; Ciesek, S.; May, S.; Bombace, S.; Marsal, S.; Pigazzini, S.; Klein, S.; Pelusi, S.; Wilfling, S.; Bosari, S.; Volland, S.; Brunak, S.; Raychaudhuri, S.; Schreiber, S.; Heilmann-Heimbach, S.; Aliberti, S.; Ripke, S.; Dudman, S.; Wesse, T.; Zheng, T.; Bahmer, T.; Eggermann, T.; Illig, T.; Brenner, T.; Pumarola, T.; Feldt, T.; Folseraas, T.; Cejudo, T. G.; Landmesser, U.; Protzer, U.; Hehr, U.; Rimoldi, V.; Monzani, V.; Skogen, V.; Keitel, V.; Kopfnagel, V.; Friaza, V.; Andrade, V.; Moreno, V.; Albrecht, W.; Peter, W.; Poller, W.; Farre, X.; Yi, X.; Wang, X.; Khodamoradi, Y.; Karadeniz, Z.; Latiano, A.; Goerg, S.; Bacher, P.; Koehler, P.; Tran, F.; Zoller, H.; Schulte, E. C.; Heidecker, B.; Ludwig, K. U.; Fernández, J.; Romero-Gómez, M.; Albillos, A.; Invernizzi, P.; Buti, M.; Duga, S.; Bujanda, L.; Hov, J. R.; Lenz, T. L.; Asselta, R.; de Cid, R.; Valenti, L.; Karlsen, T. H.; Cáceres, M.; Franke, A..
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-330452

ABSTRACT

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ~0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

10.
Blood ; 138:4004, 2021.
Article in English | EMBASE | ID: covidwho-1736297

ABSTRACT

Dysregulated inflammatory responses are characterized by inappropriate levels of inflammatory markers, speed of generation, degree, and major site of production, such as a vital organ. COVID-19 severity and mortality are strongly associated with interleukin (IL)-6 levels. High IL-6 levels are also observed in idiopathic Multicentric Castleman Disease (iMCD). Previously, we developed the first anti-IL-6 monoclonal antibody (mAb) treatments and showed that C-reactive protein (CRP) production could be fully controlled by IL-6 in humans. Using mathematical modeling, with CRP as an IL-6 surrogate marker, we predicted the ability of an anti-IL-6 mAb to block plasma IL-6 activity and showed IL-6 inhibition was dependent on the extent of whole-body IL-6 production. We postulate that in patients (pts) in whom IL-6 concentration at the site of inflammation is higher than in the plasma, full blockade of plasma IL-6 activity, shown by complete CRP inhibition, is the minimum requirement to achieve clinical efficacy. CRP inhibition with tocilizumab (TCZ) in pts with COVID-19. We identified 35 published studies evaluating the efficacy or potential role of anti-IL-6 therapy in pts with severe COVID-19. Surprisingly, only one (Luo et al. J Med Virol 2020;92:814) reported dynamics of CRP reduction for individual patients throughout treatment. We fitted a hypothetical curve of CRP reduction required to completely block IL-6, based on the half-life of CRP, and added data points of CRP serum levels from pts treated with anti-IL-6 receptor (IL-6R) therapy, TCZ, in this study. Complete reduction of CRP was not achieved in all patients: 3 pts who died had CRP levels ≥12.8 mg/l. Of 2 pts whose disease worsened, CRP levels were 93.5 mg/l and 6.3 mg/l. However, pts whose condition stabilized (n=9), or whose symptoms improved (n=1), had CRP levels close to the theoretical curve that is likely required to fully block IL-6 (CRP levels ≤5.0 mg/l). Half of these pts had been given repeated doses of TCZ. Siltuximab (SIL) treatment (NCT01024036 trial) for pts with iMCD. To assess the impact of baseline CRP levels on response to anti-IL-6 therapy, SIL, patients were divided into low and high CRP groups based on a baseline CRP level threshold of 40 mg/l (corresponding to ~40 pg/ml of IL-6;Fig 1). In patients with low baseline CRP levels (<40 mg/l;n=35), CRP levels were significantly reduced with SIL treatment on day 8 (n=26;P=0.0003) and day 15 (n=22;P=0.0043) post-dosing. In patients with high baseline CRP levels (>40 mg/l;n=17), CRP levels were significantly reduced on day 8 (n=17;P<0.0001) and day 15 (n=15;P<0.0001) post-dosing (Fig 1). A significant increase in CRP levels from day 8 to day 15 was observed in these patients (P=0.0120);this increase was not observed in patients with low baseline CRP levels (P=0.243;Fig 1). There was a negative correlation between maximum CRP and hemoglobin change (P<0.001). Inhibition of IL-6 activity by anti-IL-6 (SIL 700 mg) and anti-IL-6R (TCZ 800 mg) as monotherapy, intensified, or combined therapy. To evaluate the effect of therapy on IL-6 activity, our algorithm modeled inhibition of IL-6-(IL-6R/soluble IL-6R)-gp130 transducer complexes. This serves as a proxy for IL-6 bioactivity and accounts for the buffering capacity of gp130, which can be overwhelmed in inflammatory situations with high IL-6 concentrations. Due to uncertainty over the concentration of mAbs in alveoli relative to plasma, we modeled the effects of SIL and TCZ at local concentrations of 100%, 10%, and 1% (Fig 2) of those in plasma. Our model demonstrated that anti-IL-6 was associated with stronger inhibition of CRP than anti-IL-6R. However, only the association of both anti-IL-6 and anti-IL-6R mAbs was associated with a total blockade of CRP, which is probably necessary when IL-6 levels are associated with high risk to the patient. Different administration schedules to intensify anti-IL-6 therapy were modeled, including the repeated or combined use of anti-IL-6 and anti-IL-6R mAbs. The results form a basis to optimize treatment trategies to avoid the cytokine storm in several diseases, including cancer, iMCD, and autoimmune disorders. The feasibility of the theoretically defined approaches needs to be evaluated, particularly the potential side-effect profile for a combined treatment approach. In conclusion, in clinical practice, IL-6 inhibition should be individualized based on pathophysiology and regular CRP monitoring. [Formula presented] Disclosures: Rossi: E-SANA Inc: Other: Co-founder of E-SANA Inc;EUSA Pharma: Consultancy;LEO Pharma: Consultancy;NPO Petrovax Pharm: Consultancy. Levon: E-SANA Inc: Other: Co-founder of E-SANA Inc. Kanhai: EUSA Pharma: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;Pfizer: Other: Study drug for clinical trial of sirolimus. OffLabel Disclosure: Siltuximab is approved for the treatment of iMCD. Tocilizumab is approved for the treatment of Rheumatoid arthritis, Giant cell arteritis, Cytokine release syndrome, Systemic juvenile idiopathic arthritis and Polyarticular juvenile idiopathic arthritis. Combination therapy using Siltuximab and Tocilizumab has not yet been approved.

11.
Journal of Investigative Medicine ; 70(2):594-595, 2022.
Article in English | EMBASE | ID: covidwho-1704925

ABSTRACT

Case Report Chronic respiratory sequelae are well documented in adults after COVID-19 infection, however, in young children and infants, evidence is still evolving. Here we report an infant with significant chronic respiratory complications after COVID-19. Case Report A 10 month old female with no significant past medical history was admitted to the PICU secondary to hypoxemia, respiratory distress, and respiratory failure following COVID-19 infection in January 2021. She was also positive for Rhinovirus and Enterovirus. CXR displayed worsening bilateral alveolar infiltrates, and she developed subsequent pneumothorax requiring a chest tube. Apart from mechanical ventilation, she received supportive treatment and broad spectrum antibiotics. Cardiac echocardiogram revealed pulmonary hypertension, PFO, and PDA. Due to worsening respiratory status and hypoxemia, she received bronchodilators, inhaled nitric oxide, sildenafil, steroids, and magnesium. After 3 weeks, her respiratory status improved and she was discharged. The patient required another hospitalization in March and an ER visit in April for persistent cough and shortness of breath. After evaluation by pulmonology, she began inhaled steroids and airway clearance treatments including chest physical therapy, hypertonic saline, and bronchodilators. Further workup ruled out cystic fibrosis, primary ciliary dyskinesia, and immunodeficiency. Chest CT showed diffuse bilateral patchy airspace opacities representing atelectasis and scarring. Despite a short period of improvement, the patient was hospitalized for respiratory distress in June, where she was hypoxemic and diagnosed with pneumonia. She required repeated outpatient visits to the PCP for persistent respiratory symptoms. PDA closure was performed in September. The patient continues to have persistent respiratory symptoms addressed with outpatient respiratory treatment regimen. Conclusion As we have ruled out other underlying causes, the patient's chronic lung disease and persistent respiratory symptoms occurred most probable secondary to COVID-19. This case report highlights the importance of monitoring respiratory symptoms in pediatric patients with severe COVID-19 infection for early identification of chronic respiratory sequelae.

12.
Journal of Investigative Medicine ; 70(2):624, 2022.
Article in English | EMBASE | ID: covidwho-1703411

ABSTRACT

Learning Objective Pneumomediastinum possible sequelae of post-COVID presentation with minor COVID infection Case presentation A 42-year male with Covid-19 pneumonia presented following an episode of presyncope with associated severe weakness and hemoptysis. The patient had Covid-19 pneumonia two months earlier and needed no hospitalization. At this presentation, he tested negative for Covid-19, with a 30-pound diet-related weight loss, brain fog, occasional shortness of breath, and night sweats since his infection. Respiratory rate 23/minute, occasional wheezing. Besides normal hemoglobin, WBC 12.7 with elevated ANC, normal electrolytes except slightly elevated chloride, D-Dimer of 0.85, ferritin of 907.8, CRP of 19.6, normal BNP, and normal troponin. Chest CTA demonstrated ground-glass opacities, small anterior pneumothoraxes, and moderate pneumomediastinum with a cystic lesion in the right upper lobe that may reflect a pneumatocele. Head CT and EKG were unrevealing. He was managed conservatively with breathing treatments and cough suppressants. The patient complained of neck pain the next day, and a repeat chest x-ray revealed subcutaneous emphysema in the neck area. Despite this, the patient had no further clinical manifestations during his hospital stay with stable pneumomediastinum and pneumothorax on follow-up chest x-rays with a reduction in subcutaneous neck emphysema. He denied repeat episodes of hemoptysis or presyncope and was subsequently discharged three days after admission with a followup chest x-ray in two weeks. Discussion Post-Covid complications including cough, dyspnea, and pulmonary fibrosis may contribute to alveolar barotrauma and subsequent pneumomediastinum, which may contribute to serious complications, including cardiac tamponade. Pneumatoceles are air-filled cavitary lesions usually seen post-infection, trauma, or more extensive cystic disease of the lung. The evolution happens post pneumonia, inflammation, and narrowing of the bronchus leads to the formation of an endobronchial ball valve, leading to the distal dilatation of bronchi and alveolar space. The obstruction is thought to be caused by inflammatory exudates in the airway lumen, permitting air to enter the cystic space but not to leave it. Subsequent enlargement of the pneumatocele occurs either due to pressure from the adjacent pneumatocele or intraluminal inflammatory exudates. 2 This case demonstrates the need to consider pneumomediastinum as a complication even in non-serious Covid infections with no acute hypoxic respiratory failure presentation. Conclusion Many case reports have detailed spontaneous pneumomediastinum in patients with active Covid-19 pneumonia, especially in intubated patients. Few publications have linked pneumomediastinum to post-Covid pneumonia. Pneumomediastinum should be an important consideration in patients with active Covid-19 and those who have recovered from even minor infection.

13.
Kidney International Reports ; 7(2):S59-S60, 2022.
Article in English | EMBASE | ID: covidwho-1703259

ABSTRACT

Introduction: Double-positive vasculitis with anti-polynuclear cytoplasm (ANCA) and anti-glomerular basement membrane (GBM) antibodies is a rare entity of systemic vasculitis defined by the presence of ANCA and anti-GBM antibodies. Methods: We report a rare case of pulmonary-renal syndrome with atypical clinical presentation. Results: A 52 year-old smoking man with a history of exposure to hydrocarbons and uretheral lithiasis, presented in April 2021 epigastralgia and vomiting. the investigations concluded to H.pylori gastritis and ulcer and he received a quadruple therapy. The kidney function was correct in April 2021. The evolution was marked by the persistence of symptoms and urine output had decreased for a few days. He was found to have renal dysfunction (serum creatinine: 2000 µmol/L). Abdominal CT scan without iodinated contrast injection showed severe hydronephrosis of the right pelvicalyceal system with cortical thinning and dilatation of the right ureter. The two kidneys had regular outlines seat multiple bilateral renal cysts with exophytic development. He had a nephrosomy with secondarily a right double-J stent with slight improvement of renal function. The patient presented then with acute respiratory distress.Testing for COVID-19: PCR and serology were negatives. Chest CT scan showed alveolar syndromeevoking pulmonary overload. No pneumopathy covid was shown. The evolution was marked by the non improvement by depletion and he developed hemoptic sputum and low-abundance epistaxis. The attitude was non-invasive ventilation and broad-spectrum antibiotics therapy. Control chest CT showed emphysematous lung with signs of fibrosis with bilateral subpleural nodules. A rereading of the scanner showed intraalveolar hemorrhage which has regressed on the imaging of the control. Based on these data, pneumo renal syndrome was suspected and a bronchoscopy was performed showing alveolar hemorrhage with 70% siderophageswith Gold score superior to 100. Anti-GBM and p-ANCA and antibodies were positive at a high titer. Electroneuromyogram was without anomaly. Kidney biopsy was not done because of the presence of multiple cysts. The patient received pulse methylprednisone for three days followed by oral prednisone and underwent eleven sessions of plasmapheresis. Intraveinous Cyclophosphamide has been started. He showed remarkable recovery as his lung fields cleared with negativity of GBM antibodies. Kidney function didn't improved and he remained dependent on dialysis. Conclusions: Our observation is exceptional since the clinical and radiological presentation of the patient was not that of a pulmonary-renal syndrome. The elements of this syndrome have in fact been masked by the obstacle on the urinary tract on one hand and the hypothesis of a covid19 pneumonia on the other hand in the face of the epidemiological context. Atypical feature of pulmonary renal syndrome should be kept in mind to avoid diagnostic and treatment delays. No conflict of interest

14.
Journal of Clinical and Diagnostic Research ; 16(1):TJ01-TJ03, 2022.
Article in English | EMBASE | ID: covidwho-1702531
15.
Journal of Investigative Medicine ; 70(2):562-563, 2022.
Article in English | EMBASE | ID: covidwho-1701061

ABSTRACT

Introduction Coronavirus 19 (COVID-19) is a viral illness that is caused by SARS-CoV-2. It has a surface spike protein that binds to human angiotensin-converting enzyme 2 receptors expressed in the kidneys, lung, and vascular endothelium. Here we present a case of a 73-year-old critically ill male with COVID pneumonia and acute respiratory distress syndrome (ARDS), who developed compartment syndrome and rhabdomyolysis as a consequence of extensive right lower extremity arterial thrombosis related to a COVID induced hypercoagulable state. Case A 73-year-old COVID positive male with past medical history of coronary artery disease status-post triple coronary artery bypass 10 years ago and type 2 diabetes mellitus presented to the emergency department with progressively worsening dyspnea for one week. His initial oxygen saturation on room air measured 85%, so he was placed on 3 liters per minute supplementation via nasal cannula. CXR showed bilateral diffuse alveolar infiltrates and he was admitted for observation. He developed worsening respiratory failure five days into hospitalization, placed on maximum supplementation via high flow nasal cannula (HFNC), and transferred to the medical ICU. Ultimately, he was intubated and mechanically ventilated for the remainder of his hospitalization due to severe ARDS. After three days in the ICU, his right lower extremity was cold, without palpable nor detectable pulses via bedside Doppler from the femoral to pedal landmarks. Formal ultrasound Doppler that morning confirmed arterial clot extending from the right external iliac to posterior tibial arteries. The patient received embolectomy, stenting, and therapeutic heparin. Within 24 hours, though his creatinine kinase was normal, he developed significantly elevated myoglobin, lactate and worsening acidosis. The patient had a fasciotomy to the right lower extremity at bedside. The next day, he was anuric, with severe acidosis, hyperkalemia, and hypotension, requiring continuous renal replacement therapy (CRRT) and vasopressor support. Discussion Compartment syndrome is characterized by increased pressure within fascial compartments, leading to circulatory compromise, cellular necrosis, and rhabdomyolysis. In this case, the COVID-19 viral effect on coagulation led to extensive arterial thrombosis, complicated by compartment syndrome and renal failure necessitating CRRT. While the exact pathophysiology of the hypercoagulable state in COVID-19 illness is debated, we have observed its manifestations ranging from deep venous thrombosis (DVT), pulmonary embolism (PE), to stroke. Conclusion COVID-19 is known to be a virulent, multifactorial, intelligent virus with myriad end-organ and vascular consequences. When attending to the most critically ill patients with COVID-19, it is wise to consider all forms of vascular thromboembolism.

16.
Critical Care Medicine ; 50(1 SUPPL):568, 2022.
Article in English | EMBASE | ID: covidwho-1691820

ABSTRACT

INTRODUCTION: SPE is a rare entity reported in medical literature. Clandestine silicone application has been increasing in Mexico, leading to increased rates of SPE and death. Symptoms include dyspnea, chest pain, fever, cough, diffuse alveolar hemorrhage (DAH), and acute respiratory distress syndrome. In Mexico, from 2005-2014, 21.8% SPE deaths have been reported related to cosmetic procedures. DESCRIPTION: A 21-year-old, previously healthy transgender patient, with a history of multiple cosmetic surgeries, underwent to a gluteal augmentation procedure through injection of 1000 cc of liquid silicone in an outpatient clinic. The procedure was canceled after administration of 500 cc of silicone due to dyspnea and cough, and the patient was discharged. Two days later, the symptoms worsened, and she was admitted to the emergency department, with a blood pressure of 90/64 mmHg, SpO2 60%, respiratory rate of 40 bpm, and heart rate of 125 bpm. She was intubated and admitted to ICU. On clinical examination, we identified basal crackles, petechial hemorrhage, and erythematous puncture sites. CT pulmonary angiogram showed bilateral basal ground-glass opacities, ruling out thrombus in pulmonary circulation;and lung ultrasound with B pattern. Blood test showed thrombocytopenia, hypoxia (Pa02:FiO2 97 mmHg), elevated alveolar-arterial gradient, negative PCR SARS-CoV-2, and no renal failure. She was diagnosed with SPE;supportive management with lung protective ventilation, prone positioning (PP) and systemic steroids (SS) was initiated. She also had hemoptysis, new pulmonary infiltrates, and abnormal liver enzymes at ICU, which resolved spontaneously. After 8 sessions of PP, oxygenation improved, tracheostomy was performed due to ICU acquired weakness and was discharged home after 20 days of hospital stay. DISCUSSION: There is a paucity of reports of this complication. Our patient showed a significant improvement after administration of SS, which consists with an immunomediated mechanism. Studies have reported mortality from 24 to 33%, but can reach up to 100% if neurological symptoms are present. It is important to recognize that silicone injections are not safe and can lead to serious complications. Recognizing rare manifestations can help to distinguish this entity from other etiologies.

17.
Critical Care Medicine ; 50(1 SUPPL):587, 2022.
Article in English | EMBASE | ID: covidwho-1691814

ABSTRACT

INTRODUCTION/HYPOTHESIS: Acute Respiratory Distress Syndrome (ARDS) is a proinflammatory acute lung injury (ALI) that leads to noncardiac pulmonary edema. In humans, ARDS can be caused directly through damage of the epithelial tissue or indirectly through damage of the endothelial tissue. Different animal models to induce ALI have been developed to mimic the complex pathophysiology of ARDS, including the use of oleic acid injections. Oleic acid induces clinical ARDS by inducing an extensive immune response, including having direct effects on innate immune cells in the lungs triggering direct inflammatory mediator production, damaging the alveoli-capillary unit with increase of alveolar leakage and impairment of gas exchange. There is a paucity of data available to characterize the use of cytokine markers in pediatric ARDS swine models. We hypothesize that in a pediatric swine model of oleic acid ARDS, pro and anti-inflammatory cytokine mRNA in plasma will display at differing concentrations than the baseline at ARDS. METHODS: Seven juvenile swine were sedated, intubated, and mechanically ventilated. ARDS was established using continuous oleic acid infusion at 0.05-0.6 mL/kg. Blood samples were taken from the femoral artery before oleic acid infusion was initiated, an hour after and at the start of ARDS. Plasma was collected and mRNA was extracted from blood mononuclear cells (MNC). Quantitative polymerase chain reaction (qPCR) was performed on samples testing for the presence of mRNA for IFN-γ, TNF-α, IL-17, IL-10, and IL-6. RESULTS: 4-5 10 mL blood samples were collected from each animal and analyzed. When compared to baseline, IFN-γ collected at ARDS onset significantly decreased by a foldchange of 0.53±0.4 at ARDS (p=0.028). IL-6 trended down at ARDS onset, although this was not significant (p=0.087). Changes of TNF-α, IL-17 and IL-10 levels at ARDS onset were not significant (p=0.740, p=0.262, and p=0.342) respectively. CONCLUSIONS: In an oleic acid swine model, ARDS is characterized by decreasing IFN-γ levels. This data does correlate with severe ARDS caused by COVID in human patients. Future studies are warranted to better characterize the role of pro-and anti-inflammatory cytokine in developing ARDS and confirm our model.

18.
International Journal of Pharmacy and Pharmaceutical Sciences ; 14(2):21-30, 2022.
Article in English | EMBASE | ID: covidwho-1689625

ABSTRACT

Objective: To see the effects of Raj Nirwan Bati (RNB) on the hematobiochemical parameters, coagulation tests, and histopathological changes in the lungs, liver, kidneys and spleen and also to evaluate the immunomodulatory activity of RNBin Wistar rats. Methods: A total of 24 adult albino Wistar rats (of bodyweight 200-250 g) of either sex were divided into 3 groups. In the normal control group (n=8), no drug was administered and in the rest of the groups (A and B), RNB@ 26 mg/kg body weight./day and 260 mg/kg body weight/day respectively were administered orally for a period of 14 d. The blood samples were collected from the jugular vein at zero d (before drug administration) and after the 14th d of drug administration in both groups (A and B). The organ samples (lungs, liver, kidneys, and spleen) were collected after euthanizing the rats using Ketamine anesthesia overdose intraperitoneally (IP) after the 14th d of drug administration. White Blood Cells (WBC), Red Blood Cells (RBC), Hemoglobin (Hb), Hematocrit (HCT), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin(MCH), Mean Corpuscular Hemoglobin Concentration(MCHC), number of platelets, Differential Leucocyte Count(DLC) i.e. the percentage of neutrophils, lymphocytes, eosinophils, monocytes and basophils, neutrophil adhesion percentage, Prothrombin test (PT), Activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimer, Lactate Dehydrogenase (LDH), urea, creatinine, Aspartate Amino Transferase (AST), Alanine amino Transferase (ALT), Alkaline Phosphatase (ALP), C-Reactive Protein (CRP) were evaluated and histological examination of organs were done. Results: After statistical analysis, it was found that the decrease in TLC, RBC, Hb, HCT, and LDH in Wistar rats after RNB intervention in Group A as compared to that of before RNB intervention, was found to be statistically significant (P=0.001, P=0.002, P=0.001, P=0.039, and P=0.008). On the other hand, an increase was observed in MCV, Urea, Creatinine and ALT values in the Wistar rats after RNB intervention in Group ‘A’ as compared to that of before RNB intervention and this increase in values was statistically significant (P=0.007, P=0.001, P<0.001 and P=0.038). After RNB intervention in Group B, the increase in MCH, fibrinogen concentration, and monocytes percentage, was found to be statistically significant (P=0.004, P=0.033, and P=0.001) as well as the decrease in PT and APTT was statistically significant (P=0.007and P=0.002). After comparing the Mean Hematobiochemical and coagulation test parameters in the rats of Group A and Group B, after RNB intervention, it was observed that the concentration of Urea, Creatinine, APTT, and D-dimer were less in Group B as compared to that of Group A and this difference was statistically significant(P<0.001, P<0.001, P<0.001 and P=0.022). Histologically the findings in the lungs of group B were more distortion of lung architecture, most of the alveoli become collapse and make emphysematous changes, more diffuse inflammatory infiltrate within interalveolar septa and around bronchioles as compared to Group A. In the liver of group B rats, the histological findings were mild to moderate distortion of lobular architecture, healthy hepatocytes with more activation of kupffer cells as well as larger and more aggregates of inflammatory cells as compared to group A. Histological findings of kidneys in group A and group B rats were similar to that of control group rats. Conclusion: The results suggest that the RNB is having an immunomodulatory effect. It might be helpful in the restoration of coagulation factors and can help treat the COVID patients. No harmful effects on the lungs, liver, kidney, and spleen were seen. These findings may act as baseline data for planning further clinical trials in human study subjects to evaluate the effects on various comorbidities.

19.
Chest ; 161(1):A119, 2022.
Article in English | EMBASE | ID: covidwho-1636540

ABSTRACT

TYPE: Case Report TOPIC: Chest Infections INTRODUCTION: COVID19 leads to Acute Respiratory Failure (ARF) with dyspnea and respiratory exhaustion, ultimately progressing to Acute Respiratory Distress Syndrome (ARDS). The authors present a case of an awake proning/reposition (APR) strategy in a patient with COVID19-ARF. CASE PRESENTATION: A 65-year-old man was admitted for severe COVID19 in February, 2021. At presentation, he was dyspneic on the 10th disease day, had mild hypoxemia and mild systemic inflammation. Immediately, dexamethasone 6mg qd, prophylactic anticoagulation and conventional oxygen therapy (COT) were started. In the first 48 hours, ARF kept worsening and increasing COT demand was needed. APR was started, leading to hypoxemia and polypnea improvement. The patient was ultimately transferred to the Intensive Care Unit (ICU), where non-invasive-ventilation (NIV) and APR were maintained for one week and invasive ventilation (IV) avoided. After twenty days of hospitalization, the patient was discharged without COT. DISCUSSION: Proning position (PP) is an already largely diffused strategy in ICU patients, which improves ARF and prevents ARDS and IV. Supine position leads to dorsal alveoli atelectasis by causing direct (compression) and indirect (over-inflation of ventral alveoli) pressure, which ultimately leads to V/Q mismatch. PP improves V/Q mismatch, reduces shunt and recruits posterior alveoli. APR is a PP strategy in awake/conscious patients, which improves oxygenation and dyspnea, and maybe prevents IV. APR can be autonomously achieved, which can be relevant during a pandemic context. CONCLUSIONS: APR leads to oxygenation and respiratory comfort improvement, possibly improving COVID19 prognosis and avoiding IV. Moreover, it may become a standard of care in ARF by other acute respiratory diseases. DISCLOSURE: Nothing to declare. KEYWORD: Awake proning

20.
Circulation ; 144(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1630232

ABSTRACT

Background: Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) disease (COVID19) mainly affects the respiratory system, but cardiac complications occur very often. SARS-CoV-2 entry in host cells is mediated by the interaction between the viral Spike (S) glycoprotein and the host angiotensin-converting enzyme 2 (ACE2). The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) might influence the expression of ACE2 and viral infection, but not much is known about these interactions. Aim: To evaluate the effects of ACEIs and ARBs during active viraemia. Methods: We tested the ACEI Lisinopril (at 100nM and 500nM) and the ARB Valsartan (at 10uM and 50uM) for one week on two cell types: cardiomyocytes derived from hiPSC (hiPSC-CMs) as heart model and a lung epithelial cancer cell line (16HBE) as pulmonary model. The SARS-CoV-2 wild strain was inoculated in the two treated cell types for one hour. Cell viability was measured 72 hours after infection. Supernatants were collected and titrated to verify the presence of infectious virus using a micro-neutralization assay on VERO-E6 cells. Levels of ACE2 mRNA and protein content on cell lysates were quantified after each treatment by RT-qPCR and western blot, respectively. Results: ACEI and ARB at both concentrations affected the viability of neither hiPSC-CMs nor 16HBE cells in the absence of virus. Vice versa, viral infection significantly decreased viability of both hiPSC-CMs (-46%;p<0,01) and 16HBE (-19%;p<0,05). Viral titration revealed that SARSCoV-2 replicated in both cell lines and was actively released in supernatants. Importantly, pretreatment with Valsartan 50uM increased the viability of both hiPSC-CMs and 16HBE after infection, while Lisinopril and the lower dose of Valsartan had neutral effect. Of note, Valsartan 50uM treatment decrease ACE2 mRNA level in both hiPSC-CMs (-47%, p<0,01) and 16HBE (-37%, p<0,01). Also ACE2 protein levels were reduced in cell lysates of hiPSC-CMs and 16HBE treated with Valsartan 50uM. Conclusion: These data suggest that ACEIs and ARBs do not worsen the SARS-CoV-2 infection. On the contrary, Valsartan seems to be protective against SARS-CoV-2 infection, possibly by reducing ACE2 expression.

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