Resistin Forms A Network With Inflammatory Cytokines And Endothelial Damage Markers And Provides Prognostic And Therapeutic Information For COVID-19 (preprint)

Background: Resistin increases in septic subjects and is associated with severity and prognosis. Its role in Coronavirus disease 2019 (COVID-19) is unknown. We investigated relationships between resistin and the severity, prognosis and time to wean off mechanical ventilation (MV) in two cohorts. Methods: : Plasma resistin was available for 306 mild-to-critical COVID-19 patients on days 1, 4 and 8 from the Massachusetts General Hospital Emergency Department COVID-19 (MGH) cohort public proteomics data. The relationship between resistin and severity (World Health Organization COVID-19 outcomes) and the prognosis were evaluated. A cohort of 62 critical COVID-19 patients (Osaka cohort) was used to evaluate the relationship between resistin on days 1 (day of ICU admission), 2–3, 6–8 and 11–15 and the prognosis and time to wean off MV. Correlations among resistin, inflammatory cytokines and endothelial damage markers were evaluated. Results: : In the MGH cohort, day 1 resistin was associated with severity and predicted the prognosis in an ROC analysis (AUC, 0.739; 95% CI, 0.659–0.819). Twenty-eight-day non-survivors showed significantly greater resistin levels than 28-day survivors on days 1, 4 and 8. In the Osaka cohort, a Cox proportional hazards model (time dependent) showed a significant relationship between resistin and time to wean off MV (crude hazard ratio, 0.702 [95% CI, 0.508–0.969]). Resistin formed a network with inflammatory cytokines and endothelial damage markers. Conclusions: : Resistin was associated with severity, prognosis and time to wean off MV in COVID-19 patients. Resistin formed a network with inflammatory cytokines and endothelial damage markers, suggesting its contribution to the pathogenesis of COVID-19.

Complement Activation Induces Excessive T Cell Cytotoxicity in Severe COVID-19 (preprint)

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies assessing pathogenic T cell functions and inducing signals. We identified activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16 + cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.Funding: This work was supported by the German Research Foundation (DFG): SA1383/3-1 to B.S.; SFB-TR84 114933180 to L.E.S., S.B., P.G., S.H. and W.M.K. INST 37/1049-1, INST 216/981- 1, INST 257/605-1, INST 269/768-1, INST 217/988-1, INST 217/577-1, and EXC2151- 390873048 to J.L.S.; GRK 2168 – 272482170, ERA CVD (00160389 to J.L.S.; SFB 1454 – 432325352 to A.C.A. and J.L.S.; SFB TR57 and SPP1937 to J.N.; GRK2157 to A.-E.S.; and ME 3644/5-1 to H.E.M.; RTG2424 to N.B.; SFB-TRR219 322900939, BO3755/13-1 Project- ID 454024652 to P.B.; the Berlin University Alliance (BUA) (PreEP-Corona grant to L.E.S. and V.M.C.); the Berlin Institute of Health (BIH) (to L.E.S., V.M.C.,B.S. and W.M.K.); Helmholtz- Gemeinschaft Deutscher Forschungszentren, Germany (sparse2big to J.L.S.), EU projects SYSCID (733100 to J.L.S.); European Research Council Horizon 2020 (grant agreement No 101001791 to P.B.); the DZIF, Germany (TTU 04.816 and 04.817 to J.N.); the Hector Foundation (M89 to J.N.); the EU projects ONE STUDY (260687), BIO-DrIM (305147) and INsTRuCT (860003) to B.S.); German Registry of COVID-19 Autopsies through Federal Ministry of Health (ZMVI1-2520COR201 to P.B.); Federal Ministry of Education and Research (DEFEAT PANDEMICs, 01KX2021 and STOP-FSGS-01GM1901A to P.B.); the Berlin Senate to German Rheumatism Research Centre (DRFZ); the Berlin Brandenburg School for regenerative Therapies (BSRT) to C.B.; the German Federal Ministry of Education and Research (BMBF) projects RECAST (01KI20337) to B.S., V.M.C., L.E.S and M.R.; VARIPath (01KI2021) to V.M.C.; NUM COVIM (01KX2021) to L.E.S., V.M.C., F.K., J.L.S., J.N. and B.S.; RAPID to and S.H.,; SYMPATH to N.S. and W.M.K.; PROVID to S.H. and W.M.K.; ZissTrans (02NUK047E) to N.B; National Research Node ‘Mass spectrometry in Systems Medicine (MSCoresys) (031L0220A) to M.R. and N.B.; Diet–Body–Brain (DietBB) (01EA1809A) to J.L.S.; the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Francis Crick Institute through the Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), the Wellcome Trust (FC001134 and IA 200829/Z/16/Z) to M.R.; a Charité 3R project (to B.S., S.H., W.M.K.); and an intramural grant from the Department of Genomics & Immunoregulation at the LIMES Institute to A.C.A. We are grateful to the patients and donors volunteering to participate in this study making this research possible in the first place and wish for a speedy and full recovery.Conflict of Interest: V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding SARS-CoV-2 diagnostics via antibody testing. A.R.S. and H.E.M. are listed asinventors on a patent application by the DRFZ Berlin in the field of mass cytometry.Ethical Approval: The study was approved by the Institutional Review board of Charité(EA2/066/20).

Sudden Sensorineural Hearing Loss in COVID-19: A Case Report and Literature Review (preprint)

This report describes the case of a 53-year-old man with SARS-CoV-2 infection and occurrence of complete unilateral sensorineural hearing loss, adding new evidence to the association between COVID-19 and hearing loss. Whether this is the result of endothelial cell dysfunction in the cochlea or central auditory pathways remains unclear.

Microvascular Angiopathic Consequences of COVID-19 (preprint)

The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first appeared in Wuhan, China in December, 2019. Ever increasing data is emerging about COVID-19 and its effects on the arterial and venous circulation. Clinical features associated with COVID-19 suggest that endothelial cell dysfunction and microvascular thrombosis are to a large part contributing to resultant multi-organ complications. This review is aimed at highlighting the critical aspects associated with COVID-19 and its presumed microvascular angiopathic complications leading to multi-organ dysfunction.

Is COVID-19 a Systemic or Local Pathological Process? (preprint)

Severe acute respiratory syndrome COVID-19 targets clinicians primarily to the processes in lung tissue. In other cases, however, clinical evidence reflects the conclusion of endotheliitis development in different parts of vascular bed of SARS-CoV-2 patients. ACE2 dysfunction leads to abnormal activation of renin-angiotensin system and systemic endotheliitis, which is accompanied by abnormal coagulation and sepsis. Sepsis and thrombi formation in various parts of blood vessel bed are of fundamental importance for reasonable choice of preventive and therapeutic tactics in COVID-19. Systemic nature of pathological processes in COVID-19, medical procedures from the first minutes of hospitalization of a patient will be focused on timely diagnosis and therapy of both local and systemic manifestations of COVID-19. There is a difference in the manifestation of risk factors associated with COVID-19 between sexes and age. Many clinicians focus on the fact that severe acute respiratory syndrome COVID-19, called coronavirus SARS-CoV-2, is a systemic disease, which is accompanied by development of pathological processes in lungs and in fact all the organs of human body. The dominant local symptoms of COVID-19 in pulmonary ventilation system in patients at the beginning of pandemic development fix the attention of clinicians on prevention of primarily fatal processes in lung tissue. However, in many cases, it is advisable to immediately after diagnosis establishment begin intensive therapeutic measures aimed at correcting the functions of cardiovascular system, central nervous or digestive systems. Clinical observations accumulating during development of COVID-19 pandemic indicate a variety of systemic pathological events in the body of SARS-CoV-2 patients. Asymptomatic COVID-19 is present also in a currently unknown fraction of the affected patients. Somewhat paradoxically, asymptomatic people had a weaker immune response to SARS-CoV-2 infection. These data formed the basis for development of preventive and therapeutic measures aimed at correction of functions of cardiovascular, immune, endocrine, nervous, digestive, excretory and other functional systems of the body. The older patient (especially smoking) is the more chronic pathological processes are present in his organism (hypertension, ischemic heart disease, asthma and other pathologies). A peculiar pattern of disease is formed in SARS-CoV-2 patients, which reflects both systematicity of the pathology and pronounced individuality of symptoms appearance. Therefore, prophylaxis, therapy and rehabilitation in COVID-19 should be focused on management of systemic pathology including Severe Acute Respiratory Syndrome with respect to local pathological processes and individual features of SARS-CoV-2 patients.