Telerehabilitation improves physical function and reduces dyspnoea in people with COVID-19 and post-COVID-19 conditions: a systematic review.

QUESTION: How effective and safe is telerehabilitation for people with COVID-19 and post-COVID-19 conditions? DESIGN: Systematic review of randomised trials. PARTICIPANTS: People with COVID-19 and post-COVID-19 conditions. INTERVENTION: Any type of telerehabilitation. OUTCOME MEASURES: Satisfaction, quality of life, adverse events, adherence to telerehabilitation, dyspnoea, functional performance, readmissions, mortality, pulmonary function and level of independence. RESULTS: Database searches retrieved 2,962 records, of which six trials with 323 participants were included in the review. Breathing exercises delivered via telerehabilitation improved 6-minute walk distance (MD 101 m, 95% CI 61 to 141; two studies), 30-second sit-to-stand test performance (MD 2.2 repetitions, 95% CI 1.5 to 2.8; two studies), Multidimensional Dyspnoea-12 questionnaire scores (MD -6, 95% CI -7 to -5; two studies) and perceived effort on the 0-to-10 Borg scale (MD -2.8, 95% CI -3.3 to -2.3; two studies), with low certainty of evidence. Exercise delivered via telerehabilitation improved 6-minute walk distance (MD 62 m, 95% CI 42 to 82, four studies), 30-second sit-to-stand test performance (MD 2.0 repetitions, 95% CI 1.3 to 2.7; two studies) and Multidimensional Dyspnoea-12 scores (MD -1.8, 95% CI -2.5 to -1.1; one study), with low certainty of evidence. Adverse events were almost all mild or moderate and occurred with similar frequency in the telerehabilitation group (median 0 per participant, IQR 0 to 2.75) as in the control group (median 0 per participant, IQR 0 to 2); Hodges-Lehmann median difference 0 (95% CI 0 to 0), with low certainty of evidence. CONCLUSION: Telerehabilitation may improve functional capacity, dyspnoea, performance and physical components of quality of life and does not substantially increase adverse events. REGISTRATION: PROSPERO CRD42021271049.

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).

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 also contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly 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 of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.