Tissue-specific immunopathology in fatal COVID-19

Funding: Inflammation in COVID-19: Exploration of Critical Aspects of Pathogenesis (ICECAP) receives funding and support from the Chief Scientist Office (RapidResearch in COVID-19 programme [RARC-19] funding call, “Inflammation in Covid-19: Exploration of Critical Aspects of Pathogenesis; COV/EDI/20/10” to D.A.D., C.D.L., C.D.R., J.K.B., and D.J.H.), LifeArc (through the University of Edinburgh STOPCOVID funding award to K.D., D.A.D., and C.D.L.), UK Research and Innovation (UKRI) (Coronavirus Disease [COVID-19] Rapid Response Initiative; MR/V028790/1 to C.D.L., D.A.D., and J.A.H.), and Medical Research Scotland (CVG-1722-2020 to D.A.D., C.D.L., C.D.R., J.K.B., and D.J.H.). C.D.L. is funded by a Wellcome Trust Clinical Career Development Fellowship(206566/Z/17/Z). J.K.B. and C.D.R. are supported by the Medical Research Council (grant MC_PC_19059) as part of the International Severe AcuteRespiratory Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC-4C). D.J.H., I.H.U., and M.E. are supported by the Industrial Centre for Artificial Intelligence Research in Digital Diagnostics. S.P. is supported by Kidney Research UK, and G.T. is supported by the Melville Trust for the Cure and Care of Cancer. Identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and sequencing work was supported by theU.S. Food and Drug Administration grant HHSF223201510104C (“Ebola Virus Disease: correlates of protection, determinants of outcome and clinicalmanagement”; amended to incorporate urgent COVID-19 studies) and contract 75F40120C00085 (“Characterization of severe coronavirus infection inhumans and model systems for medical countermeasure development and evaluation”; awarded to J.A.H.). J.A.H. is also funded by the Centre of Excellence in Infectious Diseases Research and the Alder Hey Charity. R.P.-R. is directly supported by the Medical Research Council Discovery Medicine North Doctoral Training Partnership. The group of J.A.H. is supported by the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England and in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.Rationale: In life-threatening Covid-19, corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of SARS-CoV-2 or an independent immunopathologic process is unknown. Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses, and the relationships between viral presence, inflammation, and organ injury. Methods: Tissue was acquired from eleven detailed post-mortem examinations. SARS-CoV-2 organotropism was mapped by multiplex PCR and sequencing, with cellular resolution achieved by in situ viral spike protein detection. Histological evidence of inflammation was quantified from 37 anatomical sites, and the pulmonary immune response characterized by multiplex immunofluorescence. Measurements and main results: Multiple aberrant immune responses in fatal Covid-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues. An arteritis was identified in the lung, which was further characterised as a monocyte/myeloid-rich vasculitis, and occurred along with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticulo-endothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues. Conclusions: Tissue-specific immunopathology occurs in Covid-19, implicating a significant component of immune-mediated, virus-independent immunopathology as a primary mechanism in severe disease. Our data highlight novel immunopathological mechanisms, and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma cell responses as well as promoting pathogen tolerance in Covid-19.Publisher PDFPeer reviewe

Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria

<p>Abstract</p> <p>Background</p> <p>There are limited data on the evolution of the leukocyte and platelet counts in malaria patients.</p> <p>Methods</p> <p>In a clinical trial of chloroquine vs. chloroquine plus doxycycline vs. doxycycline alone against <it>Plasmodium vivax </it>(n = 64) or <it>Plasmodium falciparum </it>(n = 98) malaria, the total white cell (WCC) and platelet (PLT) counts were measured on Days 0, 3, 7 and 28 in 57 indigenous Papuans with life long malaria exposure and 105 non Papuan immigrants from other parts of Indonesia with limited malaria exposure.</p> <p>Results</p> <p>The mean Day 0 WCC (n = 152) was 6.492 (range 2.1–13.4) × 10⁹/L and was significantly lower in the Papuans compared to the non Papuans: 5.77 × 10⁹/L vs. 6.86 × 10⁹/L, difference = -1.09 [(95% CI -0.42 to -1.79 × 10⁹/L), P = 0.0018]. 14 (9.2%) and 9 (5.9%) patients had leukopaenia (<4.0 × 10⁹/L) and leukocytosis (>10.0 × 10⁹/L), respectively. By Day 28, the mean WCC increased significantly (P = 0.0003) from 6.37 to 7.47 × 10⁹/L (73 paired values) and was similar between the two groups. Ethnicity was the only WCC explanatory factor and only on Day 0.</p> <p>The mean Day 0 platelet count (n = 151) was 113.0 (range 8.0–313.0) × 10⁹/L and rose significantly to 186.308 × 10⁹/L by Day 28 (P < 0.0001). There was a corresponding fall in patient proportions with thrombocytopaenia (<150 × 10⁹/L): 119/151 (78.81%) vs. 16/73 (21.92%, P < 0.00001). Papuan and non Papuan mean platelet counts were similar at all time points. Only malaria species on Day 0 was a significant platelet count explanatory factor. The mean D0 platelet counts were significantly lower (P = 0.025) in vivax (102.022 × 10⁹/L) vs. falciparum (122.125 × 10⁹/L) patients.</p> <p>Conclusion</p> <p>Changes in leukocytes and platelets were consistent with other malaria studies. The Papuan non Papuan difference in the mean Day 0 WCC was small but might be related to the difference in malaria exposure.</p

Manifestations of a Massive Black Hole in the Galactic Center

A young star cluster is a less contrived explanation than a massive black hole for many of the features seen in the Galactic center. However from a Copernican point of view, this explanation is less attractive than a black hole. The evidence for a ~ 10^6 M_⊙ black hole is becoming progressively less convincing, but the case against it is no stronger. We describe the development of a singular star cluster, as well as the processes of stellar disruption, merging, and gas accretion in such a cluster. Recently merged stars and tidally stripped giants may be detectable within an arcminute of the Galactic Center. We examine the physics of star formation in the inner parsecs of the galaxy, and the problem of maintaining the two parsec molecular torus

Relative Nucleus Pulposus Area and Position Alters Disc Joint Mechanics.

Aging and degeneration of the intervertebral disc are noted by changes in tissue composition and geometry, including a decrease in nucleus pulposus (NP) area. The NP centroid is positioned slightly posterior of the disc's centroid, but the effect of NP size and location on disc joint mechanics is not well understood. We evaluated the effect of NP size and centroid location on disc joint mechanics under dual-loading modalities (i.e., compression in combination with axial rotation or bending). A finite element model was developed to vary the relative NP area (NP:Disc area ratio range = 0.21 - 0.60). We also evaluated the effect of NP position by shifting the NP centroid anteriorly and posteriorly. Our results showed that compressive stiffness and average first principal strains increased with NP size. Under axial compression, stresses are distributed from the NP to the annulus, and stresses were redistributed towards the NP with axial rotation. Moreover, peak stresses were greater for discs with a smaller NP area. NP centroid location had a greater impact on intradiscal pressure during flexion and extension, where peak pressures in the posterior annulus under extension was greater for discs with a more posteriorly situated NP. In conclusion, the findings from this study highlight the importance of closely mimicking NP size and location in computational models that aim to understand stress/strain distribution during complex loading and for developing repair strategies that aim to recapitulate the mechanical behavior of healthy discs

Relative Nucleus Pulposus Area and Position Alter Disk Joint Mechanics.

Aging and degeneration of the intervertebral disk are noted by changes in tissue composition and geometry, including a decrease in nucleus pulposus (NP) area. The NP centroid is positioned slightly posterior of the disk's centroid, but the effect of NP size and location on disk joint mechanics is not well understood. We evaluated the effect of NP size and centroid location on disk joint mechanics under dual-loading modalities (i.e., compression in combination with axial rotation or bending). A finite element model (FEM) was developed to vary the relative NP area (NP:Disk area ratio range = 0.21-0.60). We also evaluated the effect of NP position by shifting the NP centroid anteriorly and posteriorly. Our results showed that compressive stiffness and average first principal strains increased with NP size. Under axial compression, stresses are distributed from the NP to the annulus, and stresses were redistributed toward the NP with axial rotation. Moreover, peak stresses were greater for disks with a smaller NP area. NP centroid location had a greater impact on intradiscal pressure during flexion and extension, where peak pressures in the posterior annulus under extension was greater for disks with a more posteriorly situated NP. In conclusion, the findings from this study highlight the importance of closely mimicking NP size and location in computational models that aim to understand stress/strain distribution during complex loading and for developing repair strategies that aim to recapitulate the mechanical behavior of healthy disks