Tissue-Specific Immunopathology in Fatal COVID-19.

Rationale: In life-threatening coronavirus disease (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 severe acute respiratory syndrome coronavirus 2 (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 among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using 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 between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial 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 the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Unenhanced PMCT in the diagnosis of fatal traumatic brain injury in a charred body.

Traffic incidents are one of the most frequent causes of death in young adults worldwide. Depending on the location of the incident, the velocity of the vehicle(s), the weather condition, traffic incidents are often complicated making the investigation of the circumstances difficult. Here we report a case of an incinerated body involved in a vehicle incident. Differential diagnosis included natural cause of death during driving, fatal traumatic injuries, death due to fire and positional asphyxia. The body was submitted to PMCT prior to autopsy as part of a research protocol (N. 1388/2016) at the Department of Medical Imaging of the University Hospital of Heraklion in Crete, Greece. Unenhanced PMCT revealed craniofacial fractures, a thin film of subdural haemorrhage and an epidural fluid collection. The findings were interpreted as consistent with an impact to the face, causing craniofacial fractures mainly on the right side, and an acute subdural hematoma. Autopsy findings corroborated the diagnosis. The epidural hematoma was deemed to be post-mortem heat-induced. This case is an excellent example of the diagnostic value of PMCT in the medicolegal investigation of death.

Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism.

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5-24.5 µSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion:18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI.

Ex vivo 18F-fluoride uptake and hydroxyapatite deposition in human coronary atherosclerosis.

Early microcalcification is a feature of coronary plaques with an increased propensity to rupture and to cause acute coronary syndromes. In this ex vivo imaging study of coronary artery specimens, the non-invasive imaging radiotracer, 18F-fluoride, was highly selective for hydroxyapatite deposition in atherosclerotic coronary plaque. Specifically, coronary 18F-fluoride uptake had a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity. Areas of 18F-fluoride uptake are associated with osteopontin, an inflammation-associated glycophosphoprotein that mediates tissue mineralisation, and Runt-related transcription factor 2, a nuclear protein involved in osteoblastic differentiation. These results suggest that 18F-fluoride is a non-invasive imaging biomarker of active coronary atherosclerotic mineralisation.

The role of mobile computed tomography in mass fatality incidents.

Mobile multi-detector computed tomography (MDCT) scanners are potentially available to temporary mortuaries and can be operational within 20 min of arrival. We describe, to our knowledge, the first use of mobile MDCT for a mass fatality incident. A mobile MDCT scanner attended the disaster mortuary after a five vehicle road traffic incident. Five out of six bodies were successfully imaged by MDCT in c. 15 min per body. Subsequent full radiological analysis took c. 1 h per case. The results were compared to the autopsy examinations. We discuss the advantages and disadvantages of imaging with mobile MDCT in relation to mass fatality work, illustrating the body pathway process, and its role in the identification of the pathology, personal effects, and health and safety hazards. We propose that the adoption of a single modality of mobile MDCT could replace the current use of multiple radiological sources within a mass fatality mortuary.

Unexpected active tuberculosis on Post Mortem CT: A case report and review of the literature.

Unexpected active tuberculosis (TB) at autopsy represents a serious transmissible health risk to mortuary and laboratory staff. Post Mortem CT (PMCT) is widely accepted as a valuable adjunct to autopsy throughout the world, but the uptake and implementation varies from country to country. We present a case of unexpected active TB on PMCT and review the literature on the incidence of and risks from the condition. We use this unexpected finding, and the fact that PMCT was in this case also able to provide the information for parts I and II of the Death Certificate as a further argument for the routine use of PMCT by all Forensic Institutes.

Multiple self-inflicted stab wounds to neck, chest and abdomen as a unique manner of suicide.

This is a case report of a 30-year-old man found dead in his flat lying on the floor with multiple stab wounds over the body, surrounded by an extensive volume of blood. Examination of the scene of death showed a secure flat, locked from inside. A blood-stained knife was present close to the body and two unstained notes left on the sofa at the locus. A small plastic bag containing white powder (which following toxicological examinations appeared to be cocaine) and an almost full bottle of beer were present on a table. Autopsy revealed more than 40 stab wounds to neck, chest, and abdomen arranged in isolated groups within which the wounds showed similar directions and had a transverse orientation. Together with hesitation marks located on the neck and wrists these characteristics allowed to interpret this case as a suicide.

A screwdriver in the skull : A case report of an unusual finding.

The examination of the body of a murdered adult female found in her apartment revealed the presence of a 6-inch screwdriver in the skull cavity that had been inserted through the medial border of the left eye. The presence of a small bruise around the medial aspect of the eye together with the absence of fresh hemorrhage along the tract of the screwdriver was consistent with a postmortem origin. Death, however, was caused by a large incised wound of the neck and multiple skull fractures consistent with hammer blows.