key: cord-0916641-zjstyhoo
authors: Filograna, Laura; Manenti, Guglielmo; Grassi, Simone; Zedda, Massimo; Mecchia, Daniele; Briganti, Flavia; Ryan, Colleen P.; Pascali, Vincenzo L.; Floris, Roberto; Oliva, Antonio
title: Analysis of the role of PMCT during the COVID-19 pandemic: a systematic review
date: 2022-05-26
journal: nan
DOI: 10.1016/j.fri.2022.200505
sha: 2bf5790dcc6bdaf0f4e1dad7ce0adb301a0732d3
doc_id: 916641
cord_uid: zjstyhoo

Objectives : During COVID-19 pandemic PMCT has been proposed as a forensic investigation method. This systematic review is aimed to systematize evidence and peer-reviewed opinions reported during the first two years of pandemic, to evaluate the role of PMCT during the COVID-19 pandemic. Materials and methods : An online literature search was performed to identify publications on PMCT during the COVID-19 pandemic between December 2019 and March 2022. For each publication included, the following data were collected: title and abstract, year of publication, type of article, number and type of individuals examined. The selected publications were also categorized based on PMCT findings, histopathological results, the comparison between PMCT and histopathological findings, cause of death and proposed role of PMCT during the pandemic. Results : A total of 20 publications were included, mostly case reports (9/20). All cases examined included adults. The most frequent PMCT pattern in positive cases was diffuse mixed densities with prevalence of consolidations (pattern 1) (54%). In 97% of the cases where a comparison between PMCT and histological results was performed, a correspondence was found. In 82% of the cases the principal cause of death was COVID-19 pneumonia. PMCT has been proposed as a pre-autopsy screening tool in 62%, and as a method for augmenting post-mortem data in 50% of the papers reporting this issue. Conclusion : This systematic review suggests that PMCT should be regarded as a highly valuable investigative technique for the forensic evaluation of deaths with ascertained or suspected COVID-19 pneumonia.

Virtual autopsy is a term first used by Thali to describe the radiological techniques applied to postmortem investigations [1, 2] . Even though this term may refer to many different techniques, wholebody post-mortem CT (PMCT) scan remains the most used tool in forensic practice [3, 4] .

According to current evidence [5, 6] , the main indications of PMCT regard traumatic cases with skeletal injuries and/or hyperdense foreign objects (e.g., bullets) [7] [8] [9] [10] . Nevertheless, PMCT is known to have several limitations, especially, in natural death cases. For instance, it can easily fail to show minor vascular injuries [11] . However, it has been reported that it can help the pathologist in evaluating sudden deaths [12] due to conditions like hemopericardium [13] [14] [15] and in cases of suspected cardiomyopathies [16] [17] [18] .

More recently, many authors underlined the importance of PMCT in COVID-19 cases. PMCT has been reported to be of great help in exploring signs of this disease at both the pulmonary and extrapulmonary (e.g., brain hypodensities and hemorrhagic lesions, intestinal wall thickening) level [19] [20] [21] [22] . In particular, PMCT has been proposed both as a "screening tool" to assess the biological risk before the autopsy (and thusfor instancechose the facility where the autopsy should be performed and the personal protective equipment that should be given to the executors). Moreover, PMCT in combination with percutaneous biopsies to avoid autopsies when the autopsy facility is not adequate for the COVID-19 biological risk [23] . The pre-autopsy application of PMCT is of great medico-legal and public health value [24] [25] [26] [27] . Furthermore, it has been proved that COVID-19 cases, especially in untreated patients, can expose the autopsy room operators to a significant biological risk [24] [25] [26] [27] . It should be also considered that, as a screening tool, PMCT has been reported to have a high sensitivity, even higher than that of a microbiological testing [28] .

Moreover, in 2022, Filograna et al. described a correlation between lung PMCT and histopathological findings, finding that PMCT can even suggest the degree of severity of COVID-19 in forensic cases [29] .

In this paper, we performed a systematic review focused on the use PMCT imaging during COVID-19 pandemic. Our aim was to systematize evidence and peer-reviewed opinions reported during the first two years of the pandemic, to evaluate whether PMCT should be implemented as a standard best practice of forensic investigations during COVID-19 pandemic. The methods of the systematic review and exclusion criteria were defined in advance according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [30] .

Titles and abstracts were independently screened by the investigators to exclude non-post-mortem CT imaging papers. The inclusion criteria were all types of articles and related only to humans. The exclusion criteria were articles for which full text was not available or were not in English.

Duplicates were discarded. From the articles retrieved in the first round of search, additional references were examined by a manual search among the cited references. When a publication was considered potentially relevant, its full text was independently read by two authors (LF and SG).

For each publication selected (table I), the following information was collected: title and abstract, year of publication, the type of article (original article, case report/brief report/short communication (if 5 or less cases were reported)), narrative review or letter to the editor), number and type of the subjects examined (adults, infants/children). From the papers data were extracted exclusively pertaining cases with ante-mortem or post-mortem SARS-CoV-2 RTPCR positive cases examined with PMCT. The results of PMCT analysis with particular focus on the lungs were recorded, when available. Among the cases with PMCT imaging analysis, some of the stored data were whether an autopsy was performed or not, the results of PMCT imaging analysis, the results of eventually performed (also with percutaneous biopsies) histopathological analysis. Moreover, the eventual comparison between PMCT and histological results and between the cause of death and PMCT pattern were recorded. Finally, the potential use of PMCT in COVID-19 suspected or ascertained cases as proposed by the papers included in the review was recorded. 

According to the search terms and manual search through references, 20 publications were retrieved [23, 29, [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] . The results of our systematic review are reported in Table I in chronological sequence. As expected, all the papers were published between 2020, the beginning of pandemic, and March 2022.

Most papers were case reports (9/20), followed by original articles (6/20), narrative reviews (3/20) and letters to the Editor (2/20).

From the 20 papers, information about 515 cases with SARS-CoV-2 Real-time PCR (RTPCR) positivity and examined through PMCT were available. Seventeen papers [29, 31-35, 37-44, 46-48] provided detailed information about cases. All cases regarded adults.

Of the 515 cases examined, 289 cases underwent autopsy from 14 articles [29, 31-35, 37, 39-41, 44, 46-48] , 234/289 of the study of Fitzek et al. [39] . In one paper of Silva et al. [43] , although the 5 cases presented were not autopsied, they underwent ultrasonography (US) guided biopsies of major organs including the lungs, and histopathological data were available. Thus, histopathological analysis of lungs was performed in a total 294 cases positive for SARS-CoV-2 infection examined with PMCT.

Characteristics of the included studies. 

Of the 20 papers included in the study, 14 reported detailed description of PMCT lung findings for each case [29, 31-35, 37, 38, 40, 41, 43, 44, 47, 48] , with a total amount of 82 cases among the 515 included in the review. In fact, for the 411 cases reported by Fitzek et al. [39] a detailed description of PMCT pulmonary findings was not provided. paving, with or without hypostasis; pattern 3 some upper areas of GGO with or without hypostasis; pattern 4 airless lungs (almost completely or completely consolidated lungs with very few or absent aerated areas); pattern 5 other findings with or without hypostasis; pattern 6 hypostasis alone.

In detail (Table I) , of the 82 cases, pattern 1 (i.e. mixed densities with prevalence of consolidations) was found in 44 cases (54%) [29, 31-33, 35, 37, 40, 41, 43, 47, 48] , pattern 2 in 15 cases (18%) [29, 34, 38, 40, 41, 43, 48] pattern 3 in 4 cases (5%) [29, 41] , pattern 4 in 4 cases (5%) [31, 41, 44] , pattern 5 in 11 (13%) [31, 41] and pattern 6 in 4 (5%) [41] .

As reported in 

As reported in the In 260/267 cases (97%) a concordance between PMCT and histopathological findings was reported.

In the remaining 7 belonging to the study of O'Donnell et al [41] , on the contrary, a discrepancy was found.

A grading of both PMCT and histological findings related to pulmonary SARS-CoV-2 involvement was analyzed only in the 8 cases of the study of Filograna et al. and a complete correspondence was demonstrated.

The cause of death was reported in 501 of the total 515 cases examined [29, 32- 

In all 16 cases where a comparison between PMCT imaging and histopathological results could be performed [29, 33, 34, 47, 48 ] and a precise cause of death was attributed, the recognized PMCT pattern was the pattern 1 (10/16 cases) (62%) and 2 (6/16 cases) (38%). In the 2 cases with pattern 3 reported by Filograna et al. [29] , the death was attributed to a cause different by COVID-19 pneumonia.

Regarding the role of PMCT during COVID-19 pandemic, it was explicitly mentioned in 16 In 1/16 studies (6%) [45] , in presence of SARS-CoV-2 positivity confirmed with viral swabs, typical findings of COVID-19 on PMCT were sufficient to attribute the cause of death to COVID-

This systematic review provided 20 articles focused on PMCT imaging during COVID-19

pandemic [23, 29, [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] . Thus, a relatively high number of studies has been published since the beginning of COVID-19 pandemic [34] . Case reports represented most of the eligible papers (45%), Concerning PMCT findings, our analysis of the literature evidenced that the most frequent PMCT was the pattern 1, represented by diffuse mixed densities with prevalence of consolidations (54%) [29, 31-33, 35, 37, 40, 41, 43, 47, 48] , followed by the pattern 2, represented by diffuse mixed densities with prevalence of GGO with or without crazy paving (18%) [29, 34, 38, 40, 41, 43, 48] .

The pattern 3 constituted by some not dependent areas of GGO with or without hypostasis in 4 cases (5%) [29, 41] . The same percentage (5%) was retrieved for pattern 4 (airless lungs) [31, 41, 44] .

According to these results, it could be proposed that, in accordance with the clinical and postmortem literature, the patterns 1, 2, 3 and even 4, reflect different stages of COVID-19 affecting the lungs [33, 41, 42, 49] . Following this interpretation, the diffuse mixed densities with prevalence of consolidations (pattern 1) and the completely airless lungs (pattern 4), might be the expression of more advanced stages of lung pathology due to SARS-CoV-2 infection till the complete consolidations of both lungs as occurs in ARDS [33, 41, 42, 49] . In line with this interpretation, the diffuse mixed densities with prevalence of GGO with or without crazy paving of the pattern 2 [29, 34, 38, 40, 41, 43, 48] resembles the most typical imaging alteration of patients who died by the second week after symptom onset [50] . Finally, the scant not dependent areas of GGO (typical of COVID-19 early stages in clinical setting) with or without hypostasis of the pattern 3 [29, 41] might be interpreted as typical of early stages of COVID-19 [50] . Thus, it might be hypothesized that PMCT imaging might be a valid tool not only for the diagnosis of COVID-19 pneumonia, but also for staging the lung involvement.

Regarding histopathological analysis, of the 288 cases studied with PMCT, where histopathological data were available, [29, 31-35, 37, 39, 41, 46-48] , the majority (282 cases) showed histopathological signs of DAD and/or clear COVID-19 interstitial pneumonia, as it occurs in advanced stages of pulmonary infections by SARS-CoV-2.

This data is in accordance with the pertinent literature reporting histopathologic findings of lung pathology related to COVID-19 [51] [52] [53] [54] [55] [56] [57] [58] [59] .

Three progressive phases of pulmonary involvement by COVID-19 have been identified by Buja et al. [56] : acute/exudative, organizing/proliferative, proliferative/fibrotic. In general, according to current literature, the main COVID-19-related histopathological is DAD. The extent of DAD varies depending on the stage and severity of the disease. DAD may be associated with intra-alveolar exudates, pneumocyte hyperplasia/atypia, hyaline membrane, proteinaceous exudates and alveolar edema, with major inflammatory infiltration [51, 52, 55] . Moreover, DAD may be associated with possible consolidation with fibroblastic proliferation [48, 52] , and/or pulmonary thromboemboli [54, 58] .

Furthermore, in a recent study Romanova et al. [59] reported that for the 91% of cadavers positive for SARS-CoV-2 infection, where autopsy ascertained cause of death was other than COVID-19, histopathological analysis of the lungs did not show DAD.

Based on this evidence, DAD can be considered the predominant histopathological findings in deaths with ascertained SARS-CoV-2 infection, and it seems to be the expression of severe lung involvement by COVID-19.

On the other hand, in the 260/267 cases [29, 33, 34, 39, 41, 43, 47, 48] where a proper comparison between PMCT imaging and pulmonary histopathological analysis results was performed a concordance between PMCT and histopathological findings was ascertained.

Through analysis of table I, 5 papers with 16 cases can be identified [29, 33, 34, 47, 48] , where a proper comparison between the revealed PMCT pattern and the histopathological analysis can be conducted for each case and a precise cause of death was attributed for each case. It can be noted that patterns 1 and 2, considered here as the typical pattern of diffuse COVID-19 involvement of the lungs, were found in 10 cases and 4 cases respectively [29, 33, 34, 47, 48] . Regarding the possible or applied role of PMCT during COVID-19 pandemic, the majority of the papers that explicitly mentioned this issue (16/20 papers) [23, 29, 31-34, 36, 38, 40-43, 45-48] proposed PMCT imaging as a pre-autopsy screening tool for COVID-19 (14/16 papers) [23, 29, 31-34, 36, 41-43, 45-48] . A possible bias of PMCT is the presence of post-mortem changes [14] that might obscure PMCT findings of early stages of COVID-19 pneumonia [23, 29, 33, 34, 36, 41, 48] .

Moreover, PMCT was suggested as a method to increase of quantity of post-mortem data, especially when performing a classical autopsy is not possible in 8/16 articles [23, 29, 33, 36, 38, 40, 42, 46] .

About the possibility to attribute the cause of death with PMCT imaging, without histopathological confirmation, the 10 papers that mention this issue [23, 29, 33, [41] [42] [43] [44] [45] [46] 48] (except for the article by Moreover, it has been demonstrated that clinical radiologists are able to differentiate COVID-19

pneumonia from other viral pneumonia on CT imaging with moderate to high accuracy [60] .

Indeed, the major weakness of PMCT in being equally accurate in detecting COVID-19 pneumonia depends on the specific characteristics of PMCT imaging and its interpretation.

On the other hand, as suggested by O'Donnell [41] , agonal (e.g., aspiration of gastric contents, reduced ventilation, and effects of resuscitation), previous lung disease, or superadded complications of COVID-19 pneumonia, peri-mortem changes, for example a superimposed ARDS due to concomitant pathology may obscure the SARS-CoV-2 pneumonia. In general post-mortem changes [61, 62] , may obscure underlying COVID-19 changes.

Moreover, other pathologies related to COVID-19 other than pneumonia can cause the death in an individual affected by SARS-CoV-2 infection, such as thromboembolism and multiorgan failure [54] .

However, in the context of the pandemic peak, Roberts et al. [45] , suggests that if COVID-19

pneumonia is suspected based on PMCT, and SARS-CoV-2 positivity is confirmed with viral swabs, it is possible to avoid autopsy and to attribute the cause of death to COVID-19 pneumonia.

This systematic review suggests that virtual autopsy with PMCT imaging should be regarded as a 

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Characteristics of the included studies.

Type of article 

Virtopsy, a new imaging horizon in forensic pathology: virtual autopsy by postmortem multislice computed tomography (MSCT) and magnetic resonance imaging (MRI)--a feasibility study

VIRTOPSY: minimally invasive, imaging-guided virtual autopsy

The rise of forensic and post-mortem radiology-Analysis of the literature between the year

The development of forensic imaging in Italy. A systematic review of the literature

State of the art in post-mortem computed tomography: a review of current literature

A Practical Guide to Virtual Autopsy: Why, When and How

The importance of Post Mortem Computed Tomography (PMCT) in the reconstruction of the bullet trajectory

Postmortem computed tomography (PMCT) and autopsy in deadly gunshot wounds--a comparative study

Postmortem CT and autopsy findings in nine victims of terrorist attack

Importance of 3D-CT imaging in single-bullet cranioencephalic gunshot wounds

Postmortem imaging findings and cause of death determination compared with autopsy: a systematic review of diagnostic test accuracy and meta-analysis

Postmortem radiological imaging of natural causes of death in adults -a review

The role of post-mortem CT (PMCT) imaging in the diagnosis of pericardial tamponade due to hemopericardium: A case report

Forensic relevance of post-mortem CT imaging of the haemopericardium in determining the cause of death

The role of post-mortem imaging in a case of sudden death due to ascending aorta aneurysm rupture

Update on the Diagnostic Pitfalls of Autopsy and Post

Mortem Genetic Testing in Cardiomyopathies

Myocardial fat at cardiac imaging: how can we differentiate pathologic from physiologic fatty infiltration? Radiographics

Post-Mortem Imaging Adjudicated Sudden Death: Causes and Controversies

Extension of Collagen Deposition in COVID-19 Post Mortem Lung Samples and Computed Tomography Analysis Findings

COVID-19 and intracerebral haemorrhage: causative or coincidental? New Microbes New Infect

COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features

Fibrotic progression and radiologic correlation in matched lung samples from COVID-19 postmortems

Potentials of post-mortem CT investigations during COVID-19 pandemic: a narrative review

Liability of Health Care Professionals and Institutions During COVID-19 Pandemic in Italy: Symposium Proceedings and Position Statement

GEMELLI AGAINST COVID-19 group. SARS-CoV-2 viral load and replication in postmortem examinations

COVID-19: Postmortem Diagnostic and Biosafety Considerations

Coronial postmortem reports and indirect COVID-19 pandemic-related mortality

Diagnostic Performance of CT and Reverse Transcriptase Polymerase Chain Reaction for Coronavirus Disease 2019: A Meta-Analysis

Postmortem CT pulmonary findings in SARS-CoV-2-positive cases: correlation with lung histopathological findings and autopsy results

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

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Complete post-mortem data in a fatal case of COVID-19: clinical, radiological and pathological correlations

Evidence for systematic autopsies in COVID-19 positive deceased: Case report of the first German investigated COVID-19 death

Post-Mortem Investigation Through Virtual Autopsy Techniques: Proposal of a New Diagnostic Approach to Reduce the Risks of Operators During Emergencies

Germany's first COVID-19 deceased: a 59-year-old man presenting with diffuse alveolar damage due to SARS-CoV-2 infection. Virchows Arch

Reliable Postmortem Computed Tomography Scan Diagnosis of COVID-19 Pneumonia

consecutive SARS-CoV-2-associated death cases. Sci Rep

COVID-19 lungs in post-mortem computed tomography

Post-mortem CT lung findings at a medicolegal institute in SARS-CoV-2 RT-PCR positive cases with autopsy correlation

Use of post-mortem chest

Postmortem Chest Computed Tomography in Fatal COVID-19: A Valuable Diagnostic Tool for Minimally Invasive Autopsy

Post-mortem CT lung findings at a medicolegal institute in SARS-CoV-2 RT-PCR positive cases with autopsy correlation

Use of post-mortem computed tomography during the COVID-19 pandemic

Dying "from" or "with" COVID-19 during the Pandemic: Medico-Legal Issues According to a Population Perspective

A case of persistent severe sequelae of COVID-19 infection: potential role in sudden death?

Postmortem radiologic and pathologic findings in COVID-19: The Toronto experience with pre-hospitalization deaths in the community

Chest computed tomography scan findings of coronavirus disease 2019 (COVID-19) patients: a comprehensive systematic review and meta-analysis

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan China: a descriptive study

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

COVID-19) Pneumonia in Two Patients with lung cancer

Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

Postmortem Examination of Patients With COVID-19

Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19

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Performance of radiologists in differentiating COVID-19 from Non-COVID-19 viral pneumonia at chest CT

Freshwater drowning in a child: A case study demonstrating the role of post-mortem computed tomography

Post-mortem CT imaging of the lungs: pathological versus nonpathological findings

 [47] Case report