Why misinterpretation of electron micrographs in SARS-CoV-2-infected tissue goes viral
Authors: Carsten Dittmayer, Jenny Meinhardt, Helena Radbruch, Josefine Radke, Barbara Ingold Heppner, Frank L Heppner, Werner Stenzel, Gudrun Holland, Michael Laue
Journal: The Lancet (2020)

With interest we follow the publications that show the presence of putative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by electron microscopy (EM) in patient tissues and the debate about these results, which should have sufficiently raised attention to their correct interpretation.1Goldsmith CS Miller SE Martines RB Bullock HA Zaki SR Electron microscopy of SARS-CoV-2: a challenging task.Lancet. 2020; 395: e99Summary Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 2Miller SE Brealey JK Visualization of putative coronavirus in kidney.Kidney Int. 2020; 98: 231-232Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar Nevertheless, ultrastructural details in autopsy tissues have been misinterpreted as coronavirus particles in recent papers. Bradley and colleagues3Bradley BT Maioli H Johnston R et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Lancet. 2020; 396: 320-332Summary Full Text Full Text PDF PubMed Scopus (578) Google Scholar described "coronavirus-like particles" in autopsy specimens of the "respiratory system, kidney, and gastrointestinal tract", and in a case report Dolhnikoff and colleagues4Dolhnikoff M Ferreira Ferranti J Apericida de Almeida Monteiro R et al.SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome.Lancet Child Adolesc Health. 2020; 4: 790-794Summary Full Text Full Text PDF PubMed Scopus (184) Google Scholar described "viral particles" in "different cell types of cardiac tissue" of a deceased child. However, the images in these publications show putative virus particles that lack sufficient ultrastructure for an unambiguous identification as virus. Some of these particles definitely represent other cellular structures, such as rough endoplasmic reticulum (eg, Dolhnikoff and colleagues,4Dolhnikoff M Ferreira Ferranti J Apericida de Almeida Monteiro R et al.SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome.Lancet Child Adolesc Health. 2020; 4: 790-794Summary Full Text Full Text PDF PubMed Scopus (184) Google Scholar figure 3B), multivesicular bodies (Bradley and colleagues,3Bradley BT Maioli H Johnston R et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Lancet. 2020; 396: 320-332Summary Full Text Full Text PDF PubMed Scopus (578) Google Scholar figure 5C) and coated vesicles (Bradley and colleagues,3Bradley BT Maioli H Johnston R et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Lancet. 2020; 396: 320-332Summary Full Text Full Text PDF PubMed Scopus (578) Google Scholar figure 5B, G). Moreover, it is remarkable that Dolhnikoff and colleagues4Dolhnikoff M Ferreira Ferranti J Apericida de Almeida Monteiro R et al.SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome.Lancet Child Adolesc Health. 2020; 4: 790-794Summary Full Text Full Text PDF PubMed Scopus (184) Google Scholar referred to findings, described by Tavazzi and colleagues,5Tavazzi G Pellegrini C Maurelli M et al.Myocardial localisation of coronavirus in COVID-19 cardiogenic shock.Eur J Heart Fail. 2020; 22: 911-915Crossref PubMed Scopus (709) Google Scholar of "viral particles" in interstitial cells, which are clearly non-viral structures, such as coated vesicles.4Dolhnikoff M Ferreira Ferranti J Apericida de Almeida Monteiro R et al.SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome.Lancet Child Adolesc Health. 2020; 4: 790-794Summary Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 5Tavazzi G Pellegrini C Maurelli M et al.Myocardial localisation of coronavirus in COVID-19 cardiogenic shock.Eur J Heart Fail. 2020; 22: 911-915Crossref PubMed Scopus (709) Google Scholar Furthermore, Bradley and colleagues3Bradley BT Maioli H Johnston R et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Lancet. 2020; 396: 320-332Summary Full Text Full Text PDF PubMed Scopus (578) Google Scholar quoted publications as a reference for their virus particle identification, which, in our opinion, both identified non-coronavirus structures as coronavirus particles, as already discussed by Goldsmith and colleagues1Goldsmith CS Miller SE Martines RB Bullock HA Zaki SR Electron microscopy of SARS-CoV-2: a challenging task.Lancet. 2020; 395: e99Summary Full Text Full Text PDF PubMed Scopus (154) Google Scholar and by Miller and Brealey.2Miller SE Brealey JK Visualization of putative coronavirus in kidney.Kidney Int. 2020; 98: 231-232Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar EM is complementary to other techniques used for studying diseases, and it continues to be a valuable tool in certain diagnostic fields. In studies of infectious diseases, EM is considered the gold standard to prove the presence of an infectious unit; in the case of COVID-19 diagnosis, the presence of SARS-CoV-2 particles (figure, A–D) complements the molecular traces of SARS-CoV-2-specific proteins or nucleic acids. Furthermore, EM allows the exact localisation of viruses in tissues and within cells. This, in turn allows target cells of virus infection to be specified (figure E) and informs about the reproduction of the virus. As diagnostic EM requires both specialised staff and expensive equipment, and has been replaced by other methods (eg, immunohistochemistry) in several fields of application, its use has been in decline in the past decades, resulting in irreversible loss of expertise that now becomes dramatically overt during the SARS-CoV-2 pandemic. This dilemma of diagnostic EM should alarm us all, as misleading information on the presence of SARS-CoV-2 in tissue has already made its way into the scientific literature and seems to be perpetuated. We declare no competing interests. Using EM data to understand COVID-19 pathophysiology – Authors' replyWe fully agree with Marisa Dolhnikoff and colleagues that we should aim to understand COVID-19 pathophysiology. However, their arguments directed at our Correspondence,1 which should support their Case Report2 on ultrastructural identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patient tissue, are not convincing. As in other fields of ultrastructural research, identification of subcellular structures is made on the basis of ultrastructural features, which are characteristic for each structure. Full-Text PDF Using EM data to understand COVID-19 pathophysiologyThe pathophysiology of multisystem inflammatory syndrome in children is not completely understood, but it is a field in COVID-19 under extensive investigation. Evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on extrapulmonary tissues is essential for understanding the disease's course and treatment. Full-Text PDF