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Comments to: A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression

2020; Elsevier BV; Volume: 34; Issue: 8 Linguagem: Inglês

10.1038/s41379-020-0631-z

1530-0285

Rafael Parra‐Medina, Sabrina Herrera, Jaime Piracoca Mejìa,

Long-Term Effects of COVID-19

We reviewed the excellent systematic article published by Pola et al. [1Polak SB, Van Gool IC, Cohen D, von der Thüsen JH, van Paassen J. A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod Pathol. 2020. https://doi.org/10.1038/s41379-020-0603-3.Google Scholar] about the pathological findings in COVID-19. Based on the 250 COVID-19 autopsies found during our systematic review through March 30, 2020; we concur with the article hypothesis of mechanisms of infection and the tissular injury. However, we would like to highlight two topics that the authors did not discuss. The first, the autopsies findings could support the hypothesis of macrophages hyperactivation. This has already been reported in other coronavirus such as SARS-CoV1 and MERS [2Merad M Martin JC Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.Nat Rev Immunol. 2020; 20: 355-36210.1038/s41577-020-0331-4Crossref PubMed Scopus (1496) Google Scholar]. In the initial autopsies in COVID-19 patients, the presence of CD68+ macrophages in lung and heart tissues [3Fox E Akmatbekov A Harbert JL Li G Quincy Brown J Vander Heide RS Pulmonary and cardiac pathology in Covid-19: the first autopsy series from New Orleans.Lancet Respir Med. 2020; 8: 681-68610.1016/S2213-2600(20)30243-5Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar, 4Yao XH Li TY He ZC Ping YF Liu HW Yu SC et al.[A pathological report of three COVID-19 cases by minimal invasive autopsies].Zhonghua bing li xue za zhi = Chinese J Pathol. 2020; 49: 411-417PubMed Google Scholar] and the presence of CD169+ macrophages in lymph node subcapsular spaces and in splenic marginal zone were reported. These macrophages expressed the SARS-CoV-2 entry receptor ACE2 and contained SARS-CoV-2 nucleoprotein [5Feng Z, Diao B, Wang R, Wang G, Wang C, Tan Y, et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv. 2020. https://doi.org/10.1101/2020.03.27.20045427.Google Scholar]. Disorders of macrophages as secondary hemophagocytic lymphohistiocytosis (sHLH) have been reported in COVID-19 [6Prilutskiy A, Kritselis M, Shevtsov A, Yambayev I, Vadlamudi C, Zhao Q, et al. SARS-CoV-2 infection associated hemophagocytic lymphohistiocytosis: an autopsy series with clinical and laboratory correlation. medRxiv. 2020.Google Scholar, 7Mehta P McAuley DF Brown M Tattersall RS Manson JJ COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-103410.1016/S0140-6736(20)30628-0Abstract Full Text Full Text PDF PubMed Scopus (6277) Google Scholar]. In autopsies, hemophagocytosis has been observed in lung, lymph node, bone marrow, liver, and spleen [6Prilutskiy A, Kritselis M, Shevtsov A, Yambayev I, Vadlamudi C, Zhao Q, et al. SARS-CoV-2 infection associated hemophagocytic lymphohistiocytosis: an autopsy series with clinical and laboratory correlation. medRxiv. 2020.Google Scholar, 8Adachi T, Chong J-M, Nakajima N, Sano M, Yamazaki J, Miyamoto I, et al. Clinicopathologic and immunohistochemical findings from autopsy of patient with COVID-19, Japan. Emerg Infect Dis. 2020;26. https://doi.org/10.3201/eid2609.201353.Google Scholar, 9Bradley BT, Maioli H, Johnston R, Chaudhry I, Fink SL, Xu H, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections. The Lancet. 2020.Google Scholar, 10Nunes Duarte‐Neto A, de Almeida Monteiro RA, da Silva LFF, Malheiros DMAC, de Oliveira EP, Theodoro Filho J, et al. Pulmonary and systemic involvement of COVID‐19 assessed by ultrasound‐guided minimally invasive autopsy. Histopathology. 2020;14160. https://doi.org/10.1111/his.14160.Google Scholar]. sHLH is a hyperinflammatory syndrome characterized by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is mostly triggered by viral infections, autoimmune diseases and neoplasms [11Ramos-Casals M Brito-Zerón P López-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome.Lancet. 2014; 383: 1503-151610.1016/S0140-6736(13)61048-XAbstract Full Text Full Text PDF PubMed Scopus (796) Google Scholar], and occurs in 3.7–4.3% of sepsis cases [12Karakike E Giamarellos-Bourboulis EJ Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis.Front Immunol. 2019; 10: 5510.3389/fimmu.2019.00055Crossref PubMed Scopus (165) Google Scholar]. The diagnosis of sHLH is based on clinical, laboratory, and morphologic criteria. The main features are: unremitting fever, cytopenias, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia [13Gupta S Weitzman S Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy.Expert Rev Clin Immunol. 2010; 6: 137-15410.1586/eci.09.58Crossref PubMed Scopus (146) Google Scholar, 14Debaugnies F Mahadeb B Ferster A Meuleman N Rozen L Demulder A et al.Performances of the H-score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients.Am J Clin Pathol. 2016; 145: 862-87010.1093/ajcp/aqw076Crossref PubMed Google Scholar]. Severe COVID-19 could be considered a hyperferritinemic syndrome by the clinical similarities detected [15Colafrancesco S Alessandri C Conti F Priori R COVID-19 gone bad: a new character in the spectrum of the hyperferritinemic syndrome?.Autoimmun Rev. 2020; 19: 10257310.1016/j.autrev.2020.102573Crossref PubMed Scopus (176) Google Scholar]. In these conditions, Ferritin plays a critical role in the immune response. The production and secretion of extracellular ferritin is derived from macrophages [16Recalcati S Invernizzi P Arosio P Cairo G New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity.J Autoimmun. 2008; 30: 84-8910.1016/j.jaut.2007.11.003Crossref PubMed Scopus (212) Google Scholar]. The second is the presence of orchitis associated with fibrin microthrombi in COVID-19 patients [10Nunes Duarte‐Neto A, de Almeida Monteiro RA, da Silva LFF, Malheiros DMAC, de Oliveira EP, Theodoro Filho J, et al. Pulmonary and systemic involvement of COVID‐19 assessed by ultrasound‐guided minimally invasive autopsy. Histopathology. 2020;14160. https://doi.org/10.1111/his.14160.Google Scholar, 17Buja LM Wolf DA Zhao B Akkanti B McDonald M Lelenwa L et al.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.Cardiovasc Pathol. 2020; 48: 10723310.1016/j.carpath.2020.107233Crossref PubMed Scopus (267) Google Scholar]. This condition has also been reported in cases with SARS-CoV-1 and in other viral infections like hepatitis B and C, mumps, Epstein–Barr virus, HIV, and HPV [18Xu J Qi L Chi X Yang J Wei X Gong E et al.Orchitis: a complication of severe acute respiratory syndrome (SARS) 1.Biol Reprod. 2006; 74: 410-41610.1095/biolreprod.105.044776Crossref PubMed Scopus (311) Google Scholar]. The mechanism of orchitis in SARS-CoV-2 is possibly related to the interaction of the virus with the ACE2 receptor. This receptor is expressed in spermatogonia and Leydig and Sertoli Cells [19Wang Z Xu X scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, leydig and sertoli cells.Cells. 2020; 9: 92010.3390/cells9040920Crossref PubMed Scopus (386) Google Scholar]. We believe the relationship between hormone levels and testicular compromise deserve further study. Ma et al. reported 81 patients with COVID-19 with testosterone to luteinizing hormone (T to LH) ratio dramatically decreased in comparison with 100 healthy males (p < 0.0001) [20L Ma, W Xie, D Li, L Shi, Y Mao, Y Xiong, et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. medRxiv. 2020.Google Scholar]. The authors declare that they have no conflict of interest.