To the Editor:
We reviewed the excellent systematic article published by Pola et al. [1] 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 [2]. In the initial autopsies in COVID-19 patients, the presence of CD68+ macrophages in lung and heart tissues [3, 4] 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 [5]. Disorders of macrophages as secondary hemophagocytic lymphohistiocytosis (sHLH) have been reported in COVID-19 [6, 7]. In autopsies, hemophagocytosis has been observed in lung, lymph node, bone marrow, liver, and spleen [6, 8, 9, 10]. 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 [11], and occurs in 3.7–4.3% of sepsis cases [12]. The diagnosis of sHLH is based on clinical, laboratory, and morphologic criteria. The main features are: unremitting fever, cytopenias, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia [13, 14]. Severe COVID-19 could be considered a hyperferritinemic syndrome by the clinical similarities detected [15]. In these conditions, Ferritin plays a critical role in the immune response. The production and secretion of extracellular ferritin is derived from macrophages [16].
The second is the presence of orchitis associated with fibrin microthrombi in COVID-19 patients [10, 17]. 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 [18]. 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 [19]. 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) [20].
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
References
- 1.Polak 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. 10.1038/s41379-020-0603-3. [DOI] [PMC free article] [PubMed]
- 2.Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355–362. doi: 10.1038/s41577-020-0331-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Fox 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;8:681–686. doi: 10.1016/S2213-2600(20)30243-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Yao 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;49:411–417. doi: 10.3760/cma.j.cn112151-20200312-00193. [DOI] [PubMed] [Google Scholar]
- 5.Feng 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. 10.1101/2020.03.27.20045427. [DOI]
- 6.Prilutskiy 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. [DOI] [PMC free article] [PubMed]
- 7.Mehta P, McAuley DF, Brown M, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034. doi: 10.1016/S0140-6736(20)30628-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Adachi 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. 10.3201/eid2609.201353. [DOI] [PMC free article] [PubMed]
- 9.Bradley 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. [DOI] [PMC free article] [PubMed]
- 10.Nunes 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. 10.1111/his.14160. [DOI] [PMC free article] [PubMed]
- 11.Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383:1503–1516. doi: 10.1016/S0140-6736(13)61048-X. [DOI] [PubMed] [Google Scholar]
- 12.Karakike E, Giamarellos-Bourboulis EJ. Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis. Front Immunol. 2019;10:55. doi: 10.3389/fimmu.2019.00055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010;6:137–154. doi: 10.1586/eci.09.58. [DOI] [PubMed] [Google Scholar]
- 14.Debaugnies 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;145:862–870. doi: 10.1093/ajcp/aqw076. [DOI] [PubMed] [Google Scholar]
- 15.Colafrancesco S, Alessandri C, Conti F, Priori R. COVID-19 gone bad: a new character in the spectrum of the hyperferritinemic syndrome? Autoimmun Rev. 2020;19:102573. doi: 10.1016/j.autrev.2020.102573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Recalcati 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;30:84–89. doi: 10.1016/j.jaut.2007.11.003. [DOI] [PubMed] [Google Scholar]
- 17.Buja 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;48:107233. doi: 10.1016/j.carpath.2020.107233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Xu 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;74:410–416. doi: 10.1095/biolreprod.105.044776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Wang 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;9:920. doi: 10.3390/cells9040920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.L 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.