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Testicular Changes Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

To the Editor.--We are writing in response to a recent communication by Flaifel et al (1) describing morphologic alterations in the testis and epididymis from 10 deceased patients with verified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The authors attributed sloughing of spermatocytes, elongation of spermatids, and swelling of Sertoli cells to the observed hypercoagulability state and oxidative stress. However, since the reverse transcriptase polymerase chain reaction for the 3 coronavirus disease 2019 (COVID-19) genes (ORFlabb, N gene, and E gene) was negative in all 6 tested specimens, the authors concluded that direct viral injury of the testis is unlikely. Similar conclusions were drawn by other authors from a study at the time of a second SARS-CoV pandemic in 2006 with analogous histopathologic alterations and negative in situ hybridization for the virus. (2)

The novel COVID-19 along with other coronaviruses that caused SARS-CoV pandemics in 2002-2006 recruits angiotensin-converting enzyme 2 (ACE-2) for cell entry that potentially makes testis one of the targets. (3,4) However, only 2 published studies from China demonstrated direct invasion of the testicular epithelium and Leydig cells with electron microscopy; the finding was further fortified by either in situ hybridization or immunohistochemistry with anti-SARS-CoV spike S1 protein. (5,6) Although we agree that histopathologic changes are generally nonspecific and often reflect the preexisting medical conditions, in our recent study viral particles were detected in seminiferous tubules by transmission electron microscopy (TEM) in 2 of 5 tested patients. (7) Similarly to Flaifel et al, (1) we observed the presence of inflammatory infiltrate in the testicular interstitium. Moreover, positive TEM from a seroconverted man in our study who clinically recovered 4 weeks prior to the biopsy supports that the COVID-19 virus can linger in the testis at least this long after the direct hematogenous spread during the acute phase of infection. Finally, the degree of spermatogenic failure was inversely correlated with expression of ACE-2.

In summary, SARS-CoV-2 effect on testis seems to have a complex pathogenesis. Although many changes seen by light microscopy are likely attributable to injury from terminal premortem oxidative stress and cytokine storm, it also appears that the virus can penetrate the blood-testis barrier and invade testicular parenchyma. Levels of ACE-2 expression potentially play an important role in tissue susceptibility to the viral infection. Most data are derived from postmortem studies, and the effect on spermatogenesis and testicular function in recovered men is not clear. Studies evaluating long-term male fertility in COVID-19 survivors will be critical to understanding the true impact of this infection on testicular function.

(1.) Flaifel A, Guzzetta M, Occidental M, et al. Testicular changes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Arch Pathol Lab Med. 2021;145(1):8-9.

(2.) Xu J, Qi L, Chi X, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod. 2006;74(2):410-416.

(3.) Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8.

(4.) Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14(2):185-192.

(5.) Zhao JM, Zhou GD, Sun YL, et al. Clinical pathology and pathogenesis of severe acute respiratory syndrome [in Chinese]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2003;17(3):217221.

(6.) Ma X, Guan C, Chen R, et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. Cell Mol Immunol. 2021;18(2):487-489.

(7.) Achua JK, Chu KY, Ibrahim E, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. World J Mens Health. 2021; 39(1):65-74.

Accepted for publication February 12, 2021.

Published online March 31, 2021.

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2021-0014-LE

Oleksii A. Iakymenko, MD [1]; Ranjith Ramasamy, MD [2,3,4]; Oleksandr N. Kryvenko, MD [1,3,4]

[1] Department of Pathology and Laboratory Medicine; [2] The Interdisciplinary Stem Cell Institute; [3] Department of Urology; and the [4] Silvester Comprehensive Cancer Center, at University of Miami Miller School of Medicine, Miami, Florida

In Reply.--We thank Dr Iakymenko and colleagues for their comments and description of transmission electron microscopy findings. (1,2) While we and others did not observe direct virus invasion in the testis, other recent studies have found the presence of the virus particles in the testicular parenchyma when using various modalities (transmission electron microscopy, immunohistochemical, and in situ hybridization studies). (3) The infrequency or inability to detect viral particles in the testis raises different possibilities: that either tissue sampling, the timing of tissue sampling, or the sensitivity of the detection method may play a role. Clearly demonstrating direct invasion is an important finding, and its clarification on the pathogenesis of the disease in the testis awaits further studies.

The morphologic evaluation of the testes of patients with coronavirus disease 2019 (COVID-19) provides insight beyond that derived from identifying the viral particles. By comparing the postmortem histology of the testes from COVID-19-positive patients to a control group, we observed an injury pattern suggestive of acute oxidative damage to the testes in more than half of the cases in the COVID-19-positive cohort. This suggests that toxic metabolic effects of prolonged illness--the cytokine storm that characterizes severe COVID-19 or even direct invasion by the virus--may all contribute to these histopathologic changes. Importantly, the presence of microthrombi in the testicular vasculature suggests microvascular thrombotic ischemic injury as has been described in severe COVID-19 cases. [4]

The pathogenesis of the COVID-19 disease in the testes is complex and further studies evaluating the long-term effects on COVID-19 survivors are critically needed. As these and other reports emerge, we should be able to gain a better understanding of the true impact of this virus on the testes, and we will be able to further refine diagnostic and therapeutic modalities.

Abdallah Flaifel, MD; Jonathan Melamed, MD; Fang-Ming Deng, MD, PhD

Department of Pathology, NYU Langone Medical Center, New York University School of Medicine, New York

(1.) Flaifel A, Guzzetta M, Occidental M, et al. Testicular changes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Arch Pathol Lab Med. 2021;145(1):8-9.

(2.) Achua JK, Chu KY, Ibrahim E, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. World J Mens Health. 2021; 39(1):65-74.

(3.) Ma X, Guan C, Chen R, et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. Cell Mol Immunol. 2021;18(2):487-489.

(4.) Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020; 383(2):120-128.

Accepted for publication March 1, 2021. Published online March 31, 2021.

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2021-0090-LE
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Author:Iakymenko, Oleksii A.; Ramasamy, Ranjith; Kryvenko, Oleksandr N.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Jul 1, 2021
Words:1150
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