The effect of COVID-19 on the male genitourinary system

REVIEW

The effect of COVID-19 on the male genitourinary system

Carlo Giulioni 1, Vito Lacetera 2

1 Università Politecnica delle Marche-Azienda Ospedaliera Ospedali Riuniti Torrette di Ancona; 2 Azienda Ospedaliera Ospedali Riuniti Marche Nord, Division of Urology, Pesaro.

SUMMARY

Objective. To discuss the impact of COVID-19 and anti-SARS-CoV-2 vaccination on the genitourinary system. Material and methods. A literature search was performed through MEDLINE via PubMed and

Web of Science. Results. SARS-CoV-2 induces cytokine storm in kidney and testis, due to their expression of ACE2 and TMPRSS2. Acute renal failure is a real concern for patients with COVID-19 and the monitoring of its function is mandatory. Even male fertility seems to be affected through sperm cells damage and hormonal profile alteration, although further studies are necessary to ascertain it. Patients treated with intravescical instillation of Bacillus Calmette-Guerin have the same incidence of being affected by COVID-19 and should be strictly monitored due to increased risk of severe complications. COVID-19 vaccination implies rare side effects related to the genitourinary system and lymph node enlargement. To avoid tumor overstaging, diagnostic imaging is not recommended soon after its administration. Conclusions. Kidney and testis are susceptible to SARS-CoV-2 infection. Urologists should be updated on COVID-19 implications on urogenital organs.

KEY WORDS: COVID-19; Urology; Acute kidney injury; Male infertility; SARS-CoV-2..

INTRODUCTION

Since Coronavirus disease 2019 (COVID-19) was declared a global public health emergency on 30 January 2020, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has had a noteworthy impact on the global health care industry. As of July 24, 2021, over 192 million confirmed cases of COVID-19 and over 4 million were reported on World Health Organization (WHO) website (1). It is already known that COVID-19 affects the respiratory system in the first instance, causing severe respiratory illness up to acute respiratory distress syndrome (ARDS) (2). SARS-CoV-2 penetrates the cell through its affinity for Angiotensin I converting enzyme 2 (ACE2) receptor and the activation of its S protein via serine protease TMPRSS2 (3). These two proteins are mainly present in alveolar cells, although they may occur in other types of endothelial cells, determining several extrapulmonary dysfunctions. Indeed, sequencing Single-cell RNA, SARS-CoV2 was reported from several organs, including the heart, ileum, esophagus, bladder, and kidney (4). Besides, Fan et al. demonstrated the high expression of ACE2 in kidney and testis (5). Virus infection and male genitourinary tract involvement have only partially been addressed by current literature. Andrologists and Urologists must be updated on evidence based on the latest research. Therefore, the literature was screened and the main results were summarized in a narrative review.

METHODS

Our objective was to perform a narrative review to assess the effect of COVID-19 on the urogenital system. A comprehensive literature search was performed on July 24, 2021, through MEDLINE via PubMed and Web of Science, finding the most discussed topic. The following Medical Subject Headings were used: COVID-19, SARS-COV-2, genitourinary system, acute kidney injury, male infertility, bacillus Calmette-Guérin, and anti-COVID-19 vaccination.

RESULTS

Figure 1. The pathogenesis of acute kidney injury related to COVID-19.

Figure 2. The pathogenesis of male infertility related to COVID-19. HPG: Hypothalamic-Pituitary-Gonadal.

ACUTE KIDNEY INJURY Acute kidney injury (AKI) affects 6.7% of patients with SARS-CoV-2 (6) and it is the most frequent extrapulmonary manifestation associated with ARDS (7). Nephron damage is attributable to primary infection and secondary causes (Figure 1): 1. Virus damage on endothelial cells and glomerular basement membrane: the virus may directly induce interleukin cascade generating complement activation (8). Under electron microscopy, glomerular endothelial cells are swollen with vacuolar degeneration inside, thrombus may be seen in the capillaries, and protein casts and pigment casts are visible in the lumen (9). Moreover, glomerular diseases may indirectly occur in patients with SARS-CoV-2: collapsing glomerulopathy is the most frequent, especially in individuals of African descent with high-risk APOL1 genotypes, but antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, anti-glomerular basement membrane disease and immunoglobulin A vasculitis have been reported (10). 2. Virus damage on renal bloodstream: thrombotic microangiopathy (and consequent cortical necrosis) and endothelial dysfunction (with cell apoptosis) are consequences of Disseminated intravascular coagulation (DIC), secondary to SARS-CoV2 infection (11). 3. COVID-19 complications affecting renal function: - renal hypoperfusion (hypovolemia related to fluid loss: fever, vomit, or diarrhea) - renal hypoperfusion related to septic shock - tubular damage related to organ cross-talk between myocardial and kidney, defined as

Cardiorenal Syndrome (12).

According to Cheruiyot et al., AKI is associated with SARS-CoV-2 severity (OR= 18.5; 95% CI 8.9938.08) and mortality (OR= 23.9; 95% CI 18.8430.31). In multivariate analysis, these relationships are not affected by patient’s comorbidities (as cardiovascular disease, hypertension, or diabetes) (13). Anyway, history of diabetes (p=0.02), hypertension (p<0.01), and baseline serum creatinine levels (p=0.04) were positively related to AKI incidence (14). Regard the management of these patients, volume overload, metabolic acidosis, and hyperkalemia should be corrected as in AKI with septic shock (11). If it is not possible to achieve values within threshold ones, dialysis may be necessary. To summarizing, the incidence of acute renal failure is greater in overall patients with SARS-CoV2 infection, especially in severe ones, and it increases mortality. Therefore, monitoring the glomerular filtration rate during the hospital stay is recommended.

MALE INFERTILITY Examining the pathological modifications in the testis of six patients deceased of COVID-19, Xu et al. reported a significant widespread germ cells damage, few or absent spermatozoa in the seminiferous tubules and inflammatory infiltrate composed of T lymphocytes and histiocytes (15). As showed in Figure 2 the pathogenesis of male fertility impairment may be related to two targets: germ cells damage and Leydig cells damage, which affects the Hypothalamic‐Pituitary‐Gonadal Axis. We suggest that SARS-Cov-2 may overcome the blood-testis-barrier (BTB), which controls the passage of molecules only suitable for spermatogenesis. Although it is formed by several structures (tight junctions, ectoplasmic specializations, desmosomes, and gap junctions), more than 30 different types of viruses entry the seminiferous tubules, triggering the inflammation process and altering semen quality (16). Once the virus passed the BTB, serine protease TMPRSS2 and ACE2 receptor let the virus infect testis cells. Stanley et al. showed that TMPRSS2 is expressed in spermatogonia and elongated spermatids (19). A recent study reported the expression of ACE2 receptor by spermatogenic stem cells (17), other than Sertoli and Leydig cells (18). This study showed that overexpression of ACE2 in germ cells was positively associated with male infertility. ACE2 receptor activates 5‐Hydroxytryptamine Receptor 3A (HTR3A), which triggers apoptosis indirectly via TNF‐α production (17). We do not know if SARS-CoV-2 infection of the testis is correlated to detectable virus presence in the semen. Only two studies investigated this possible association. SARS‐CoV‐2 was found in 2/23 (8.3%) cured patients and 4/15 (26.7%) patients in the acute phase (20). The other study did not confirm previous authors’ results: SARSCoV-2 was not identified in the- semen samples of 34 patients in acute phase of COVID-19 (21). Even in 6 patients with scrotal discomfort, suggesting viral orchitis, SARS-CoV-2 was not found (21). Although the mechanisms of virus diffusion into the semen may be related also to prostatic involvement, the temporary inflammatory obstruction of seminal pathways could explain this phenomenon. The second source of male infertility is related to hormonal profile, which in turn depends on two factors. As previously described, the inflammation involves also Leydig cells, where ACE2 and angiotensin 1–7-Mas receptor, fundamental for testosterone (TT) synthesis, are pronounced (22). Therefore, these receptors, allow the virus to enter and, subsequently, stop the TT production. As a matter of fact, in 81 reproductive-aged men with SARS-CoV-2 infection, the ratio of testosterone (TT) to luteinizing hormone (LH) was lower and serum LH was significantly higher than in the control group (23). Even Cinislioglu et al. investigated serum TT levels and discovered that it was significantly lower in patients with COVID-19 than in healthy men (p< 0.001) and that blood concentration was decreased in severe and dead patients than, respectively, in moderate (p<0.001) and survivors (p<0.001) ones (24). Moreover, psychological disorders play a key role in poor male fertility: stress may affect semen quality (especially in terms of total sperm count, sperm concentration, and semen volume) and sperm DNA fragmentation (25). Testosterone replacement is the suggested therapy: the decay in hypogonadism may be resolved and metabolic and cardiovascular diseases secondary to COVID-19 could benefit (26). Another noteworthy element is the hormonal profile after recovery from COVID-19. Currently, only one study was published, reporting no relationship between low serum testosterone and post-acute COVID-19 syndrome in 41 patients (27). Therefore, further prospective studies, with a control group and a bigger sample size are required to achieve more robust data. In summary, the virus seems to induce sexual dysfunction in several pathways. Although no evidence emerged in the literature, the follow-up of serum Testosterone level may be suggested. In young men, a consultation regarding their fertility may be necessary.

INTRAVESCICAL INSTILLATION OF BACILLUS CALMETTE-GUÉRIN IN COVID-19 ERA Bacillus Calmette-Guerin (BCG) vaccine derives from Mycobacterium bovis and it was used against tuberculosis for several decades. According to the European Association of Urology (EAU), BCG treatment is recommended for intermediate- and high-risk Non-muscle-invasive Bladder Cancer (NMIBC) (28). BCG enhances the immunity system conferring non-specific protection against respiratory infections. The etiology seems to be linked to “trained immunity” of memory B and T cells that recognizes these mycobacterium antigens and, due to molecular similarity, viral ones (29). Therefore, it was supposed a protective role of the BCG vaccine against SARS-CoV-2 (30). However, de Chaisemartin rejected this hypothesis affirming that it implies no effect on COVID-19 (31). Even in retrospective studies on patients treated with BCG, no relationship was noted. Karabay et al. reported no significant difference between the BCG case and control group in terms of COVID-19 diagnosis (p> 0,05) and PCR test positivity (p non-available) (32). In the paper with the biggest cohort (2803 cases), no evidence of a protective role was showed (33). Furthermore, Fedeli et al. stated that risks of infection, hospitalization, and adverse outcomes is greater [as also confirmed by a systematic review, especially regarding ARDS (34)] with risks of untreated bladder cancer. Only Gallegos et al. reported that the mortality rate was lower in patients between 70 and 79 years, although similar COVID-19 incidence was observed (35). Briefly, scientific research reported that not only does the intravescical instillation of BCG has not a protective role against SARS-CoV-2, but also it increases the incidence of complications related to hypersensitivity and cytokine storm.

ANTI-SARS-COV-2 VACCINATION The last hint is dedicated to the COVID-19 vaccination. The frequency of side effects related to the urologic system is under 1% of cases, which consist of urinary infections, lower urinary tract symptoms, and, less frequently, hematuria (36). Anyway, after administration of the first or second dosage of vaccine ipsilateral lymphadenopathy (LAP) may occur. In a literature search, recruiting 19 studies, 68 cases of LAP were reported, especially after PfizerBioNTech® and Moderna® types (37). This has to be

encountered in oncologic patients, due to the risk of overstaging with diagnostic imaging. Indeed, Özütemiz et al. reported that vaccination mimicked metastasis in five cases and the biopsies in two of them confirmed reactive LAP (38).

CONCLUSIONS

In conclusion, all findings seem to suggest a relationship between COVID-19 and acute kidney injury and seminal impairment. We have dealt with the mechanisms underlying the damage of the urogenital system. We hope that this review will lay the groundwork for further studies. Moreover, patients with bladder cancer and treated with BCG should be strictly monitored due to adverse outcomes overlapped. Therefore, although COVID-19 manifestation predominantly affects the respiratory system, urogenital previous disease and complications should be contemplated during the patient’s management, considering the transition from pandemic to endemic by SARSCoV-2.

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CORRESPONDENCE

Carlo Giulioni Department of Urology, University Hospital “Ospedali Riuniti”. 71 Conca Street, 60126, Ancona – Italy Email: carlo.giulioni9@gmail.com Phone: +39 320/7011978 ORCID: 0000-0001-9934-4011