The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has disrupted the world, with the World Health Organization declaring it a global emergency in early 2020. As of January 2023, the pandemic has affected approximately 600 million individuals worldwide.
While COVID-19 primarily presents as a respiratory illness, it has become increasingly evident that SARS-CoV-2 affects various extra-respiratory systems, leading to diverse clinical manifestations. One of the intriguing aspects of this viral infection is its impact on the male lower urinary tract, particularly the prostate gland.
Understanding the Pathophysiology
The entry of SARS-CoV-2 into host cells is mediated by the angiotensin-converting enzyme 2 (ACE2) receptor. This process is facilitated by the co-expression of the surface protease TMPRSS2. The wide distribution of ACE2 and TMPRSS2 in various organ systems accounts for the systemic effects of SARS-CoV-2 infection. Notably, prostate epithelial cells are known to co-express ACE2 and TMPRSS2, suggesting that the male lower urinary tract, including the prostate, is susceptible to SARS-CoV-2 infection .
These include androgen-receptor-dependent TMPRSS2 expression, the initiation of inflammatory cascades, and metabolic dysregulation associated with the virus.
Metabolic syndrome and related disorders like diabetes mellitus are known risk factors for lower urinary tract symptoms (LUTS) and may contribute to prostate-related issues. Notably, SARS-CoV-2 infection has been linked to the onset of metabolic complications, such as hyperglycemia, ketoacidosis, and diabetes, which could further exacerbate LUTS .
The Clinical Significance
Benign prostatic hypertrophy (BPH) is a common urological condition affecting aging men and is characterized by an enlargement of the prostate gland. BPH often leads to bothersome lower urinary tract symptoms (LUTS), including increased urinary frequency, urgency, weak stream, nocturia, and incomplete emptying. It significantly impacts the quality of life of patients and can result in complications like retention of urine (ROU), urinary tract infections (UTI), hematuria, and bladder stone formation.
The prevalence of BPH and LUTS increases with age, and it is estimated that more than 80% of patients over the age of 70 are affected by BPH . This demographic coincidence is worth noting, as advanced age is also a significant risk factor for severe COVID-19 outcomes .
Given the existing knowledge about the co-expression of ACE2 and TMPRSS2 in prostate cells and the various pathophysiological pathways through which SARS-CoV-2 affects the prostate gland, it is plausible to hypothesize that male patients infected with SARS-CoV-2 are more likely to experience BPH complications compared to non-infected individuals.
Current Research Gap
While there have been preliminary studies investigating the clinical correlation between COVID-19 and male LUTS, the available literature consists of small-scale case series and observational studies. These studies have reported statistically significant increases in LUTS scores, such as the International Prostate Symptom Score (IPSS) or the National Institute of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), after COVID-19 compared to before COVID-19 [12-16]. Additionally, bladder diary data has shown worsening LUTS in COVID-19 patients . However, the existing evidence is limited in scope and scale.
This study aims to bridge the research gap by examining the correlation between SARS-CoV-2 infection and BPH outcomes using large-scale real-world data. The objective is to comprehensively assess the potential impact of COVID-19 on male LUTS and BPH, providing valuable insights into the clinical management of these conditions and their association with SARS-CoV-2 infection.
To investigate the proposed hypothesis, this study will employ a large-scale, retrospective, observational approach. A diverse sample of male patients with a confirmed history of COVID-19 will be analyzed. This sample will be compared to a control group of males without COVID-19 to assess the differences in the prevalence and severity of BPH complications and LUTS.
- Patient Demographics: Collecting data on age, ethnicity, and other demographic variables to account for potential confounding factors.
- COVID-19 History: Recording the date of COVID-19 diagnosis, severity of the infection, and any relevant medical interventions.
- BPH and LUTS Assessment: Utilizing standardized tools such as the IPSS and NIH-CPSI to evaluate LUTS before and after COVID-19.
- Metabolic Profile: Assessing metabolic parameters, including glucose levels, to identify potential associations between metabolic dysregulation and LUTS.
- Clinical Outcomes: Documenting BPH-related complications such as ROU, UTI, hematuria, and bladder stone formation.
Statistical analyses will be conducted to evaluate the data, including t-tests, chi-squared tests, logistic regression, and multivariate analyses to control for confounding factors.
This comprehensive study represents a significant contribution to our understanding of the urological manifestations of SARS-CoV-2 infection in male patients. The research findings indicate a strong association between COVID-19 and increased incidence of benign prostatic hypertrophy (BPH) complications, specifically retention of urine (ROU), urinary tract infection (UTI), and hematuria, as well as the addition of combination therapy. These results align with the initial hypothesis that male patients infected with SARS-CoV-2 are more likely to experience the deterioration of lower urinary tract symptoms (LUTS).
The biological plausibility of this association is rooted in the co-expression of angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 in the prostate, which renders it vulnerable to SARS-CoV-2 infection. This viral invasion can trigger inflammation, which may explain the observed outcomes. Additionally, SARS-CoV-2-related metabolic dysregulation may accelerate pathophysiological mechanisms that increase systemic inflammation and oxidative stress, contributing to the worsening of LUTS. Furthermore, the psychological and environmental stress experienced during a SARS-CoV-2 infection episode could also contribute to lower urinary tract dysfunction [27, 28].
Impact of Age
Subgroup analyses revealed that the statistically significant increase in BPH complications was consistently observed across different age groups, particularly in individuals aged 50 years and older. This aligns with the observation that COVID-19 has a more severe impact on older patients. The association between age and BPH complications is not surprising, given that BPH naturally progresses with age, resulting in an enlarging prostate and worsening symptoms.
Notably, there was no significant difference in the incidence of urinary retention, hematuria, or the addition of 5-alpha reductase inhibitors (5ARI) for combination therapy across different clinical severities of COVID-19. This suggests that even patients with asymptomatic or mild COVID-19 infections, representing the majority of cases, can still experience SARS-CoV-2-related urological complications. Conversely, the lower incidence of UTI and bacteriuria in patients with low-severity COVID-19 may be attributed to the higher risk of UTI in patients with more severe disease due to immunocompromised states and potential catheterization. Nevertheless, subgroup analysis excluding patients with heparin and steroid use consistently demonstrated a higher incidence of hematuria and UTI, reaffirming that the study’s results are not solely due to adjunctive therapies for COVID-19.
Despite the valuable insights provided by this study, several limitations need to be considered. As a retrospective cohort study, it is subject to bias due to the lack of randomization and blinding. Efforts have been made to minimize bias through propensity score matching and the selection of objective primary outcomes to reduce reporting bias. However, the use of existing clinical data introduces the possibility of missing information and coding errors. Nevertheless, the accuracy of the Clinical Data Analysis and Reporting System (CDARS) has been verified in previous studies.
The relatively short follow-up duration of the cohort, averaging 54-55 days, limits the study’s ability to assess long-term effects. Future research with extended follow-up periods could shed light on the potential long-term impact of SARS-CoV-2 on LUTS and the need for surgical interventions. Additionally, the lack of universal polymerase chain reaction (PCR) testing in the cohort has resulted in the control group being selected based on the absence of positive PCR test results for SARS-CoV-2, rather than PCR negativity. This choice was made to minimize bias, but it may introduce a degree of contamination in the control group.
In summary, this large-scale cohort study provides compelling evidence of the urological manifestations of SARS-CoV-2 infection in male patients. The findings highlight the significantly higher incidence of BPH complications associated with COVID-19, including ROU, hematuria, and medication addition, even in patients with asymptomatic or mild infection. Clinicians and urologists should be aware of these urological manifestations, which can occur regardless of COVID-19 severity. Given the high infectivity and widespread impact of COVID-19, the urological symptoms and complications identified in this study represent a substantial clinical burden that demands attention and consideration in the management of affected patients. Further research and longer-term follow-up are essential to fully understand the implications of SARS-CoV-2 infection on male LUTS and BPH.
reference link : https://onlinelibrary.wiley.com/doi/10.1111/joim.13719