Does COVID‐19 cause or worsen LUT dysfunction, what are the mechanisms and possible treatments? ICI‐RS 2023

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes coronavirus disease 2019 (COVID‐19) and produced a worldwide pandemic in 2020. There have been 770,875,433 confirmed cases and 6,959,316 attributed deaths worldwide until September 19, 2023. The virus can also affect the lower urinary tract (LUT) leading to bladder inflammation and producing lower urinary tract symptoms (LUTS) in both the acute and chronic phases of disease.


| INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID- 19), has significantly impacted public health, and has posed numerous challenges for healthcare systems worldwide.There have been 770,875,433 confirmed cases of COVID-19 and 6,959,316 deaths as a result of infection up to September 19, 2023. 1 Respiratory distress is the most significant consequence of SARS-CoV-2 that leads to hospital admission.However, it is increasingly recognized that there are nonrespiratory results of infection and that organs such as liver, kidney, gut, and heart can also be severely damaged. 2,3During the pandemic, a patient group was recognized who after an acute viral infection experienced a variety of chronic symptoms.Up to as many as 10% of patients have continued or developed new symptoms following their initial illness, some of which have persisted for years. 4These continuing symptoms have been named the disease entity known as long COVID or postacute sequelae of COVID-19 (PASC). 5Symptoms reported include chronic fatigue, joint pain, cough, shortness of breath, "brain-fog," chest pain, and in some patients, new bladder symptoms or lower urinary tract symptoms (LUTS). 6We are continuing to define long COVID and learn about it as its impact on patients globally including those of working age emerges. 7rabbert et al. published a report of increased urinary frequency in patients hospitalized with SARS-CoV-2. 8Since this publication, there have been several reports of similar observations of new LUTS, even beyond the acute infection.Dhar et al. found that urinary frequency and the incidence of nocturia increased with COVID-19 infection, and that some patients also reported bladder pain. 9Continued research into long COVID is essential as the societal and economic burden reveals itself postpandemic.With so many individuals having experienced infection and reinfection worldwide the long-term effects of SARS-CoV-2 on various tissues, and the impact on different organs' functioning, remains unknown. 10,11Understanding the impacts of SARS-CoV-2 infection on the bladder may be useful: • To help diagnose and treat LUTS associated with acute COVID-19 infection and long COVID.• To understand the inflammatory mechanisms of COVID-associated LUTS which may reveal more about other inflammatory conditions of the bladder that remain poorly defined-such as interstitial-cystitis/ bladder pain syndrome (IC/BPS).
In this paper, we aim to explore the existing literature surrounding the connection between COVID-19 and bladder function, with a specific focus on the development and exacerbation of LUTS.By examining the available evidence, we hope to gain insights into the underlying mechanisms that lead to LUTS in COVID, the clinical implications, and the future directions for research to lead to improved treatment of symptoms.

| SYMPTOMATOLOGY
The lower urinary tract has arisen as one of the many organ systems that can be impacted by COVID-19.COVID infection has been reported to have an effect on the bladder, urethra, and prostate producing a spectrum of LUTS, including asymptomatic microscopic and gross hematuria, bladderstorage symptoms, and voiding dysfunction (Figure 1). 12,13mmonly reported LUTS in patients with COVID-19 infection include urinary urgency, frequency, nocturia, and bladder pain, it has not been possible to separate the increasing overactive bladder (OAB) symptoms and the possibility of viral cystitis. 9One study showed that the degree of LUTS seems to correlate with the severity of COVID-19, with the worst bladder symptoms attributed to those with more severe respiratory symptoms. 14Increased urinary frequency has also been reported in patients with COVID-19 infection independent of acute renal injury or urinary tract infection in a small series of hospitalized patients. 15In a similar study, LUTS, especially storage symptoms, were found to occur early in COVID infection and the authors of this article recommended that clinicians include questions about the urinary tract during routine history taking in patients with suspected infection. 16A survey-based symptomatic assessment completed in 350 patients with COVID, with a median age and length of hospital stay of 64.5 years (range 47-82) and 10 days (range 5-30), respectively, showed that new (n = 250, 71.4%) or worsening OAB symptoms (n = 100, 28.6%) persisting for many weeks after discharge home, had a significant negative impact on quality of life. 17However, these findings may not be applicable for those with asymptomatic, mild, or moderate COVID infection that did not require admission to the hospital.
There have also been some studies showing that COVID infection is not associated with a significantly increased incidence of urinary symptoms, and that there was no reported change in prescription rates for OAB during the pandemic. 18In one study, approximately 25% of participants with positive urine viral RNA, denied any LUTS. 19

| PATHOPHYSIOLOGY
Regarding the potential mode of action of the virus within the lower urinary tract, several theories exist (Table 1).
Data from the pediatric literature shows an increased incidence of children with urinary retention after COVID infection. 27Neurological examination and imaging findings of these children did not reveal any abnormality and the median time from diagnosis of COVID-19 infection to the onset of LUTS was recorded to be 3 months.Incomplete bladder emptying/urinary retention was supported by urodynamic findings of increased bladder compliance, high residual urine volumes, and absence of detrusor pressure increase during the voiding phase. 24 systematic review of 52 articles investigating the association of COVID-19 infection with benign prostatic hypertrophy (BPH) in men, found that COVID-19 infection may accelerate BPH and therefore worsen LUTS such as acute urinary retention.The authors have suggested that pro-inflammatory pathways triggered by COVID may lead to prostate damage and enlargement. 23

| VIRAL CYSTITIS
In acute COVID-19 infection, it has been hypothesized that the SARS-CoV-2 virus itself may directly cause a viral cystitis.][27] The main virulence factor of SARS-CoV-2 is the spike protein, responsible for viral attachment to host cells via angiotensin-converting 2 enzyme receptors (ACE-2), TMPRSS-1 receptors, and vimentin (extracellular), then enabling viral entry. 21,28A single-cell RNA-sequencing study, which examined datasets from multiple organs, revealed that approximately 1% of type II alveolar cells in the lungs exhibited ACE2 positivity, with a standard deviation of 1%.On this basis, cell types with >1% of ACE2-positive cells were considered at "high risk" of SARS-CoV-2 infection.This group found that 2.4% of bladder urothelial cells expressed the ACE2 receptor, putting the bladder into this "high risk" category for viral invasion. 20Therefore, it has been postulated that SARS-CoV-2 may directly infiltrate the urinary tract, resulting in local inflammation and subsequent disruption of normal bladder physiology.
This theory is supported by some reports of SARS-CoV-2 viral RNA being detected in urine; however, the exact localization of urothelial ACE2 receptors is unknown. 21Zou et al. produced cell scatter plots by analyzing published scRNA-sequencing data from the urinary system and found high expression of ACE-2 receptors on urothelial cells but this finding does not reveal whether there is one or many cell layers responsible for this high receptor expression (apical, intermediate, or basal). 21Effect on the bladder may be due to a COVID-viraemia with viral entry from the bloodstream and therefore basal side, or from urine, with viral invasion from the luminal side.It is still unknown whether the virus can be isolated routinely in urine, and at what stage of the disease there is viral shedding into the urinary system. 13It remains undetermined whether viral replication in urothelial cells themselves produces LUTS, or whether symptoms are the result of local and/or systemic inflammation. 29

| INFLAMMATORY CYTOKINES
Another possible explanation for LUTS experienced during acute COVID-19 is the effect of pro-inflammatory cytokines on the bladder.During severe acute systemic infection, the normal homeostasis of pro-and anti-inflammatory cytokines is disrupted leading to widespread abnormal activation of T A B L E 1 Proposed pathophysiological mechanisms underlying COVID-LUTS. 13

Local
Bladder inflammation: Increased expression of urinary inflammatory cytokines (IL-6, IL-8) Expression of ACE2 receptors on urothelial cells. 20,21ast cell activation by COVID-driven cytokines/growth factors augmenting inflammatory response of the cytokine storm. 22ostatic inflammation: Inflammatory mediators have been shown to play an important role in the progression and severity of LUTS secondary to benign prostate obstruction in men. 23[26] Psychological Fear and anxiety related to prolonged hospitalization, including ICU care because of COVID.
immune cells and an unregulated extensive release of proinflammatory mediators known as a cytokine storm.Such a generalized response has a widespread and potentially damaging effect on host tissue including the bladder.1][32] Lamb et al. reported elevated urinary cytokine levels of IL-6, IL-8, and IP-10 in a small cohort of patients with COVID-19 when compared to those without COVID infection or any urological diagnoses.This group went further to suggest that persistent LUTS found in patients with long COVID, may represent a chronic inflammatory cycle in the bladder. 20This may be supported by the finding that the SARS-CoV-2 virus can produce toxin-related peptides such as conotoxins, phospholipases, phosphodiesterases, zinc metal proteinases, and bradykinins in urine, as these peptides may produce a direct inflammatory response in the bladder. 33,34

| VIRAL PERSISTENCE/ REACTIVATION
The relationship between the inflammation seen in acute COVID infection, and the pathophysiology of long COVID is not yet understood.The reason why a subset of patients should develop LUTS or go on to have chronic LUTS also remains unknown.However, there is a growing body of evidence to support that in some, SARS-CoV-2 may persist long beyond the acute infection.Both viral messenger RNA and the spike protein itself have been detected in the gut and urinary tract many months after primary infection. 35his may mean that SARS-CoV-2 could behave in a similar fashion to herpes viruses or Lyme, which stay dormant and then reactivate opportunistically. 36Viral persistence or reactivation may both trigger intermittent immune responses that lead to long-term LUTS.

| SARS-CoV-2 AS A BACTERIOPHAGE
Contrary to our initial understanding that SARS-CoV-2 replicates solely in eukaryotic cells, there is evidence that it may invade and even replicate in bacteria of the gut.Petrillo et al showed that SARS-CoV-2 replicates spontaneously in the gut bacteria of those infected with COVID. 37Brogna et al. also found viral particles in bacteria cultured from the stool samples of COVID-infected individuals and demonstrated viral replication. 38This suggests that SARS-CoV-2 can live within the gut, hidden within the gut microbiome.Some groups have shown that those with COVID-19 have altered gut flora.The "COVID gut microbiome" has been shown to have reduced bacterial diversity, with pathogenic and pro-inflammatory bacteria increasing in number, and normal anti-inflammatory and beneficial species diminished. 39These changes in the gut bacterial populations cause gut dysbiosis which has been associated with many chronic inflammatory conditions such as Crohn's disease and ulcerative colitis.Gut dysbiosis, which increases epithelial permeability and dysfunction through damage, allows for the passage of pathogenic material from the gut into the bloodstream causing an immune response.This could be another mechanism by which there is promotion of a chronic systemic inflammatory response that may be affecting many organ systems in long COVID. 40here are data showing that the microbiome of the bladder and the gut are closely linked. 41One group has shown that over 60% of urinary flora are also found in the intestine. 42There is therefore a possibility that COVID-19 not only causes a gut dysbiosis but also potentially a bladder dysbiosis, causing urothelial dysfunction, a vulnerability to infection, and a local inflammatory response in the bladder. 43

| CONCLUSION
The link between COVID-19 and LUTS is well documented in the literature.There is evidence that de novo and worsening of pre-existing LUTs are seen both in acute covid infection, and in those who are unfortunate enough to develop long COVID.The exact mechanisms of how COVID results in bladder symptoms are not known for sure but may be different in the acute and chronic phases.
In the initial primary infection with SARS-CoV-2, the virus itself may be able to access the urinary system by targeting the ACE-2 receptors expressed on the urothelial cells of the bladder.This may cause local inflammation and a viral cystitis.The systemic effect of COVID and the initiation of a cytokine storm also has potential to damage the bladder tissue in the same way that it damages other organs such as the lungs.
Following acute COVID infection, chronic bladder symptoms could be caused by viral reservoirs in the gut allowing SARS-CoV-2 to intermittently reactivate and trigger immune response.COVID's effect on the microbiota of the intestines may dampen the body's defense against pathogenic bacteria by inducing epithelial dysfunction, in turn promoting a systemic inflammatory response.Furthermore, we may find evidence in the future that dysbiosis as a consequence of COVID is not only reserved to the gut but also may affect the bladder.

Research questions
1. What is the correlation between LUTS and initial COVID infection severity?The following studies are suggested: • Population study of hospitalized patients and those not requiring hospitalization • Symptom questionnaires to assess COVID severity (respiratory symptoms) • Validated symptom questionnaires for LUTS, that is, ICIQ-FLUTS 2. How does COVID-19 vaccination influence the development of LUTS?The following study is suggested: • Large population study of vaccinated and unvaccinated individuals with validated symptom questionnaire for LUTS, that is, ICIQ-FLUTS 3. Can urine or blood-based biomarkers be used to predict the onset and severity of LUTS?The following study is suggested: • Urinary and bladder biopsy cytokines in acute COVID, long COVID, and asymptomatic individuals 4. How does COVID-LUTS evolve?Is spontaneous resolution likely?When and how should we treat patients with persistent/prolonged COVID-LUTS?The following studies are suggested: • Long-term follow-up of cohort of hospitalized patients with COVID-associated LUTS in the acute phase • Long-term follow-up of patients who develop LUTS as part of long COVID 5. Association between long COVID symptoms and types of urinary tract bacteria infections-are they acting as bacteriophages?The following studies are suggested: • Differences in bladder microbiome in COVID infection, long COVID, and asymptomatic individuals-in bladder tissue • Associations between gut and bladder microbiome changes in association with COVID • Any evidence of SARS-CoV-2 as bacteriophage in the bladder 6. Treating urinary tract bacterial infections and do they have an impact on long COVID symptoms?The following study is suggested: • Long-term antibiotics/rotational antibiotics/promotion of healthy urinary microbiome as treatment modalities for COVID-associated LUTS