Are Viruses Causes Urinary Tract Infections? A Narrative Review

1. Introduction

Urinary tract infections (UTIs) are common public health problems that are primarily caused by bacterial pathogens and occasionally by viruses, typically in individuals with weakened immune systems [1,2,3]. However, viruses are increasingly acknowledged as the source of lower urinary tract infections, particularly in individuals with weakened immune systems [1,3,4]. Although urine has traditionally been believed to be sterile in healthy individuals, the urinary system includes a variety of viruses in both populations [5,6,7]. Recent studies employing 16S rRNA sequencing have challenged the notion of urinary sterility by showing that a complex microbial community exists in the urine of a healthy human bladder [5,8].

These studies demonstrated that several bacterial species identified by 16S rRNA sequencing could in fact be cultured in the lab, providing strong evidence for the presence of bacterial communities in the human urinary system [9,10]. Given that both bacteria and viruses can be found in many human organs with an established microbiome, such as the skin, respiratory system, oral cavity, and gut, the existence, composition, and role of viral communities in a healthy human urinary system are far less understood [10]. Additionally, an investigation that combined an epifluorescence microscopy study with a metagenomic approach to search for viral communities in urine revealed the presence of herpes virus, human papillomavirus, polyomavirus, adenovirus, human polyomavirus (BK virus), cytomegalovirus, and herpes simplex virus type-1 and type-2 in patients without UTIs [1,2,10]. Further research revealed viruses in individuals experiencing symptoms related to the urinary tract, such as sepsis, pain when urinating, prostate pain, abdominal pain, or vaginal bleeding [2].

Immunocompromised individuals are most frequently affected by viral infections of the lower urinary tract, especially those who have received solid organ and hematopoietic stem cell transplants. The most common cause of hemorrhagic cystitis in this population is viral infections. Although there are other types of lower urinary tract infections (UTIs), including cystitis, prostatitis, seminal vesiculitis, and urethritis, viral lower tract infections most commonly attack the bladder and ureters. Urine should be sterile and free of microorganisms in healthy people, particularly men [1,4]. This is one of the main distinctions between bacterial and viral pathogens of the lower urinary tract.

Before the development of sophisticated diagnostic tools, hemorrhagic cystitis (HC) was thought to be a side effect of radiation and chemotherapy; however, it is now more commonly recognized as a viral infection [1,11,12,13]. HC is a type of virus-caused UTI characterized by necrosis of the bladder transitional epithelium and associated blood vessels, resulting in dysuria, suprapubic pain, and sudden onset of hematuria [11,12], For instance, HC occurred in 25.5% of patients in a prospective trial of more than 100 juvenile bone marrow transplant recipients, with a 95% virus-related etiology [13], Keep in mind that the diagnosis of viral infection requires the presence of related symptoms [7,14]. Hematuria linked to HC can range in severity from minor illnesses that go away on their own to potentially fatal conditions that need surgery and blood transfusions [15]. According to the DeVries classification, hematuria is classified as (i) mild when there is no change in hematocrit level, (ii) moderate when gross hematuria necessitates a transfusion of less than six units of blood, and (iii) severe when gross hematuria necessitates a transfusion of more than six units of blood. Furthermore, the Vela-Ojeda classification uses a grading system wherein (i) grade one denotes microscopic hematuria, (ii) grade two denotes macroscopic hematuria, (iii) grade three denotes hematuria with clots, and (iv) grade four denotes hematuria with clots combined with azotemia and urinary obstruction [15].

Due to its high morbidity, relative rarity, and absence of a proven standard treatment, HC is difficult to manage [16,17]. The nature of viral pathogenesis makes managing viral infections difficult. For example, viruses can only multiply inside living cells, show specificity for specific host cells, and prosper only within those cells [17,18]. The achievement of global vaccination coverage is still hampered by vaccine hesitancy, misinformation, and unequal access to healthcare, even though vaccines and antiviral treatments are available for some viral infections and there is currently no universal cure for all viral diseases [17,19].

Antiviral treatments are also essential for treating viral infections [20]. Antiviral medications have dramatically decreased morbidity and death globally, including antiretroviral therapy for HIV/AIDS, antivirals for influenza, and more recent hepatitis C medicines [21]. However, there are many obstacles to the development and marketing of antiviral drugs, including restricted availability, high costs, and virus resistance [22].

In order to stop the spread of viral diseases, public health measures are crucial. Travel restrictions, contact tracing, quarantine procedures, disease surveillance, and other measures can help contain epidemics, especially in their early stages. Additionally, health education, better cleanliness, and public awareness campaigns are essential for encouraging preventative behaviors and lowering viral transmission [17,23].

While viral urinary tract infections, also known as hemorrhagic cystitis, have gotten relatively little attention, bacterial urinary tract infections have been thoroughly investigated and analyzed. Thus, the purpose of this study is to give a narrative overview of virus-associated UTIs, emphasizing the common viral infections involved and the various management techniques.

Figure 1. General mechanisms of immune responses to viral infection, adapted from Conway Morris A and Smielewska A (2023) [24] https://doi.org/10.1111/anae.15946. Viruses may cause infection through direct cellular damage and lysis or induce host tissue injury via immune activation and immunopathology. Viral disease often arises from a combination of these mechanisms, potentially compounded by secondary infections or the consequences of secondary organ failure. An exhaustive overview of viral pathogenic mechanisms is beyond the scope of this review.

Figure 1. General mechanisms of immune responses to viral infection, adapted from Conway Morris A and Smielewska A (2023) [24] https://doi.org/10.1111/anae.15946. Viruses may cause infection through direct cellular damage and lysis or induce host tissue injury via immune activation and immunopathology. Viral disease often arises from a combination of these mechanisms, potentially compounded by secondary infections or the consequences of secondary organ failure. An exhaustive overview of viral pathogenic mechanisms is beyond the scope of this review.

2. Selected Viruses Causing Urinary Tract Infection with Their Selective Potential Management

2.1. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS_COV2)

Acute Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a spherical, enclosed, single-stranded RNA virus with a diameter of 120–160 nm that is a member of the genus Betacoronavirus, family Coronaviridae, and order Nidovirales [25,26,27,28]. Random changes in SARS-CoV-2 can result in either increased or decreased pathogenicity [29,30]. Inhaling respiratory droplets released by infected people when they cough or sneeze [31,32,33] and touching the mouth, nose, or possibly the eyes after coming into contact with virus-contaminated surfaces [30,31,32] are the main ways that the virus spreads. Furthermore, it has been determined that uninfected people may become infected by direct contact with the urine or feces of infected people [34].

While respiratory symptoms like dyspnea, coughing, and sputum production are the most common manifestation of SARS-CoV-2 infection, a number of studies have linked COVID-19 to urinary symptoms (US) [35,36], such as hematuria, frequency of urination, glucosuria, and proteinuria [37,38]. According to reports, 36.6% of COVID-19 patients had COVID-19-associated cystitis [39], with 14.7% to 22% of those patients developing symptoms of de novo overactive bladder (OAB) [39,40]. Urinary frequency and urgency were the most common symptoms, and patients with symptomatic COVID-19 had a roughly twice increased chance of developing OAB symptoms compared to asymptomatic patients [39].

One possible underlying cause of COVID-19-related urinary symptoms is cytokine cystitis. Elevated inflammatory cytokines may be released into the urine in reaction to SARS-CoV-2 infection, which can either worsen pre-existing US [41] or impact the bladder and cause de novo US [42,43]. Different studies revealed, COVID-19 infection caused de novo urine symptoms in patients who had no prior history of US [43].

Although the exact pathophysiology of SARS-CoV-2 infection is still unknown, both cell-mediated [44,45] and antibody-mediated [31] immune responses are triggered once the virus eludes the innate immune system [46]. CD4⁺ and CD8⁺ T cells are part of the cell-mediated immune response and are essential for the removal of viruses [44,45]. While interferon-gamma (IFN-γ) helps remove the virus from oligodendrocytes, perforin-mediated immune cells help remove the virus from microglia and astrocytes [47,48].

The main receptor for the SARS-CoV spike protein, angiotensin-converting enzyme 2 (ACE2), is found in around 2.4% of urothelial cells and is expressed in several organs, including the kidneys and lungs [49,50].This pattern of expression points to a possible pathway for urothelial infection through urine and capillaries. SARS-CoV-2 RNA was found in urine samples using RT-PCR in a case study involving a single COVID-19 patient, and it was demonstrated that the infectious virus isolated from the urine could successfully infect Vero cells [51]. Additionally, postmortem electron microscopy examinations of COVID-19 patients revealed viral infection of podocytes and renal tubular epithelial cells [52].

According to a Brazilian investigation, urine samples had a 5.71% (2/35) SARS-CoV-2 RNA positive rate, with virus loads ranging from 2.22 x 10² to 2.49 × 10¹ genome copies (G.C.)/mL and a median of 1.36 × 10¹ G.C./mL [53]. In a similar vein, an Italian investigation discovered that 14% of urine samples included SARS-CoV-2 RNA [54]. When combined, discoveries of direct renal infection, ultrastructural evidence from electron microscopy, and the isolation of infectious SARS-CoV-2 from urine demonstrate that SARS-CoV-2 is spread through infected urine [2].

Several antiviral medications have been tested against SARS-CoV-2 since the start of the COVID-19 pandemic. These include Paxlovid (nirmatrelvir co-administered with ritonavir), a protease inhibitor that disrupts viral polyprotein processing and replication [55], Favipiravir, which inhibits viral RNA-dependent RNA polymerase and suppresses viral replication [56]. and Remdesivir, which inhibits viral RNA-dependent RNA polymerase and thereby blocks viral replication [57]. These medications are among the most well-known antivirals that have been researched; they have been shown to be effective in shortening recovery times, especially for hospitalized patients with severe COVID-19.

2.2. Zika Virus

The Zika virus (ZIKV) is a positive-sense, single-stranded RNA virus that is a member of the genus Flavivirus and family Flaviviridae, which also includes viruses that cause dengue, West Nile, Japanese encephalitis, and yellow fever [58]. In 1947, while conducting surveys for yellow fever, the virus was initially isolated from sentinel monkeys in Uganda’s Zika Forest [59]. Humans contract ZIKV mostly via the bites of infected Aedes mosquitoes [60]. During a jaundice outbreak in eastern Nigeria in 1954, three patients were found to have the first human cases of ZIKV infection [61].

ZIKV infections can cause fever, rash, arthritis or arthralgia, conjunctivitis, myalgia, headache, retro-orbital pain, or Guillain-Barré syndrome [62] while some infections are asymptomatic [63]. Before the epidemic on the Yap Islands of Micronesia in 2007, ZIKV infections were rare. Between 2013 and 2014, they moved to the Pacific Islands [64] with relatively mild and self-limiting clinical outcomes described [64]. However, ZIKV was linked to severe congenital conditions in infants born to infected women in Brazil in 2015, including microcephaly, intrauterine growth restriction, congenital contractures, fetal death, and ocular abnormalities [64,65,66].

Numerous bodily fluids, including blood, saliva, urine, semen, vaginal secretions, rectal swabs, perspiration, cerebrospinal fluid, amniotic fluid, and breast milk, have been found to contain ZIKV RNA [67,68]. Furthermore, the majority of clinical research has shown that both adult and pediatric patients’ urine samples contain high levels of ZIKV virus loads [69]. After an infected mosquito bites a human kidney, the virus enters the bloodstream, travels to the kidney through the renal circulation, enters the glomerulus through the afferent arterioles and glomerular capillaries, and infects the renal corpuscle, including glomerular endothelial cells and other parts of the glomerular parenchyma [70].

Evidence suggests that human embryonic kidney (HEK) cells are susceptible to ZIKV infection, and it has been shown that ZIKV can reproduce in glomerular parenchymal cells of the adult human kidney. Notably, high viral loads and increased expression of the ZIKV nonstructural protein NS1 have been noted in the absence of overt cytopathic consequences, suggesting that the kidney may be a preferred site for persistent ZIKV replication [64,71]. The persistent high-level viruria seen in ZIKV-infected patients is probably caused by infection of podocytes, glomerular endothelial cells, and mesangial cells [70]. Podocyte damage, severe proteinuria, and eventually end-stage renal disease can be caused by a persistent infection of these cells [72].

The increased viral load seen in podocytes and the stimulation of the pro-inflammatory cytokine RANTES, whose expression is correlated with viral replication in glomerular cells, may be responsible for these adverse results [64,70]. After the acute phase of infection, the virus usually clears from bodily fluids in a few days to weeks; nevertheless, protracted persistence of ZIKV RNA has been documented in urine, saliva, and semen [63,67]. Reverse transcription polymerase chain reaction (RT-PCR) has been used to identify ZIKV genomic RNA, and real-time quantitative RT-PCR has been used to quantify it. Urine samples showed up to 2.53 x 10³ ZIKV RNA copies/mL in one documented instance [63].

The successful isolation of infectious ZIKV particles from patients’ urine using Vero cell cultures has demonstrated the existence of a replication-competent virus [63]. Interestingly, RT-PCR-based diagnostic tests reveal that ZIKV is more frequently detected in saliva and urine than in blood. It has been suggested that ZIKV concentrations are highest in saliva at the onset of the disease, even though viral RNA may be present in urine for a long time [73,74]. Although a number of substances with possible anti-ZIKV action have been found, there is currently no approved antiviral treatment for Zika virus (ZIKV) infection. These include: (i) emricasan, which lessens virus-induced cellular death by inhibiting caspase-3 activity [75], and (ii) bromocriptine, which inhibits the viral NS2B–NS3 protease [76], (iii) GSK126, which strongly inhibits ZIKV infection in pretreated cells [77], and (iv) sofosbuvir, a nucleoside inhibitor that binds to amino acid residues critical for ribonucleotide incorporation and interacts strongly with the ZIKV RNA-dependent RNA polymerase [78].

2.3. West Nile Virus

Humans are incidental dead-end hosts due to the low and fleeting levels of virus in their bloodstream. Serious symptoms develop in about 1% of infected individuals, with increased morbidity observed particularly in those over 50 years old, often manifesting as neurological complications. Additionally, rare modes of transmission include infection via infected donor blood, organs, breast milk, or through transplacental transmis-sio West Nile virus is an RNA virus belonging to the Flaviviridae family and Flavivirus genus [2]. It primarily infects humans through mosquito bites, with the Culex species being the predominant vector.

West Nile virus (WNV) is a positive-sense, single-stranded RNA virus that belongs to the Flaviviridae family [79,80]. WNV was first discovered in Uganda in 1937 [81], For over 60 years, the virus spread enzootically by mosquitoes throughout Africa, the Middle East, Russia, and Europe [82,83]. Lineage 2 was the most common strain during this time [84], and infections were usually subclinical or accompanied by a low fever [82]. Clinical symptoms typically start with an abrupt headache and can develop into muscle soreness, weakness, appetite loss, nausea, vomiting, and rash. Neurological symptoms such tremors resembling Parkinson’s disease have also been seen in severe cases [85,86].

Humans contract the disease mostly through mosquito bites, with Culex species acting as the main carriers. Because of their low and temporary viremia, humans are regarded as unintentional dead-end hosts. About 1% of infected people get severe illness, and those over 50 have higher morbidity, which often manifests as neurological symptoms. Blood transfusions, organ transplants, nursing, and transplacental transmission are examples of uncommon means of transmission [80,87]. About 20% of infected people experience mild, influenza-like symptoms that last two to seven days, while the majority of WNV infections are asymptomatic or subclinical. Meningitis, encephalitis, and/or acute flaccid paralysis are the hallmarks of neuroinvasive illness, which develops in less than 1% of cases [88,89].

When WNV-specific IgM antibodies are found in blood or cerebrospinal fluid, a likely diagnosis of West Nile virus (WNV) infection is made. These antibodies usually show up three days after the onset of symptoms and can last up to ninety days, possibly indicating a prior infection. IgG seroconversion is still the most accurate measure of prior exposure because immune responses differ from person to person. Viral isolation, the identification of viral antigens or nucleic acids, a fourfold or higher increase in antibody titers in paired serum samples, the presence of WNV-specific IgM along with neutralizing antibodies, or the detection of WNV-specific IgM in CSF in the absence of antibodies to other endemic arboviruses are all methods used in laboratories to confirm acute WNV infection [85,86].

Viral RNA can be found in urine even when it is no longer detectable in serum using nucleic acid amplification tests [90]. The West Nile virus has been effectively isolated and propagated in Vero E6 and BHK21 cell lines [90,91]. Urine may therefore be a more sensitive specimen for WNV detection than serum. There have been occasional reports of acute urine retention linked to infection, although urinary shedding of WNV has not been connected to structural damage of the urinary system [92].

In line with these conclusions, two out of five patients with suspected WNV infection who were admitted to Near East University Hospital in Nicosia, Northern Cyprus, in October 2023 had WNV RNA found in CSF, serum, and urine samples using an optimized multiplex RT-qPCR assay. The results were consistent with IgM and IgG serology. Interestingly, WNV RNA was found in urine more frequently than in CSF [86]. Recent research confirms that urine-based RT-qPCR offers higher sensitivity than plasma or CSF in symptomatic cases [86,90,93,94] and shows larger viral loads and extended viral shedding in urine during acute WNV infection [95].

These results confirm that the West Nile virus has not been known to induce acute damage to the urinary system [92], despite the fact that it is present in urine at greater viral levels [95] as shown by several modern diagnostic techniques. While supportive care is still the mainstay of treatment for symptomatic infection and there are presently no licensed antiviral treatments for West Nile virus (WNV) sickness, a number of medicines have shown in vitro action against WNV. These include: (i) remdesivir, which inhibits WNV replication [96], (ii) favipiravir, which appears to drive viral extinction and reduce virus-specific infectivity [97], (iii) rilpivirine, which inhibits WNV replication [98], and (iv) sofosbuvir, which also inhibits WNV replication [99].

2.4. BK Viruse/ Human Polyomavirus

BK virus (BKV) is a member of the Polyomaviridae family, which also includes other known human polyomaviruses like JC virus (JCV) and more recently identified members like KI virus (KIV), WU virus (WUV), polyomaviruses 6, 7, and 9, and Merkel cell polyomavirus (MCV). BKV and JCV share about 75% sequence homology [100]. Gardner et al. isolated the virus from a renal transplant recipient’s urine in 1971. It is a small, non-enveloped virus with a diameter of around 40 nm, an icosahedral capsid of 72 capsomers, and a single molecule of covalently closed circular double-stranded DNA [101,102]. BKV infection is more common in adults (up to 90%) than in children under five (around 50%) [103].

Fecal–oral transmission, pulmonary exposure, blood transfusion, organ transplantation, transplacental transmission, and seminal fluid are among the modes of infection [104,105]. BKV is not entirely eradicated from the host after the initial infection. Rather, it creates permanent latency, mostly in renal tubular epithelial cells, where the immune system inhibits viral multiplication [106]. Up to 20% of healthy people have asymptomatic and clinically inconsequential viruria; however, viral shedding is more common during pregnancy and in immunocompromised persons [105].

Renal tubular epithelial cells and bladder transitional epithelial cells are the main locations of BKV tenacity. BKV is dormant under normal circumstances, but in clinical contexts linked to compromised immunocompetence, viral replication may be triggered. These include the administration of immunosuppressive chemotherapy or biologic treatments, pregnancy, multiple sclerosis, solid organ transplantation, hematopoietic stem cell transplantation, and acquired immunodeficiency syndrome (AIDS) [104].

Immunohistological analysis of a renal biopsy specimen is the gold standard for diagnosing BK virus-associated nephropathy (BKVAN) [104,107]. In practical practice, however, noninvasive diagnostic techniques are more frequently employed. These include urine cytology and the microscopic identification of epithelial cells called “decoy cells,” which have a peripheral border of chromatin and distinctive intranuclear viral inclusions. The detection of viral load in plasma and urine using quantitative techniques, especially real-time quantitative polymerase chain reaction (qPCR), is the most dependable marker for patient follow-up.

This approach is a useful tool for preventing the clinical effects of BKV reactivation and for prospective surveillance of it. High levels of viruria and detectable BKV DNA in plasma (viraemia) are common in patients with active infection [108]. According to a number of studies, substantial viruria (with a suggested cut-off value of ≥10² copies/mL) may precede viraemia and the progression to BKVAN and is a risk factor for the development of nephropathy [109]. qPCR is an excellent method for tracking therapy response because of its high sensitivity and broad dynamic range. As a result, specialists in transplant programs advise at-risk patients to undergo routine BKV screening [102].

Midstream urine samples collected in sterile containers and subjected to real-time quantitative polymerase chain reaction (rt-qPCR) analysis were used in a study at the University of Alberta Hospital to assess the BK virus (BKV). Every receiver of a kidney transplant had BKV viruria. All urine samples and 60% of plasma samples proved positive for BKV DNA when BK virus-associated nephropathy (BKVAN) was diagnosed [109]. These results highlight the urinary tract as the main site of viral replication and a significant contributor to BKV-related urinary tract problems by showing that BKV is more commonly found in urine than in other bodily fluids.

Supportive treatment, immunosuppression reduction, and leflunomide have historically been used to treat BK virus (BKV) infection, with generally unsatisfactory results [110]. Cidofovir has shown efficacy with comparatively minimal toxicity when given intravenously or intravesically in recent years [111]. Since intravesical cidofovir lowers the risk of nephrotoxicity while maintaining action against BKV, CMV, and adenovirus, it may be recommended for hemorrhagic cystitis after supportive treatments [111]. Viral load reduction and hematuria resolution serve as indicators of treatment response. Even though BKV is the most common viral cause of cystitis, only a small percentage of viruria patients experience hemorrhagic cystitis, therefore routine prophylaxis is not recommended; nonetheless, early preventive treatment may lower morbidity [112]. Although the exact mechanism is yet unknown, ciprofloxacin prophylaxis has been linked to a decreased BKV viral load [112].

2.5. Adenoviruses

Adenoviruses (AdVs) are non-enveloped double-stranded DNA viruses that typically cause moderate or asymptomatic respiratory and gastrointestinal infections [113,114,115]. Their linear genomes range from 26 to 45 kb [113,114,115], with a diameter of 80–90 nm [116]. But AdVs can also cause serious illnesses such encephalitis, hepatitis, pancreatitis, hemorrhagic colitis, hemorrhagic cystitis, and nephritis [113]. Young children are more likely to experience these severe symptoms, mostly because their humoral immunity is still developing [113]. Rowe and associates first identified the virus in 1953 from tonsillar and adenoidal tissues taken from youngsters undergoing surgery. The same virus was then discovered in 1954 in individuals suffering from acute conjunctivitis and pharyngitis [116,117,118].

The same year, U.S. Army recruits with pharyngoconjunctival fever were found to have a virus known as I-67, which was later determined to be an adenovirus [116,119]. About 5–10% of all viral infections are caused by adenoviral illnesses, which are more common in the winter. There have been reports of both isolated incidents and epidemic breakouts. The most vulnerable groups are military personnel and children between the ages of six months and five years. During the first two to three months of close contact, a particularly high prevalence is seen in newly established groups of adults and children [113,116].

Nasopharyngeal secretions, sputum, conjunctival discharge, feces, and urine are the main sources of infection in immunocompromised people with acute illness symptoms, patients in the convalescent stage, or asymptomatic virus carriers. Adenoviral infections are mostly spread by airborne droplets, conjunctival inoculation, and possibly the feco-oral route, suggesting that they affect not only the respiratory system but also several other organs, including the urinary tract [113,116].

Human adenoviruses (HAdVs) have been linked to urethritis in a number of investigations [120,121,122], with HAdVs found in the urine of afflicted individuals. HAdV-B species type 11 and HAdV-D species types 8, 19, 37, 56, and 64 have been identified [120,123,124,125]. Since these viruses were first discovered, it has been known that HAdVs are involved in the urinary system, with special attention paid to HAdV-B type 11 (HAdV-B11) [126] and HAdV-D type 37 (HAdV-D37) [127]. Despite these findings, little is known about the clinical characteristics and underlying mechanisms of HAdV-associated urinary tract disease. HAdV-B11 has drawn a lot of interest as an opportunistic pathogen in immunocompromised people, especially patients of kidney and other solid-organ transplants, and is most frequently linked to hemorrhagic cystitis [125,128,129].

Additionally, utilizing real-time PCR as the diagnostic technique, a study carried out at the Melbourne Sexual Health Centre between January 2006 and April 2014 revealed that adenovirus was found in 93% of urethritis patients [120]. Adenovirus type 11 was isolated from the urine of 11 out of 25 patients in another study that assessed the viral etiologies of acute hemorrhagic cystitis using virological and serological analyses of unstored urine samples collected between 1967 and 1972; in total, viruses were isolated from 11 out of 12 subjects examined [126]. Adenovirus type 19-associated ocular infections were first reported in Perth, Western Australia, in 1977, despite the fact that eye swabs had been regularly examined in cell cultures for adenovirus type 19 isolations since 1968. Adenovirus type 19 was also recovered from urethral and cervical tissues from male and female patients visiting a Perth sexually transmitted illness clinic during and after this outbreak [130]. When taken as a whole, these results show that adenoviruses of various species can be important causes of UTIs and may be linked to a variety of clinical consequences.

Nevertheless, no antiviral medication is both extremely effective and toxic-free. Despite worries regarding nephrotoxicity[131], cidofovir is increasingly being utilized as a first-line treatment for adenoviral cystitis; however, lower-dose regimens used in recipients of renal transplants may be less effective against co-infections [132]. Compared to youngsters, recipients of HLA-matched bone marrow transplants have better results from ribavirin’s limited action against adenovirus [132]. Although it has been used to treat hemorrhagic cystitis, ganciclovir is mostly used for CMV prevention [133]. Although it is less successful in cases of disseminated adenoviral infection, vidarabine is an alternate treatment for hemorrhagic cystitis, probably as a result of high urinary drug concentrations [134].

2.6. Cytomegaloviruses

The archetypal member of the Betaherpesvirinae subfamily is human cytomegalovirus (HCMV), commonly referred to as human herpesvirus 5 [135]. Ribbert originally described it in 1881, and Goodpasture and Talbert suggested in 1921 that a viral agent was the cause of the disorder known as “cytomegalia.” Later, in 1950, Smith and Vellios proved that HCMV infection may happen in utero [136]. HCMV causes a lifetime of latency in the host after the initial infection [135]. Since efficient immune regulation restricts viral replication and avoids the large viral loads linked to end-organ illness, infection is typically asymptomatic in immunocompetent people. However, mounting evidence indicates that persistent immunological activation and chronic cell-mediated inflammation often referred to as indirect effects may contribute to long-term negative outcomes from chronic HCMV [137].

On the other hand, immunocompromised populations frequently have symptomatic CMV infection, which is linked to a wide range of clinical symptoms. While urinary tract involvement is uncommon and has mostly been described in recipients of hematopoietic stem cell transplants, intestinal, ophthalmic, and neurological problems are widely documented in AIDS patients [138]. It is extremely rare for HIV/AIDS individuals without a history of transplantation to develop CMV hemorrhagic cystitis. There have only been four identical occurrences reported globally, and a recent example from South Africa is the first known occurrence in this clinical environment. In every case that has been documented, a bladder biopsy was used to diagnose individuals who had bladder discomfort or haematuria [139].

In wealthy nations, the prevalence of CMV infection is believed to be 40–60% among adults, but in underdeveloped nations, it often surpasses 90% [140]. The detection and measurement of viral DNA in blood is the main method used in clinical practice to diagnose and track CMV infection. This method is frequently augmented by the identification of viral DNA or antigens in other biological fluids or tissue biopsies [140]. Urine has traditionally been one of the primary materials for viral isolation, and the viral shedding of CMV in urine is well known [141].

The primary cellular locations of viral replication are still unclear, despite the urogenital tract’s obvious involvement in CMV infection. The kidney is an important location of viral replication, as evidenced by in vitro studies showing that CMV may replicate in a variety of primary human renal cells of glomerular, tubular, and vascular origin [142]. Fibroblasts and macrophages are two further types of renal cells that are susceptible to CMV infection and may aid in the excretion of the virus in urine [140]. Local viral immunosuppressive effects and the compartmentalization of particular viral variants within different cells or tissues of the urinary tract may promote continued viral replication, even though the role of systemic immunosuppression in the development or persistence of CMV viruria cannot be ruled out [140].

Furthermore, renal illness linked to CMV has been reported in kidney transplant recipients. Renal biopsies may reveal CMV nephropathy, even when receivers who are CMV-negative receive kidneys from donors who are CMV-positive. On further biopsies, these cases have shown CMV glomerulopathy and CMV-associated interstitial nephritis; histological findings include CMV-positive endothelial cells in glomerular capillaries and CMV-infected monocytes in capillary lumens [143].

Most patients get ganciclovir prophylaxis following solid organ donation; however, foscarnet may be administered in cases of active disease [1,107]. When BK virus (BKV) co-infection is present, cidofovir can be utilized [1,144]. Therefore, cidofovir may be the recommended drug for patients who experience hemorrhagic cystitis following solid organ or hematopoietic stem cell transplantation [1].

3. Prevention and Control Strategies of Viral Infections

Effective prevention and control methods play a major role in shaping the transmission and impact of infectious illnesses in human populations, even if host genetics modulates host-pathogen interactions. Vaccination; environmental sanitation; vector control; population growth management and urban planning; sex education and promotion of safe sexual practices; testing, diagnosis, and treatment; promotion of hygienic practices; food security and adequate nutrition; reduction of contact with livestock and wildlife; reduction of social inequality; and surveillance of infectious diseases are some of the key tactics. Additionally, the prevention and management of infectious diseases brought on by viruses, bacteria, parasites, and other pathogens depend heavily on the preservation of biodiversity, the mitigation of climate change, and the creation of novel antimicrobial medications [145].

The review concludes that urinary tract infections (UTIs) continue to be a significant global public health issue, especially among immunocompromised people, despite the limited scope of this narrative review, which was restricted to identifying viral evidence for the occurrence of UTIs rather than their management. Even though bacteria are the primary cause of UTIs, new research suggests that viral infections are also playing a bigger role. Six viruses were the subject of this narrative review: adenoviruses, CMV, West Nile virus, BK virus (human polyomavirus), Zika virus, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). With the exception of West Nile virus, which has been discovered in urine but does not seem to seriously harm the urinary tract, all of these viruses were found to be capable of causing serious damage to the urinary tract. Thus, infection rates and related problems can be greatly decreased by implementing treatment, prevention, and control techniques appropriately.