Lower Urinary Tract Signs and Symptoms in COVID-19 infected Patients


 Background:The type of pneumonia that is caused by the new coronavirus (SARS-CoV-2) has spread across the world in a pandemic. It is not clear if COVID-19 patients have any lower urinary tract signs or symptoms.Methods:The effect of COVID-19 on lower urinary tract function was studied in a multi-centre study including 238 patients who were admitted with symptoms caused by COVID-19 to the university hospital of Aachen in Germany and Tabriz in Iran. Results:None of the patients reported to have any lower urinary tract symptoms. SARS-CoV-2 was found in the urine of 19 % of the tested patients. The mortality rate in COVID-19 infected patients with microscopic haematuria together with white blood cells in their urine, was significantly increased from 48% to 61% in the Tabriz cohort (p-value=0.03) and from 30 % to 35% in the Aachen cohort (p-value =0.045). Furthermore, in the group of patients with SARS-CoV-2 urine PCR, the mortality rate rose from 33% to 50%. (p-value =0.039).Conclusion:Patients admitted with COVID-19 infection did not report to have any lower urinary tract symptoms even those patient who had a positive Urine SARS-CoV-2 PCR.In addition, hematuria, WBC in urine as well as COVID-19 positivity in urine were found to be strong negative prognostic factors in admitted COVID-19 patients.

The mortality rate in COVID-19 infected patients with microscopic haematuria together with white blood cells in their urine, was signi cantly increased from 48% to 61% in the Tabriz cohort (p-value=0.03) and from 30 % to 35% in the Aachen cohort (p-value =0.045). Furthermore, in the group of patients with SARS-CoV-2 urine PCR, the mortality rate rose from 33% to 50%. (p-value =0.039).

Conclusion:
Patients admitted with COVID-19 infection did not report to have any lower urinary tract symptoms even those patient who had a positive Urine SARS-CoV-2 PCR.
In addition, hematuria, WBC in urine as well as COVID-19 positivity in urine were found to be strong negative prognostic factors in admitted COVID-19 patients.

Background
The latest and most momentous threat to our world is the pandemic caused by the new coronavirus known as COVID-19. Priorities in medical and surgical healthcare have shifted drastically due to this pandemic. All elds and specialties are facing new challenges and urology is no exception.
The 2019 novel Coronavirus (2019-nCOV) was isolated on the 7 th of January by Chinese scientists who then commenced genome sequencing which was later provided to the World Health Organization (WHO) on January 12 th 2020 [1].
The WHO revealed the causative virus as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the pneumonia as Coronavirus Disease 2019 (COVID-19). COVID-19 was declared a pandemic on March 11 th 2020 by the WHO [1].
Although respiratory symptoms are the predominant presentation of COVID-19 among symptomatic infected patients, it is important to emphasize that multiple organ involvement including the gastrointestinal tract, central nervous system, cardiovascular system, liver, bone marrow and kidney have already been reported in patients infected with SARS-CoV-2. [2,3] Besides severe lung failure i.e. Acute Respiratory Distress Syndrome (ARDS), heart and kidney failure have been recorded among infected patients [4].
Hematuria associated with SARS-CoV-2 infection has also been reported in both adults and children. [3,5] Moreover, in both human and animal studies, limited persistence of SARS-COV-2 has been detected [6,7]. We recorded patient data and comorbidities (including obesity, arterial hypertension, and existing respiratory disease), the time of symptom onset, and the date of admission as well as past medical history.
For pathogen diagnosis (viral, bacterial, fungal), bronchoscopy and broncho-alveolar lavage with a total volume of 160 ml was performed in all intubated patients.
For SARS-CoV-2 detection the viral load was recorded by real-time polymerase chain reaction (PCR) of respiratory material. Threshold cycles for the S-gene <20 were classi ed as high. Values >30 were considered low viral load; values between 20 and 30 were classi ed as moderate viral load.
Serum, urine, and stool were also tested for SARS-CoV-2. In addition, urine parameters were recorded over time, such as erythrocyte count (RBC), white blood cell count (WBC) and proteinuria. Descriptive and analytical statistics including chi-square test and Fisher's Exact test was employed using IBM SPSS (version 24). All analyses were considered signi cant when p<0.05.

Results
The study population was made up of two cohorts of COVID-19 patients who were hospitalized in the University Hospitals Aachen in Germany and Tabriz in Iran. A total of 238 patients were included in our study. The two cohorts existed of: 133 patients (41 females -92 males) who were admitted at the University Hospital in Aachen, Germany and 105 patients (39 females and 66 males) who were admitted at the University Hospital of Tabriz in Iran. The patients' data and characteristics are listed in table 1.
The average age of all patients studied was 65 years. In the Tabriz-cohort, the average age was 60 years (range 16-89) and in the Aachen-cohort it was 65 years (25-88). The majority of admitted COVID-19 patients in both Aachen and Tabriz were male, 70% and 63%, respectively.
The main primary symptoms that were reported were: fever, shortage of breath and coughing. None of the studied patients reported to have any lower urinary tract symptoms. In addition, the urine of 63 patients admitted in Aachen, was checked for SARS-CoV-2 presence by PCR. From these patients, 51 were negative (81%) of whom 13 patients died (25,5%). Moreover, 12 patients tested positive for SARS-CoV-2 in their urine (19%). From these 12 patients, 7 patients died (58%). This means that, in the group of patients with SARS-CoV-2 urine PCR, the mortality rate rose from 33% to 50%. The mortality rate in COVID-19 infected patients with microscopic hematuria together with white blood cells in their urine, was signi cantly increased from 48% to 61% in the Tabriz cohort (p-value=0.03) and from 30 % to 35% in the Aachen cohort (p-value =0.045), as shown in table 2.

Discussion
The diagnosis of COVID-19 can be challenging as patients often present with unclear or even subclinical signs of disease. [8] In our study, none of the COVID-19 patients reported any LUTS or had urinary retention or incontinence.
Even in those 12 patients who tested positive for viral RNA in their urine. A study that focused on an increase in urinary frequency as a symptom of COVID-19 identi ed this in seven males out of 57 patient admitted with COVID-19 [5]. Interestingly, no viral RNA was found in the urine of these patients [5] In our series the two cohorts of Tabriz and Aachen, were not statistically different regarding age and male-female ratio (p-value 0,18 and 0,28).
The mortality rate in Tabriz (48%) was signi cantly higher than in Aachen 30% (p-value 0.001). This might be explained by the availability of resources as well as patient comorbidities which was not investigated in our study. There were signi cantly less patients who had a urine culture in the Tabriz cohort which would explain the differences in the positive culture rates.
Microscopic haematuria was seen in a majority of tested COVID-19 patients of Tabriz and Aachen (68% and 78%, respectively) and was not due to a positive bacterial urine culture in most cases (Table 1).

Hematuria has been reported in other viral respiratory infections including in uenza A and B as well as
adenovirus [9]. Moreover, kidney injury in hospitalized patients with COVID-19 appears to be a frequent nding. [10] Different symptoms have been reported ranging from, from mild hematuria to severe renal failure [9]. The underlaying pathophysiology is not well known. However, hypotheses have been put forward on the cytopathic effects of the virus as well as the immune-complexes mediated damage [9]. Furthermore, indirect effects on renal tissue, including hypoxia, and rhabdomyolysis due to the cytokine in ammatory response to the virus might play a role as well.
In our study, we have found increase white blood cells (WBC) in the urine of about half of the tested COVID-19 patients ( Table 2). In most of the cases there was a negative bacterial urine culture.
The time from suspected exposure to the onset of COVID-19 and worsening hematuria ranged between 5 and 8 days in the reported cases.
In the face of a possible increase and new waves of the pandemic, clinicians should be aware that a nontypical course of hematuria or increased WBC in urine might be related to a COVID-19 infection, especially in patients with a preexisting condition of the urinary tract. [10] It is known that the mortality rates are high between the COVID-19 patients with acute kidney injury (60-90%) [11]. Viral RNA has been identi ed in the urine samples of COVID-19 patients even after recovery from respiratory symptoms [6]. In our study, SARS-CoV-2 was found in the urine of 19 % of the tested patients.
Angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 and responsible for host cell entry might be a another possible link to multi organ failure of the COVID-19 patients. ACE2 is expressed different organs such as the hearth, the gastrointestinal tract, bone marrow and kidneys and bladder. [12] Recent studies revealed the cell-surface protein angiotensin-converting enzyme 2 (ACE2) as the main receptor for the SARS-CoV-2 spike protein [13]. Investigations of the distribution across many different tissues revealed that ACE2 expression was highest in lung, intestines, and kidney, but it was also high in 2.4% of urothelial cells, which might be a link with lower urinary tract symptoms [14] . In Next to the kidney tissue bladder urothelium has cells that express ACE2 [10,14,15] We hypothesize a possible link between the lower urinary system and SARS-CoV-2 through the ACE2. (Figure 1) Regarding the urine analysis of COVID-19 patients in our study, we can state that the presence of WBC and RBC in the urine as well as the presence of COVID-19 virus in urine, seems directly related to an increase of mortality in these patients (table 2). In patients with microscopic hematuria together with white blood cells in their urine, the mortality was signi cantly increased from 48% to 61% in the Tabriz cohort (p-value=0.03) and from 30 % to 35% in the Aachen cohort (p-value =0.045). In addition, Moreover, in the group of patients with SARS-CoV-2 urine PCR, the mortality rate rose from 33% to 50%.

Declarations
Ethics approval and consent to participate: The Study was conducted in accordance to our local university Ethic Committee (Uniklinik RWTH Aachen, Germany) guidelines and approval.All patient data were anonymized. There were no additional administrative permissions required to access the raw data used in our study.

Consent to publish: not applicable
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.  Figure 1 Cartoon of SARS-CoV-2 Infection in the Urinary Bladder