Diagnosis and Treatment Outcomes of Urethritis-like Symptoms in Young Males: A Retrospective Cohort Study

doi:10.21203/rs.3.rs-2592650/v1

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Diagnosis and Treatment Outcomes of Urethritis-like Symptoms in Young Males: A Retrospective Cohort Study

https://doi.org/10.21203/rs.3.rs-2592650/v1

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Background

Urethritis in young males is most commonly caused by sexually transmitted pathogens, although other non-infectious diseases can cause similar symptoms. The study evaluated the prevalence of gonorrhoea and chlamydia infections in sexually active young males with urethritis-like symptoms and their treatment outcomes.

Methods

Data of 20–50-year-old males who visited our clinic with urethritis symptoms between March 2019 and April 2022 were retrospectively collected. All patients underwent urinalysis, urine culture, and urinary polymerase chain reaction (PCR) testing for gonorrhoea and chlamydia at the first visit. Student’s t-test and Pearson’s chi-square test were used to compare the differences between participants with at least one positive test result and those with negative results in all three tests. Regression analyses were used to evaluate the predictive factors for positive PCR results for gonorrhoea or chlamydia in patients with negative urinalysis and urine culture results.

Results

Of the 365 participants with urethritis symptoms, those with negative results (39%) in all tests were significantly older and showed less frequent urethral discharge than those with at least one positive result. Among the 202 patients with negative urinalysis and urine culture results, 29.7% were diagnosed with gonorrhoea or chlamydia using PCR. The presence of discharge was an independent predictor of positive PCR results for gonorrhoea or chlamydia. For patients showing negative results in all tests, the most common tentative diagnosis was balanitis. Patients with negative results for all three tests have good prognosis.

Conclusion

The present study outlined the high frequency of negative urinalysis and urine culture results in young male patients with gonorrhoea- and chlamydia-related urethritis and indicated the importance of a history of urethral discharge as an indicator for antibiotic treatment of gonorrhoea and chlamydia in these patients. The findings of this study will be valuable for urologists treating young males with urethritis symptoms, and the insights provided here will facilitate appropriate management and patient satisfaction in such cases.

Chlamydia trachomatis

Neisseria gonorrhoeae

urethritis

diagnosis

young males

The symptoms of urethritis include acute-onset dysuria or increased urinary frequency and urgency. Some patients may present with purulent discharge from the urethral meatus, dyspareunia, haematuria, and haematospermia. Among young males, urethritis is most commonly caused by sexually transmitted infections (STIs), including Neisseria gonorrhoeae and Chlamydia trachomatis infections. Thus, urethritis can be categorized as gonococcal urethritis, non-gonococcal urethritis, or non-chlamydial non-gonococcal urethritis based on the results of urine culture and multiplex polymerase chain reaction (PCR).^1,2 Possible pathogens in cases of non-chlamydial non-gonococcal urethritis include Mycoplasma genitalium, Ureaplasma urealyticum, and Trichomonas vaginalis,^3,4 while other non-infectious diseases may also result in symptoms similar to those of urethritis.

Urinalysis and urine culture are the initial examinations performed in patients with urethritis symptoms. However, diagnosis of urethritis based on urinalysis and urine culture is not always feasible in clinical practice. Although PCR can yield more accurate diagnoses of urethritis, it is costly and not always available in every clinic. Previous studies have showed that most of those with potential STIs were commonly negative for urinalysis and urine culture.⁵ Given that a proportion of urinalyses and urine cultures yield false negatives, it is important to avoid missed STIs cases and to ensure adequate treatment. In the present study, we retrospectively collected and analysed data pertaining to the clinical presentations, possible aetiologies, treatment, and prognosis of young adult males with symptoms of urethritis. Further, we aimed to investigate the prevalence of gonorrhoea and chlamydia infections in these patients. We assumed other non-infectious diseases can also cause similar symptoms. The findings of the present study will be helpful for urologists in treating young patients with symptoms of urethritis.

Study Population

All young adult male patients (aged 20–50 years) with symptoms of urethritis who visited our clinic between March 2019 and April 2022 were retrospectively recruited. In total, 365 patients were included in the study and 42 participants were excluded due to lost follow up. This study was approved by the Institutional Review Board of Taipei City Hospital (TCHIRB-11106012-E) and the need for informed consent was waived due to the retrospective nature of the study. Urethritis-like symptoms included dysuria, increased urination frequency, and urethral discharge. Demographic data, including age at presentation, and symptoms associated with urethritis were collected. Considering their symptoms and young age, all patients underwent urinalysis, urine culture, and urinary PCR for N. gonorrhoeae and C. trachomatis at the first visit. Treatments were administered based on the initial urinalysis results and clinical judgment of the urologists. All patients were asked to return to our clinic after one week of treatment for repeated urinalysis. The treatment was changed depending on the patient’s response to the initial treatment or positive results in urine culture or urinary PCR. HIV and syphilis tests were recommended for those with positive results of urinary PCR. For patients showing triple-negative findings (i.e., negative results in urinalysis, urine culture, and urinary PCR), follow-up data for symptom resolution were collected one month later.

Statistical analysis

All data were expressed as number (percentage) or mean ± standard deviation. Student’s t-test and Pearson’s chi-square test were used to compare the differences in continuous and categorical parameters between participants in the triple-negative and any-positive groups. A Venn diagram was used to demonstrate the test patterns in patients with urethritis-like symptoms. Univariate and multivariate logistic regression analyses were used to evaluate the predictive factors for positive gonorrhoea or chlamydia PCR results in patients with negative urinalysis and urine culture results. Statistical analyses were performed using IBM SPSS Statistics for Mac ver. 25 (IBM Corp., Armonk, NY, USA). All statistical analyses were performed using 2-sided tests and a p value < 0.05 was considered statistically significant.

In total, 365 young adult males with symptoms of urethritis were included in the study. Table 1 shows the demographic characteristics of the patients, including the age at diagnosis, presence of comorbidities, and associated symptoms. Unprotected sexual intercourse in the previous two weeks was only reported in 26.6% of the patients. Besides urethral discharge and dysuria, painful sensation at the scrotum was the most common associated symptom (12.6%). Persistent symptoms were observed in 22 (6.0%) patients after initial empirical therapy. We also classified participants on the basis of their test results. Patients with triple-negative urinalysis/culture/PCR results (triple-negative group) were significantly older (37.0 ± 9.5 years vs. 34.0 ± 8.2 years, p = 0.001) but had less frequent reports of urethral discharge (8.5% vs. 82.1%, p < 0.001) and less symptom persistence (0% vs. 9.9%, p < 0.001) than those with positive results in any of the three tests (any-positive group). The incidences of prior unprotected sexual intercourse, comorbidities, and other associated symptoms were similar between the two groups.

Table 1

Characteristics patients with urethritis symptoms and differences between patients in the any-positive and triple-negative groups
Characteristics	Total patients (n = 365)		Triple-negative group (n = 142)		Any-positive group (n = 223)		p value
Age: years (SD)	35.2	(8.8)	37.0	(9.5)	34.0	(8.2)	0.001
Comorbidity: no. (%)	11	(3.0%)	1	(0.7%)	10	(4.5%)	0.056
Unprotected sex: no. (%)	97	(26.6%)	34	(23.9%)	63	(28.3%)	0.364
Discharge: no. (%)	195	(53.4%)	12	(8.5%)	183	(82.1%)	< 0.001
Scrotal pain: no. (%)	46	(12.6%)	20	(14.1%)	26	(11.7%)	0.520
Haematuria: no. (%)	13	(3.6%)	4	(2.8%)	9	(4.0%)	0.773
Haematospermia: no. (%)	9	(2.5%)	4	(2.8%)	5	(2.2%)	0.740
Erectile dysfunction: no. (%)	8	(2.2%)	3	(2.1%)	5	(2.2%)	0.934
Premature ejaculation: no. (%)	2	(0.5%)	0	(0.0%)	2	(0.9%)	0.523
Perineal pain: no. (%)	5	(1.4%)	0	(0.0%)	5	(2.2%)	0.161
Persistent symptoms: no. (%)	22	(6%)	0	(0.0%)	22	(9.9%)	< 0.001
Triple-negative group = negative results in urinalysis and urine culture and gonorrhoea/chlamydia PCR; any-positive group = positive results in urinalysis, urine culture, or gonorrhoea/chlamydia PCR

Figure 1 shows a Venn diagram of the results of urinalysis, urine culture, and PCR in 365 patients with symptoms of urethritis. Among the 121 patients showing pyuria on urinalysis, only 37 (30.6%) showed positive urine culture results, including suspected contamination in 24 urine specimens, and PCR results confirmed gonococcal or chlamydial urethritis in 64 (52.9%) patients. In total, 244 patients with symptoms of urethritis showed no pyuria on urinalysis. Although 42 (17.2%) patients showed positive urine culture results, only 2 (0.8%) were confirmed to have gonococcal infection on urine culture. A total of 60 (24.6%) patients showed gonococcal or chlamydial urethritis in PCR analysis. The N. gonorrhoeae isolates in all 15 cases diagnosed by urine culture were susceptible to cefoxitin, cefotaxime, and ceftriaxone.

Among the 202 patients showing negative results in urinalysis and urine culture, 60 (29.7%) were diagnosed as having gonorrhoea or chlamydia through PCR (Table 2). In the univariate and multivariate logistic regression analyses, the presence of discharge was an independent predictor for a diagnosis of gonorrhoea or chlamydia by PCR (odds ratio, 32.669; 95% confidence interval, 13.67–78.09; p < 0.001), after adjustment for age and history of unprotected sexual intercourse.

Table 2

Predictive factors of positive gonorrhoea or chlamydia PCR test results for patients with negative urinalysis and urine culture results
	Univariate analysis		Multivariate analysis
Characteristics	Odds ratio (95% CI)	p value	Odds ratio (95% CI)	p value
Age (years)
> 30	(ref)		(ref)
< 30	1.83 (0.96, 3.48)	0.065	1.08 (0.44, 2.66)	0.871
Unprotected sex
no	(ref)		(ref)
yes	1.71 (0.89, 3.30)	0.109	0.914 (0.36, 2.34)	0.851
Discharge
no	(ref)		(ref)
yes	32.50 (14.15, 74.63)	< 0.001	32.669 (13.67, 78.09)	< 0.001
ref: reference; CI: confidence interval

However, 142 (38.9%) of the young adult males with symptoms of urethritis showed negative results in urinalysis, urine culture, and PCR (Fig. 1). Table 3 shows the treatments administered to these patients. The most common diagnosis was balanitis (20.4%), followed by bladder outlet obstruction (14.1%), epididymo-orchitis (5.6%), and varicocele (3.5%). Medications such as alpha-blockers (19.7%), non-steroidal anti-inflammatory drugs (16.9%), phenazopyridine (28.2%), and empirical antibiotics (68.3%), including doxycycline, cefadroxil, and levofloxacin, were prescribed on the basis of the clinical assessment. Symptoms subsided after one week of treatment in all these patients and these non-infectious diseases were cured through adequate evaluation and treatment with good outcomes.

Table 3

Treatment in patients with triple-negative test results
Treatment	Total (n = 142)
Alpha blocker	28	(19.7%)
Anticholinergics or beta-3 agonist	8	(5.6%)
NSAID	24	(16.9%)
Phenazopyridine	40	(28.2%)
Empirical antibiotics	97	(68.3%)
Cefadroxil	20	(14.1%)
Levofloxacin	13	(9.1%)
Doxycycline	64	(45.1%)
NSAID: non-steroidal anti-inflammatory drug

Complaints of urethritis symptoms, including dysuria, increased urination frequency, and urethral discharge, are common in urology clinics. However, the diagnosis and treatment of this condition may be occasionally challenging. In the present study, 39% of the 365 patients with urethritis symptoms showed negative results in urinalysis, urine culture, and PCR tests for chlamydia and gonorrhoea. The results further highlighted the high frequency of negative urinalysis and urine culture results in young male patients with gonorrhoea- and chlamydia-related urethritis (29.7%) and indicated the importance of a history of urethral discharge (odds ratio: 32.6, p < 0.001) as an indicator for antibiotic treatment of gonorrhoea and chlamydia in these patients. In the triple-negative group, balanitis was the most common tentative diagnosis, and the symptoms subsided in these patients after one-week of empirical treatment. These findings will be of value for urologists treating young males with urethritis symptoms, and the insights provided in this study will facilitate appropriate management and patient satisfaction in such cases.

Urinalysis and urine culture are the initial examinations performed in patients with urethritis symptoms. The present study showed that the prevalence of pyuria was 33% and that of positive urine cultures was 21%. A study by Shipman et al. showed similar results, wherein the prevalence of pyuria was 37%, and among the cases with pyuria, 74% had sterile pyuria.⁵ Among patients with symptoms of urethritis but negative urinalysis and culture results, up to 30% were diagnosed with gonorrhoea or chlamydia using PCR. Therefore, PCR testing is particularly important in patients with negative urinalysis and urine culture results.² However, PCR testing is costly and time-consuming and is not always available in every clinic. In the present study, urethral discharge was reported in 53.4% of all patients and 82% of patients in the any-positive group. A study by Bellinato et al. reported urethral discharge in 86% of patients with PCR-identified urethritis.⁶ This result is consistent with our findings. Patients with gonococcal urethritis usually present with a purulent discharge, whereas non-gonococcal urethritis is associated with the presence of a transparent discharge.⁷ In our study, the presence of discharge was independently associated with PCR positive results for gonorrhoea or chlamydia and could be a guide to prescribe antibiotics against gonorrhoea and chlamydia in clinical practice, in the absence of PCR testing ability.

Other studies have also reported that a significant proportion of men with urethritis symptoms have no detectable pathogens.^8,9 In the present study, patients with triple-negative tests were significantly older and had less frequent reports of urethral discharge. Therefore, we attempted to identify the possible non-infectious aetiologies of urethritis-like symptoms in this patient population. Balanitis was the tentative diagnosis in 20.5% of the patients, indicating that physical examination of the genital area is mandatory in patients complaining of urethritis-like symptoms. Moreover, all patients reported symptom relief after one week of empirical treatment including empirical antibiotics, phenazopyridine, non-steroidal anti-inflammatory drugs, and alpha-blockers. However, we could not determine whether the improvement in symptoms was due to the empirical treatment or if the sterile urethritis-like symptoms were self-limited in our patients. Dowd et al. suggested that urethral syndrome could be a self-limited illness with a short episode in patients without causality of organisms.¹⁰

In the present study, the prognosis of urethritis-like symptoms was quite good even when a pathogen could not be identified. No antibiotic resistance was identified in patients with N. gonorrhoeae infection. The study showed that 94% of the patients were clinically cured on the first return visit, and no symptom recurrence was noted at the 3-month follow-up. Only 6% of patients complained of persistent discomfort after initial empirical treatment. In another retrospective cohort study, 91.5% and 6.5% of the patients presenting with urethral discharge syndrome were considered clinically cured at the first and second visits, respectively.¹¹ In addition to medical treatment, reassurance and emotional support may be helpful in improving anxiety associated with urethritis-like symptoms.

Based on the findings of the present study, we have provided a flowchart for the management of young male patients with urethritis-like symptoms (Fig. 2). For patients presenting with positive urinalysis results, we suggest empirical treatment for both N. gonorrhoeae and C. trachomatis, in accordance with the sexually transmitted disease treatment guidelines.^11,12 The same empirical treatment is also recommended for patients showing negative urinalysis results but with urethral discharge.⁹ Urinary PCR can be performed for patients without pyuria on urinalysis but with a history of urethral discharge, and empirical treatments based on clinical assessment by urologists could be provided to these patients. On the return visit, treatment may be tailored depending on the treatment response and the results of urine culture or urinary PCR.

This study had some limitations that require consideration. First, it was conducted at a single community hospital, potentially leading to a bias in the prevalence and distribution of microorganisms as well as their resistance to antibiotics. Second, the prevalence of unprotected sexual intercourse may have been underestimated in the present study, which is common in clinical practice. Third, other causative pathogens of STIs, such as M. genitalium, U. urealyticum, and T. vaginalis, were not further investigated in this study. Although the specificity of PCR test is greater than 99%, there is still a potential for a false-positive result. However, the present study will be valuable to urologists practicing. We have provided a simple flowchart for real-time and cost-effective management of young adult males presenting with symptoms of urethritis. We believe that the results of the present study can help prevent the spread of STIs, avoid unwanted complications such as urethral stricture or arthritis, and improve satisfaction in patients with urethritis.

Young male patients with urethral N. gonorrhoeae and C. trachomatis infections frequently show negative results in urinalysis and urine culture. A history of urethral discharge may be an indicator for antibiotic treatment against N. gonorrhoeae and C. trachomatis in patients without pyuria on urinalysis. Patients showing negative urinalysis, urine culture, and urinary PCR results have good prognosis; urologists should provide empirical treatment based on their clinical judgment and help relieve their anxiety through reassurance.

PCR: polymerase chain reaction

STI: sexually transmitted infection

Ethics approval and consent to participate: The study protocol for this research project has been approved by the Institutional Review Board of Taipei City Hospital, and it conforms to the provisions of the Declaration of Helsinki. The requirement for informed consent was waived by the Ethics Committee of (Institutional Review Board of Taipei City Hospital, Approval No. TCHIRB-11106012-E) because of the retrospective nature of the study.

Consent for publication: 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.

Competing interests: The authors declare that they have no competing interests.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author contributions: YTH was a major contributor in writing the manuscript, performed the conceptualization, and administered the project. TYC analyzed and interpreted the patient data. JCH did the resources and data curation. WC was a major contributor in review and supervision. All authors read and approved the final manuscript.

Acknowledgements: not applicable

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No competing interests reported.

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Diagnosis and Treatment Outcomes of Urethritis-like Symptoms in Young Males: A Retrospective Cohort Study

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Background

Methods

Results

Conclusion

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Background

Methods

Study Population

Statistical analysis

Results

Discussion

Conclusions

Abbreviations

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References

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