COVID-19 is associated with a variety of urologic manifestations in adult patients. The most common urologic complication of COVID-19 is acute kidney injury with a prevalence of 7.58%, while other less common genitourinary sequelae in adults include ischemic priapism, lower urinary tract dysfunction, and epididymo-orchitis (EO) (7–9). However, the current literature is lacking with respect to the viruses’ urologic effect in pediatric COVID-19 patients. Recently published case reports of ischemic priapism in a 12-year-old boy and torsion of appendix testis in an 8-year-old boy provide some insight into the genitourinary manifestations of SARS-CoV-2 (10, 11). Additionally, there have been some reports of EO associated with SARS-CoV-2 in pediatric patients. However, no systematic reviews of the genitourinary manifestations of SARS-CoV-2 within the pediatric patient, specifically EO, currently exist.

Epididymitis is defined as inflammation of the epididymis, orchitis is defined as inflammation of the testis, and EO is defined as the presence of both epididymitis and orchitis (12–14). These conditions most commonly present with scrotal pain, redness, and swelling, and ultrasound findings characteristically include enlargement of the testis and/or epididymis, thickening of the tunica albuginea, and increased flow on Doppler ultrasound (12–15). The incidence of EO has been estimated at 1.2 out of 1,000 annually in boys aged 2-14 years old, while a recent review of retrospective studies on epididymitis and EO indicated a mean incidence of 37.3% in pediatric patients presenting with an acute scrotum (16, 17). EO may be caused by a variety of etiologies, including infection (Chlamydia trachomatis, Neisseria gonorrhea, tuberculosis, mumps), medications (amiodarone), and systemic inflammatory conditions such as Kawasaki Disease, Henoch-Schoenlein Purpura, and, most recently, SARS-CoV-2 related MIS-C (12–14, 18, 19). In addition to acute and systemic inflammation, SARS-CoV-2 may also directly infect cells of the testis via its functional receptor angiotensin converting enzyme 2 (ACE2) (20). ACE2 is also expressed in testicular tissue, suggesting a potential novel pathophysiologic mechanism of EO (20).

Given that SARS-CoV-2 may directly infect the genitourinary tract and may cause systemic inflammation, particularly within the pediatric population, epididymitis, orchitis, and EO are uncommon but significant manifestations in pediatric patients. Herein, we present a systematic review of the known pediatric cases of epididymitis, orchitis, and EO associated with COVID-19. Our objective is to investigate the clinical presentations of cases, including initial signs and symptoms, subsequent management, and outcomes in pediatric patients with concurrent COVID-19 infection and epididymitis, orchitis, and EO.

Our initial query using the previously described search criteria produced 60 results ( Figure 1 ). After 21 duplicates were removed, the remaining 39 results were screened based on title and abstract for the inclusion criteria, resulting in 7 manuscripts appropriate for full text review. An additional 4 manuscripts were found based on cross-referencing, resulting in a total of 11 manuscripts for full text review. Of the 11 reviewed, 5 articles were excluded resulting in 6 case reports for subsequent synthesis ( Table 1 ) (23–28). Two manuscripts were excluded due to no clear diagnosis in a case series, and 3 manuscripts were excluded as they described retrospective cohorts without detailed clinical courses (5, 19, 29–31).

The 6 case reports included in this systematic literature review described a total of 6 male patients with a mean age of 9.5 years (range 5-14). All 6 reports fulfilled all 8 items of the JBI Critical Appraisal Checklist for Case Reports. Table 1 describes the clinical characteristics of the 6 patients included in this systematic review. All 6 patients had fever and genitourinary symptoms on initial presentation, while 5 patients had documented testicular or scrotal swelling subjectively. Onset of any symptom of SARS-CoV-2 to presentation was on average 4 days (range 2-8), while onset of genitourinary symptoms to presentation was on average 3.5 days (range 2-8) ( Table 2 ). One patient experienced possible prodromal symptoms with 2 days of high fever that spontaneously resolved 2 weeks prior to admission. One patient was diagnosed with acute epididymitis and 5 patients were diagnosed with EO. Physical exam findings commonly included scrotal swelling, erythema, and tenderness. All patients were admitted to the hospital for their conditions.

Five patients had confirmed COVID-19 via nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). 1 patient was negative for SARS-CoV-2 on nasopharyngeal RT-PCR though had a positive anti-SARS-CoV-2 IgG with a confirmed positive sick-contact ( Table 2 ). Four of the 6 cases were associated with MIS-C. All 6 patients had documented hematologic derangements, including either leukocytosis, lymphopenia, or lymphopenic leukocytosis. Additionally, all 6 patients had elevated inflammatory markers, most commonly C-reactive protein and erythrocyte sedimentation rate, though procalcitonin, ferritin, and D-dimer were also elevated in some patients. Of the 5 cases with documented urine studies (urinalysis or urine culture), only 1 urinalysis was positive for leukocytes and leukocyte aggregates in a patient experiencing dysuria and urinary frequency; no urine culture results were reported for this patient and SARS-CoV-2 RT-PCR of his urine was negative. Five out of 6 patients had additional infectious studies documented including viral serologies (Epstein-Barr Virus, Cytomegalovirus, Mycoplasma pneumoniae), antistreptolysine O, and blood cultures. Other than one patient with a positive outpatient rapid streptococcal antigen test, all other infectious studies were negative. For all 6 patients, no sexually transmitted infection testing was reported (i.e., Chlamydia trachomatis, Neisseria gonorrhoeae), and there were no comments documented on the patients’ sexual activity. Scrotal ultrasounds were performed on all 6 patients to support the diagnoses, with common findings including increased testicular volume, hypervascularity, and reactive hydrocele. Interestingly, 1 patient had an initial ultrasound which revealed “testicular torsion” prompting surgical intervention, though during scrotal exploration, no torsion was found (28). The initial ultrasound findings to suggest torsion were not described in the case report, and repeat ultrasound showed findings more consistent with EO with thickening of the tunica albuginea and vasitis.

Treatment for all cases of epididymitis, orchitis, and EO included antibiotics most commonly with a third-generation cephalosporin (cefdinir, ceftriaxone), though other antibiotics utilized include cefdinir, vancomycin, and levofloxacin ( Table 1 ). Two patients were treated prior to admission with antibiotics prescribed by their primary care physicians (cefuroxime and amoxicillin/clavulanic acid). All cases associated with MIS-C were treated with intravenous immunoglobulin (IVIG) and methylprednisolone, though other medications included aspirin, proton pump inhibitors (omeprazole), vasoactive medications (dopamine), and anti-coagulants (enoxaparin, heparin). All patients were hospitalized with a mean hospital stay of 7.5 days (range 3-10). 2 patients reportedly required admission to the pediatric intensive care unit (PICU) for hemodynamic instability, and all patients eventually recovered from their illness with no mortalities. Only 2 cases indicated any follow-up after admission, with Gagliardi et al. describing “progression to normality” at 8 days after discharge and Sudeep et al. reporting their patient was asymptomatic at 1 month follow-up.

To our knowledge, this is the first systematic review to critically evaluate the published cases of epididymitis, orchitis, and EO associated with COVID-19 in pediatric patients. Along with the 6 cases described in this systematic review, our literature search also resulted in 1 case of epididymitis, 2 cases of orchitis, and 1 case of EO documented across three retrospective cohorts of pediatric patients with COVID-19, though these cases were excluded in the present systematic review due to lack of detailed information regarding symptomatology, management, and outcomes (5, 30, 31). Although relatively few cases have been reported since the beginning of the COVID-19 pandemic, the cases included in this systematic review were severe and associated with complex COVID-19, each requiring at least 6 days of admission. Additionally, given the nature of case reports which typically describe the most severe cases, there may be many children who experience relatively mild symptoms at home without contacting their health care providers. All patients survived and were discharged in significantly improved conditions.

The majority of the cases included in our systematic review were associated with MIS-C. Additionally, all 4 of the previously mentioned cases excluded (due to insufficient data) were associated with MIS-C (5, 30, 31). Furthermore, we also reviewed 2 pediatric case series in MIS-C patients which described 2 patients with signs and symptoms of epididymitis, orchitis, and EO. This included scrotal pain in one patient and signs of hyperemia of the testes and epididymes in the other patient (19, 29). In consideration of these factors, male patients with MIS-C should be carefully monitored for genitourinary symptoms. Epididymitis, orchitis, and EO should be considered as possible diagnoses in COVID-19 patients with urinary or scrotal symptoms.

Epididymitis, orchitis, and EO in pediatric patients are relatively common conditions potentially caused by infection, reflux or stasis of urine, trauma, or systemic inflammatory conditions. SARS-CoV-2 may be another causative virus due to a combination of cellular susceptibility to infection and systemic inflammation. Similar to its predecessor SARS-CoV-1, SARS-CoV-2 uses ACE2 as its functional receptor and transmembrane serine protease 2 (TMPRSS2) for priming its spike protein (32, 33). In human tissues, ACE2 is highly expressed in the lungs, oral and nasal mucosae, and within the gastrointestinal tract, suggesting potential sites of initial infection and routes of transmission (32, 33). Furthermore, the distribution of ACE2 and TMPRSS2 expression correlates with common sequelae of COVID-19, including within the respiratory system (cough, rhinorrhea, pneumonia) and gastrointestinal system (vomiting, diarrhea) (32). ACE2 and TMPRSS2 have been shown to be expressed within the testis including in Sertoli cells, Leydig cells, and spermatogonia, suggesting potential susceptibility of these cells to direct COVID-19 (20, 34).

Along with the biomolecular susceptibility of the male reproductive system, several objective laboratory and radiologic findings are associated with COVID-19. In a cohort of adult male patients with confirmed COVID-19 at single center in Wuhan, China, 32/142 (22.5%) met ultrasonographic diagnostic criteria of epididymitis, orchitis, or EO (15). Autopsy studies of patients infected with SARS-CoV-2 showed findings consistent with interstitial orchitis as well evidence of germ cell infection with scarcity of Sertoli and Leydig cells and decreased spermatogenesis (35, 36). Several studies have found hormonal derangements in patients infected with SARS-CoV-2, with increasing severity of infection associated with increasing magnitude of hormonal change (37, 38). Furthermore, certain etiologies of epididymitis, orchitis, and EO are associated with chronic and irreversible sequelae including infertility due to germ cell destruction and damage to the seminiferous tubules including mumps and chronic C. trachomatis and N. gonorrhoeae (12, 14, 39). While SARS-CoV-2 is not known to cause irreversible infertility, it has demonstrated an ability to alter sperm analyses with effects on sperm motility and sperm count (40). In light of this, within the pediatric population, the potential for COVID-19 to adversely affect sexual development and puberty should be considered, and future investigations assessing long-term outcomes in this developing population are warranted.

Along with the previously published cases of ischemic priapism and torsion of the appendix testis, SARS-CoV-2 may present with multiple acute genitourinary symptoms and may even mimic acute urologic emergencies, as exemplified by the case in this systematic review who underwent surgical exploration for suspected testicular torsion. Providers should be cognizant of the urologic manifestations of SARS-CoV-2 in pediatric patients and have a high suspicion for epididymitis, orchitis, or EO in pediatric SARS-CoV-2 patients with genitourinary symptoms, particularly in the setting of MIS-C. Future investigations should be directed towards exploring the long-term sequelae of COVID-19 within the genitourinary tract, including the potential effects on male fertility. Furthermore, consideration of these factors may be taken when counseling pediatric patients and their families regarding immunization against SARS-CoV-2.

Limitations of this study include the descriptive observational nature of case reports and case series which are, by nature, prone to biases. Furthermore, as previously described, case reports and case series often display the most severe clinical courses seen at academic centers, and it is possible that more benign cases of epididymitis, orchitis, and EO are occurring in the general population without medical evaluation. This systematic review also includes a relatively small number of included articles which may limit the generalizability. However, the complications investigated in this study are relatively rare and the long-term effects of COVID-19 on sexual development in pediatric patients still need to be elucidated; therefore, this systematic review of the published cases is warranted to assemble and synthesize the limited data regarding this clinically significant manifestation. Our systematic review was also not registered through PROSPERO as data collection had begun prior to registration, though we followed the guidelines to the best of our ability and have uploaded our PRISMA checklist and protocol in the supplementary files.