Although
Chlamydia trachomatis,
Mycoplasma genitalium, and
Trichomonas vaginalis were traditionally considered the main pathogens responsible for the acquisition of NGU, recent advances in NAAT proved the rule of several other pathogens such as Ureaplasmas, Herpes simplex viruses (HSV), and Adenoviruses [
1]. While
Chlamydia trachomatis is the only non-gonococcal bacterium causing urethro-cystitis which is routinely screened for and is detected in approximately 20–50% of patients [
19],
Mycoplasma genitalium has become the second most frequently encountered pathogen in NGU cases [
19‐
21]. A combined infection with
Chlamydia trachomatis and
Mycoplasma genitalium has also been reported in up to 5 to 15% of patients [
22]. However, neither
Chlamydia trachomatis nor
Mycoplasma genitalium has been detected in approximately 30–60% of NGU cases [
23,
24]. This finding has classically been demonstrated in older patients and those without symptoms or discharge [
23,
25]. Classically implicated in the pathophysiology of NGU besides increasing the risk of human immunodeficiency virus transmission up to threefold,
Trichomonas vaginalis has a prevalence rate of 2.5–17% in the USA and is more common in females than in males and in African American patients [
25‐
31]. Likewise, Ureaplasmas are ocassionally associated with NGU [
32]. Despite initially failing to differentiate between
Ureaplasma urealyticum (biovar 2) and
Ureaplasma parvum (biovar 1), there is growing body of literature not only that
Ureaplasma urealyticum is solely pathogenic but also that
Ureaplasma urealyticum is not pathogenic in all infected patients [
33‐
35]. Although some studies demonstrated that this pathogenic
Ureaplasma urealyticum can account for up to 5–10% of NGU cases, these cases often have no evidence of urethro-cystitis making diagnosis and treatment still debatable [
36]. Accounting for 2–4% of NGU cases, Adenoviruses often lead to concomitant conjunctivitis [
37‐
39]. HSV types 1 and 2 are another cause of viral urethro-cystitis accounting for 2–3% of cases [
39]. HSV-1 is often responsible for the first episode of genital herpes, while HSV-2 is usually encountered in recurrent genital herpes [
40,
41]. The presence of monocytes in microscopical smear is a typical feature of viral urethro-cystitis [
38]. Other rare etiologies of NGU include
Neisseria meningitidis,
Haemophilus species,
Candida species, bacterial vaginosis-associated bacteria, urethral stricture, foreign bodies, and possibly Epstein Barr Virus [
42‐
44]. Although modern techniques enabled detection of many pathogens, there may still be unidentified pathogens implicated in the pathogenesis of urethro-cystitis. Accordingly, some organism-negative or idiopathic NGU cases that are currently considered non-infective may later prove infective, but we just did not have the sufficient tools to identify all implicated pathogens [
45,
46].
Diagnosis
Classically, the first step in diagnosis of NGU is the exclusion of gonococcal infections via GSS, NAAT, or culture [
47]. However, high-risk symptomatic patients can be diagnosed and empirically treated for both chlamydia and gonorrhea [
49]. The validity of the traditional method of diagnosis of NGU via the demonstration of polymorphonuclear leucocytes (PMNL) in the absence of the gram-negative diplococci of
Neisseria gonorrhoeae in urethral discharge has been recently put into question. This is largely because some NGU patients present with symptoms such as itching, dysuria, and/or tingling in the absence of urethral discharge [
1,
50]. Moreover, the conventional definition of urethro-cystitis as the demonstration of ≥ 5 PMNL per high-power field microscopy (HPF) in GSS from the anterior urethra [
51] has recently proved non-applicable for NGU. Orellana et al. [
52] and Rietmeijer et al. [
53] reported high prevalence of
Chlamydia trachomatis in low-grade urethro-cystitis of 3–5 PMNL/HPF. Additionally, Sarier et al. [
54] reported that the sensitivity of GSS for NGU diagnosis was significantly higher when the threshold was lowered from ≥ 5 to ≥ 2 PMNL/HPF. Accordingly, the Centers for Disease Control and Prevention (CDC) and the European Association of Urology (EAU) acted in favor of the findings from recent literature with the former lowering the threshold to ≥ 2 PMNL/HPF in its 2015 Sexually Transmitted Disease (STD) treatment guidelines and the latter recommending application of the threshold of ≥ 5 PMNL/HPF only for diagnosis of GU in its 2017 guidelines [
55]. Based on the above, NAAT has largely replaced GSS in the diagnosis of both gonococcal and non-gonococcal urethro-cystitis despite having lower efficacy in identification of other infective pathogens [
56,
57]. NAAT for chlamydia, gonorrhea, trichomoniasis, and possibly
Mycoplasma genitalium is generally recommended over culture due to its high sensitivity and specificity [
2]. The NAAT should be performed on a maximum of 10 ml of FVU as increasing the volume decreases the sensitivity [
47] (Table
2).
Treatment
When approaching a patient with signs and symptoms of urethro-cystitis, the first step is to identify whether it is gonococcal or non-gonococcal urethro-cystitis [
58]. After confirming NGU, patient with severe symptoms should receive empirical treatment with either doxycycline or azithromycin immediately without waiting for the test results [
57,
59]. On the other hand, patients with mild symptoms should receive pathogen-directed treatment after NAATs, culture, and microscopy as sometimes urethro-cystitis can resolve without treatment, but it is important to consider that NAATs identify pathogen but not susceptibility to antibiotics [
57,
60].
In cases of
Chlamydia trachomatis or
Ureaplasma, azithromycin or doxycycline is often used for at least 7 days. Fluroquinolones can also be used as a second-line treatment in selected cases [
36,
61,
62]. Manhart et al. [
63] and Schwebke et al. [
64] reported an equal efficacy of both doxycycline and azithromycin in management of NGU. However, doxycycline is still often preferred because of its higher chlamydial cure rates and lower risk of macrolide resistance [
47,
63,
64]. Treatment of trichomoniasis often requires a single dose of metronidazole [
57,
65,
66]. On the other hand,
Mycobacterium genitalium can be treated with doxycycline, macrolides, and moxifloxacin [
63,
64,
67].
To lower the risk of re-infection, it is important to advise the patient to abstain from sexual intercourse for at least 7 days after starting therapy, to screen and treat all sexual partners over the past 60 days, and to screen for other STDs including syphilis and HIV [
6‐
8,
56,
68,
69] (Table
2).