J Infect Chemother xxx (2017) 1e3

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Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Case Report

Clinical courses of herpes simplex virus-induced urethritis in men

Shin Ito a, Mitsuru Yasuda b, Hiromi Kondo b, Yoshiteru Yamada b, Keita Nakane b,
Kosuke Mizutani b, Tomohiro Tsuchiya b, Shigeaki Yokoi b, Masahiro Nakano b,
Takashi Deguchi b, *
a
iClinic, 5-9-6 Naga-machi, Taihaku-ku, Sendai 982-0011, Japan
b
Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan

a r t i c l e i n f o a b s t r a c t

Article history: We retrieved clinical data of 13 men having herpes simplex virus (HSV)-induced non-gonococcal ure-
Received 28 February 2017 thritis (NGU) without visible herpetic lesions. They visited a clinic in Sendai, Japan, between April 2013
Received in revised form and December 2015. All the men complained of dysuria. Meatitis was observed in 9 of the 13 men.
22 March 2017
Mononuclear cells were observed in the urethral smears from 9 men. The 13 men were treated with
Accepted 27 March 2017
Available online xxx
azithromycin or sitafloxacin regimen. First-voided urine (FVU) specimens became negative for HSV in 8
of the 10 men who returned to the clinic after antibacterial treatment, and urethritis symptoms were
alleviated. However, herpetic lesions were observed at the follow-up visits in 3 men, and 2 of them were
Keywords:
Genital herpes
still positive for HSV in their FVU. HSV could be a cause of acute urethritis without causing visible
Herpes simplex virus herpetic lesions. The shedding of HSV from the urethra would spontaneously cease with alleviation of
Non-gonococcal urethritis urethritis symptoms in most cases of HSV-induced NGU without antiviral therapy. However, new
herpetic lesions could be developed in some cases. Early antiviral therapy is beneficial for patients with
HSV infections. The development of meatitis and the mononuclear cell response in the urethral smear
could be helpful to diagnose HSV-induced NGU. Therefore, we should presumptively initiate anti-HSV
therapy for patients with signs and symptoms suggestive of HSV-induced NGU at their first presentation.
© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

1. Introduction positive urethritis practiced unprotected oral sex; more patients

Herpes simplex virus (HSV) has been detected in the urethral
swabs and first-voided urine (FVU) specimens collected from men
suffering from acute urethritis without visible herpetic lesions
[1e6]. A study suggested that HSV might be detected more often in
men with non-gonococcal urethritis (NGU) than in control men
without NGU [3]. In our previous study, we reported that the
respective positive rates of HSV type 1 (HSV-1) and HSV type 2
(HSV-2) were 2.8% and 0.9% in men with acute urethritis, 3.7% and
1.3% in those with non-gonococcal urethritis (NGU), and 7.1% and
2.6% in those with non-chlamydial NGU (NCNGU) and that no
visible herpetic lesions were observed in 8 (73.7%) of 11 men with
HSV-1-positive NCNGU and in 3 of 4 men with HSV-2-positive
NCNGU [4]. We also reported the characteristics of HSV-positive
monomicrobial urethritis as follows: all of the patients with HSV-
* Corresponding author. Fax: þ81 58 230 6339.
E-mail address: deguchit@gifu-u.ac.jp (T. Deguchi).
complained of intense dysuria rather than urethral irritation; no
patients reported urethral discharge; urethral discharge was scant
and its nature was serous in all cases on genital examination;
meatitis and/or balanitis were often observed; and leukocyte
counts in FVU were relatively low [4]. However, most characteris-
tics were superimposed on those of NGU caused by other micro-
organisms such as Chlamydia trachomatis and Mycoplasma
genitalium. If visible herpetic lesions were not coincidentally
observed in men suffering from NGU, it would be difficult to predict
HSV as a causative microorganism of their NGU in clinical settings.
In addition, point-of-care tests for HSV are not preformed to di-
agnose HSV-positive NGU. Therefore, these patients might well be
diagnosed as having NGU caused by bacterial pathogens and be
treated not by antiviral agents but by antibacterial agents. However,
the clinical courses after treatment in such patients have rarely
been documented.
We retrieved clinical data from the medical records of men who
had HSV-positive urethritis not accompanied by visible herpetic
lesions and were treated by the regimens recommended for the

http://dx.doi.org/10.1016/j.jiac.2017.03.017
1341-321X/© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Ito S, et al., Clinical courses of herpes simplex virus-induced urethritis in men, J Infect Chemother (2017),
http://dx.doi.org/10.1016/j.jiac.2017.03.017
2 S. Ito et al. / J Infect Chemother xxx (2017) 1e3

treatment of NGU in Japan [7]. We attempted to clarify the clinical
courses of these patients with HSV-associated NGU after treatment
with antibacterial agents.
2. Case report
This retrospective case report was approved by the Institutional
Review Board of the Graduate School of Medicine, Gifu University,
Gifu, Japan (reference number 20-94). However, the consent of the
subjects was not obtained when this study was conducted because
they could not be traced. Therefore, we sufficiently anonymized
their information.
Thirteen men positive for HSV-1 or HSV-2, but without visible
herpetic lesions, were enrolled in this study, including 9 men
involved in our previous study [4]. They visited the iClinic, Sendai,
Japan, between April 2013 and December 2015, complaining of
dysuria and/or urethral irritation. They underwent genital exami-
nations, and their Gram-stained urethral smears were examined for
the presence of leukocytes and Gram-negative diplococci. Their
FVU specimens were examined for quantification of leukocytes
with automated quantitative urine particle analyzers (UF-1000i,
Sysmex Corporation, Kobe, Japan) according to the manufacturer's
instructions. The urethral swabs and/or FVU were subjected to tests
for Neisseria gonorrhoeae, C. trachomatis, M. genitalium, Mycoplasma
hominis, Ureaplasma parvum, Ureaplasma urealyticum, Haemophilus
influenzae, Streptococcus pneumoniae, HSV, human adenovirus, and
Trichomonas vaginalis, as reported previously [4].
The 13 men ranged in age from 20 to 42 years (median age, 34
years). As for their sexual partners, 8 reported female sex workers,
and 5 reported girl friends or wives. However, there was no infor-
mation regarding HSV infections of the sexual partners in the pa-
tients' medical records. HSV-1 was more often detected than HSV-2
in the men with HSV-positive urethritis (Table 1). In addition to the
HSV-1 positivity, one man (case 2) was coincidentally positive for
M. hominis and U. urealyticum, and another man (case 8) was pos-
itive for U. urealyticum. The remaining 11 men were positive only
for HSV-1 or HSV-2. None of the men had a history of sexually
transmitted infections, including genital herpes and urethritis. All
of the men complained of dysuria (Table 1). Meatitis was observed
in 9 of the 13 men (Supplemental Fig. 1). Although they did not
report urethral discharges, urethral exudates, which were small or
moderate in amount and serous or mucoid in nature, were
observed on genital examination in all of the men. Three men had
5 leukocytes per high-power (1000) microscopic field in their
Gram-stained urethral smear and 10 leukocytes per 1 ml of their
FVU, whereas 7 had only the former and two had only the latter.
The rate of detecting significant leukocytes in FVU seemed to be
lower than that in urethral smears in the men with HSV-positive
urethritis.
In 9 men, mononuclear cells were observed in the urethral
smears as well as polymorphonuclear leukocytes (Supplemental
Fig. 2a). In 5 men, mononuclear cells accounted for 90% of leu-
kocytes in the urethral smears (Supplemental Fig. 2b).
Eight and 5 of the 13 men were treated with a 7-day regimen of
100-mg sitafloxacin twice daily and with a single-dose regimen of
2-g extended-released azithromycin (azithromycin-SR), respec-
tively, at the first visit without waiting for the microbiological re-
sults. Three men did not visit the clinic for follow-up (Table 1). The
remaining 10 men returned to the clinic 7e19 days after the
administration of the antimicrobial agents. Two men who were
positive for HSV-2 at the first visit still complained of mild dysuria,
but the other 8 men, 3 of whom complained anew of urethral
irritation, had no dysuria. Meatitis was observed in only one man
(case 9). Serous urethral discharges were still observed in 5 men on
examination, but the other 5 men had no urethral discharges. In 8
of the 10 men, the leukocyte counts in FVU were <10 cells/ml. In the

Table 1
Clinical courses of 13 men with HSV-positive urethritis.

Case no. At the first visit At the second visit

Urethritis Meatitis Urethral Leukocytes in Leukocytes in Mononuclear Days Urethritis Meatitis Urethral Leukocyte in HSV Visible
symptoms discharge FVU (cells/ml) urethral smear cells (%) symptoms discharge FVU (cells/ml) in FVU herpetic
(Nature) (cells/HPFf) (Nature) lesion

HSV-1-positive urethritis treated with the sitafloxacin regimen

1 þa (Db) þc þd (Se) 14.0 1e4 NDh 7i ea ec ed 4.2 k ec
2 þþ (D) þ þ (S) 8.9 10e19 ND 19 þ (U) e e 1.9  e
3 þþ (D) þ þþ (M) 5.5 10e19 ND 10 þ (U) e e 3.9  e
4 þ (D) þ þ (M) 73.7 1e4 <10 Lj
5 þþ (D) þ þ (S) 7.1 10e19 90 17 e e e 8.8  e
6 þþ (D) e þ (S) 9.6 5e9 90 14 e e þ (Se) 8.1 þ þ
HSV-1-positive urethritis treated with the extended-release azithromycin regimen
7 þþ (D) e þþ (S) 7.4 5e9 20e29 14 þ (U) e e 1.1  e
8 þ (D) e þ (M) 6.2 20 90 L
9 þþ (D), þ (U) þ þ (S) 13.1 10e19 80e89 12 e þ þþ (S) 22.0  e
10 þ (D) þ þþ (S) 5.8 20 20e29 L
HSV-2-positive urethritis treated with the sitafloxacin regimen
11 þ (D), þ (U) þ þþ (S) 12.8 NTg NTg 19 e e þþ (S) 1.9  e
12 þþþ(D) e þþ (M) 23.0 20 90 9 þ (D) e þ (S) 14.0 þ þ
HSV-2-positive urethritis treated with the extended-release azithromycin regimen
13 þþ (D), þ (U) þ þþ (S) 11.3 10e19 90 11 þ (D) e þ (S) 6.8  þ
a
e, none; þ, mild; þþ, moderate; þþþ, severe.
b
D, dysuria; U, urethral irritation.
c
e, not observed; þ, observed.
d
e, none; þ, scant; þþ, intermediate; þþþ, profuse.
e
S, serous; M, mucoid.
f
HPF, high-power (x1000) microscopic field.
g
NT, not tested.
h
ND, not documented.
i
After the first visit.
j
L, lost to follow-up.
k
, negative; þ, positive.

Please cite this article in press as: Ito S, et al., Clinical courses of herpes simplex virus-induced urethritis in men, J Infect Chemother (2017),
http://dx.doi.org/10.1016/j.jiac.2017.03.017
 S. Ito et al. / J Infect Chemother xxx (2017) 1e3
FVU specimens, HSV-1 was detected from only from one man (case
6), and HSV-2 was also only detected in one man (case 12). Herpetic
lesions on the skin were observed at the follow-up visits in 3 men
(cases 6, 12, and 13). No antiviral agents were given to cases 1 and 2.
The other 8 men, including 5 with HSV-negative FVU specimens at
the second visit, were treated with a 5-day regimen of 500-mg
valaciclovir twice-daily based on the positive results for HSV at the
first visit. None of the patients, including cases 1 and 2, returned to
the clinic complaining of recurrent urethritis symptoms or herpetic
lesions after the second visit.
3. Discussion
All the patients were treated with antibacterial agents. Their
urethral symptoms and/or signs were disappeared or alleviated,
and the FVU became negative for HSV in the 8 men at the follow-up
visit after the treatments. HSV would have had to spontaneously
disappear from the urethra, because sitafloxacin and azithromycin
have no activity against HSV. By contrast, 3 men developed visible
herpetic lesions, and 2 of them were positive for HSV in their FVU.
In this study, our patients had no history of urethritis and genital
herpetic lesions. Although the serologic testing for HSV infections
was not performed, the HSV-positive NGU in our patients might be
not a recurrent but first-episode genital HSV infection. It is rec-
ommended that all patients with a clinical diagnosis of first-
episode genital herpes should be treated with antiviral agents [8].
Early use of therapy will alleviate systemic manifestations of herpes
and prevent local extension of lesions and frequent development of
new lesions that occur during the latter part of episode. We did not
prescribe antiviral agents for 2 HSV-negative men with no herpetic
lesions, but prescribed for 3 patients with visible hepatic lesions
and for 5 HSV-negative patients with no herpetic lesions at their
second visits. It is unclear whether the delayed administration of
valaciclovir more than 9 days after the onset of NGU symptoms
would be helpful in such HSV-negative patients with no herpetic
lesions. However, the delayed initiation of anti-herpes therapy
might have decreased risk of development of new lesions in our
patients, because any patients complaining of new herpetic lesions
did not return to the clinic.
Recent studies have shown the clinical features of HSV-induced
NGU, including the frequency of meatitis [4,6]. In addition to
meatitis, we also observed high proportions of mononuclear cells in
the urethral smears in most of our patients. In HSV infections, the
initial cellular response is predominantly polymorphonuclear, fol-
lowed by a lymphocytic response [7]. The observation of meatitis
and mononuclear cells in the urethral smears could be useful in
diagnosing HSV infections in the urethra. Early antiviral therapy is
beneficial for patients with HSV infections [7]. Therefore, we should
presumptively treat patients with such signs and symptoms sug-
gestive of HSV-induced NGU with anti-HSV agents at their first
presentation without waiting for diagnostic test results.
In conclusion, HSV could be a cause of acute urethritis without
causing visible herpetic lesions. The shedding of HSV from the
Please cite this article in press as: Ito S, et al., Clinical courses of herpes simplex virus-induced urethritis in men, J Infect Chemother (2017),
http://dx.doi.org/10.1016/j.jiac.2017.03.017
3
urethra should spontaneously cease in most cases of HSV-positive
NGU without antiviral therapy, and urethritis symptoms would
be alleviated. The development of meatitis and the mononuclear
cell response in the urethral smear could be helpful to diagnose
HSV-induced NGU. We should presumptively initiate anti-HSV
therapy for patients with signs and symptoms suggestive of HSV-
induced NGU at their first presentation. However, we are fully
aware of some limitations of this study, including the small number
of patients, no presumptive prescription of antiviral agents for HSV-
induced NGU at the time when the patients were complaining of
urethritis symptoms, no assessment of the effects of the pre-
sumptive antiviral therapies for HSV-induced NGU, no assessment
of the effects of the delayed antiviral therapies for men with
negativity for HSV in the urethra and alleviation of urethritis
symptoms, and no information regarding whether HSV-positive
NGU recurs as do herpetic lesions on the skin. Nevertheless, this
study provides some data to understand the clinical courses of
HSV-induced NGU, but further studies will be needed to compre-
hend HSV-induced NGU sufficiently and to manage patients with
HSV-induced NGU appropriately.
Conflict of interest
The authors have no conflicts of interest to disclose.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jiac.2017.03.017.
References
[1] Madeb R, Nativ O, Benilevi D, Feldman PA, Halachmi S, Srugo I. Need for
diagnostic screening of Herpes simplex virus in patients with nongonococcal
urethritis. Clin Infect Dis 2000;30:982e3.
[2] Totten PA, Schwartz MA, Sjo € stro
€ m KE, Kenny GE, Handsfield HH, Weiss JB, et al.
Association of Mycoplasma genitalium with nongonococcal urethritis in het-
erosexual men. J Infect Dis 2001;183:269e76.
[3] Bradshaw CS, Tabrizi SN, Read TR, Garland SM, Hopkins CA, Moss LM, et al.
Etiologies of nongonococcal urethritis: bacteria, viruses, and the association
with orogenital exposure. J Infect Dis 2006;193:336e45.
[4] Ito S, Hanaoka N, Shimuta K, Seike K, Tsuchiya T, Yasuda M, et al. Male non-
gonococcal urethritis: from microbiological etiologies to demographic and
clinical features. Int J Urol 2016;23:325e31.
[5] Frølund M, Lidbrink P, Wikstro € m A, Cowan S, Ahrens P, Jensen JS. Urethritis-
associated pathogens in urine from men with non-gonococcal Urethritis: a
case-control study. Acta Derm Venereol 2016;96:689e94.
[6] Ong JJ, Morton AN, Henzell HR, Berzins K, Druce J, Fairley CK, et al. Clinical
characteristics of herpes simplex virus urethritis compared with chlamydial
urethritis among men. Sex Transm Dis 2017;44:121e5.
[7] Japanese Society for Sexually Transmitted Diseases. Guidelines for the diagnosis
and treatment of sexually transmitted diseases 2006. Jpn J Sex Transm Dis
2006;17 Suppl:35e67.
[8] Corey L, Wald A. Genital herpes. In: Holmes KK, Sparling PF, Stamm WE, Piot P,
Wasserheit JN, Corey L, et al., editors. Sexually transmitted diseases. 4th ed.
New York: McGraw-Hill Companies, Inc.; 2008. p. 399e437.