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NON CHLAMYDIAL NON GONOCOCCAL URETHRITIS (NCNGU) IS SIGNIFICANTLY MORE COMMON THAN GONORRHEA AND CHLAMYDIA IN SYMPTOMATIC PATIENTS WHICH COMMONLY GOES UNDETECTED DUE TO LACK OF TESTING

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  • Dr. Arani Medical Center

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Based on recent retrospective study conducted in Los Angeles STD Institution, a sample of 105 symptomatic male patients was evaluated for urethritis from January 2016 to May 2016. Out of these 105 patients, 8 (7.6%) were positive for Chlamydia, and 10 (9.5%) for Gonorrhea, while 34 (32%) had NCNGU. Rest of the 53 (50.4%) patients had negative study for urethritis. It is an alarming rate, i.e. 32% NCNGU as compared to 7.6% and 9.5% of chlamydia and gonorrhea cases respectively, at which NCNGU significantly surpassed Gonorrhea and Chlamydia. NCNGU which could get categorized as the most common STD after HPV. It is expected that this trend would take sharper rise as we continue to fail to diagnose this condition. Patient with negative Gonorrhea and Chlamydia does not necessarily means that are free from other bacterial, fungal, parasitic or viral infections which can get transmitted by sexual contact, including oral sex. Majority of patients were unaware of the possibility and existence of non-chlamydial non-gonococcal urethritis. Public is well aware of Gonorrhea and Chlamydia due to public health awareness programs and education, however NCNGU which seems to be much more common now is least known to the the public. According to the current guidelines patients with muco-purulent discharge should receive broad spectrum antibiotic without evaluating for NCNGU and objective diagnosis and partner therapy mainly recommended for Gonorrhea and Chlamydia infected patients.
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JOURNAL ARTICLE
NON CHLAMYDIAL NON GONOCOCCAL
URETHRITIS (NCNGU) IS SIGNIFICANTLY MORE
COMMON THAN GONORRHEA AND CHLAMYDIA
IN SYMPTOMATIC PATIENTS WHICH
COMMONLY GOES UNDETECTED DUE TO LACK
OF TESTING
Siavash Arani, M.D. Former instructor and assistant clinical professor of Loma Linda University, School
of Medicine, author of ‘HPV the silent Intruder’, Founder and director of DAML sexually transmitted
Infection laboratory based in Los Angeles, California
ISBN 978-0-9890635-17
08/31/16
ABSTRACT
Based on recent retrospective study conducted in Los Angeles STD Institution, a sample of 105
symptomatic male patients was evaluated for urethritis from January 2016 to May 2016. Out of
these 105 patients, 8 (7.6%) were positive for Chlamydia, and 10 (9.5%) for Gonorrhea, while 34
(32%) had NCNGU. Rest of the 53 (50.4%) patients had negative study for urethritis. It is an
alarming rate, i.e. 32% NCNGU as compared to 7.6% and 9.5% of chlamydia and gonorrhea
cases respectively, at which NCNGU significantly surpassed Gonorrhea and Chlamydia.
NCNGU which could get categorized as the most common STD after HPV. It is expected that
this trend would take sharper rise as we continue to fail to diagnose this condition. Patient with
negative Gonorrhea and Chlamydia does not necessarily means that are free from other bacterial,
fungal, parasitic or viral infections which can get transmitted by sexual contact, including oral
sex. Majority of patients were unaware of the possibility and existence of non-chlamydial non-
gonococcal urethritis. Public is well aware of Gonorrhea and Chlamydia due to public health
awareness programs and education, however NCNGU which seems to be much more common
now is least known to the the public. According to the current guidelines patients with muco-
purulent discharge should receive broad spectrum antibiotic without evaluating for NCNGU and
objective diagnosis and partner therapy mainly recommended for Gonorrhea and Chlamydia
infected patients.
INTRODUCTION
Urethritis, or urethral inflammation, is in the majority of cases caused by sexually transmitted
agents. Typically it presents with urethral discharge, dysuria, urethral stinging/itching and penile
tip irritation, but many times it may be asymptomatic. Urethritis involves local mucous
membrane epithelial cell damage or invasion by an infectious agent (bacterial, viral, or fungal)
followed by inflammatory changes including accumulation of leukocytes and chemical mediators
(antibodies, cytokines, and interleukins) with resultant swelling, discharge, and pain.
Non gonococcal Non Chlamydia Urethritis (NGNCU) is a common sexually transmitted disease
in men, with approximately 10-30 % of the cases being infected by Mycoplasma genitalium.
Other causes are Ureaplasma urealyticum (19.5%), Trichomonas vaginalis (1.3%), H influenzae
(14.3%), N meningitidis (3.9%), Herpes simplex virus (10%) and adenovirus (16.2%). (Ito S,
2016). M. genitalium may be associated with human immunodeficiency virus (HIV), human
papilloma virus (HPV), and herpes simplex transmission and infection. M genitalium has been
associated with treatment failure.
Unusual infectious causes of urethritis include herpes genitalis, syphilis, mycobacterium,
adenovirus, cytomegalovirus, as well as typical bacteria (usually gram-negative rods) associated
with cystitis in the presence of urethral stricture or following insertive anal sex.
The diagnosis of urethritis is made by identifying an excess of polymorpho-nuclear leucocytes
(PMNs) in a stained smear. An excess of mononuclear leucocytes in the smear indicates a viral
cause. In patients with symptoms of urethritis, the diagnosis should be confirmed by microscopy
of a stained smear. Nucleid acid amplifications tests (NAAT) for Neisseria gonorrhoeae, C.
trachomatis and for M. genitalium. For viral or protozoal causes, NAAT for HSV, adenovirus
and T.vaginalis could be performed.
According to CDC 2010 STD treatment guidelines, urethritis is characterized by urethral
inflammation from infectious or noninfectious conditions. Diagnosis is confirmed by
microscopic evaluation of urethral secretion. Urethritis is defined as either gonococcal, when
Neisseria gonorrhoeae is the causative agent, or non-gonococcal (NGU) when it is not. In 30-
80% of the cases with NGU neither C.trachomatis nor M.genitalium is identified. The term
nonspecific urethritis (NSU) also applies to NCNGU. In many men with urethritis a known
pathogen is not identified. Adenoviruses or Herpes simplex viruses may account for 2-4% of
symptomatic patients. N. meningitidis, Haemophilus sp., Candida sp., urethral stricture and
foreign bodies are also responsible for a small proportion of NCNGU (Patrick J, 2016).
METHODS
We picked 105 male patients with an age range of 25-84 years old. The time span in which the
study was conducted was from January 2016 to May 2016. These patients sought medical
attention after recently having sexual contact and were having symptoms. Their symptoms
included urethral discharge, painful urination, burning and itching at the tip of the penis, frequent
urination, urethral swelling and irritation. 1 patient came in with the complaint of blood in urine.
In general, 34 (32.3%) patients showed urethral discharge, 38 (36.1%) had urethral discomfort
while 33 (31.4%) had other urinary symptoms. The onset of symptoms ranged from few days to
months. They were all belong to 3 main sexual preference category, i.e. male-sex with-female
(MSF) (95), male-sex with-male (MSM) (6) and male-oral sex with-female (MSF-O) (5).
All patients were tested besides obtaining history and physical examination. One of the patients
who were diagnosed positive for gonorrhea did not get tested for Chlamydia. A leukocyte
esterase dipstick on the FVU for all specimens was done. Urethral swab or discharge specimen
was also examined for existence of ≥5 PMNs/hpf indicating urethritis. Urethral swab from
anterior urethra was taken. The method comprised of cotton tipped swab which was
introduced about 1-2 cm into the urethra. In case of urethral discharge, the smear was sampled
without placing the cotton swab inside the meatus. Microscopy of a Gram stained was done.
Urethritis was confirmed by evidence of PMNs in the smear, containing ≥5 PMNL per high
power (hpf) (x1000) microscopic field. Nucleid acid amplifications tests (NAAT) for Neisseria
gonorrhoeae, C. trachomatis were done.
RESULTS
Out of the 52 patients with proven urethritis, 34 (65.3%) were positive for NCNGU, while only 8
(15.3%) were chlamydial positive and 10 (19.2%) were gonorrhea positive. 4 out of 5 MSF-O
were NCNGU positive. There were no con-infection of both gonorrhea and chlamydia among 7
Gonococcal positive patients who also got tested for Chlamydia and for 8 chlamydia positive
patients who all got tested for gonorrhea as well in our study group. 51 (96%) patients with
negative urethritis were also negative for Urine Leukocyte esterase while only 2 (3.9%) with
negative urethritis showed positive leukocyte esterase. Out of 52 patients with positive urethritis,
3l (59.6%) were urine leukocyte esterase positive. 16 (30.7%) patients with NCNGU, 10 (19.2%)
with gonorrhea and 5 (9.6%) with chlamydia were urine leukocyte esterase positive while 18
patients with NCNGU and 3 with chlamydia were leukocyte esterase negative. Out of the 34
patients who came with the complaint of urethral discharge, 19 (55%) were diagnosed with
NCNGU, while 8 (23.5%) with gonorrhea, 3 (8.8%) with chlamydia and 10 (29.4%) patients
negative for urethritis. Among 5 patients who had unprotected oral sex 4 had NCNGU and 1 had
gonorrhea. We did not include rest of the individuals because they had intercourse with or
without oral sex, so oral sex leading to urethritis might have been under-reported in this study.
All patients with urethritis regardless of Gonorrhea, Chlamydia, NCNGU had positive urethral
swab discharge microscopic analysis as mentioned in method. Out of 10 patients who were
positive for gonococcal on microscopic smear 7 were tested with urine PCR and all became also
positive.
Table 1 Comparison Result Table of symptomatic male patients evaluated for urethritis
Total Patients Chlamydia Gonorrhea NCNGU Negative
Urethritis
105 8 (7.6%) 10 (9.5%) 34 (32.3%) 53 (50.4%)
Table 2 Relations between Urine Leukocyte Esterase and Diagnosis
Chlamydia Gonorrhea NCNGU Negative urethritis
Positive Urine LE 5 (4.7%) 10 (9.5%) 16 (15.2%) 2 (1.9%)
Negative Urine LE 3 (2.8%) 0 (0%) 18 (17.1%) 51 (48.5%)
Table 3 prevalence of symptoms in chlamydia, gonorrhea, NCNGU and urethritis negative patients
Urethral Discharge Urethral Discomfort /Urinary
Symptoms
37(35.2%) 68 (64.7%)
Table 5, Relations Between Nature of the Symptoms and the Diagnosis, Siavash Arani, M.D.
Chlamydia Gonorrhea NCNGU Negative Urethritis
Urethral Discharge 3 (2.8%) 8 (7.6%) 16 (15.2%) 10 (9.5%)
Urethral
Discomfort/urinary
symptoms (No
Discharge)
5 (4.7%) 2 (1.9%) 18 (17.1%) 43 (40.9%)
Table 7, Relations Between oral sex only group and Diagnosis, Siavash Arani, M.D.
Patients with only Oral
Sex exposure Chlamydia Gonorrhea NCNGU
5 (4.7%) 0 1 (20%) 4 (80%)
DISCUSSION
Non-chlamydial non-gonococcal urethritis (NCNGU) is usually infectious condition involving
urethral inflammation without Neisseria gonorrhea or chlamydial infection. Being one of the
most common forms of sexually transmitted infections in men, it is a challenging disease in
clinic because of its minimally symptomatic manifestation. Various other pathogens like
Mycoplasma and herpes simplex virus are also involved in non-chlamydial non-gonococcal
urethritis in men. The diagnosis is confirmed by few laboratory investigations. The diagnosis is
positive if a Gram stain of urethral discharge shows more >5 WBCs per oil-immersion field, or
when a microscopic examination of FVU reveals >10 WBCs, or if leukocyte esterase test of
FVU is positive
Men with severe symptoms should be treated as soon as the diagnosis is made without any delay
or waiting for test results. In case of positive laboratory tests and persistent microscopic
urethritis, antimicrobial treatment should be commenced. If the laboratory tests are negative,
treatment is given only if the patient is symptomatic and there is a microscopic evidence of
urethritis.
20–30% of NCNGU may recur within 6 weeks of resolution of symptoms. The cause of
recurrence may be an incorrect diagnosis, multiple sexually transmitted infections, incomplete or
noncompliance of treatment, and reinfection by an infected sexual partner. Men diagnosed with
NCNGU have a higher probability of recurrence within 6 months after treatment. Therefore it is
recommended to reevaluate all patients with NCNGU 3–6 months after treatment.
Unnecessary Antibiotics for symptomatic Patients with Negative Study
According to a new study presented at the 43rd Annual Conference of the Association for
Professionals in Infection Control and Epidemiology, done at the emergency department of St.
John Hospital & Medical Center in Detroit, Michigan, on more than 1,103 patients with
symptoms of STDs, three out of four patients treated with antibiotics were actually tested
negative for these sexually transmitted diseases.
Based on our study 50.5 % of patients with sexual contact and symptoms did not have proven
urethritis. Therefore no treatment for urethritis was recommended for those patients unless they
had other related symptoms. Many men after sexual contact especially those with multiple sex
partners are concerned about having STDs, so they usually search online about STDs and keep a
close check on appearance of any possible symptoms which most of the times ends up having
patients creating symptoms and they consult their doctors asking for medicines. However,
inappropriate or over prescribing of antibiotics for patient without confirming urethritis or
making a diagnosis could lead to drug resistant organisms which are a challenge to eradicate
leading to treatment failures and a matter of concern at national level. When patients are
confirmed to be positive then the therapeutic regimen is recommended equally for the sexual
partner in order to check the spread and to avoid making it an epidemic. However, currently the
routine approach by urgent cares, primary care physician, ER and other outpatient community
clinics and hospitals is to prescribe empirical treatment for symptomatic patients for Gonorrhea
and Chlamydia, and on positive lab results the sexual partner is recommended with treatment as
well. This practice has result in incorrect diagnosis and overlooking of the more common
NCNGU, which never gets treated with appropriate and microorganism sensitive antibiotics.
Therefore, the exact diagnosis remains unknown and the infection continues to spread out while
overlooked or undiagnosed. If the laboratory tests are negative for gonorrhea and chlamydia,
treatment is given only if the patient is symptomatic and there is a microscopic evidence of
urethritis, or an obvious significant urethral discharge on examination Based on our study, about
half of symptomatic patients who had no microscopically proven urethritis or urethral discharge
did not undergo any unnecessary treatment.
Growing Online STD Testing Might Contribute To The Uprising of Infectious Diseases
Healthcare industry, like every other industry has been shifting to online market in recent years.
Numerous online STD testing arrangements are available without any real direct physician
involvement including physical examination. Patients usually order their own STD testing kits or
laboratory arrangement and get their tests done without in person doctor’s consultation or
recommendation. They go to the national chain medical laboratories and under License lab
account of a physician and get their lab reports directly. So these patients with urethral discharge
might have actually non chlamydial non gonococcal urethritis but they get their STD testing
panel done for Gonorrhea and Chlamydia. On getting negative results for chlamydia and
Gonorrhea, they have a false sense of being uninfected, carrying on with their sexual activities
and continuing to infect others with NCNGU which is more common than Chlamydia or
gonoccocal urethritis. Many patients do not use their names and real contact and despite being
even positive for Chlamydia and Gonorrhea there is no evidence or trace backs to contact the
patients to confirm treatment and follow up. This trend is significantly jeopardizing public
health.
Oral Sex is Sex
Oral contamination has a direct effect on the transmission of infection. Oral sex can transfer the
oral, respiratory, and genital pathogens to the sexual partner; therefore it is essential to use
protection and safer sex precautions to avoid infection spread. In our study 5 of the patients with
infected urethritis had a history of having only oral sex. Out of these, one had Gonorrhea and 4
had NCNGU and none accounted for Chlamydia. This number could be higher but we did not
account rest of the group because they were involved both oral sex and intercourse. Chlamydia
can be caught via oral sex but more extensive study needs to be done on this topic. In our
institution many of oral sex related urethritis is attributed to NCNGU. Oral sex is a common
practice sex and can be unsafe if done without protection. This is to remove any false conception
of many, who believe oral sex is usually safe which is not true. If we don’t test or evaluate
symptomatic patients for NCNGU then we would easily miss the positive aforementioned cases.
Public health education for protected oral sex is highly recommended.
Urine Infection is Not Common in Men
Many sexually active men with urinary symptoms self-medicate for UTI or get misdiagnosed by
of a mere positive urine dipstick analysis. Widely use terminology of Urinary tract infection
(UTI) is majorly misunderstood by men as well as by health care providers. One of the
challenges in diagnosing urinary tract infections in males is the fact that dysuria, with or without
urethral discharge, is typically a chief complaint with urethritis, which is a more common
condition than UTI in males. In our study, 53 (50.4%) out of 105 symptomatic patients were
proven negative for urethritis. Only 2 (3.7%) of these patients with symptoms and negative
urethritis were urine leukocyte esterase positive which is diagnostic of UTI. However, 31
(59.6%) out of 52 patients with urethritis (Gonorrhea, Chlamydia, NCNGU) had also positive
urine analysis. In other words, urine infection is uncommon among sexually active men. In
evaluation of male patients with positive urinalysis (leukocyte esterase positive), urethritis must
always be considered because urine infection is not common in men. It should also be considered
that UTI should be better termed as a simple ‘urine infection’ as urethra is part of urinary tract
and this creates confusion while choosing a treatment because the treatment regimens of
urethritis and urinary tract infection are entirely different. Although the symptoms among the
negative urethritis group could be because of nonsexual infection such as prostatitis but this
study was designed to evaluate STD patients.
Gonorrhea is More Common Than Chlamydia in Symptomatic Males
There is a preconceived notion of Chlamydia infections being more common than Gonorrhea. It
could be somewhat correct in general screening of Sexually Transmitted Infection testing.
However, our study revealed that symptomatic male patients with urethritis have relatively same
or more chances to have Gonorrhea than Chlamydia but less as compared to NCNGU. Patients
who were Chlamydia positive were 8 (7.6%) and Gonorrhea positive were 10 (9.5%). We
believe that it is more likely to have symptom such as urethral discharge associated with
Gonorrhea rather than with Chlamydia and this study was involved symptomatic male only and
urethral discharge so leaded to higher number of gonorrhea than Chlamydia. Many patients with
symptom such as urethral discharge get empirical treatment for Gonorrhea without testing or
follow up so true number of gonorrhea prevalence is somewhat masked as not getting reported or
partner not getting proper care. This could be one of main complaint that might support recent
rising incidence of Gonorrhea.
CONCLUSION
NCNGU is much more common than Gonorrhea and Chlamydia in symptomatic male patients.
Further studies might be needed as well to evaluate the non-symptomatic patients. The rate of
undiagnosed and untreated NCNGU can cause significant complications such as epididymitis,
pelvic inflammatory disease, prostatitis, infertility and Reiter’s syndrome. Undetected uprising,
Non gonococcal Non Chlamydia Urethritis (NCNGU) is expected to infect millions of
Americans due to lack of public awareness and diagnostic testing. NCNGU could get categorized
as the most common STDs after HPV in the U.S. Instead of Chlamydia. Emphasis on education
of using protection for oral sex must get more attention, as many cases of NCNGU are
transmitted by unprotected oral sex. The misconception of oral sex being safe should be cleared
and educated. Urethral Swab analysis is the most reliable test to detect urethritis. However, most
of the patients prefer urine test to more uncomfortable swab test, but it is not a matter of
convenience or choice anymore; but a matter of public health concern to detect the rising trend in
STDs. Until better diagnostic modalities are developed, the clinicians are advised to perform a
swab analysis to rule out NCNGU caused by multiple different pathogens other than Gonorrhea
or Chlamydia. Physicians must keep NCNGU in mind whenever they encounter a patient with
symptoms of urethritis.
Bibliography
Ito S, H. N. (2016, Feb 4). Male non-gonococcal urethritis: From microbiological etiologies to
demographic and clinical features. Int J Urol.
Patrick J, K. B. (2016). 2016 European Guideline on the management of non-gonococcal urethritis.
Retrieved June 16, 2016, from NCBI:
http://www.iusti.org/regions/europe/pdf/2016/2016EuropeanNGUGuideline.pdf

Supplementary resource (1)

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Article
Full-text available
We present the updated International Union against Sexually Transmitted Infections guideline for the management of non-gonococcal urethritis in men. This guideline recommends confirmation of urethritis in symptomatic men before starting treatment. It does not recommend testing asymptomatic men for the presence of urethritis. All men with urethritis should be tested for Chlamydia trachomatis and Neisseria gonorrhoeae and ideally M. genitalium using a NAAT as this is highly likely to improve clinical outcomes. If a NAAT is positive for gonorrhoea, a culture should be performed before treatment. In view of the increasing evidence that azithromycin 1 g may result in the development of antimicrobial resistance in Mycoplasma genitalium azithromycin 1 g is no longer recommended as first line therapy, which should be doxycycline 100 mg bd for 7 days. If azithromycin is to be prescribed an extended of 500 mg, then 250 mg daily for 4 days is to be preferred over 1 g stat. In men with persistent NGU, M. genitalium NAAT testing is recommended if not previously undertaken, as is Trichomonas vaginalis NAAT testing in populations where T. vaginalis is detectable in >2% of symptomatic women.
Article
Objectives: To detect microorganisms responsible for male acute urethritis and to define the microbiology of non-gonococcal urethritis. Methods: The present study comprised 424 men with symptoms and signs compatible with acute urethritis. Their urethral swabs and first-voided urine underwent detection of the microorganisms. Demographic characteristics and clinical features of Mycoplasma genitalium-, Ureaplasma urealyticum-, Haemophilus influenza-, adenovirus- or Herpes simplex virus-positive monomicrobial non-gonococcal urethritis, or all-examined microorganism-negative urethritis in heterosexual men were compared with urethritis positive only for Chlamydia trachomatis. Results: Neisseria gonorrhoeae was detected in 127 men (30.0%). In 297 men with non-gonococcal urethritis, C. trachomatis was detected in 143 (48.1%). In 154 men with non-chlamydial non-gonococcal urethritis, M. genitalium (22.7%), M. hominis (5.8%), Ureaplasma parvum (9.1%), U. urealyticum (19.5%), H. influenzae (14.3%), Neisseria meningitidis (3.9%), Trichomonas vaginalis (1.3%), human adenovirus (16.2%), and Herpes simplex virus types 1 (7.1%) and 2 (2.6%) were detected. Although some features of monomicrobial non-chlamydial non-gonococcal urethritis or all-examined microorganism-negative urethritis were significantly different from those of monomicrobial chlamydial non-gonococcal urethritis, most features were superimposed. Conclusions: Predicting causative microorganisms in men with non-gonococcal urethritis based on demographic and clinical features is difficult. However, the present study provides useful information to better understand the microbiological diversity in non-gonococcal urethritis, and to manage patients with non-gonococcal urethritis appropriately.