NON-GONOCOCCAL URETHRITIS (NGU)

Maj. M. P. Vora

Maharashtra Medical Journal

Vol. XXXII, No.8 of November 1985; Pages: 179-184

Review Article

The galloping increase in the incidence of NGU and the potential risk of grave complications of sexually transmitted Chlamydia trachomatis infection are a serious concern to the health authorities and the medical profession as well. This pathogenic agent is responsible for many cases of epididymitis, prostatitis, proctitis, pelvic inflammatory diseases, infertility, Reiter’s syndrome, infant pneumonias etc. It would be valuable to describe clinical manifestations of NGU, its diverse etiologies, methods of diagnosis, the management of the patient and his or her sexual partner or partners.

NGU has assumed lately to be the most common STD. Its incidence exceeds that of gonorrhoea in men by a ration of 1:2 in Great Britain, Sweden and U.S.A. It is extremely common in men of high economic group today and notoriously resistant to treatment. It has a tendency to recur and is a major medical problem encompassing all fields of medical practice. According to the Centre for disease Control, “nearly 0.8 to 1 million cases of NGU occurred, while male gonorrhoea trailed slightly behind in 1978 in the United States”. “The New York City Health Department reported 149 cases of NGU in 1951 as against 14,886 in 1978”. But this does not give the true incidence of NGU as the most of the reported cases were from the Municipal V.D. Clinics. NGU is more prevalent than gonorrhoea among higher economic groups and university students, who rarely attend public or Municipal V.D. Clinics.

Urethritis can be divided into two types i.e., gonococcal and non-gonococcal, both types may be present at times, in the same patient and may be contracted at the same time from the same sexual contact. Occasionally, the clinical differentiation between the two types may be difficult in some cases since there is a possibility of overlapping signs and symptoms of both types. The incubation period of NGU varies normally from 1 to 3 weeks but it may extend occasionally over a few months. Patients with NGU complain of mild discomfort, mucoid or clear urethral discharge after awakening or penile stripping, dysuria, burning, urgency and frequency of urination etc. It is a low grade urethritis. In contrast, the incubation period of gonococcal urethritis is usually 2 to 6 days; urethritis is acute with purulent and profuse urethral discharge; the external urethral meatus is red, edematous and its lips pouting out. There is intense burning while passing urine. The condition becomes milder and less painful after about 15 to 21 days.

Several agents can produce NGU (a) local irritants, trauma, chemicals. Intraurethral ulcer, warts, stone, stricture, urethral infection by several microorganisms other than gonococci, staphylo streptococci, proteus, yeast, pseudomonas, enterococcus, viruses etc. (b) metabolic disorders like Oxaluria, Phosphaturia, amorphous urates, uric acid crystals and (c) physiologic discharges like Urethorrhoea, prostatorrhoea and pollutions may mimic urethral discharges and masquerade the diagnosis of NGU. Chlamydia trachomatis has lately shown to be frequently and closely related with NGU. Chlamydiae are obligate intracellular organism that produce inclusion bodies in the cells but have characteristic properties of bacteria. They duplicate by binary fission in the cytoplasm of their host cells are susceptible to tetracyclines, contain both RNA and DNA and possess ribosome and cell walls similar to those of Gram-negative bacteria. They need living media for their recovery and show no detectable metabolic activities. The genus Chlamydiae show two distinct species: (1) C psittaci, the cause of human and avian psittacosis and (2) C trachomatis often associated with human trachoma, inclusion conjunctivitis, ano-genital tract infection and lymphogranuloma venereum. The two species can be recognised by physical, biochemical and pharmacologic characters. Microimmunofluorescent antibody-typing tests have shown 15 serotypes within C trachomatis: types A, B, Ba, and C are mainly associated with endemic adult trachoma and genital infection: types D,E, F, G, H, I, J and K are associated with urethral, cervical and occular infections; three early defined types L1, L2 and L3 cause another STD called lymphogranuloma venereum (LV).

The etiology of C trachomatis in the causation of NGU is based on its isolation in large number of patients with urethritis and on serologic studies in which sero-conversion from negative to positive occurs in Chlamydia-positive NGU cases examined within ten days of the onset of symptoms. In addition, complete alleviation of symptoms of urethritis and the effective elimination of Chlamidiae with sulfisoxazole or tetracycline confirm the etiologic basis of C trachomatis. The same organism is often detected in cases of post-gonococcal urethritis, which follows successful treatment of N Gonorrhoea with penicillin. Penicillin eradicates N gonococci but not concomitant Chlamydia infection. Sine “C trachomatis could be isolated from about 40 to 50 per cent of patients with NGU”, it was natural to suspect some other agent capable of producing NGU. Two organisms i.e. Ureaplasma urealyticum and Corynebacterium genitalium were thought of anf could be recovered quite often in Chlamydia negative NGU patients, confirming their implication in some cases of NGU. U urealyticum is also known as T mycoplasma. It is a minute coccobacillary organism that forms pinpoint colonies and is often found in association with or within the cytoplasma of urethral cells. It differs from the true mycoplasma by its ability to hydrolyse urea and its failure to grow in vitro in the conventional mycoplasma media to more than 10 7 colony-forming units per ml. Since it is present in many healthy persons without urethritis, the precise role of U urealyticum in the causation of NGU is difficult to assess. There is, however, circumstantial evidence that U urealyticum is responsible for some non-Chlamydial NGU cases. Studies on its recovery rates and satisfactory response of NGU to the treatment with select antimicrobial agents support an association of U urealyticum with NGU in some cases. “Corynebacterium genitalium type I was isolated from 42% of NGU patients or their consorts”, thus confirming its etiology in the causation of some NGU, “U urealyticum was responsible for 27% of NGU cases” and “Chlamydia trachomatis accounted for the remaining 31% of NGU cases”. Since C genitalium type I is sensitive to both tetracycline and erythromycin, it may play a limited role in non-chlamydial and non-ureaplasmic NGU and is considered of minor importance. Besides, Trichomonas vaginalis, Candida albicans, Herpes simplex virus, Mycoplasma hominis, shigellae, B streptococcus, Entamoeba histolytica, B coli, allergy, H.ducreyi etc. are capable of causing NGU. Malingering to escape duty, some recruits tend to initiate NGU. It is important that the diagnosis of NGU should not be made until gonorrhoea is ruled out and a number of various possible etiologic factors have been studied, differentiated, excluded and finally precise etiology is determined. It is unwise to label any patient with urethritis without adequate evidence or careful follow-up. Proper management of NGU requires thorough appreciation of various causes involved in NGU. The major concern in the diagnosis lies in the ability to distinguish between an early uncomplicated urethritis and the late complicated urethritis. An initial assessment of the level of the urethral involvement, its extent, nature - edema, soft infiltrations or fibrous stricture etc. is necessary.

Complications of Chlamydial Genital Infections : If diagnosed incorrectly, manged improperly or treated inadequately, Chlamydia trachomatis urethritis is likely to cause grave sequelae in both the male and the female; anogenital tract involvement, proctitis in those who engage in rectal intercourse with sexual partners who have Chlamydial NGU, posterior urethritis with soft infiltrations or stricture, recurrent attacks of acute or chronic urethritis, acute epididymitis, Reiter’s syndrome, acute or chronic arthritis, prostatitis, infection of paraurethral gland ducts, which are, in fact, vestigial remnants of the prostate, hypertrophic erosion of the cervix, purulent or mucoid cervical discharge, salpingitis, pelvic inflammatory disease (PID) in the female sexual contacts of men with Chlamydial NGU and infertility in both sexes have been frequently observed. These complications were confirmed by cultural and serologic evidence of Chlamydia-positive synovial fluid. “In 95 or two-thirds out of 143 women with PID, the etiology of C trachomatis was confirmed on the strength of serodiagnostic and clinical criteria”. C trachomatis can be responsible for infertility in both sexes since they can cause epididymitis in the male and PID in the female. Neonates may get infected at the time of delivery from their mothers, who are already infected with Chlamydiae and likely to suffer from inclusion conjunctivitis, nasopharyngitis and otitis media 1 to 2 weeks after the birth and pneumonias when infants become 1 to 4 months old. “It has been observed that nearly 30% of pneumonia cases in infants below the age of 6 months were due to C trachomatis infection”. A proved case of Chlamydial endocarditis was also reported; Chlamydiae were identified by electron-microscope and many-fold rise in IgM antibody to sera-type F was noted in the patient who had a history of vaginal discharge only. There is a danger of infection to others from Chlamydiae carriers. It is time to make available precise methods of identification of organisms in the laboratories and hospitals. Also time it is to provide expertise in medical services, since not all cases of NGU have the same etiology and pathogenesis.

Diagnosis of NGU is not easy. Several agents may produce an identical response. IT depends on clinical findings, history, physical examination and laboratory procedures to differentiate various etiologies and finally pin-point the exact etiology. Such a conclusion is difficult without well-planned and adequate investigations and specific tests. The first step is to exclude N gonococcal urethritis by history, clinical findings, smear, culture, fermentation tests and fluorescent test. Next, the two most commonly recovered microorganisms in NGU cases are Chlamydia and Ureaplasma. However, facilities for their isolation and identification are, unfortunately, not freely available. It is not enough to rule out gonorrhoea or to establish the presence of urethritis. One has to identify and confirm one of the various etiologies that cause NGU such as C trachomatis, U urealyticum, T vaginalis, C albicans, viruses, urethral warts, ulcer, stone, stricture and other microorganisms. Without precise knowledge of the causative agent, neither the effective treatment can be prescribed nor can essential procedures such as contact-tracing and investigation and treatment of the contact can be undertaken. Hence, diagnostic procedures ought to be methodical and thorough. The specific problem of the patient deserves a special attention and should be considered and tackled ably. Reassurance, warm and sympathetic attitudes on the part of the doctor form an important aspect of the medical care. A microscopic examination of Gram-stained urethral smear and the urinary sediment of the second half of the fresh urine sample, obtained after cleaning the external genitalia or blocking the vaginal contamination with sterile gauge tampon and about 4 hours after the last urination; it is then centrifuged for five minutes at 3000 r.p.m. and then cultured for N gonococcus on suitable medium. If there is no obvious discharge, gently stripping the urethra from the base of the meatus a few times may help to get it. IF the patient is without symptoms and signs, one can collect the fresh first voided over-night urine after due precautions, centrifuge it, stain it and examine it carefully at least on three consecutive occasions. All too often the busy doctor allows a single negative report of the test to be decisive factor in his diagnosis. Too much dependence on inadequate and inappropriate procedures is likely to lead to a wrong conclusion. The fresh sample of urine should be examined immediately to avoid deterioration in quality. If gram-stained smear shows polymorph leucocytes without intracellular Gram-negative diplococci or only typical extra cellular Gram-negative diplococci, it is not characteristic or diagnostic of either N gonococcal or NGU, “Nearly 15% of Gram-stained smears show this pattern and 20% of these show positive cultures for N gonococci, confirming gonorrhoeal urethritis”. Importance of culture to confirm or rule out gonococcal etiology will be appreciated. Additionally, one has to exclude candidial and trichomonal origin by microscopic examination of a dry or wet preparation. Negative reports of microscopic examination for N gonococci, candida and trichomonas form the basis for the consideration of NGU, which becomes firmer with the presence of increased polymorphonuclear leucocytes only, 15 or more per field with low magnification (x 400) or 5 or more polymorphs per field with high magnification (x 1000). This is a definite proof of urethral inflammation or urethritis. The negative urethral smear, fluorescent test and culture for n gonococci rule out the presence of gonorrhoea. In addition, culture isolation and identification of Chlamydia trachomatis and Ureaplasma urealyticum have to be done in specialised laboratories for their confirmation or exclusion.

Treatment and follow-up:

It is important to determine the exact etiology of urethritis and to separate the early uncomplicated urethritis from the late complicated urethritis, because approaches and implications to the two conditions are different. In the complicated urethritis, an initial assessment of the level of urethral involvement, its extent, nature and duration has to be ascertained to plan an effective treatment. Chlamydia-positive NGU as well as cervicitis can persist for many months and result in serious complications and sequelae, if an early and proper treatment is not given. Since laboratory facilities to determine the etiology of C trachomatis or U urealyticum are generally unavailable, the ideal treatment of uncomplicated urethritis of either etiology is empirical; tetracycline or its analogue and erythromycin in adequate dosage over an adequate period of time are effective against both organisms; it is the treatment of choice. A small percentage of cases, however, may fail occasionally due to various causes: (1) resistance of organisms to drugs; (2) concomitant multiple microbial infection, not thought of or identified initially; (3) local complications like urethral infiltrations incidiously processing to urethral stricture; and (4) persistence of paraurethral gland duct infection. It is likely that continual urethral or paraurethral duct involvement plays a permissible role in the perpetuation of infection. Hence more exhaustive investigations need to be undertaken before drugs are selected and employed. In the chronic stage of urethritis - whatever may be the etiology - urethroscopy to find out the condition of the urethra is necessary. In fact, it has become an increasingly routine technique in patients with chronic urethritis; for it permits a direct view of the urethral mucosa. With the advent of fibrotic instruments or photographic fibrotic urethroscopy it has gained popularity and become indispensable. However, urethroscopy should not be done without full considerations of contra-indications. The presence of an acute infection or an acute exacerbation, the top of chronic urethritis debars urethroscopy till it subsides. Strict observance of asepsis is essential.

In chronic acute urethritis, one must aim to detect early soft urethral infiltrations and treat them with local therapy in addition to chemotherapy or antibiotics. The local therapy consists of urethral wash out before and after urethral instrumentation with non-astringent antiseptic solution before and then astringent solution after. Complete asepsis must be observed; no force must be used, if blood is noticed, it is better to postpone dilatation. According to the site of infiltrations, straight dilators are used for penile urethra and curved dilators are used for posterior urethra. One size is used at a sitting once a week and gentle massage is given over the dilator. Prostatic massage is given on a full bladder once a week but not on days of dilatation. The solution for urethral irrigation employed is oxycyanide of mercury 1 in 6000 to 8000 at 104 oF to 110 oF temperature; irrigation can be kept 3ft. high from penile level.

At each session, next higher dilator is used. In all 10 to 12 sittings each of dilation and prostatic massage are completed with either chemotherapy or antibiotic. This prevents formation of the urethral stricture and enhances greatly the result of action of drugs. However, these procedures are not meant for a novice. Only those who have a thorough knowledge of procedures and have an adequate practical experience can adopt these measures in conjunction with chemotherapy or antibiotic drug. It is tempting to postulate that antibiotics or sulpha can “Cure” a patient with urethral complications. But it should be remembered that sole reliance on antibiotics for a ‘Cure’ is not physiologically sound in local complications since these drugs do not react or affect deep-seated foci of organisms. Dilation and massage plus warm urethral washes do wonderful job to break deep-seated foci, permit drainage and improve local blood supply and make chemotherapy or antibiotics more effective. On the days of urethral dilatation or prostatic massage, 500 mg of tetracycline 2 hours before and after should be the rule in addition to 250 mg four times a day. Normally French size no. 20 to 30 can be used. If size 18 cannot be easily passed, the presence of a formed stricture is to be noted and with great caution, it needs to be dilated. This is the result of lack of recognition and failure to employ early therapy.

For an early uncomplicated urethritis, one to two weeks oral treatment with tetracycline 500 mg four times a day, on the first day, then three times a day for six days followed by 250 mg four times a days for another week should be adequate and effective. For chronic and complicated stage, a long-term therapy with local measures is indicated both in gonorrhoea or NGU. The dosage for longer duration along with local measures has to be adjusted for nearly 8 to 10 weeks or longer. If the infection is mixed one i.e. N gonococcal and C trachomatis and happens to be treated with penicillin, the post-gonococcal urethritis with C trachomatis is sure to follow. Such cases deserve careful study and demand awareness of mind among doctors.

In case the patient is unable to tolerate tetracycline, erythromycin can be substituted in the same dosage over the same period. The tendency for spontaneous remissions of C trachomatis infection makes the valuation of therapy difficult. Hence, at the first inkling of recurrent symptoms, active therapy should be re-instituted as a prophylactic measure only after careful microbiologic study and continued for 2 to 3 weeks. As a matter of routine, every patient must have tests of ‘Cure’ including the quantitative VDRL test at the beginning and then again within 3 to 4 months to exclude the possibility of incubating syphilis. Every patient should be persuaded to name his or her sexual contacts, who are then contacted and indeed to under a medical check-up. Sexual contacts of men with NGU comprise a large reservoir of Chlamydial and other microbial infected persons; however, no efforts are made to trace, examine and treat them, if necessary. “Nearly 70% of the female contacts of men with Chlamydial NGU are found to be infected by Chlamydiae”. Most female contacts of heterosexual men with NGU and passive contacts of active homosexuals with Chlamydia NGU are often without symptoms. A check may reveal proctitis or cervicitis. The clinical relapses or reinfections in number of cases result from original sex-partner, who had received no treatment. Sexual contacts should be given the same course of treatment except in early pregnancy, wherein erythromycin should replace tetracycline. During the course of therapy, sexual activity as well as ingestion of alcohol should be avoided. Simultaneous treatment of both sex partners should be a rule in the management of V.D. Moreover, all patients should be examined and tested to exclude other STDs, which occasionally associate with NGU.

These figures cited here have been taken from the clinical review by Dr. Felman and Mr. Nikitas, the Bureau of V.D. Control, New York City Health Department.