Globally, tuberculosis (TB) is the most common cause of infection-related death. About 5 to 45% of TB cases have extrapulmonary manifestations, and of those, the urogenital tract is involved in 30 to 40% of cases.
Genitourinary TB (GUTB) is defined as an infection of the urinary tract (UTI) or genitals, caused by bacilli of the Mycobacterium tuberculosis complex (MTB).
After pulmonary TB, about 2 to 20% of people may develop GUTB after a latency of 5 to 40 years. GUTB may refer to TB that affects the urethra, bladder, ureters, or kidneys in both sexes, the scrotum, penis, testicles, epididymis, or vas deferens in men, and the vulva, vagina, cervix, uterus, ovaries or fallopian tubes in women. However, urinary tract TB occurs more frequently than genital TB.
TBGU becomes important as it is often diagnosed late, and this delay can lead to complications such as urethral or ureteral stricture, kidney failure, infertility, and a host of other complications that require specialized care.
| Etiology |
TBGU, as with other cases of TB, is usually caused by infection with MTB . However, other mycobacterial species of the MTB complex, such as M. bovis , M. africanum , M. pinnipedii , M. microti , M. caprae , and the TB vaccine bacillus Calmette-Guérin (BCG), rarely can cause the disease.
TBGU usually occurs as a result of hematogenous dissemination of mycobacteria during initial infection. These bacilli can remain latent in the urogenital tract and become active in the setting of immunosuppression. In addition to hematogenous seeding during initial infection, other routes of infection may include lymphatic dissemination and sexual transmission.
Diabetes, older age, low body mass index, concurrent cancers, immunosuppression, and renal failure may increase the risk of reactivation, with the risk estimated to be up to 15%.
| Epidemiology |
TBGU occurs in 2 to 20% of pulmonary TB cases.
In developed countries, the percentage is 2 to 10%. In developing countries, the incidence tends to be higher, around 15 to 20%. More than 90% of TBGU cases have been reported in developing countries. A study from Brazil based on autopsies found that 9.8% of all TB cases also had GUTB.
In a UK study, 13.5% of patients with GUTB also had concurrent pulmonary TB. In the US, TB incidence was 3 cases/100,000 population in 2013, but similar data on TBGU incidence are lacking. In a large-scale autopsy-based study from Germany, 3.1% of 5,424 autopsied subjects were found to have evidence of TBGU.
| Pathophysiology |
The pathophysiology of TBGU is not entirely clear, but several hypotheses have been proposed. Primary infection with any of the mycobacterial species of the MTB complex occurs after infection by inhalation or ingestion.
The bacilli then multiply in tissues at the site of inhalation (lung) or ingestion (gut) and trigger a complex series of immune responses. This may result in complete elimination of the bacilli or containment of the organism through the formation of primary granulomas (termed primary Ghon focus).
The slow replication rate of the organisms in the MTB complex and the intracellular location of the bacilli within macrophages lead to a gap after primary infection, for clinical TBGU to develop. Some people are naturally resistant to infection and eradicate mycobacteria due to innate immunity.
Evidence suggests that these individuals are resistant to latent MTB complex infections, even if there is prolonged or intense exposure. In susceptible people, primary TB lesions can usually be found in the lungs, tonsils or intestine, but, in rarer cases, they can also affect other organs.
In addition to inhalation and ingestion, cases of primary genital TB (vulvar, vaginal, or cervical) may rarely occur in women whose male partners have pulmonary TB or active GUTB. In these cases, transmission may be through semen or In contrast, TB of the penis can occur as a primary or secondary disease.
It can develop after a circumcision performed by a person with pulmonary TB, which can be transmitted to the penis through ejaculation, contaminated clothing, contact with endometrial secretions of a partner with active uterine TB, or, as a secondary disease after previous pulmonary or extrapulmonary TB.
| Histopathology |
Primary granuloma at the site of primary infection usually consists of a compact focal collection containing inflammatory and immune cells, including neutrophils, T and B lymphocytes, macrophages, Langhans cells, epithelioid cells, and fibroblasts, with associated central caseous necrosis.
The mycobacteria then spread through the lymphatic vessels, where they can cause lymphangitis, and regional lymph node involvement, where they can cause lymphadenitis. The lymph nodes may then undergo caseous necrosis while the nodes fuse to form matted nodes. In the lungs or intestine, this triad includes a primary Ghon focus; lymphangitis and lymphadenitis, called primary Ghon complex.
| History and physics |
The clinical presentation of the patient with TBGU can vary from asymptomatic to nonspecific symptoms related to the affected organ.
The patient may come from a high prevalence region or have a history of pulmonary TB. Involvement of any part of the urogenital system may present with constitutional symptoms and signs, such as fever, night sweats, anorexia, and weight loss. TB should also be considered in the case of recurrent urinary tract infections that do not respond to standard antibiotic therapy.
> Renal TB : it is the most common form of TBGU. Symptoms and signs are usually nonspecific. Due to a delay in diagnosis there may be extensive involvement of the renal parenchyma with subsequent obstructive nephropathy with features of end-stage renal failure.
> Ureteral TB : the most affected part of the ureter is the lower segment followed by the ureteropelvic junction. Uereteral TB is almost always associated with renal TB. Symptoms and signs are not specific, but in case of ureteral obstruction or stricture formation they can lead to hydronephrosis and subsequent renal failure. Patients may have hematuria or abdominal pain.
> Bladder tuberculosis : usually occurs due to renal TB after the bacilli enter the urine and subsequently the urinary bladder. It can also occur by lymphatic or hematogenous seeding that involves other areas, either through genital retrograde dissemination of the tubercle bacillus. Bladder TB has also been reported due to intravesical administration of BCG for bladder cancer. Similar to ureteral TB, there may be inflammation and subsequent stricture formation, leading to hydroureteronephrosis and subsequent renal failure. Features of a UTI may also occur without response to standard antibiotic therapy.
> Prostatic tuberculosis : usually occurs as a result of hematogenous spread from a primary focus. At first, patients may be asymptomatic. This may be followed by nonspecific emptying symptoms. In the later stages, there may be dysuria, nocturia, or frequency due to an enlarged prostate. There may also be acute or chronic pelvic pain caused by prostatitis and sexual dysfunction.
> Scrotal tuberculosis : tuberculous orchiepididymitis can present as a unilateral or bilateral involvement with painful or painless, acute or chronic scrotal inflammations. Patients may have oligozoospermia or azoospermia due to destruction or obstruction of the vas deferens or epididymis.
> TB of the penis : may present as single or multiple inflammations or ulcers on the penis, which may or may not be painful. It can also present as cold papules, nodules or abscesses and inguinal lymphadenopathy. Likewise, there may be urethritis, urethral discharge, associated urethral strictures or fistulas, erectile dysfunction.
> Tuberculosis of the vulva, vagina or cervix : the presentation may be nonspecific and the symptoms depend on the site of the lesion. Dyspareunia, postcoital bleeding, pelvic pain, and infertility are frequently reported. Long-standing disease can also cause fistulas that can involve multiple organs.
> Uterine tuberculosis : symptoms are usually nonspecific. Patients may experience irregular menstrual bleeding, dysmenorrhea, and vaginal discharge. They may also complain of abdominal masses and abdominal pain unrelated to menstruation.
> Tuberculosis of the ovary and fallopian tubes : patients are usually asymptomatic. Some may experience acute or chronic abdominal pain. However, the vast majority of cases are diagnosed when infertility is investigated.
| Assessment |
Evaluation of a patient with TBGU requires a detailed history, physical examination, and a combination of laboratory and radiographic investigations.
The gold standard test for the diagnosis of TBGU or TB generally involves the demonstration of causative MTB in clinical specimens. In TBGU, the sample may include, but is not limited to, urine, prostate massage fluid, biopsy tissue, pus, or discharge fluid. The organism can be identified directly using any of the following techniques:
> Smear microscopy : performed using Ziehl-Neelsen (ZN) or auramine staining. Light-emitting diode-based fluorescent microscopy has also been found to have similar sensitivities and specificities, but is 3 times faster than ZN microscopy. The sensitivity is around 40%.
> GeneXpert MTB/RIF Assay : Recently, WHO has recommended this assay for rapid diagnosis of TB. In addition to a fast response time, it is also affordable. It can detect MTB and the presence of rifampin resistance by detecting mutations in the rpoB gene simultaneously in pulmonary TB. The sensitivity has been found to be between 63% and 91% in different types of samples. At TBGU, the sensitivity of GeneXpert has been found to be between 63% and 94%, depending on the gold standard used in the study.
> Mycobacterial culture : Mycobacterial culture remains the gold standard for diagnosing active TB. In case of suspected TBGU, 3 early morning urine samples are taken on consecutive days for smear microscopy and culture. Traditionally, mycobacterial culture was used with Lowenstein-Jensen media or liquid culture media, but recently there has been a shift toward rapid automated liquid culture systems, linear probe assays (LPA), and the GeneXpert MTB/RIF assay. According to the WHO, the MGIT liquid culture system is the current gold standard confirmatory test.
> Whole genome sequencing (WGS) and next generation sequencing : WGS can provide the near-entire genome of the bacilli in a sample and detailed sequencing information for multiple gene regions or entire genomes of particular interest. They are much faster than mycobacterial cultures, but are not yet widely available due to associated costs and specialized infrastructure requirements.
> Histology : the characteristics of TB and granulomatous inflammation in the biopsy tissue, and the presence of acid-fast bacilli are characteristics of TB.
There may also be indirect methods that can provide supporting evidence of TB, including:
> Blood tests : in case of suspected TBGU, complete blood counts, CRP and kidney function tests should be routinely performed. An elevated CRP and serum creatinine should raise suspicion for TBGU in the appropriate clinical context. These tests are useful adjuncts to more confirmatory tests and may be useful in evaluating the disease’s response to treatment.
> Urinary lipoarabinomannan (LAM) : it is a constituent part of the MTB cell wall and is detected in the urine of patients with active TB. LAM can be detected in all forms of TB, not just TB bacilli in urine.
> Imaging : X-rays, ultrasounds, urograms, CT scans, MRIs and PET scans can be useful in TBGU, especially if there is no microbiological diagnosis, as well as for direct samples, such as a biopsy for microbiology and histopathology.
> Others : include endoscopies with cystourethroscopy, ureteroscopy, hysteroscopy and laparoscopy and hysterosalpingography. These studies are also useful in obtaining samples for confirmatory testing using the microbiological or histopathological techniques mentioned above.
| Treatment and management |
> Medical treatment
TBGU is generally treated like pulmonary TB, with a 4-drug regimen (rifampicin, isoniazid, pyrazinamide, and ethambutol) for 6 months. This is started for the first 2 months, then isoniazid and rifampicin are added for 4 months. Patients who may require longer treatment are those with HIV co-infection, kidney abscesses, or bone infiltration. Patients with multidrug-resistant TB require treatment with regimens including fluoroquinolones, bedaquiline, delaminide, aminoglycosides, etc., which may extend up to 18 to 24 months.
> Surgical treatment
Patients with TBGU complicated by ureteral stricture and hydronephrosis should undergo early stenting or percutaneous nephrostomy. Nephrectomy is indicated in patients with nonfunctioning kidneys, or with coexisting renal cell carcinomas, and those with extensive disease affecting the entire kidney.
| Differential diagnosis |
• Urinary tract infections
• Urethritis
• Epididymitis
• Prostatitis
• Malignancy (renal cell carcinoma, testicular tumor)
• Chronic pyelonephritis
• Infertility
• Urethral stricture
• hydrocele
• Spermatocele
• Cystitis due to Bacillus Calmette Guerin (BCG)
| Management of toxicity and adverse effects |
Common Side Effects of Anti-TB Drugs
• Isoniazid : hepatitis, toxic neuropathy, headache
• Rifampin : red/orange urine, arthralgia
• Pyrazinamide : painful joints due to hyperuricemia
• Ethambutol : optic neuropathy
| Management of side effects |
Hepatotoxicity may occur with isoniazid, rifampin, or pyrazinamide. Therefore, liver function tests should be performed every 2 months. If such tests are abnormal, the offending medications should be discontinued immediately. Pyridoxine is used to prevent peripheral neuropathy, which may be caused by isoniazid or ethambutol. The latter can cause optic atrophy. Before starting ethambutol, visual acuity and color vision should be checked for deterioration.
| Forecast |
The prognosis of TBGU is excellent if it is detected early and if the patient complies well with anti-tuberculosis treatment. The cure rate with that therapy is around 90%. Relapses have been reported to occur in up to 6.3% of cases after an average of 5.3 years of adequate anti-tuberculosis treatment.
| Complications |
• Super added infections
• Stenosis
• Fistula
• Renal hypertension. Chronic kidney failure
• Infertility
• Prostatic abscess
• Reduced bladder capacity
• Tuberculous interstitial nephritis
• Tuberculous vaginal ulcers
| Consultations |
The management of TBGU should involve a multidisciplinary approach that includes the infectious disease specialist, the urologist in case of any complications related to the urinary tract and the gynecologist if the woman has infertility or involvement of the reproductive organs, radiologist, health doctor public and pharmaceutical of infectious diseases.
The goal of therapy in TBGU is early detection and treatment with antituberculosis agents. Patients should be aware of the need to strictly adhere to such treatment and to have a balanced diet.
In cases with doubtful adherence, directly observed therapy can be applied. Patients should also be given appropriate warnings about the side effects of anti-tuberculosis drugs and should be asked to return immediately if side effects occur.
Patients can be infectious and transmit the infection through sexual contact for up to 4 weeks after starting specific therapy.
| Improving healthcare team outcomes |
TBGU is becoming a major public health problem in the developing world. Patients from an endemic area who present with symptoms or clinical signs of TBGU should be investigated without delay.
Eradicating TBGU requires early detection of the disease, timely and appropriate anti-tuberculosis treatment, patient education, and adequate long-term follow-up.
TBGU case management involves a multidisciplinary team approach that includes an infectious disease expert, a urologist, a gynecologist, a radiologist, a public health physician, and an infectious disease pharmacist. With early detection and proper management, TBGU has a good prognosis and a low relapse rate.
