INTRODUCTION
Tuberculosis (TB) ranks above human immunodeficiency virus (HIV) in terms of being a public health problem, when it comes to infectious diseases with the highest mortality rate. However, during the current pandemic of COVID-19, the incidence and treatment trends showed a changing trend. As per the World health organization report (WHO 2021 report), there were 5.8 million cases of TB in 2020. Moreover, COVID-19 hospitalizations and bed occupancy led to a decreased access to the treatment of other infectious diseases (also TB), which resulted in increased deaths due to TB. The WHO 2021 report showed that around “1.3 million TB deaths occurred among HIV-negative people in 2020 (up from 1.2 million in 2019) and an additional 214 000 among HIV-positive people in 2020 (up from 2,09,000 in 2019).”[ 1 ]
In TB, the causative organism is Mycobacterium TB , which attacks the lungs (primary TB).[ 2 ] The spread of M. TB can also occur either via lymph or blood to any organ in the body. When any organ other than the lungs is affected, it is known as extrapulmonary TB (EPTB).[ 3 ] The most affected sites are peripheral lymph nodes, genitourinary TB sites (GUTB), pleura, abdomen, bones and joints, and the central nervous system.[ 4 ]
Out of the annual incidences of TB, EPTB was found in 45% of the patients.[ 5 ] EPTB is most frequently found in the urogenital system, with the urinary tract being more commonly affected compared to the genital organs. GUTB accounts for nearly 25% of all EPTB cases in the world. The prevalence of GUTB varies by geographical region, ranging from 15% to 20% in Africa, Asia, Eastern Europe; and Russia to 2% to 10% in Western Europe and the United States; and 1% to 19% in India.[ 5 , 6 ] The developing countries account for >90% of GUTB cases. GUTB is the second most common cause of EPTB in these areas.[ 7 ] In an Indian study by Naik et al .,[ 8 ] GUTB was present in 15.7% of the women who attended infertility clinic for treatment.
Barring the studies that have been published on different organs of genitourinary system[ 9–11 ] or generalised EPTB,[ 4 , 12 , 13 ] not many studies have focused on the genitourinary TB as a whole, especially in India which caters to a large population burden of TB.
TB, in its any form, needs early diagnosis and management. GUTB, because of its varied presentation, requires research on the clinical presentations, diagnostic modalities, and management.
Thus, we conducted this study with an aim to determine the demographic and clinical profile of the patients with GUTB, along with their diagnostic evaluation and management.
METHODS
A retrospective study was conducted on 117 patients with GUTB, who were admitted between January 2007 to December 2016 in the Urology Department of Ramaiah Medical College and Hospitals, Bengaluru. Due to the retrospective nature of the study, ethical clearance and patient consent was waived off. Moreover, the study fell under exempt criteria for Institutional Review Board under section 45 code of federal regulations (CFR) 46.101(b) (4) as the research involved the collection or study of existing data, documents, and records, without disclosure of the patient details.
The details were collected of patients who had confirmed TB, on either urine acid-fast bacilli (AFB) staining, or AFB culture, or histopathology, or serological techniques.
GUTB was confirmed when minimum one of the following criteria was present along with the clinical features: (1) using the Ehrlich–Ziehl–Neelsen technique, minimum one out of every three early morning urine samples tested positive for AFB; (2) positive urine or tissue culture for M. TB complex; (3) positive polymerase chain reaction (PCR) for M. TB complex; and (4) histological evidence of TB such as chronic granulomatous inflammation with Langhans giant cells with or without caseation.[ 14 ]
The case records of all cases diagnosed as GUTB were analyzed for clinical presentation, urine AFB staining, chest X-ray, urine M. TB culture, urine PCR for M. TB , intravenous pyelogram (IVP), and histopathological examinations if available.
All patients were scheduled to receive 6-month chemotherapy with isoniazid, rifampicin, and ethambutol or pyrazinamide according to the Centers for Disease Control and American Thoracic Society protocol.[ 15 ]
Follow-up period was 1 year to 10 years. The outcome measures were adverse effects of medications and requirement of surgical management.
Statistical analysis
The presentation of the categorical variables was done in the form of number and percentage (%). On the other hand, the quantitative data were presented as the means ± standard deviation and as median with 25th and 75th percentiles (interquartile range). The data entry was done in the Microsoft Excel spreadsheet and the final analysis was done with the use of Statistical Package for the Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, version 21.0. For statistical significance, P < 0.05 was considered statistically significant.
RESULTS
Four thousand seven hundred thirty-three patients were admitted in our department during a recent 10-year period, of whom 117 were admitted owing to GUTB. Most patients were aged >30 years (63.2%) and there was female sex predominance. The mean age of the patients was 32.5 ± 6.4 years. The common clinical symptoms included irritative voiding symptoms, hematuria, flank pain, constitutional symptoms, and recurrent urinary tract symptoms in 66.47%, 47.6%, 33.8%, 32.6%, and 18.9%, respectively [Table 1 ].
Table 1: Demographic and clinical characteristics genitourinary tuberculosis patients
A past history of pulmonary TB was detected in 22 (18.9%) patients and spine TB in one patient.
Urinalysis was nonspecific, which revealed sterile pyuria in 73 (62.4%), proteinuria in 68 (57.4%), and hematuria in 72 (61.5%) patients. Except for seven patients, all patients underwent at least one of the following tests: the urine AFB staining test, the urine culture test, and PCR. Of these patients, 101 (86.4%) were positive for at least one test; the positivity rate was 21.6% of the urine AFB staining test, 35.4% for the urine M . TB culture test, and 67.7% for PCR. Chest X-ray was positive in 25.6% (30), erythrocyte sedimentation rate was raised in 62.5%, and Mantoux was positive in 61.2% of patients.
In IVP, kidney was the major primary site of involvement (76 cases), followed by ureter (32 cases) and bladder (20 cases). In 76 cases of renal involvement, 56 patients had unilateral involvement, while 20 had bilateral involvement. A representative case image is shown in Figure 1 .
Figure 1: IVP of GUTB patients showing nonexcretory kidney left side, small capacity bladder. IVP: Intravenous pyelogram, GUTB: Genitourinary tuberculosis
Epididymis was involved in six patients; three of them detected on evaluation of scrotal swelling, two as stricture associated with vas difference on infertility workup and one as scrotal sinus. Seminal vesicle was involved in one patient in hematospermia workup. Prostate involvement was detected incidentally in one patient after transurethral resection of prostate (T. U. R. P.) and in three patients, after transrectal ultrasonography (TRUS)-guided prostatic biopsy.
As for adverse reactions, abnormal liver function was observed in four, pruritus in three, and skin eruption in one patient. At least one of the urine tests (urine AFB staining test, urine culture test, and PCR) was positive in 101 (86.4%) patients before the start of chemotherapy, but it became negative in all patients within 3 months of chemotherapy. Surgical procedures were needed in 71 (60.13%) patients [Table 2 ].
Table 2: Organs involved and surgical procedure performed in genitourinary tuberculosis patients
All operated cases were on regular follow-up without any recurrence of the disease.
DISCUSSION
The present study showed that the demographic profile of the patients with GUTB is in similarity with the primary TB and EPTB cases.
The mean age as seen in our study was 32.5 ± 6.4 years, which was in line with the mean age in the studies by Chandrasekhar and Jose[ 16 ] (36 years), Krishnamoorthy et al .[ 13 ] (35.4 years), and So and Villanueva (35.79 years)[ 17 ] who conducted studies on GUTB and mean ages of Tola et al .[ 18 ] (32 years) and Sharma et al .[ 19 ] (32.65 years), who conducted the studies on primary TB patients.
This shows that as for GUTB, the varied nature lies primarily in the clinical presentations depending on the organs affected. The most common clinical presentation in our study was irritative voiding symptoms, followed by hematuria and flank pain, constitutional symptoms, and recurrent urinary tract symptoms owing to the involvement of kidney.[ 16 ] Among other studies, Chandrasekhar and Jose[ 16 ] also found irritative voiding symptoms (65.71%) to be present in most of the patients, followed by sterile pyuria (62.85%) and flank pain (57.14%). Krishnamoorthy et al .[ 13 ] reported that the loin pain (27%) was the most common presentation, followed by storage symptoms (25.5%) and hematuria (11%). Chandra et al .[ 20 ] found that irritative voiding symptoms, flank pain, hematuria, and sterile pyuria were present in 56%, 56%, 44%, and 40% of patients. So and Villanueva.[ 17 ] reported that weakness, difficulty of breathing, and flank pain were the common symptoms present in 14.29%, 12.5%, and 11.61% of patients, respectively.
History of primary TB can precede the cases of GUTB as was seen in 19.6% cases. Among other studies, Chandrasekhar and Jose[ 16 ] reported that family history of TB was present in 11.42% of patients. Chandra et al .[ 20 ] found 36% of the patients to have the previous history of TB. In the study by So and Villanueva[ 17 ] prior history of TB was present in 12.5% of patients.
In GUTB, the varied organs involved can be urological and genital. The epididymis among males and the fallopian tube among females are the principal sites of infection in the genitalia. The genital tract is frequently involved during the reproductive age. In 10%–55% of males with urogenital TB, the epididymis is affected. Acute infection, chronic infection, and infertility are all possible manifestations. The manifestation of the acute infection may be in the form of combined epididymo-orchitis that presents with tenderness, pain, as well as scrotal swelling. This is found to be the most common manifestation in about 40% of the patients, with other features being scrotal or testicular mass or abscess with or without pain. In nearly 10% of cases, the presenting feature is infertility. TB is rarely found in the testis. In most cases, testicular involvement occurs concurrently with epididymal involvement.[ 21 ]
In the present study, epididymis was involved in 6 patients. In a similar Indian study, epididymis involvement was found in 5.13% of patients out of 117 cases of GUTB.[ 21 ] In another Indian study, Krishnamoorthy et al .[ 13 ] reported epididymis involvement in 6 patients out of 110 patients of GUTB. Chandra et al .[ 20 ] found epididymis involvement in 12% of patients out of 25 cases of GUTB. In India, probability of tubercular involvement of epididymis is generally neglected. It is assumed to be the result of a nonspecific infection or filarial infection. In comparison, in a study conducted in Taiwan, Huang et al .[ 22 ] reported that epididymis was involved in 5.26% of patients out of 57 cases of GUTB.
TB is transmitted by the hematogenous or lymphatic routes to the seminal vesicle among males and the uterus and ovarian tube in females. The involvement of seminal vesicle was seen in one patient in the present study, which was diagnosed during workup for hematospermia and infertility. In this study, seminal vesicle was involved in one patient. Singh et al .[ 21 ] reported involvement of seminal vesicle in 2.8% of patients.
The occurrence of TB in prostate is rarely found. Infection may be from hematogenous or descending route. Most of the patients are asymptomatic; however, perineal sinus or reduction in ejaculatory volume may be present in some advanced cases. The gland is generally nontender, nodular, and enlarged on digital rectal examination. Pathologists are the most likely to make the diagnosis after a prostate biopsy or TURP. The prostate involvement was seen in four patients; out of these, 3 patients were diagnosed through TRUS-guided biopsy and 1 patient through prostatectomy done for other causes.[ 7 ]
The presence of Mycobacterium in urine or body fluid and granulomatous lesion on histology are used to diagnose GUTB. Changes in radiographic studies (computed tomography, IVP, and chest X-ray) and an elevated ESR are markers that aid in diagnosis. Although the urine AFB staining test is an easy, inexpensive, and rapid, it has limited sensitivity and specificity for M. TB . Although sterile pyuria is a common finding in urine examinations, the presence of mycobacterium is the major diagnostic test.[ 7 ]
There is low yield of direct AFB staining test and reported to be positive among 30% of the patients.[ 21 ] About 6–8 weeks are taken by the culture in special medium. It is found to be sensitive in 20% to 97%, and its specificity is greater than that of urine AFB test.[ 21 ] In the cases where negative results are found on urine AFB test and the urine M. TB culture test, M. TB can be detected by urine PCR in few hours of DNA extraction from the sample.[ 23 ]
It has a reported sensitivity approach to 94% with specificity 88%.[ 23 ] In the present study, the diagnostic positivity rate for PCR, urine M. TB culture test, and urine AFB test was 67.7%, 35.4%, and 21.6%, respectively. In a similar study, Singh et al .[ 21 ] reported that the positivity rate for the urine AFB test, the urine M. TB culture test, and PCR was 41.6%, 55.4%, and 67.7%, respectively. The positivity rate for urine PCR was 31.4% in the study by Sharma et al .[ 24 ] The reason for low sensitivity of PCR could be presence of nontuberculous mycobacteria or hemoglobin in hematuria. So and Villanueva.[ 17 ] found that the positivity rate of urine AFB staining, urine PCR, and urine culture was 50%, 14.29%, and 16.07%, respectively.
Several collections of urine samples, collecting high-quality samples like the early morning urine, elimination of PCR inhibitors, and elevating urine concentration by centrifugation prior to analysis are all ways for reducing false PCR negativity.[ 7 ]
Imaging tests carry a significant role in the diagnosis of GUTB. The tests that are performed initially include X-ray (abdomen and chest). On plain X-ray abdomen, there may be calcification mainly in kidney (7% to 14%). However, calcification in bladder wall, seminal vesicle, or ureter is rarely seen. Although ultrasonography is a poor technique for detecting morphological changes, it is more beneficial for follow-up than for initial diagnosis. The intravenous urogram test is beneficial because it offers anatomical and functional characteristics of the kidney, ureter, and bladder. The loss of sharpness or blunting of small calyces may be the first change identified in GUTB. On progression of disease, calyces may show “moth eaten appearance” or there may also be “lost calyces, infundibular stenosis, renal cavitation, pseudotumor, or renal scarring and nonfunctioning kidney.”[ 7 ] In the present study, kidney, ureter, and bladder were involved in 76, 32, and 20 patients. The predominant renal findings included calyx and infundibular deformity (n = 39) and hydronephrosis (n = 31). Similarly, Singh et al .[ 21 ] reported that the main renal findings were calyces and infundibular irregularities.
In the case of suspicion of malignancy, it is recommended to perform cystoscopy with bladder biopsy. The commonly seen findings include local hyperemia, erosion and ulceration of mucosa, development of tubercle, irregular ureteral meatus, and decreased capacity of bladder. To avoid disease dissemination, it should be performed after 6 weeks of medical treatment. Bladder biopsy is reported to be 18.5%–52% sensitive.[ 7 ] In the present study, bladder was involved in 20 patients. Singh et al .[ 21 ] reported that bladder involvement was present in 17% of the patients, with all cases being positive on bladder biopsy.
For the management of TB, the standard of care is considered to be the short-course chemotherapy. The accelerated rates of culture conversion as well as the lowest rates of relapse are reported after 6-month regimens comprising pyrazinamide and rifampicin.[ 7 ]
In spite of the availability of efficient antitubercular treatment (ATT), surgery is still used to treat GUTB. Before surgery, ATT is recommended for at least 4 weeks, which provides stabilization of the lesion and proper planning of reconstructive surgery. When TB of the testis or epididymis persists despite therapy with antituberculous medicines, surgical treatment needs to be taken into account.[ 7 ]
Limitations
There are a few limitations of this study. The retrospective design of the study was one of the limitations. Furthermore, it included patients of the study center; this could have introduced selection bias in the study. As the present study relied on positivity of the urinary PCR, high false positive rate may be present.
CONCLUSION
Our findings demonstrate that GUTB was slightly more common among females and mostly in the third decade of life. It presents with varied clinical presentations. To make a comprehensive diagnosis of GUTB, high index of suspicion is needed, as well as a wide variety of diagnostic methods. The best treatment is a combination of multidrug chemotherapy and surgery, when needed. Despite the fact that short-term antituberculous chemotherapy demonstrated good treatment outcomes with less adverse drug reactions, a large number of patients with GUTB may require surgery, unlike TB of other organs.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. World Health Organization. Global Tuberculosis Report 2021 Available from:
https://www.who.int/teams/global-tuberculosis-programme/tb- reports/global-tuberculosis-report-2021 [Last accessed on 2022 Jan 29].
2. Selmane S, L'Hadj M. Epidemiology and clinical characteristics of tuberculosis in Leon Bernard tuberculosis unit in Algeria. Int J Mycobacteriol 2020;9:254–60.
3. Webster AS, Shandera WX. The extrapulmonary dissemination of tuberculosis:A meta-analysis. Int J Mycobacteriol 2014;3:9–16.
4. Varghese B, Al-Hajoj S. Mapping the epidemiology and trends of extra-pulmonary tuberculosis in Saudi Arabia. Int J Mycobacteriol 2015;4:261–9.
5. Muneer A, Macrae B, Krishnamoorthy S, Zumla A. Urogenital tuberculosis –Epidemiology, pathogenesis and clinical features. Nat Rev Urol 2019;16:573–98.
6. Sharma JB, Sharma E, Sharma S, Dharmendra S. Female genital tuberculosis:Revisited. Indian J Med Res 2018;148:S71–83.
7. Mantica G, Ambrosini F, Riccardi N, Vecchio E, Rigatti L, De Rose AF, et al. Genitourinary tuberculosis:A comprehensive review of a neglected manifestation in low-endemic countries. Antibiotics (Basel) 2021;10:1399.
8. Naik SN, Chandanwale A, Kadam D, Sambarey PW, Dhumal G, DeLuca A, et al. Detection of genital tuberculosis among women with infertility using best clinical practices in India:An implementation study. Indian J Tuberc 2021;68:85–91.
9. Chowdhury TS, Naser MF, Haque M. A long journey to be diagnosed as a case of tuberculous cystitis:A Bangladeshi case report and review of literatures. Int J Mycobacteriol 2020;9:248–53.
10. Pereira FG, Leal MD, Cavadas S, Ladeira I. Isolated testicular tuberculosis with ethambutol cutaneous toxicity:A combination of two rare entities. Int J Mycobacteriol 2020;9:322–4.
11. Fatima T, Hasan R, Malik FR, Ahmed I, Bartlett LA, Gravett MG, et al. Female genital tuberculosis in Pakistan –A retrospective review of 10-year laboratory data and analysis of 32 cases. Int J Mycobacteriol 2021;10:66–70.
12. Ramos JM, Isea-Peña MC, Tesfamariam A, Balcha S, Reyes F, Górgolas M. Mammary, testicular and adnexal tuberculosis diagnosed by histology in a rural hospital in Southern Ethiopia. Int J Mycobacteriol 2012;1:212–4.
13. Krishnamoorthy S, Palaniyandi V, Kumaresan N, Govindaraju S, Rajasekaran J, Murugappan I, et al. Aspects of evolving genito urinary tuberculosis –A profile of genito urinary tuberculosis (GUTB) in 110 patients. J Clin Diagn Res 2017;11:PC01–5.
14. Altiparmak MR, Trabulus S, Balkan II, Yalin SF, Denizli N, Aslan G, et al. Urinary tuberculosis:A cohort of 79 adult cases. Ren Fail 2015;37:1157–63.
15. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Executive summary:Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines:Treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016;63:853–67.
16. Chandrasekhar I, Jose PA. Clinical study and management of genitourinary tuberculosis. IAIM 2019;6:48–57.
17. So PN, Villanueva AR. Serologic and urinary characteristics of laboratory-confirmed genitourinary tuberculosis at a tertiary hospital in the Philippines. BMC Urol 2021;21:125.
18. Tola HH, Karimi M, Yekaninejad MS. Effects of sociodemographic characteristics and patients'health beliefs on tuberculosis treatment adherence in Ethiopia:A structural equation modelling approach. Infect Dis Poverty 2017;6:167.
19. Sharma P, Verma M, Bhilwar M, Shekhar H, Roy N, Verma A, et al. Epidemiological profile of tuberculosis patients in Delhi, India:A retrospective data analysis from the directly observed treatment short-course (DOTS) center. J Family Med Prim Care 2019;8:3388–92.
20. Chandra S, Chandra H, Chauhan N, Gaur DS, Gupta H, Pathak VP, et al. Male genitourinary tuberculosis-13 years experience at a tertiary care center in India. Southeast Asian J Trop Med Public Health 2012;43:364–9.
21. Singh JP, Priyadarshi V, Kundu AK, Vijay MK, Bera MK, Pal DK. Genito-urinary tuberculosis revisited-13 years'experience of a single centre. Indian J Tuberc 2013;60:15–22.
22. Huang TY, Hung CH, Hsu WH, Peng KT, Hung MS, Lai LJ, et al. Genitourinary tuberculosis in Taiwan:A 15-year experience at a teaching hospital. J Microbiol Immunol Infect 2019;52:312–9.
23. Hemal AK, Gupta NP, Rajeev TP, Kumar R, Dar L, Seth P. Polymerase chain reaction in clinically suspected genitourinary tuberculosis:Comparison with intravenous urography, bladder biopsy, and urine acid fast bacilli culture. Urology 2000;56:570–4.
24. Sharma N, Sharma V, Singh PR, Sailwal S, Kushwaha RS, Singh RK, et al. Diagnostic value of PCR in genitourinary tuberculosis. Indian J Clin Biochem 2013;28:305–8.
