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International Journal of Urology (2014)
doi: 10.1111/iju.12549
Original Article
Nationwide survey of urogenital tuberculosis in Japan Keita Nakane,1,7 Mitsuru Yasuda,1,7 Takashi Deguchi,1,7 Satoshi Takahashi,2,7 Kazushi Tanaka,3,7 Hiroshi Hayami,4,7 Ryoichi Hamasuna,5,7 Shingo Yamamoto,6,7 Soichi Arakawa3,7 and Tetsuro Matsumoto6,7 1 Department of Urology, Graduate School of Medicine, Gifu University, Gifu, 2Department of Urology, Sapporo Medical University School of Medicine, Sapporo, 3Division of Urology, Department of Surgery Related Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, 4Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 5Department of Urology, University of Occupational and Environmental Health, Kitakyushu, 6Department of Urology, Hyogo College of Medicine, Nishinomiya, Japan, and 7Japanese Research Group for UTI, Japan
Abbreviations & Acronyms DD = doctor’s delay EB = ethambutol EPTB = extrapulmonary tuberculosis INH = isoniazid MDR-TB = multidrugresistant tuberculosis PD = patient’s delay PTB = pulmonary tuberculosis PZA = pyrazinamide RFP = rifampicin SM = streptomycin TB = tuberculosis urine PCR test = urinary polymerase chain reaction test UTB = urogenital tuberculosis Correspondence: Keita Nakane M.D., Ph.D., Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagi-do, Gifu, Gifu 501-1194, Japan. Email: [email protected] Received 26 December 2013; accepted 29 May 2014.
Objectives: To determine current epidemiology and treatment patterns of urogenital tuberculosis in Japan. Methods: A questionnaire was sent to the urological departments of 1203 Japanese hospitals. Clinical data was reviewed retrospectively; no time range was specified. Results: Of the 1203 hospitals, 399 returned questionnaires with information about 355 urogenital tuberculosis patients. Of the 399, 153 institutions reported at least one patient, and 201 patients were identified between 2000 and 2007. Infections were located in the kidneys (n = 242), ureter (n = 96), bladder (n = 100), epididymis or testes (n = 81) and prostate (n = 9). Conclusions: Urogenital tuberculosis is rare in Japan, but patients do exist, and we should not ignore them.
Key words: nationwide survey, urinary tract infection, urogenital tuberculosis.
Introduction There are various symptoms of TB, some of which indicate a delayed allergic reaction to Mycobacterium tuberculosis. As tuberculosis is primarily a sinopulmonary infection, the lungs are most commonly affected, but other infection sites are also possible. Tuberculosis is thus classified into two categories: PTB and EPTB.1 Most EPTB, including UTB, develop after PTB. In Japan, TB incidence has decreased from 698.4 patients per 100 000 people per year in 1951 to 19.0 patients per 100 000 people per year in 2009.2 In 2008, just 121 urinary tract TB patients and 34 genital TB patients were reported.3 Therefore, Japanese urologists seldom encounter UTB patients in common practice. However, UTB can occur several decades after the initial TB infection.4 The Tuberculosis Surveillance Center, which is part of the Research Institute of Tuberculosis/Japan Anti-Tuberculosis Association, provides epidemiological data on TB incidence in Japan, the number of EPTB patients and modes of treatment of all EPTB (including UTB).5 However, there is generally very little information about UTB patients. The present study examined the following: the number of recent UTB patients, the social and medical background of UTB patients, the role of urinary examination in UTB diagnosis, the incidence of drug-resistant UTB, the causes of doctor’s delay, and UTB treatment options. The academic committee of the Japanese Urological Association approved the study.
Methods A questionnaire was sent to 1203 Japanese hospitals with urological departments in April 2007. Clinical data was reviewed retrospectively; no time range was specified. The questionnaire collected information in the following seven categories: (i) patient background; (ii) clinical examinations; (iii) grounds for diagnosis; (iv) patient and doctor delay; (v) mode of therapy; (vi) prognosis; and (vii) infection control. In the “patient background” category, we collected the following information: patient’s sex, age at diagnosis, mode of symptoms, history of tuberculosis (lung, pleura, lymph nodes, bone and others); underlying disease (diabetes mellitus, end stage renal disease, HIV infection and others), socioeconomic backgrounds (coming from other countries, no permanent place of residence, having livelihood protection, medical workers and others) and infection site (kidney, ureter, bladder, testis or epididymis and prostate). In “clinical © 2014 The Japanese Urological Association
1
K NAKANE ET AL.
examinations”, we confirmed whether the UTB patients had the following examinations or not: radiological examinations, such as intravenous injection or drip infusion pyelography; computed tomography; magnetic resonance imaging and others; urinary examinations including urinalysis, urine smear microscopy, urine culture or urine PCR test; and endoscopic examinations, such as cystoscopy. In addition to these data, we asked each urologist about the grounds for diagnosis: by the result of urine smear, urine culture, urine PCR test or by the pathological diagnosis of a surgically resected specimen, or by the clinical course. In relation to diagnosis, patient and doctor delay were determined. Furthermore, we surveyed the mode of therapy of UTB patients: drug therapy alone, surgical intervention and drug therapy, or surgical intervention alone. Then, the prognosis of each patient was researched. Finally, we questioned each institution about how they managed the UTB patients from the view of infection control.
Results Of the 1203 hospitals, 399 institutions returned questionnaires with information about 355 UTB patients. Of these 399 institutions, 153 reported at least one patient, and 201 patients were identified between 2000 and 2007.
Table 1
Background of reported Japanese UTB patients 1970–2007
Background of UTB patients Characteristics
No. pts (%)
No. patients Median age, years (range) Sex (%) Male Female Unknown Social background (%) Yes No Underlying disease (%) Yes No History of TB (%) Yes No Concomitant TB other than UTB (%) Yes No Infection site Urinary tract (kidney/ureter/bladder) Genital organ (testis or epididymis/prostate)
355 (100) 57 (9–96) 208 (59) 139 (39) 8 (2) 23 (6) 332 (94) 67 (19) 288 (81) 110 (31) 288 (69) 32 (9) 323 (91) 242/96/100 81/9
Patient background Of the 355 reported UTB patients, 208 were men and 139 were women; eight questionnaires did not include information pertaining to sex. The mean age was 57 years (range 9–96 years). Distribution of the disease according to district is shown in Figure S1. With regard to significant social background, 11 patients were from other countries, four had no permanent place of residence, two had livelihood protection and one was in the care of a medical worker. The other 332 patients had no remarkable social characteristics. While 288 patients had no obvious underlying disease, other diseases were as follows: diabetes mellitus (n = 30), malignant tumor (n = 9), renal insufficiency (n = 6), immunosuppressive therapy (n = 6) and chronic hepatitis (n = 5). Previous history of TB was reported in 110 patients (31%). There were 32 UTB patients who had a concomitant focus of TB other than the urinary tract and genital organs (9%; Table 1). Infections were located in the kidneys (n = 242), ureter (n = 96), bladder (n = 100), epididymis or testes (n = 81) and prostate (n = 9). We identified 82 genital TB (prostate, scrotum, epidydimis or testis) patients. Of these patients, 16 patients have concomitant kidney lesions and 66 patients presented genital TB only. Patients presented with the following symptoms: pollakisuria, palpable scrotal mass, fever, micturition pain, lumbago or back pain, gross hematuria, sense of residual urine, flank pain, lower abdominal pain, general fatigue, anorexia and others. However, 42 patients (12%) were asymptomatic (Table 2).
Delay “PD” is defined as a period before medical consultation since the first symptom. “DD” is defined as a period before the diagnosis of TB since first medical consultation.6 In the present 2
Table 2
Symptoms of Japanese UTB patients 1970–2007
Symptoms of UTB patients Symptom
No. patients (%)
Pollakisuria Palpable scrotal mass Fever Asymptomatic Micturition pain Lumbago or back pain Gross hematuria Sense of residual urine Flank pain Lower abdominal pain General fatigue Anorexia Pus from scrotum Groin pain Cough Penile pain
80 (23) 59 (17) 46 (13) 42 (12) 35 (9) 20 (6) 20 (6) 18 (5) 17 (5) 5 (1) 3 (1) 3 (1) 2 (0.6) 1 (0.3) 1 (0.3) 1 (0.3)
study, there were 46 patients of PD and 75 patients of DD. In the former patients, the median duration of delay was 4 months (range 0.25–180 months), whereas in the latter, the median duration of delay was 7.5 months (range 0.5–44 months; Table 3). The causes of DD are listed in Table 3.
Radiographic findings Of the 355 UTB patients, radiographic examination was carried out in 235. Table 4 lists the abnormal radiographic findings, the most common of which was urinary tract obstruction (Fig. 1a), followed by deformation of the renal calyces or renal pelvis © 2014 The Japanese Urological Association
Urogenital tuberculosis in Japan
Table 3 PD and DD in reported Japanese UTB patients 1970–2007, and causes of DD in reported Japanese UTB patients 1970–2007 PD and DD PD Yes No Unknown Median duration of delay (months) DD Yes No Unknown Median duration of delay (months)
No. patients (%) 46 (13) 288 (81) 21 (6) 4 (0.25–188) No.pts (%) 75 (21) 259 (73) 21 (6) 7.5 (0.5–44)
Cause of DD (n = 75) Cause Did not include tuberculosis in differential diagnosis Diagnosed as urogenital infection, but not UTB Prolonged close inspection Consulted with another institution Misdiagnosis: urinary tract malignancy Misdiagnosis: urolithiasis Misdiagnosis: interstitial cystitis Unknown
No. patients (%) 20 (27) 16 (21) 8 (11) 5 (7) 3 (4) 3 (4) 2 (2) 18 (24)
UTB treatment UTB treatments were classified into the following three groups: (i) drug therapy alone (n = 185); (ii) surgical intervention and drug therapy (n = 127); and (iii) surgical intervention alone (n = 18). Four patients underwent no treatment. Overall, 43% of the UTB patients were treated by surgical intervention. We divided patients who were treated with drug therapy alone into four subgroups according to drugs combination. Briefly, group A: INH + RFP + SM or EB + α; group B: INH + RFP + SM, EB + PZA + α; group C: INH + RFP; and group D: INH + RFP + α. There were 98 (53%), 47 (25%), 23 (12%) and five (3%) patients treated in the group A, B, C and D, respectively (Fig. 2a). Respondents listed the treatment as unknown in 12 patients (7%). The group that underwent both surgical intervention and drug therapy included 60 nephrectomies (47%), 40 orchiectomies or epididymectomies (32%), 12 nephroureterectomies (9%) and four bladder augmentations (3%); in 15 patients, the specific interventions were unknown (12%; Fig. 2b). Details of drug therapy in this group are shown in Figure 2c. In the group that underwent surgical intervention alone, there were six orchiectomies or epididymectomies (33%), five nephrectomies (28%) and five nephroureterectomies (28%); in two patients, the specific interventions were unknown (11%; Fig. 2d).
Treatment outcome Table 4 Radiographic findings in reported Japanese UTB patients 1970–2007 Radiographic findings (n = 235) Abnormalities
No. patients (%)
Urinary tract obstruction Deformation of renal calyces or renal pelvis Kidney atrophy No abnormalities Calcification Mortar kidney Renal abscess Urinary tract malignancy Others
126 (53) 26 (11) 20 (8) 20 (8) 11 (5) 10 (4) 7 (2) 4 (1) 18 (8)
(Fig. 1b), kidney atrophy, calcification, mortar kidney, renal abscess and urinary tract malignancy.
Urinary examinations Of the 355 UTB patients, urine was examined in 319 using various techniques, such as urinalysis, urine smear microscopy, urine culture or urine PCR test. Of the 166 patients that presented with pyuria, 121 were diagnosed as UTB through urinary examination only. Urine smear microscopy, urine culture and urinary PCR for UTB were positive in 25, 101 and 112 patients, respectively.
Drug-resistant tuberculosis Antituberculosis drug susceptibility was tested in 108 clinically isolated strains. Drug resistance rates are shown in Table 5. MDR-TB was not reported. © 2014 The Japanese Urological Association
Complete recovery was reported in 292 patients. In 58 patients, treatment outcome was unknown, and four patients died of the disease. There was only one recurrent patient of UTB.
Discussion UTB is one form of EPTB that often occurs after PTB. Worldwide, UTB occurs in 30–40% in EPTB7–11 and 2–20% in PTB patients.10,12–14 Although the patients in developed countries are diagnosed as UTB earlier than those in developing countries, UTB patients are sometimes misdiagnosed and treated for other diseases in Japan.15 Our nationwide survey of UTB was intended to address this situation. To ensure collection of the maximum amount of data on UTB patients, no time range was specified with regard to registration of patients. One limitation of the present study was that data was collected retrospectively. In addition, there was no legal obligation to reply to our questionnaire; therefore, we cannot guarantee that information on all UTB patients was acquired. Although these limitations affect the accuracy of the study to some extent, we feel that it still provides valuable information as to the epidemiology and management of UTB in Japan. In the present study, male UTB patients outnumbered female patients. The peak age range of the patients was 51–60 years (data not shown). According to the Kekkaku No Toukei (TB Statistics Board of in Japan), PTB has been more prevalent in male patients since 1949 (Fig. S2).2 Because UTB usually occurs after PTB, this data fits with the male-to-female ratio in the present study. Figueiredo et al. reported that UTB affected more men than women; the male-to-female ratio was 2:1.15 After 2000, despite decreased PTB incidence, UTB patients did not decline (data not shown). This finding contradicts the reports of Kekkaku No Toukei (Fig. S3).3 As previously 3
K NAKANE ET AL.
(a)
(b)
(c)
Fig. 1 (a) White arrowheads indicate ureteral strictures as a result of UTB. Although ureteral stricture caused hydronephrosis, deformation of renal calyces or renal pelvis was not observed. (b) White arrowheads indicate multiple ureteral strictures. Black arrowhead indicates deformation of renal calyces as a result of UTB. (c) An antegrade pyelography image of a UTB patient who had contracted bladder.
Table 5 Incidence of drug-resistant tuberculosis in reported Japanese UTB patients 1970–2007 Drug resistant tuberculosis Antituberculosis drug
Drug-resistant strain (%)
INH RFP SM EB Para-aminosalicylic acid
6/108 (5.5) 4/108 (3.7) 3/92 (3.2) 2/102 (1.9) 2/82 (2.4)
mentioned, data was not available for all UTB patients, so perhaps this discrepancy derives from this limitation. The rates of the UTB patients who have a history of tuberculosis are 49.1% in developing countries and 37.9% in developed countries.15 In the present study, 31% of the UTB patients were reported to have a history of TB. Needless to say, just like other developed countries, Japanese people have a better health status than those in developing countries, therefore, PTB incidence is lower than that of developing countries.16 Then, it is not surprising that the rates of the Japanese UTB patients who have a history of PTB are lower than those of developing countries. However, the PTB incidence in Japan has been higher than other developed countries.16 One hypothesis is that Japanese doctors might fail to take a history of PTB because of being not 4
used to examining UTB patients. This hypothesis could explain one aspect of the reason why the number of Japanese UTB patients who have a history of PTB is lower than those of developed countries. Urologists should obtain a detailed medical history of these patients. We investigated diseases that could lead patients to an immunocompromised state in which TB can develop. The AIDS epidemic caused TB recrudescence not only in developing countries, but also in developed countries.15,17–21 It has been reported that 25–50% of HIV-infected people worldwide have active tuberculosis.15 In the present study, there were no UTB patients who had HIV. However, the number of people living with HIV in Japan has been increasing for years.16 Therefore, it is possible that TB and UTB recrudescence occur in Japan. M. tuberculosis infection occurs primarily in the respiratory organs, and then disseminates to the extrapulmonary organs by a hematogenous route.7 The bacilli first enter the periglomerular capillaries of the kidney, resulting in abscess formation, and gradually involving the ureter, bladder, prostate, seminal vesicle, epididymis and testes.3,4,7 Thus, it might be accurate to hypothesize that the kidney is the most frequent site of infection. In the present study, the kidney was the most common infection site. This result was compatible with the hypothesis. Of the symptoms associated with UTB, pollakisuria, micturition pain and a sense of residual urine are classified as lower urinary tract symptoms, whereas lumbago or back pain and flank pain are derived from upper urinary tract lesions. © 2014 The Japanese Urological Association
Urogenital tuberculosis in Japan
(a) Fig. 2 UTB treatments were classified into the following three groups: drug therapy alone (n = 185), surgical intervention and drug therapy (n = 127), and surgical intervention alone (n = 18). Four patients underwent no treatment. (a) In the group treated with drug therapy alone, 98 (53%), 47 (25%), 23 (12%) and five (3%) patients were treated with INH + RFP + SM or EB + α, INH + RFP + SM, EB + PZA + α, and INH + RFP, INH + RFP + α, respectively. (b) The group that underwent both surgical intervention and drug therapy included 60 nephrectomies (47%), 40 orchiectomies or epididymectomies (32%) and 12 nephroureterectomies (9%). (c) Details of drug therapy in the group that underwent both surgical intervention and drug therapy. (d) In the group that underwent surgical intervention alone, there were six orchiectomies or epididymectomies (33%), five nephrectomies (28%) and five nephroureterectomies (28%); in two patients, the specific interventions were unknown (11%). (a) , Group A: INH + RFP + SM or EB + α; , group B: INH + RFP + SM or EB + PZA + α; , group C: INH + RFP; , group D: INH + RFP + α; , unknown. (b) , Nephrectomy; , orchiectomy or epididymectomy; , nephroureterectomy; , bladder augmentation; , unknown. (c) , INH + RFP + SM or EB + α; , INH + RFP + α; , INH + RFP + SM or EB + PZA + α; , unknown. (d) , Orchiectomy or epididymectomy; , nephrectomy; , nephroureterectomy; , unknown.
(b) 7% 3%
9%
9%
12% 53%
47% 32%
25%
(c)
(d)
11%
10%
58%
11%
28%
33%
21%
Systemic symptoms were less common than urinary tract symptoms in the present survey. The explanation for this might lie in the fact that UTB patients do not always present with tuberculosis of other organs concomitantly. In the literature review, storage symptoms (50.5%), scrotal mass (48.9%) and hematuria (35.6%) were the most frequently seen symptoms in UTB patients.15 In our questionnaire, PD and DD were reported by respondents when they felt “delay”. Therefore, we did not define a specific period for PD and DD. Ohomori et al. also defined “long delay,” which was adapted to PTB; long PD was defined as 2 months or longer (>2 months), long DD was defined as 1 month or longer (>1 month) and long total delay, which was the sum of PD and DD, was defined as 3 months or longer (>3 months). Based on this definition, we analyzed 104 UTB patients for whom total delay could be calculated. The good outcome group included patients who turned negative for urine smear microscopy or urine culture or urine PCR test by drug therapy or who had reached completion of therapy by surgical intervention. The bad outcome group included patients who had not turned negative for urine examinations or suffered relapse of the disease or death from the disease. The χ2-test was carried out to determine whether a total delay of more than 3 months affects UTB patients’ outcome (data not shown). There was no significant difference between the two groups (P = 0.338). However, we could not obtain detailed information for these patients, such as change of symptoms and patients’ quality of © 2014 The Japanese Urological Association
3%
28%
life after UTB treatment. Therefore, we cannot conclude that the duration of total delay really affected UTB patients’ outcomes in the present study. In the present study, antituberculosis drug susceptibility was reported among 108 clinically isolated strains. Although MDR-TB was not found in the present study, it has been an emerging problem since the 1990s. MDR-TB is caused by strains of M. tuberculosis that develop resistance to at least two commonly used drugs, INH and RFP.1 In 2002, the estimated incidence of MDR-TB was 0.7% among new cases and 9.8% among previously treated cases.22 More recently, extensively drug-resistant TB, defined as MDR-TB plus resistance to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin) was reported.22 We must be careful in future so that MDR/extensively drug-resistant TB does not develop further.22 Poor adherence of a patient is one of the reasons that TB develops to MDR-TB; therefore, in 1995, the World Health Organization proposed directly observed treatment, short-course1 to improve the success rate of TB treatment. In Japan, the dissemination and awareness of directly observed treatment, short-course strategy is required.23 Except in patients with concomitant PTB, it is not essential for EPTB patients to be hospitalized in specialized institutions.4 In the present study, 35 UTB patients were referred to such institutions. Of these, seven patients were admitted to hospital because of concomitant PTB. Thus, 28 patients did not need to be referred to specialized institutions. 5
K NAKANE ET AL.
Of the 355 UTB patients reported here, 330 received some kind of treatment. A total of 83% of patients who received antituberculosis drug therapy alone were treated with a combination of three or four antituberculosis drugs. The median duration of therapy was 6 months. Surgical intervention and drug therapy was carried out in 127 patients, and surgical intervention alone was carried out 18 patients, respectively. Of the 127 patients who underwent surgical intervention and drug therapy, 88 patients (69%) had a combination of more than three drugs, and median duration of therapy was 6 months. Tuberculosis treatment guidelines in Japan recommend administration of INH, RFP, EB and PZA for 2 months, and INH and RFP for four additional months, or INH, RFP and EB for 2 months, and INH and RFP for seven additional months in new patients of tuberculosis.4 In the present study, although we did not investigate changes in medication, the drug selection for initial treatment of tuberculosis and duration of therapy seemed appropriate. Although urine examination, including urine culture, urine PCR and radiographic examination, are important tools for diagnosis of UTB, there were 68 UTB patients that were diagnosed by pathology only. In addition, three patients were diagnosed as urinary tract malignancies. Of the four patients who died of the disease, three had chronic renal failure and two had active PTB. These results showed that patients who are immunocompromised and have active systemic TB might be at higher risk for death. In general, UTB patients excrete M. tuberculosis in their urine, but the infection risk for TB from these patients is low unless the bacilli are spread in the air from PTB. Therefore, with respect to infection control, special management of UTB (e.g. isolation) is not necessary.24 In the present study, 246 patients (69%) received no special management (data not shown). In conclusion, because these patients do not usually present with specific symptoms, UTB is often difficult to diagnose. Although the incidence of UTB has decreased in recent years, it is possible that TB and UTB recrudescence occur in Japan by the increasing number of people who are living with HIV, human migration as a result of globalization, or by other reasons. Therefore, we should not ignore it. In order to shorten the treatment delay of UTB patients, urologists should take UTB into consideration as one of the diseases presenting with storage symptoms, hematuria and scrotal mass in clinical practice. Urologists should examine patients who are suspected to have UTB (e.g. immunocompromised state, history of PTB) by using urine examinations and ultrasonography. Takahashi et al. reported the clinical relevance of a nucleic amplification test for UTB patients, and suggested that NAAT is an effective and rapid detection method for UTB.25 Then, if morphological abnormality were found, more detailed radiographic examinations should be considered, such as intravenous pyelography or drip infusion pyelography, computed tomography, magnetic resonance imaging or retrograde pyelography. Furthermore, if the patients are diagnosed as UTB, they must treat the patients appropriately so as to not to increase MDR-TB. To compensate for the experience of the diagnosis and treatment of UTB, the nationwide archive will be required. 6
Acknowledgments The authors thank the doctors who provided the data of UTB patients for their kind cooperation in this study.
Conflict of interest None declared.
References 1 Stop TB Initiative (World Health Organization). Treatment of Tuberculosis: Guidelines, 4th edn. World Health Organization, Geneva, 2010. 2 The Tuberculosis Surveillance Center, The Research Institute of Tuberculosis/JATA. Newly Notified Cases and Case Rates per 100,000 by Sex and Age in Japan, 1969–2009. 2011. [Cited 29 May 2014] Available from URL: http://www.jata.or.jp/rit/ekigaku/en 3 Ito K. Hai-gai Kekkaku Gairon (Outline of Extrapulmonary Tuberculosis). Nippon IJI Shinpo 2010; 4473: 59–64. 4 The Japanese Society for Tuberculosis. Guideline for Tuberculosis, 1st edn. Nankodo, Tokyo, 2009. 5 The Tuberculosis Surveillance Center, The Research Institute of Tuberculosis/JATA. Statistics of TB. 2011. [Cited 29 May 2014] Available from URL: http://www.jata.or.jp/rit/ekigaku/en 6 Ohmori M, Ozasa K, Mori T et al. Trends of delays in tuberculosis case finding in Japan and associated factors. Int. J. Tuberc. Lung Dis. 2005; 9: 999–1005. 7 McAleer SJJC, Johnson WD. Gentourinary tuberculosis. In: Wein AJKL, Novick AC, Partin AW, Peters CA (eds). Campbell-Walsh Urology, 9th edn. Saunders, Philadelphia, PA, 2007; 436–47. 8 Ramanathan R, Kumar A, Kapoor R, Bhandari M. Relief of urinary tract obstruction in tuberculosis to improve renal function. Analysis of predictive factors. Br. J. Urol. 1998; 81: 199–205. 9 Carl P, Stark L. Indications for surgical management of genitourinary tuberculosis. World J. Surg. 1997; 21: 505–10. 10 Psihramis KE, Donahoe PK. Primary genitourinary tuberculosis: rapid progression and tissue destruction during treatment. J. Urol. 1986; 135: 1033–6. 11 Cek M, Lenk S, Naber KG et al. EAU guidelines for the management of genitourinary tuberculosis. Eur. Urol. 2005; 48: 353–62. 12 Gokalp A, Gultekin EY, Ozdamar S. Genito-urinary tuberculosis: a review of 83 cases. Br. J. Clin. Pract. 1990; 44: 599–600. 13 Hemal AK, Gupta NP, Kumar R. Comparison of retroperitoneoscopic nephrectomy with open surgery for tuberculous nonfunctioning kidneys. J. Urol. 2000; 164: 32–5. 14 Alvarez S, McCabe WR. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine (Baltimore) 1984; 63: 25–55. 15 Figueiredo AA, Lucon AM, Junior RF, Srougi M. Epidemiology of urogenital tuberculosis worldwide. Int. J. Urol. 2008; 15: 827–32. 16 Global Report: UNAIDS Report on the Global AIDS Epidemic 2013. UNAIDS, Geneva, 2013. 17 Glynn JR. Resurgence of tuberculosis and the impact of HIV infection. Br. Med. Bull. 1998; 54: 579–93. 18 Schubert GE, Haltaufderheide T, Golz R. Frequency of urogenital tuberculosis in an unselected autopsy series from 1928 to 1949 and 1976 to 1989. Eur. Urol. 1992; 21: 216–23. 19 Beijer U, Wolf A, Fazel S. Prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people: a systematic review and meta-analysis. Lancet Infect. Dis. 2012; 12: 859–70. 20 Aljohaney A, Amjadi K, Alvarez GG. A systematic review of the epidemiology, immunopathogenesis, diagnosis, and treatment of pleural TB in HIV-infected patients. Clin. Dev. Immunol. 2012; 2012: 842045: 1–9. 21 Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006; 61: 158–63. 22 Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response. World Health Organization, Geneva, 2010. 23 Ghotbi N, Nishimura S, Takatsuka N. Japan’s national tuberculosis control strategies with economic considerations. Environ. Health Prev Med. 2005; 10: 213–18. © 2014 The Japanese Urological Association
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24 Centers for Disease Control and Prevention. Questions and Answers About Tuberculosis. 2012. [Cited 29 May 2014] Available from URL: http://www.cdc.gov/TB/PUBLICATIONS/faqs/default.htm 25 Takahashi S, Hashimoto K, Miyamoto S, Takeyama K, Takagi Y, Tsukamoto T. Clinical relevance of nucleic acid amplification test for patients with urinary tuberculosis during antituberculosis treatment. J. Infect. Chemother. 2005; 11: 300–2.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Fig. S1 UTB patients according to district. (a) Districts listed in decreasing order. (b) Map representation of UTB incidence, 2000–2007. UTB was more prevalent in urban regions.
© 2014 The Japanese Urological Association
Fig. S2 Incidence of TB by sex in Japan. The male PTB population (solid line) was larger than the female population (dashed line) from 1949 to 2009. The year 1955 saw a peak in both males and females. The number of UTB patients in Japan Overall incidence of PTB gradually decreased during this time period. Data obtained from the Research Institute of Tuberculosis/Japan Anti-Tuberculosis Association (RIT/JATA), Tuberculosis Surveillance Center. Fig. S3 Incidence of UTB in Japan. UTB gradually declined from 2000 to 2004, and then reached a plateau. Data obtained from the Research Institute of Tuberculosis Japan AntiTuberculosis Association (RIT/JATA), Tuberculosis Surveillance Center.
7
International Journal of Urology (2014)
doi: 10.1111/iju.12549
Original Article
Nationwide survey of urogenital tuberculosis in Japan Keita Nakane,1,7 Mitsuru Yasuda,1,7 Takashi Deguchi,1,7 Satoshi Takahashi,2,7 Kazushi Tanaka,3,7 Hiroshi Hayami,4,7 Ryoichi Hamasuna,5,7 Shingo Yamamoto,6,7 Soichi Arakawa3,7 and Tetsuro Matsumoto6,7 1 Department of Urology, Graduate School of Medicine, Gifu University, Gifu, 2Department of Urology, Sapporo Medical University School of Medicine, Sapporo, 3Division of Urology, Department of Surgery Related Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, 4Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 5Department of Urology, University of Occupational and Environmental Health, Kitakyushu, 6Department of Urology, Hyogo College of Medicine, Nishinomiya, Japan, and 7Japanese Research Group for UTI, Japan
Abbreviations & Acronyms DD = doctor’s delay EB = ethambutol EPTB = extrapulmonary tuberculosis INH = isoniazid MDR-TB = multidrugresistant tuberculosis PD = patient’s delay PTB = pulmonary tuberculosis PZA = pyrazinamide RFP = rifampicin SM = streptomycin TB = tuberculosis urine PCR test = urinary polymerase chain reaction test UTB = urogenital tuberculosis Correspondence: Keita Nakane M.D., Ph.D., Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagi-do, Gifu, Gifu 501-1194, Japan. Email: [email protected] Received 26 December 2013; accepted 29 May 2014.
Objectives: To determine current epidemiology and treatment patterns of urogenital tuberculosis in Japan. Methods: A questionnaire was sent to the urological departments of 1203 Japanese hospitals. Clinical data was reviewed retrospectively; no time range was specified. Results: Of the 1203 hospitals, 399 returned questionnaires with information about 355 urogenital tuberculosis patients. Of the 399, 153 institutions reported at least one patient, and 201 patients were identified between 2000 and 2007. Infections were located in the kidneys (n = 242), ureter (n = 96), bladder (n = 100), epididymis or testes (n = 81) and prostate (n = 9). Conclusions: Urogenital tuberculosis is rare in Japan, but patients do exist, and we should not ignore them.
Key words: nationwide survey, urinary tract infection, urogenital tuberculosis.
Introduction There are various symptoms of TB, some of which indicate a delayed allergic reaction to Mycobacterium tuberculosis. As tuberculosis is primarily a sinopulmonary infection, the lungs are most commonly affected, but other infection sites are also possible. Tuberculosis is thus classified into two categories: PTB and EPTB.1 Most EPTB, including UTB, develop after PTB. In Japan, TB incidence has decreased from 698.4 patients per 100 000 people per year in 1951 to 19.0 patients per 100 000 people per year in 2009.2 In 2008, just 121 urinary tract TB patients and 34 genital TB patients were reported.3 Therefore, Japanese urologists seldom encounter UTB patients in common practice. However, UTB can occur several decades after the initial TB infection.4 The Tuberculosis Surveillance Center, which is part of the Research Institute of Tuberculosis/Japan Anti-Tuberculosis Association, provides epidemiological data on TB incidence in Japan, the number of EPTB patients and modes of treatment of all EPTB (including UTB).5 However, there is generally very little information about UTB patients. The present study examined the following: the number of recent UTB patients, the social and medical background of UTB patients, the role of urinary examination in UTB diagnosis, the incidence of drug-resistant UTB, the causes of doctor’s delay, and UTB treatment options. The academic committee of the Japanese Urological Association approved the study.
Methods A questionnaire was sent to 1203 Japanese hospitals with urological departments in April 2007. Clinical data was reviewed retrospectively; no time range was specified. The questionnaire collected information in the following seven categories: (i) patient background; (ii) clinical examinations; (iii) grounds for diagnosis; (iv) patient and doctor delay; (v) mode of therapy; (vi) prognosis; and (vii) infection control. In the “patient background” category, we collected the following information: patient’s sex, age at diagnosis, mode of symptoms, history of tuberculosis (lung, pleura, lymph nodes, bone and others); underlying disease (diabetes mellitus, end stage renal disease, HIV infection and others), socioeconomic backgrounds (coming from other countries, no permanent place of residence, having livelihood protection, medical workers and others) and infection site (kidney, ureter, bladder, testis or epididymis and prostate). In “clinical © 2014 The Japanese Urological Association
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examinations”, we confirmed whether the UTB patients had the following examinations or not: radiological examinations, such as intravenous injection or drip infusion pyelography; computed tomography; magnetic resonance imaging and others; urinary examinations including urinalysis, urine smear microscopy, urine culture or urine PCR test; and endoscopic examinations, such as cystoscopy. In addition to these data, we asked each urologist about the grounds for diagnosis: by the result of urine smear, urine culture, urine PCR test or by the pathological diagnosis of a surgically resected specimen, or by the clinical course. In relation to diagnosis, patient and doctor delay were determined. Furthermore, we surveyed the mode of therapy of UTB patients: drug therapy alone, surgical intervention and drug therapy, or surgical intervention alone. Then, the prognosis of each patient was researched. Finally, we questioned each institution about how they managed the UTB patients from the view of infection control.
Results Of the 1203 hospitals, 399 institutions returned questionnaires with information about 355 UTB patients. Of these 399 institutions, 153 reported at least one patient, and 201 patients were identified between 2000 and 2007.
Table 1
Background of reported Japanese UTB patients 1970–2007
Background of UTB patients Characteristics
No. pts (%)
No. patients Median age, years (range) Sex (%) Male Female Unknown Social background (%) Yes No Underlying disease (%) Yes No History of TB (%) Yes No Concomitant TB other than UTB (%) Yes No Infection site Urinary tract (kidney/ureter/bladder) Genital organ (testis or epididymis/prostate)
355 (100) 57 (9–96) 208 (59) 139 (39) 8 (2) 23 (6) 332 (94) 67 (19) 288 (81) 110 (31) 288 (69) 32 (9) 323 (91) 242/96/100 81/9
Patient background Of the 355 reported UTB patients, 208 were men and 139 were women; eight questionnaires did not include information pertaining to sex. The mean age was 57 years (range 9–96 years). Distribution of the disease according to district is shown in Figure S1. With regard to significant social background, 11 patients were from other countries, four had no permanent place of residence, two had livelihood protection and one was in the care of a medical worker. The other 332 patients had no remarkable social characteristics. While 288 patients had no obvious underlying disease, other diseases were as follows: diabetes mellitus (n = 30), malignant tumor (n = 9), renal insufficiency (n = 6), immunosuppressive therapy (n = 6) and chronic hepatitis (n = 5). Previous history of TB was reported in 110 patients (31%). There were 32 UTB patients who had a concomitant focus of TB other than the urinary tract and genital organs (9%; Table 1). Infections were located in the kidneys (n = 242), ureter (n = 96), bladder (n = 100), epididymis or testes (n = 81) and prostate (n = 9). We identified 82 genital TB (prostate, scrotum, epidydimis or testis) patients. Of these patients, 16 patients have concomitant kidney lesions and 66 patients presented genital TB only. Patients presented with the following symptoms: pollakisuria, palpable scrotal mass, fever, micturition pain, lumbago or back pain, gross hematuria, sense of residual urine, flank pain, lower abdominal pain, general fatigue, anorexia and others. However, 42 patients (12%) were asymptomatic (Table 2).
Delay “PD” is defined as a period before medical consultation since the first symptom. “DD” is defined as a period before the diagnosis of TB since first medical consultation.6 In the present 2
Table 2
Symptoms of Japanese UTB patients 1970–2007
Symptoms of UTB patients Symptom
No. patients (%)
Pollakisuria Palpable scrotal mass Fever Asymptomatic Micturition pain Lumbago or back pain Gross hematuria Sense of residual urine Flank pain Lower abdominal pain General fatigue Anorexia Pus from scrotum Groin pain Cough Penile pain
80 (23) 59 (17) 46 (13) 42 (12) 35 (9) 20 (6) 20 (6) 18 (5) 17 (5) 5 (1) 3 (1) 3 (1) 2 (0.6) 1 (0.3) 1 (0.3) 1 (0.3)
study, there were 46 patients of PD and 75 patients of DD. In the former patients, the median duration of delay was 4 months (range 0.25–180 months), whereas in the latter, the median duration of delay was 7.5 months (range 0.5–44 months; Table 3). The causes of DD are listed in Table 3.
Radiographic findings Of the 355 UTB patients, radiographic examination was carried out in 235. Table 4 lists the abnormal radiographic findings, the most common of which was urinary tract obstruction (Fig. 1a), followed by deformation of the renal calyces or renal pelvis © 2014 The Japanese Urological Association
Urogenital tuberculosis in Japan
Table 3 PD and DD in reported Japanese UTB patients 1970–2007, and causes of DD in reported Japanese UTB patients 1970–2007 PD and DD PD Yes No Unknown Median duration of delay (months) DD Yes No Unknown Median duration of delay (months)
No. patients (%) 46 (13) 288 (81) 21 (6) 4 (0.25–188) No.pts (%) 75 (21) 259 (73) 21 (6) 7.5 (0.5–44)
Cause of DD (n = 75) Cause Did not include tuberculosis in differential diagnosis Diagnosed as urogenital infection, but not UTB Prolonged close inspection Consulted with another institution Misdiagnosis: urinary tract malignancy Misdiagnosis: urolithiasis Misdiagnosis: interstitial cystitis Unknown
No. patients (%) 20 (27) 16 (21) 8 (11) 5 (7) 3 (4) 3 (4) 2 (2) 18 (24)
UTB treatment UTB treatments were classified into the following three groups: (i) drug therapy alone (n = 185); (ii) surgical intervention and drug therapy (n = 127); and (iii) surgical intervention alone (n = 18). Four patients underwent no treatment. Overall, 43% of the UTB patients were treated by surgical intervention. We divided patients who were treated with drug therapy alone into four subgroups according to drugs combination. Briefly, group A: INH + RFP + SM or EB + α; group B: INH + RFP + SM, EB + PZA + α; group C: INH + RFP; and group D: INH + RFP + α. There were 98 (53%), 47 (25%), 23 (12%) and five (3%) patients treated in the group A, B, C and D, respectively (Fig. 2a). Respondents listed the treatment as unknown in 12 patients (7%). The group that underwent both surgical intervention and drug therapy included 60 nephrectomies (47%), 40 orchiectomies or epididymectomies (32%), 12 nephroureterectomies (9%) and four bladder augmentations (3%); in 15 patients, the specific interventions were unknown (12%; Fig. 2b). Details of drug therapy in this group are shown in Figure 2c. In the group that underwent surgical intervention alone, there were six orchiectomies or epididymectomies (33%), five nephrectomies (28%) and five nephroureterectomies (28%); in two patients, the specific interventions were unknown (11%; Fig. 2d).
Treatment outcome Table 4 Radiographic findings in reported Japanese UTB patients 1970–2007 Radiographic findings (n = 235) Abnormalities
No. patients (%)
Urinary tract obstruction Deformation of renal calyces or renal pelvis Kidney atrophy No abnormalities Calcification Mortar kidney Renal abscess Urinary tract malignancy Others
126 (53) 26 (11) 20 (8) 20 (8) 11 (5) 10 (4) 7 (2) 4 (1) 18 (8)
(Fig. 1b), kidney atrophy, calcification, mortar kidney, renal abscess and urinary tract malignancy.
Urinary examinations Of the 355 UTB patients, urine was examined in 319 using various techniques, such as urinalysis, urine smear microscopy, urine culture or urine PCR test. Of the 166 patients that presented with pyuria, 121 were diagnosed as UTB through urinary examination only. Urine smear microscopy, urine culture and urinary PCR for UTB were positive in 25, 101 and 112 patients, respectively.
Drug-resistant tuberculosis Antituberculosis drug susceptibility was tested in 108 clinically isolated strains. Drug resistance rates are shown in Table 5. MDR-TB was not reported. © 2014 The Japanese Urological Association
Complete recovery was reported in 292 patients. In 58 patients, treatment outcome was unknown, and four patients died of the disease. There was only one recurrent patient of UTB.
Discussion UTB is one form of EPTB that often occurs after PTB. Worldwide, UTB occurs in 30–40% in EPTB7–11 and 2–20% in PTB patients.10,12–14 Although the patients in developed countries are diagnosed as UTB earlier than those in developing countries, UTB patients are sometimes misdiagnosed and treated for other diseases in Japan.15 Our nationwide survey of UTB was intended to address this situation. To ensure collection of the maximum amount of data on UTB patients, no time range was specified with regard to registration of patients. One limitation of the present study was that data was collected retrospectively. In addition, there was no legal obligation to reply to our questionnaire; therefore, we cannot guarantee that information on all UTB patients was acquired. Although these limitations affect the accuracy of the study to some extent, we feel that it still provides valuable information as to the epidemiology and management of UTB in Japan. In the present study, male UTB patients outnumbered female patients. The peak age range of the patients was 51–60 years (data not shown). According to the Kekkaku No Toukei (TB Statistics Board of in Japan), PTB has been more prevalent in male patients since 1949 (Fig. S2).2 Because UTB usually occurs after PTB, this data fits with the male-to-female ratio in the present study. Figueiredo et al. reported that UTB affected more men than women; the male-to-female ratio was 2:1.15 After 2000, despite decreased PTB incidence, UTB patients did not decline (data not shown). This finding contradicts the reports of Kekkaku No Toukei (Fig. S3).3 As previously 3
K NAKANE ET AL.
(a)
(b)
(c)
Fig. 1 (a) White arrowheads indicate ureteral strictures as a result of UTB. Although ureteral stricture caused hydronephrosis, deformation of renal calyces or renal pelvis was not observed. (b) White arrowheads indicate multiple ureteral strictures. Black arrowhead indicates deformation of renal calyces as a result of UTB. (c) An antegrade pyelography image of a UTB patient who had contracted bladder.
Table 5 Incidence of drug-resistant tuberculosis in reported Japanese UTB patients 1970–2007 Drug resistant tuberculosis Antituberculosis drug
Drug-resistant strain (%)
INH RFP SM EB Para-aminosalicylic acid
6/108 (5.5) 4/108 (3.7) 3/92 (3.2) 2/102 (1.9) 2/82 (2.4)
mentioned, data was not available for all UTB patients, so perhaps this discrepancy derives from this limitation. The rates of the UTB patients who have a history of tuberculosis are 49.1% in developing countries and 37.9% in developed countries.15 In the present study, 31% of the UTB patients were reported to have a history of TB. Needless to say, just like other developed countries, Japanese people have a better health status than those in developing countries, therefore, PTB incidence is lower than that of developing countries.16 Then, it is not surprising that the rates of the Japanese UTB patients who have a history of PTB are lower than those of developing countries. However, the PTB incidence in Japan has been higher than other developed countries.16 One hypothesis is that Japanese doctors might fail to take a history of PTB because of being not 4
used to examining UTB patients. This hypothesis could explain one aspect of the reason why the number of Japanese UTB patients who have a history of PTB is lower than those of developed countries. Urologists should obtain a detailed medical history of these patients. We investigated diseases that could lead patients to an immunocompromised state in which TB can develop. The AIDS epidemic caused TB recrudescence not only in developing countries, but also in developed countries.15,17–21 It has been reported that 25–50% of HIV-infected people worldwide have active tuberculosis.15 In the present study, there were no UTB patients who had HIV. However, the number of people living with HIV in Japan has been increasing for years.16 Therefore, it is possible that TB and UTB recrudescence occur in Japan. M. tuberculosis infection occurs primarily in the respiratory organs, and then disseminates to the extrapulmonary organs by a hematogenous route.7 The bacilli first enter the periglomerular capillaries of the kidney, resulting in abscess formation, and gradually involving the ureter, bladder, prostate, seminal vesicle, epididymis and testes.3,4,7 Thus, it might be accurate to hypothesize that the kidney is the most frequent site of infection. In the present study, the kidney was the most common infection site. This result was compatible with the hypothesis. Of the symptoms associated with UTB, pollakisuria, micturition pain and a sense of residual urine are classified as lower urinary tract symptoms, whereas lumbago or back pain and flank pain are derived from upper urinary tract lesions. © 2014 The Japanese Urological Association
Urogenital tuberculosis in Japan
(a) Fig. 2 UTB treatments were classified into the following three groups: drug therapy alone (n = 185), surgical intervention and drug therapy (n = 127), and surgical intervention alone (n = 18). Four patients underwent no treatment. (a) In the group treated with drug therapy alone, 98 (53%), 47 (25%), 23 (12%) and five (3%) patients were treated with INH + RFP + SM or EB + α, INH + RFP + SM, EB + PZA + α, and INH + RFP, INH + RFP + α, respectively. (b) The group that underwent both surgical intervention and drug therapy included 60 nephrectomies (47%), 40 orchiectomies or epididymectomies (32%) and 12 nephroureterectomies (9%). (c) Details of drug therapy in the group that underwent both surgical intervention and drug therapy. (d) In the group that underwent surgical intervention alone, there were six orchiectomies or epididymectomies (33%), five nephrectomies (28%) and five nephroureterectomies (28%); in two patients, the specific interventions were unknown (11%). (a) , Group A: INH + RFP + SM or EB + α; , group B: INH + RFP + SM or EB + PZA + α; , group C: INH + RFP; , group D: INH + RFP + α; , unknown. (b) , Nephrectomy; , orchiectomy or epididymectomy; , nephroureterectomy; , bladder augmentation; , unknown. (c) , INH + RFP + SM or EB + α; , INH + RFP + α; , INH + RFP + SM or EB + PZA + α; , unknown. (d) , Orchiectomy or epididymectomy; , nephrectomy; , nephroureterectomy; , unknown.
(b) 7% 3%
9%
9%
12% 53%
47% 32%
25%
(c)
(d)
11%
10%
58%
11%
28%
33%
21%
Systemic symptoms were less common than urinary tract symptoms in the present survey. The explanation for this might lie in the fact that UTB patients do not always present with tuberculosis of other organs concomitantly. In the literature review, storage symptoms (50.5%), scrotal mass (48.9%) and hematuria (35.6%) were the most frequently seen symptoms in UTB patients.15 In our questionnaire, PD and DD were reported by respondents when they felt “delay”. Therefore, we did not define a specific period for PD and DD. Ohomori et al. also defined “long delay,” which was adapted to PTB; long PD was defined as 2 months or longer (>2 months), long DD was defined as 1 month or longer (>1 month) and long total delay, which was the sum of PD and DD, was defined as 3 months or longer (>3 months). Based on this definition, we analyzed 104 UTB patients for whom total delay could be calculated. The good outcome group included patients who turned negative for urine smear microscopy or urine culture or urine PCR test by drug therapy or who had reached completion of therapy by surgical intervention. The bad outcome group included patients who had not turned negative for urine examinations or suffered relapse of the disease or death from the disease. The χ2-test was carried out to determine whether a total delay of more than 3 months affects UTB patients’ outcome (data not shown). There was no significant difference between the two groups (P = 0.338). However, we could not obtain detailed information for these patients, such as change of symptoms and patients’ quality of © 2014 The Japanese Urological Association
3%
28%
life after UTB treatment. Therefore, we cannot conclude that the duration of total delay really affected UTB patients’ outcomes in the present study. In the present study, antituberculosis drug susceptibility was reported among 108 clinically isolated strains. Although MDR-TB was not found in the present study, it has been an emerging problem since the 1990s. MDR-TB is caused by strains of M. tuberculosis that develop resistance to at least two commonly used drugs, INH and RFP.1 In 2002, the estimated incidence of MDR-TB was 0.7% among new cases and 9.8% among previously treated cases.22 More recently, extensively drug-resistant TB, defined as MDR-TB plus resistance to a fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin and/or capreomycin) was reported.22 We must be careful in future so that MDR/extensively drug-resistant TB does not develop further.22 Poor adherence of a patient is one of the reasons that TB develops to MDR-TB; therefore, in 1995, the World Health Organization proposed directly observed treatment, short-course1 to improve the success rate of TB treatment. In Japan, the dissemination and awareness of directly observed treatment, short-course strategy is required.23 Except in patients with concomitant PTB, it is not essential for EPTB patients to be hospitalized in specialized institutions.4 In the present study, 35 UTB patients were referred to such institutions. Of these, seven patients were admitted to hospital because of concomitant PTB. Thus, 28 patients did not need to be referred to specialized institutions. 5
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Of the 355 UTB patients reported here, 330 received some kind of treatment. A total of 83% of patients who received antituberculosis drug therapy alone were treated with a combination of three or four antituberculosis drugs. The median duration of therapy was 6 months. Surgical intervention and drug therapy was carried out in 127 patients, and surgical intervention alone was carried out 18 patients, respectively. Of the 127 patients who underwent surgical intervention and drug therapy, 88 patients (69%) had a combination of more than three drugs, and median duration of therapy was 6 months. Tuberculosis treatment guidelines in Japan recommend administration of INH, RFP, EB and PZA for 2 months, and INH and RFP for four additional months, or INH, RFP and EB for 2 months, and INH and RFP for seven additional months in new patients of tuberculosis.4 In the present study, although we did not investigate changes in medication, the drug selection for initial treatment of tuberculosis and duration of therapy seemed appropriate. Although urine examination, including urine culture, urine PCR and radiographic examination, are important tools for diagnosis of UTB, there were 68 UTB patients that were diagnosed by pathology only. In addition, three patients were diagnosed as urinary tract malignancies. Of the four patients who died of the disease, three had chronic renal failure and two had active PTB. These results showed that patients who are immunocompromised and have active systemic TB might be at higher risk for death. In general, UTB patients excrete M. tuberculosis in their urine, but the infection risk for TB from these patients is low unless the bacilli are spread in the air from PTB. Therefore, with respect to infection control, special management of UTB (e.g. isolation) is not necessary.24 In the present study, 246 patients (69%) received no special management (data not shown). In conclusion, because these patients do not usually present with specific symptoms, UTB is often difficult to diagnose. Although the incidence of UTB has decreased in recent years, it is possible that TB and UTB recrudescence occur in Japan by the increasing number of people who are living with HIV, human migration as a result of globalization, or by other reasons. Therefore, we should not ignore it. In order to shorten the treatment delay of UTB patients, urologists should take UTB into consideration as one of the diseases presenting with storage symptoms, hematuria and scrotal mass in clinical practice. Urologists should examine patients who are suspected to have UTB (e.g. immunocompromised state, history of PTB) by using urine examinations and ultrasonography. Takahashi et al. reported the clinical relevance of a nucleic amplification test for UTB patients, and suggested that NAAT is an effective and rapid detection method for UTB.25 Then, if morphological abnormality were found, more detailed radiographic examinations should be considered, such as intravenous pyelography or drip infusion pyelography, computed tomography, magnetic resonance imaging or retrograde pyelography. Furthermore, if the patients are diagnosed as UTB, they must treat the patients appropriately so as to not to increase MDR-TB. To compensate for the experience of the diagnosis and treatment of UTB, the nationwide archive will be required. 6
Acknowledgments The authors thank the doctors who provided the data of UTB patients for their kind cooperation in this study.
Conflict of interest None declared.
References 1 Stop TB Initiative (World Health Organization). Treatment of Tuberculosis: Guidelines, 4th edn. World Health Organization, Geneva, 2010. 2 The Tuberculosis Surveillance Center, The Research Institute of Tuberculosis/JATA. Newly Notified Cases and Case Rates per 100,000 by Sex and Age in Japan, 1969–2009. 2011. [Cited 29 May 2014] Available from URL: http://www.jata.or.jp/rit/ekigaku/en 3 Ito K. Hai-gai Kekkaku Gairon (Outline of Extrapulmonary Tuberculosis). Nippon IJI Shinpo 2010; 4473: 59–64. 4 The Japanese Society for Tuberculosis. Guideline for Tuberculosis, 1st edn. Nankodo, Tokyo, 2009. 5 The Tuberculosis Surveillance Center, The Research Institute of Tuberculosis/JATA. Statistics of TB. 2011. [Cited 29 May 2014] Available from URL: http://www.jata.or.jp/rit/ekigaku/en 6 Ohmori M, Ozasa K, Mori T et al. Trends of delays in tuberculosis case finding in Japan and associated factors. Int. J. Tuberc. Lung Dis. 2005; 9: 999–1005. 7 McAleer SJJC, Johnson WD. Gentourinary tuberculosis. In: Wein AJKL, Novick AC, Partin AW, Peters CA (eds). Campbell-Walsh Urology, 9th edn. Saunders, Philadelphia, PA, 2007; 436–47. 8 Ramanathan R, Kumar A, Kapoor R, Bhandari M. Relief of urinary tract obstruction in tuberculosis to improve renal function. Analysis of predictive factors. Br. J. Urol. 1998; 81: 199–205. 9 Carl P, Stark L. Indications for surgical management of genitourinary tuberculosis. World J. Surg. 1997; 21: 505–10. 10 Psihramis KE, Donahoe PK. Primary genitourinary tuberculosis: rapid progression and tissue destruction during treatment. J. Urol. 1986; 135: 1033–6. 11 Cek M, Lenk S, Naber KG et al. EAU guidelines for the management of genitourinary tuberculosis. Eur. Urol. 2005; 48: 353–62. 12 Gokalp A, Gultekin EY, Ozdamar S. Genito-urinary tuberculosis: a review of 83 cases. Br. J. Clin. Pract. 1990; 44: 599–600. 13 Hemal AK, Gupta NP, Kumar R. Comparison of retroperitoneoscopic nephrectomy with open surgery for tuberculous nonfunctioning kidneys. J. Urol. 2000; 164: 32–5. 14 Alvarez S, McCabe WR. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine (Baltimore) 1984; 63: 25–55. 15 Figueiredo AA, Lucon AM, Junior RF, Srougi M. Epidemiology of urogenital tuberculosis worldwide. Int. J. Urol. 2008; 15: 827–32. 16 Global Report: UNAIDS Report on the Global AIDS Epidemic 2013. UNAIDS, Geneva, 2013. 17 Glynn JR. Resurgence of tuberculosis and the impact of HIV infection. Br. Med. Bull. 1998; 54: 579–93. 18 Schubert GE, Haltaufderheide T, Golz R. Frequency of urogenital tuberculosis in an unselected autopsy series from 1928 to 1949 and 1976 to 1989. Eur. Urol. 1992; 21: 216–23. 19 Beijer U, Wolf A, Fazel S. Prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people: a systematic review and meta-analysis. Lancet Infect. Dis. 2012; 12: 859–70. 20 Aljohaney A, Amjadi K, Alvarez GG. A systematic review of the epidemiology, immunopathogenesis, diagnosis, and treatment of pleural TB in HIV-infected patients. Clin. Dev. Immunol. 2012; 2012: 842045: 1–9. 21 Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006; 61: 158–63. 22 Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response. World Health Organization, Geneva, 2010. 23 Ghotbi N, Nishimura S, Takatsuka N. Japan’s national tuberculosis control strategies with economic considerations. Environ. Health Prev Med. 2005; 10: 213–18. © 2014 The Japanese Urological Association
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24 Centers for Disease Control and Prevention. Questions and Answers About Tuberculosis. 2012. [Cited 29 May 2014] Available from URL: http://www.cdc.gov/TB/PUBLICATIONS/faqs/default.htm 25 Takahashi S, Hashimoto K, Miyamoto S, Takeyama K, Takagi Y, Tsukamoto T. Clinical relevance of nucleic acid amplification test for patients with urinary tuberculosis during antituberculosis treatment. J. Infect. Chemother. 2005; 11: 300–2.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Fig. S1 UTB patients according to district. (a) Districts listed in decreasing order. (b) Map representation of UTB incidence, 2000–2007. UTB was more prevalent in urban regions.
© 2014 The Japanese Urological Association
Fig. S2 Incidence of TB by sex in Japan. The male PTB population (solid line) was larger than the female population (dashed line) from 1949 to 2009. The year 1955 saw a peak in both males and females. The number of UTB patients in Japan Overall incidence of PTB gradually decreased during this time period. Data obtained from the Research Institute of Tuberculosis/Japan Anti-Tuberculosis Association (RIT/JATA), Tuberculosis Surveillance Center. Fig. S3 Incidence of UTB in Japan. UTB gradually declined from 2000 to 2004, and then reached a plateau. Data obtained from the Research Institute of Tuberculosis Japan AntiTuberculosis Association (RIT/JATA), Tuberculosis Surveillance Center.
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