The Evaluation of Non-Pulmonary Tuberculosis Cases According to Years

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1 DOI: /ttd ORIGINAL INVESTIGATION The Evaluation of Non-Pulmonary Tuberculosis Cases According to Years Abstract Beyhan Çakar 7 th Tuberculosis Control Dispensary, Tuberculosis and Pulmonary Disease Specialist, Ankara, Turkey OBJECTIVES: To evaluate gender, age, case definition, site of involvement, mode of diagnosis, the facility where treatment was instituted and treatment outcomes of non-pulmonary tuberculosis (TB) cases recorded at 7 th Tuberculosis Control Dispensary, Ankara, Turkey between 2006 and MATERIAL AND METHODS: Medical records of the cases were retrospectively reviewed. RESULTS: Overall 590 TB cases were recorded during the seven years period. Among them, there were 296 (50%) pulmonary TB (PTB), 248 (43%) non-pulmonary TB (NPTB) and 39 (7%) PTB plus NPTB cases. The percentages of NPTB cases during the study years ( ) were as follows, 31%, 37%, 38%, 42%, 49%, 53% and 56%. Female to male ratio was 156 (61%)/99 (39%), the mean age of the female cases was (range, 1-87) years, and that of male cases was 43.85±22.41 (range, 1-81) years. The most frequent type of NPTB were extrathoracic lymph node TB, pleural TB, genitourinary system TB (33%, 13%, 12%, respectively) in females and pleural TB, extrathoracic lymph node TB, bone and vertebral TB (32%, 14% and 13%, respectively) in males. Diagnosis was based on histopathological findings (74%), clinical and radiological findings (23%), and detection of acid fast bacilli (ARB) in smear (3%). None of the female cases abandoned treatment, while 2 of the male cases discontinued treatment. Tuberculosis control dispensaries ranked the first among the facilities that treatment was instituted (44%). CONCLUSION: The number of NPTB cases increased over years. The number and mean ages of female cases were higher than that of males. While extrathoracic lymph node TB was most common in females, pleural TB ranked the first place in males. KEY WORDS: Non-pulmonary tuberculosis, gender, diagnosis, site of involvement, treatment outcomes Received: Accepted: INTRODUCTION Tuberculosis (TB) is a preventable infectious airborne disease that is transmitted by Mycobacterium tuberculosis and can spread to all organs by lymphohematogenous route. Tuberculosis constitutes 25% of preventable adult deaths in developing countries. According to the estimates of the World Health Organization (WHO), 1/3 of the world s population is still infected with tuberculosis bacilli. Non-pulmonary TB (NPTB) refers to detection of bacilli in samples other than pulmonary parenchyma or presence of histological and/or clinical findings consistent with tuberculosis. Mediastinal and hilar lymph node involvement is also considered as NPTB. Patients with concurrent pulmonary TB (PTB) and NPTB are reported as PTB to the WHO. While there is a decrease in the incidence of tuberculosis in developed countries, there has been no change; in fact, there has been an increase in NPTB incidence. It has been suggested that HIV infection and use of drugs that suppress the immune system have an effect on this increase [1-3]. MATERIAL AND METHODS Among TB patients registered at 7 th Tuberculosis Control Dispensary, Ankara, Turkey between January 2006 and December 2012, TB registries and if necessary the medical files of non-pulmonary TB cases were retrospectively reviewed. Case definition, gender, age, site of involvement, mode of diagnosis (histopathological, bacteriological, clinical and radiological diagnosis), treatment outcomes, and social security coverage of the cases were evaluated. As the study was retrospective, no informed consent was obtained from the patients. Approval was obtained from the Head of the department of Tuberculosis control, Ministry of Health on 17 January 2014 (no: ) for the right of disclosure and publication. All registered patients were evaluated. 142 This study was accepted as a poster in 17 th annual Turkish Thoracic Society Congress (2-6 April 2014). Address for Correspondence: Beyhan Çakar, 7 th Tuberculosis Control Dispensary, Tuberculosis and Pulmonary Disease Specialist, Ankara, Turkey. Phone: becakar@yahoo.com Copyright 2014 by Turkish Thoracic Society - Available online at

2 In our study, case and treatment outcome definitions were performed according to the definitions involved in the TB diagnosis and treatment guidelines of the Turkish Republic Ministry of Health [3]. Case Definitions New case: Cases who have never received tuberculosis treatment or who have received tuberculosis treatment for less than one month. Relapse: Cases that have been previously diagnosed and completed treatment successfully and are diagnosed with a recurrent episode of TB. There may be more than one relapses. Treatment after default: Cases who return to treatment with sputum smear positive TB, following interruption of treatment for two or more consecutive months. Smear may sometimes be negative or active TB diagnosis may be made by clinical and radiological evaluation. Treatment after failure patients: a patient who is newly diagnosed as TB and sputum smear or culture positive at five months or later during treatment. Chronic case: Cases whose sputum smear is positive at the end of retreatment; in patients who relapsed, defaulted or failed. Transfer in: cases that have been transferred from another dispensary or abroad after being registered and started treatment. Treatment Outcomes Cure: In cases with initial positive smear, demonstration of negative sputum smear at least two times, one in maintenance period and the other after treatment completion, together with clinical and radiological improvement (used for only smear positive pulmonary TB patients). Treatment completion: Cases with clinically and radiologically completed treatment in the anticipated period (smear negative PTB and NPTB patients). Treatment failure: A patient whose sputum smear is positive at 5 months or later during treatment. Sputum smear may continue to be positive throughout the treatment or become positive after some negative results. Treatment default: A patient who did not use drugs for 2 or more consecutive months during treatment. Transfer out: A patient who has been transferred to another dispensary region or abroad and whose treatment outcome is unknown. Not TB: Patients who were started on treatment with TB diagnosis but appeared to not having TB. Death: Death of a patient for any reason during tuberculosis treatment. If the patient died due to tuberculosis or a reason other than tuberculosis without receiving treatment, this case is recorded as TB and the treatment outcome is recorded as death. On-going Treatment: If the treatment instituted at registration is on-going after twelve months of treatment initiation, these patients are included in this group. These patients have multidrug resistant TB (MDR-TB) extensively drug-resistant TB (XDR TB), patients who cannot use the major drugs due to hypersensitivity. MDR-TB: Patients who are resistant to isoniazid and rifampicin. XDR TB: Resistance against a quinolone or a parenteral drug (capreomycin, kanamycin, amikacin) together with resistance to isoniazid and rifampicin. There can be concurrent resistance to other drugs. Treatment success: Cure and treatment completion together is defined as treatment success [3]. Statistical Analysis Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, USA) statistical package program version 15 was used in the analysis of data. Descriptive statistics are presented as mean ± standard deviation for variables with normal distribution, as median (min-max) for variables with non-normal distribution, and as number of events (%) for nominal variables. Nominal variables were analysed using Pearson Chi-square or Fisher exact test. A p value <0.05 was considered to be statistically significant for all results. RESULTS A total of 590 TB cases were recorded in our dispensary over according to years. The numbers of pulmonary TB cases, non-pulmonary TB cases and cases with PTB plus NPTB were 296 (50%), 255 (43%) and 39 (7%), respectively. The numbers and percentages of 255 NPTB cases over according to years were as follows ( ) 28, 29, 31, 45, 36, 42 and 44, and 31%, 37%, 38%, 42%, 49%, 53% and 56%. The distribution of PTB, NPTB, PTB plus NPTB cases over years is presented in Table 1. The proportion of NPTB cases significantly increased over according to years (p=0.041). The number of female and male cases were 156 (61%) and 99 (39%), respectively. The number of male and female cases were similar over the years. There were no chronic cases, treatment after failure cases and treatment after default cases. There were two cases with relapse and all the other cases were new cases. One of the relapsed cases was a male patient. He had received prior treatment for cervical lymph node TB (thirty-two years ago he had received treatment for 9 months), thereafter, swelling and inflammation occurred on his left ring finger, it progressed and a nodular swelling occurred on the left elbow, the result of the biopsy was necrotizing granulomatous inflammation. The case was initiated treatment with a diagnosis of synovial TB. The other case was a female case. Four years ago, she had been treated for right sided pleurisy for 9 months; thereafter she was initiated treatment with the diagnosis of pleural TB on the left side. The mean age of the female cases was 49.41±19.48 (range, 1-87) years, and that of male cases was 43.85±22.41 (range, 1-81) years, the mean age of all cases was 47.25± years. There was a significant difference between the mean ages of 143

3 Çakar B. Non-Pulmonary Tuberculosis the cases over the years (Post hoc test: p=0.004; Table 2). Overall 22% of the female cases and 26% of the male cases were at or over 65 years of age (Table 3). There was no significant difference between the genders in terms of age groups (p=0.055) (Table 4). Table 5 presents the distribution of cases according to age groups over according to years. Extrathoracic lymph node TB, pleural TB and genitourinary system TB (33%, 13% and 12, respectively) in females and pleural TB, extrathoracic lymph node TB and bone and vertebral TB (33%, 14% and 13%, respectively) in male cases ranked the first three places. In general, extrathoracic lymph node TB, pleural and intrathoracic lymph node TB (25%, 20% and 11%, respectively) ranked as the first three most frequent NPTB types. Overall, in 34 (13%) cases, tuberculosis involved the other body sites, while 21 of these cases were female, 13 were male. Female cases (21 cases): Six breast TB, 3 skin TB, 2 eye TB, 1 auricular TB, 1 nasopharyngeal TB, 2 pericardial TB, 3 parotid TB, 1 endobronchial TB, 2 soft tissue TB. Male cases (13 cases): Six skin TB,1 eye TB,1 lip TB, 2 soft tissue TB, 1 thyroid TB, 1 oropharyngeal TB, 1 endobronchial TB. Tables 6 to 8 show involvement sites of non-pulmonary tuberculosis cases according to gender and years. Diagnosis was based on pathological findings in 189 (74%) cases, clinical and radiological findings in 59 (23%) cases, and microbiological findings in 7 (3%) cases. Among the seven cases that were diagnosed microbiologically, 2 cases were acid fast bacilli (AFB) smear negative, culture positive, 4 cases were smear positive culture negative, and 1 case was smear and culture positive. Drug susceptibility test results revealed that the three cases with positive culture were sensitive to all drugs. When the treatment initiation facilities were evaluated, it was observed that while treatment initiation in training hospitals was high , treatment institution in dispensaries was high between 2010 and In general, the rate of treatment initiation in tuberculosis control dispensaries was 44% (Table 9). TB treatment consisted of two months of HRZE plus 4 to 7 months of HR (H isovit, R rifampicin, E ethambutol, Z pyrazinamide). In cases with miliary TB and bone TB, this period was prolonged to 12 or 18 months. Two cases received minor treatment. The first case had liver and intestinal TB. Because of drug allergy, -first patch test was positive for H, thereafter as the case cannot tolerate gradual dose increment with Z and E, minor treatment was initiated. This case received ofloxacin (2 x 2) plus rifampicin (1 x 2) for 1 year. The second case had a diagnosis of miliary TB, autoimmune hepatitis and anaemia. Minor treatment was given because of hepatotoxicity; ofloxacin plus ethambutol plus streptomycin for three months, and ofloxacin plus ethambutol, thereafter. The patient was recommended to receive treatment for 18 months. All cases completed the treatment. Treatment outcomes were as follows, treatment completion in 220 (86.3%), default in 2 (0.8), another disease in 7 (2.7%), transfer out in 17 (6.7%), Table 1. The number of PTB, NPTB, PTB plus NPTB cases according to years. The percentage of NPTB cases increased throughout the years (p=0.041) Year PTB NPTB PTB+NPTB p value Table 2. The mean age of non-pulmonary tuberculosis cases according to years [Post hoc test (paired comparisons) p=0.004] Standard Years n Mean age deviation p value TB 2006 Number % Number % Number % Number % Number % Number % Number % Total Number % TB: tuberculosis; PTB: pulmonary TB; NPTB: non-pulmonary TB Total Table 3. Distribution of non-pulmonary tuberculosis cases according to gender and age group 144 Age groups (years) Female cases Number, % 3 (2%) 2 (1%) 12 (8%) 23 (15%) 18 (11%) 34 (22%) 30 (19%) 34 (22%) Male cases Number, % 6 (6%) 3 (3%) 13 (13%) 14 (14%) 15 (15%) 16 (16%) 7 (7%) 25 (28%) All Cases Number, % 9 (4%) 5 (2%) 25 (10%) 37 (14%) 33 (13%) 50 (20%) 37 (14%) 59 (23%)

4 and death in 9 (3.5%) cases (Table 10). None of the female cases abandoned treatment and had treatment failure, while two male cases had treatment failure. Among all cases 148 (58%) of them had social insurance from social security organization, 49 (19%) from retirement fund, 28 (11%) from social security organization for artisans and the selfemployed, 3 (1%) had military insurance, 21 (8%) had green card, and 6 (3%) of them had no social insurance. Table 4. Distribution of non-pulmonary tuberculosis cases according to gender and age groups Age group Gender (years) Male Females p value 0-4 Number 6 3 % Number 3 2 % Number % Number % Number % Number % Number 7 30 % >65 Number % DISCUSSION Mycobacterium tuberculosis is located in many organs as a result of bacillemia, after the spread of bacilli from primary infection focus by haematogenous or lymphogenous route. Another mechanism of NPTB development is contiguous spread of the infection from one focus to the other or development of mucosal lesions in the airways or gastrointestinal system of active pulmonary tuberculosis cases by infected Table 6. Involvement sites of non-pulmonary tuberculosis cases according to gender Gender Type of TB Male Females p value Intrathoracic TB Number % Extrathoracic TB Number % Pleural TB Number % Genitourinary Number 4 18 system % Gastrointestinal Number 9 14 <0.001 system peritoneum % Miliary TB and Number 3 7 TB meningitis % Bone and Number 13 9 vertebral TB % Other TB Number % Table 5. The distribution of non-pulmonary tuberculosis cases according to age groups and years Age group Year (years) Number % Number % Number % Number % Number % Number % Number % >65 Number %

5 Çakar B. Non-Pulmonary Tuberculosis Table 7. Involvement sites of non-pulmonary tuberculosis cases according to years Type of TB Intrathoracic TB Number % Extrathoracic TB Number % Pleural TB Number % Genitourinary Number system % Gastrointestinal Number system peritoneum % Miliary TB and Number TB meningitis % Bone and Number vertebral TB % Other TB Number % Year Table 8. Involvement sites of non-pulmonary tuberculosis cases according to gender (% values) Involvement sites of Female cases Male cases All cases non-pulmonary tuberculosis cases n. % n. % n. % p value Intra thoracic lymph node TB 15 (10) 12 (12) 27 (11) Extra thoracic lymph node TB 51 (33) 14 (14) 65 (25) Pleural TB 21 (13) 31 (32) 52 (20) Genitourinary system TB 18 (12) 4 (4) 22 (9) Gastro-intestinal system TB 14 (9) 9 (9) 23 (9) <0.001 Miliary TB and TB meningitis 7 (4) 3 (3) 10 (4) Bone and vertebral TB 9 (6) 13 (13) 22 (9) Other TB cases 21* (13) 13 # (13) 34 (13) Total 156 (100) 99 (100) 255 (100) *Female cases (21 cases): 6 breast TB, 3 skin TB, 2 eye TB, 1 auricular TB, 1 nasopharyngeal TB, 2 pericardial TB, 3 parotid TB, 1 endobronchial TB, 2 soft tissue TB. # Male cases (13 cases): 6 skin TB, 1 eye TB, 1 labial TB, 2 soft tissue TB, 1 thyroid TB, 1 oropharyngeal TB, 1 endobronchial TB. 146 sputum. In the presence of an effective host immune system, these foci remain clinically silent. In conditions where immune system is suppressed, especially the increase in global HIV infection incidence, increase in elder population and use of drugs that suppress the immune system in the recent years, result in reactivation of the latent infection. As few numbers of bacilli are sufficient for the development of the disease, diagnosis may require invasive procedures. The most important step in diagnosis, is keeping NPTB in mind. As the clinical characteristics of NPTB are specific to the organ involved, these patients are admitted to departments related to their complaints, rather than chest disease clinics. In order to make a diagnosis in these cases, questioning previous history of pulmonary TB and contact is very important. Clinical presentation is nonspecific and insidious. Diagnosis may be delayed for years. The chest X-ray is generally normal; sometimes an old or active pulmonary lesion may be identified. Microscopic examination and culture of the infected body fluids and tissue may be required for definitive diagnosis. In cases infected with tuberculosis bacilli, the lifetime risk of developing tuberculosis is 10%; 5% in the first two years, and 5% thereafter [4-7]. In the studies performed in in Turkey; NPTB cases registered at tuberculosis control dispensary (Eskişehir, Deliklitaş, Turkey) in 10 years were evaluated, and it was found that

6 Table 9. The facilities where treatment was instituted in non-pulmonary tuberculosis cases according to years Site of Treatment initiation State Training University State Private Military Year TCD Hospitals Hospitals Hospitals Hospitals Hospitals 2006 Number % Number % Number % Number % Number % Number % Number % Total Number TCD: Tuberculosis Control Dispensary % Table 10. Treatment outcomes of non-pulmonary tuberculosis cases according to years Treatment outcome Year Treatment Completion Other disease Default Transfer out Death 2006 Number % Number % Number % Number % Number % Number % Number % Total Number % % of the cases had PTB and 20.7% of them had NPTB. Overall, 59.3% of the cases were male, and the mean age was 33.1±16.3 years. The most frequent NPTB types were pleural TB (50.2%) and lymph node TB (31.6%). Diagnosis was based on clinical and radiological findings in 32.9% of the cases and histopathological methods in 55.1% of cases [6]. A study performed in Gaziosmanpasa University School of Medicine Department of Chest Diseases (Tokat, Turkey) reported an NPTB prevalence of 55% in three years. The majority of the cases were females (65.9%), and the mean age was 50.23±18.4 (range, 19-80) years, 30% of the cases were in years age group. The mostly involved sites were pleura (47.7%), lymph nodes (31.8%) and skin (6.8%). Treatment was successfully completed in 89% of the cases 147

7 Çakar B. Non-Pulmonary Tuberculosis 148 [8]. In the study performed in Manisa Tuberculosis Control Dispensary (Manisa, Turkey) between 1989 and 2003, the rate of NPTB cases was 28.4%; 55.8% of the cases were females and the disease was mostly seen in young-middle aged group. The most frequent NPTB types were pleural TB (43.4%), lymph node TB (20.9%) and genitourinary system TB (15.2%). Diagnosis was based on histopathological findings in 43% of the cases, and clinical and radiological findings in 29.6% of the cases [7]. In a study performed in İzmir Balçova Dispensary (İzmir, Turkey) between 1998 and 2001, 21.4% of the cases had NPTB, and 59.4% of them were males. Overall, 55% of them had pleural TB, 24.3% had lymph node TB and 6.7% had genitourinary system TB. Most of the patients were in years age group (24.3%) [9]. Among tuberculosis cases followed up in Şanlıurfa Centre Tuberculosis Control Dispensary (Şanlıurfa, Turkey) between 2001 and 2006, 28.8% of the cases had non-pulmonary tuberculosis. The rate of female cases was higher than the rate of male cases and NPTB diagnosis was made by biopsy in 49.8% of the cases [10]. In the studies performed abroad; Yoon et al. [11] in their 2 year study on 312 cases (47.8% male and 52% female cases) found that the ages of the cases varied between 13 and 87 years. The most frequently involved site was pleura by 35.6% of the cases. Bukhary and colleagues [12] in their 10 year study on patients admitted to the hospital ( ), 86% of the cases had NPTB, while 14% had both pulmonary and non-pulmonary TB. The mean age of the cases was 45 years, and 41% of them had lymph node TB. Heye et al. [13] in their study in 2008 reported that 20% of their cases had NPTB. The most frequent NPTB type was lymph node TB, followed by pleural, genitourinary system TB, bone and joint TB. Noertjojo et al. [14] performed a study on 5757 TB cases of which 13.7% was NPTB and 8.6% was both pulmonary and non-pulmonary TB. It was most frequently seen in females below 30 years of age and above 75 years of age. The most frequently involved sites were pleura, followed by lymph nodes. The rate of miliary TB cases was 2.9%. While lymph node TB was most common in females, pleural TB was frequent in males. In the study of Chan-Yeun et al. [15], the rate of NPTB was higher in females, and the most frequently involved site was lymph nodes. Chandir and colleagues [16] in a study performed in a hospital in Pakistan ( ), reported that 75% of the cases were females and the most frequently involved disease sites were lymph nodes and vertebra. According to the 2012 report of The Directorate of Tuberculosis Control of the Ministry of Health, 5811 NPTB cases were registered in NPTB was more frequent in male cases between 15 and 24 years of age (20.4%), and female cases between 25 and 34 years of age (19%). The rate of new cases was 91.7%. According to the report, NPTB rate increased from 28.2% in 2006 to 35.1% in According to 2010 data, NPTB involvement sites were as follows, 32.5% lymph node TB, 31.4% pleural TB, 5.8% intrathoracic lymph node TB. When data were evaluated according to gender, it was observed that 41.4% of female cases had extrathoracic lymph node TB, 20.7% had pleural TB, and 6.9% had GIS, peritoneal TB. Overall 44.5% of male cases had pleural TB, 21.6% had extrathoracic lymph node TB, and 4.4% had GIS, peritoneal TB. Treatment success was 91.1% in female cases and 88.7% in male cases; overall treatment success was reported as 89.8% [17]. In our study, the number of non-pulmonary TB cases was significantly increased over the years, but there was no significant difference in terms of gender. The number, and the mean age of our cases were higher than that of the other studies. Treatment initiation by clinical and radiological diagnosis was low. Involvement sites in NPTB cases were similar to that of the other studies. The differences between the studies might have resulted from the educational and socio-economic differences between the regions. The high number of deaths may be attributed to the fact that 23% of all cases were at or over 65 years of age. These cases had cardiac failure, hypertension, diabetes mellitus, COPD, renal failure and cancer as concomitant diseases. Treatment success was higher in comparison to that of most studies. While the rate of pulmonary TB cases is decreasing, the rate of nonpulmonary TB cases is increasing in countries where tuberculosis is taken under control, and disease occurs at advanced ages. The decrease in pulmonary TB and the increase in non-pulmonary TB cases over the years and the occurrence of disease at advanced ages in our region show that tuberculosis is being taken under control in our region. The diagnosis of non-pulmonary TB cases, other than microbiological diagnosis, was made in health facilities other than dispensary. Treatment initiation in dispensaries was high; possibly due to Ankara active surveillance study. Notification of TB cases evaluated in the outpatient clinic is made to the Ankara, Provincial Health Directorate, thereafter to the tuberculosis control dispensary. Then, the dispensary initiate treatment on an out-patient basis after talking to the notification centre (At the 5 th Provincial Tuberculosis Committee held in Ankara on , Tuberculosis Active surveillance was decided to be initiated and implemented and in accordance with this decision, Tuberculosis Active surveillance Project has been initiated since 2003 with date and Number governorship attestation, and is still on-going). According to the 2013 report of the WHO, the incidence of TB cases has been decreased by 2%. The number of deaths due to TB was 1.4 million in Our country is in the WHO European region. According to the data of the global TB 2013 report, the prevalence of TB is 23 in cases, the incidence is 22 in cases and the mortality is 0.53 in cases, case detection rate in 2012 is 87% in Turkey. Global target is to eliminate TB in The countries with TB case rates below 20 in population, and have a decreasing trend in case rates in the last 5 years are considered to be in TB elimination phase [18]. In conclusion, the number of NPTB cases diagnosed in our dispensary has been increased throughout the years. The numbers of female cases were higher than male cases, but there was no difference between genders over years, mean age gradually increased over the years. These results show that tuberculosis is being taken under control in our region. The rate of cases diagnosed based on histopathological find-

8 ings was high. All NPTB cases had been diagnosed in health institutions other than dispensaries. We think that tuberculosis control dispensaries have an important place in treatment initiation and case follow-up. Ethics Committee Approval: Consent was taken from the Ministry of Health, but ethics committee approval was waived due to the retrospective nature of the study. Informed Consent: Inform consent were not approved by patients. Because this was a retrospective study. Peer-review: Externally peer-reviewed. Acknowledgements: I thank to Zeynep Bıyıklı Gençtürk (Department of Bioistatistics, Ankara University, School of Medicine, Ankara) for her contribution to statistical analysis of the study. Conflict of Interest: No conflict of interest was declared by the author. Financial Disclosure: The author declared that this study has received no financial support. REFERENCES 1. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. Accessed Oct 9, Tuberculosis management in Europe. Task Force of the European Respiratory Society (ERS), the World Health Organisation (WHO) and the International Unionagainst Tuberculosis and Lung Disease (IUATLD) Europe Region. Eur Respir J 1999;14: [CrossRef] 3. Republic of Turkey, Ministry of Health, Guidelines on diagnosis and treatment of tuberculosis. Ankara 2011;12-13: Republic of Turkey, Ministry of Health. Department of Tuberculosis. Reference Manual for Tuberculosis Control in Turkey. Ankara 2003; Mehta JB, Dutt A, Harvill L, et al. Epidemiology of extrapulmonary tuberculosis. A comparative analysis with pre AIDS era. Chest 1991;99: [CrossRef] 6. Kolsuz M, Ersoy S, Demircan N, et al. Evaluation of Exrapulmonary Tuberculosis Cases Followed in Eskişehir- Deliklitaş Tuberculosis Dispensary. Turk Thorac J 2003;4: Çelik P, Havlucu Y, Yıldırım ÇA, et al. Assessment of Primary Tuberculosis in Manisa Tuberculosis Dispensary Between 1989 and Turkiye Klinikleri Arch Lung 2005;6: İnönü H, Köseoğlu D, Pazarlı C, et al. The Characteristics of Cases with Extrapulmonary Tuberculosis in a University Hospital. Turk Thorac J 2010;11: [CrossRef] 9. Yıldırım Y, Demir GH. Common Characteristics of Patients Followed at Balçova Tuberculosis Dispensary with Extrapulmonary Tuberculosis Cases Between İzmir Chest Hospital Journal 2003;17: Koçakoğlu Ş, Şimşek Z, Ceylan E. Epidemiologic Characteristics of the Tuberculosis Cases Followed up at Şanlıurfa Central Tuberculosis Control Dispensary between 2001 and 2006 Years. Turk Thorac J 2009;10: Yoon HJ, Song YG, Park WI, et al. Clinical manifestations and diagnosis of extrapulmonary tuberculosis. Yonsei Med J 2004;45: [CrossRef] 12. Bukhary ZA, Alrajhi AA. Extrapulmonary tuberculosis, clinical presentation and outcome. Saudi Med J 2004;25: Heye T, Stoijkovic M, Kauczor HU, et al. Extrapulmonary tuberculosis: radiological imaging of an almost forgotten transformation artist. Rofo 2011;183: [CrossRef] 14. Noertjojo K, Tam CM, Chan SL, Chan-Yeung MM. Extrapulmonary and pulmonary tuberculosis in Hong Kong. Int J Tuberc Lung Dis 2002;6: Chan-Yeung M, Noertjojo K, Chan SL, Tam CM. Sex differences in tuberculosis in Hong Kong. Int J Tuberc Lung Dis 2002;6: Chandir S, Hussain H, Salahuddin N, et al. Extra pulmonary tuberculosis: a retrospective review of 194 cases at a tertiary care hospital in Karachi, Pakistan. J Pak Med Assoc 2010;60: Republic of Turkey, Ministry of Health. Tuberculosis Fight in Turkey, 2012 Report. Ankara 2013; 34, 45, 91 thsk.gov.tr 18. World Health Organization (WHO) Global Tuberculosis Report