Assessment of Lymph Node Tuberculosis in Two Provinces in Turkey

Jpn. J. Infect. Dis., 64, 316-321, 2011

Original Article Assessment of Lymph Node Tuberculosis in Two Provinces in Turkey

Dursun Tatar, Gunes Senol1*, Serpil Alptekin2,andEbruGunes3 Department of Respiratory Medicine and 1Department of Infectious Diseases and Clinical Microbiology, Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital, Izmir; 2Esrefpasa Tuberculosis Dispensary, Izmir; and 3Van Tuberculosis Dispensary, Van, Turkey (Received November 12, 2010. Accepted May 31, 2011)

SUMMARY: The aim of this study was to evaluate lymph node tuberculosis (LNT) cases in two provinces in Turkey with different demographic and socioeconomic characteristics. A total of 109 LNT cases were reviewed retrospectively. The cases were analyzed and compared for symptoms, findings, age, vaccination status, and diagnostic procedures. Socioeconomic conditions were also assessed for the two provinces. A palpable cervical node was considered a significant predictor for all LNT. Mediastinal lymph node involvement was found to be common in cases of pulmonary manifestation of LNT. Fe- male patients were predominantly from the Van Province, while older patients were found to be from Izmir Province. LNT should be suspected in lymphadenitis patients of all age-groups especially in young adolescents with cervical lymph node enlargements. In the presence of mediastinal lymphadenopathy, pulmonary tuberculosis should be investigated.

and soon afterward, more reliable data on TB epidemi- INTRODUCTION ology became available. Turkey is a country that has a Tuberculosis (TB) is a major health concern in de- moderate level of TB with an incidence of 26/100,000, veloping countries. Its association with low socioeco- and the incidence of LNT is lower than that of pleural nomic status is well established. Of the 22 highest bur- TB according to a 2007 report of the agency. The inci- den countries that account for 80z of the global TB dence of pulmonary TB in Van and Izmir Provinces was cases, 17 are classified as low-income countries (1). The reported to be 29 and 16.4 per 100,000, while the mor- World Health Organization (WHO) estimates that 98z tality rates for TB were found to be 0.6z and 4.6z,re- of the 3 million annual TB deaths and 95z of the 8.4 spectively. TB is responsible for 0.08z and 0.27z of all million new TB cases occur in developing countries (2). deaths in Van and Izmir, respectively. The incidence of As a consequence of increasing immigration and human extrapulmonary TB was found to be 30.7/100,000 in Iz- immunodeficiency virus (HIV) prevalence, TB is also re- mir and 29.6/100,000 in Van, but LNT incidences are emerging as a health care problem in developed coun- low for both provinces. Of the extrapulmonary TB cases tries. However, recent data from the United States sug- in Turkey, extrathoracic LNT is reported in 26.7z and gest that, in the incidence of TB, socioeconomic factors intrathoracic LNT in 5.5z of the cases. However, act independently of the HIV epidemic (3). separate data for each province have not been published In practically all TB infections, regional lymph nodes (7,8). are involved. TB bacilli enter the lymphatic system and In the present study, records of the clinical features bloodstream to reach the extrapulmonary organs. Lym- and the socioeconomic and demographic characteristics pho-hematogenous spread is limited by the immune sys- of patients with LNT were retrospectively investigated tem and more than 90z of infected people recover, as in regional dispensaries. Data were evaluated for com- indicated by tuberculin skin test (TST) (4,5). Lymph paring two different provinces for LNT. node tuberculosis (LNT) occurs either by reactivation of dormant TB bacilli in lymph nodes or, very rarely, by MATERIALS AND METHODS direct exposure to infection (6). LNT is a common cause of lymphadenopathy in areas Setting: In the Turkish healthcare systems, dispensa- in which TB is endemic. In countries with a low preva- ries are the official locations where TB drugs are dis- lence of TB, LNT is the most common extrapulmonary tributed to patients free of charge and where patients form. In contrast, in high prevalence areas, the LNT in- are followed up for therapy and treatment outcomes. cidence is second to that of TB pleuritis. Two regional dispensaries that were separated by the In Turkey, the National Reference Laboratory and farthest distance possible in the country were included Epidemiology Unit was established through cooperation in the study. The first was one of the eight central dis- with the Refik Saydam National Public Health Agency pensaries in the western city of Izmir, the third largest and Japan International Cooperation Agency in 1999, city in Turkey. The second dispensary was in Van in Eastern Turkey. The populations of these two provinces have different demographic and socioeconomic charac- *Corresponding author: Mailing address: 1703 S. No: 42 D. teristics (Table 1 and Fig. 1). 3 Karsiyaka, Izmir, Turkey. Tel: ＋90 2324333333, Study subjects: Records of LNT patients who had E-mail: drshenol＠yahoo.com visited the dispensaries between 2000 and 2005 were

316 Fig. 1. Various variables of socioeconomic status.

Table 1. Demographic features of two provinces lymph nodes). TB was diagnosed in the mediastinal nodes by testing specimens from a bronchoscopic fine- Age group (y) Izmir Van Total needle biopsy. Mediastinoscopy and video-assisted Total 797,900 415,900 20,220,000 thoracoscopic surgery (VATS) were performed for º15 Male 410,100 217,800 10,453,000 mediastinal nodes. Female 387,800 198,100 9,767,000 One aliquot of the FNA sample was fixed in 95z ethyl alcohol and stained by Giemsa for cytological Total 2,243,600 441,300 43,724,625 analysis. A second aliquot was used for microscopic de- 15–64 Male 1,089,400 220,300 22,143,735 tection using Ziehl-Neelsen staining and culturing on Female 1,154,200 221,000 21,580,890 Lowenstein-Jensen medium and/or radioactive culture Total 229,500 20,240 3,859,300 (BACTEC; Becton Dickinson, Sparks, Md., USA) in À65 Male 99,500 9,940 1,750,000 cases in which bacteriological examinations were availa- Female 130,000 10,300 2,109,300 ble. The same procedure was followed for samples from lymph node excisions. Histological analyses were performed on samples fixed in formalin. Definition of socioeconomic status: Socioeconomic reexamined retrospectively. A total of 109 LNT cases status was defined at household and regional levels, and from Van and Izmir Provinces were included in the was determined on the basis of the following parame- study. Patients were divided into two groups: LNT and ters: (i) human resources, (ii) education, and (iii) access LNT associated with pulmonary manifestations (LNT- to community infrastructures and facilities (Fig. 1). PM). Statistics: SPSS 15 software was used for statistical Methods: Medical history records and physical analysis. Distribution of data was evaluated using the examination details were reviewed for all patients. Kolmogorov-Smirnov test. Analysis of parametric vari- Definitive diagnosis was established by histopathologi- ables was performed using the t test. Kruskal-Wallis and cal, bacteriological, and radiological methods. TST was Mann-Whitney tests were applied for nonparametric performed in 44 patients. PPD test tuberculin (BB- variables. Chi-square tests were used for analyzing cate- MCIPD, Sofia, Bulgaria; 5 TU/0.1 ml) was applied in- gorical data. tradermally (0.1 ml, or 5 TU). Skin responses were eval- Analysis of patient records was performed according uated 72 h after application, with a transverse diameter to the Helsinki declaration of 2008. of induration Æ10 mm being judged as a positive reac- tion. RESULTS In order to detect pulmonary manifestations, all subjects underwent chest radiography, and were asked to Van and Izmir account for 1.3z and 5.3z of the provide sputum samples for analysis. Only 9 patients population of Turkey, respectively. In Van Province, could give the sputum sample. Patients showing cavern- 52.5z of the population lives in urban areas, whereas ous or disseminated patterns on the radiographs and 85z of the population resides in cities and towns in patients with smear test (i.e., Ziehl-Neelsen staining) Izmir Province. In Turkey, 70.3z of the total popula- results that were positive for the presence of acid-fast tion lives in urban settings (10). bacilli in sputum samples were excluded. Between 2000 and 2005, a total of 109 cases were di- Histological and/or microbiological analyses for the agnosed as LNT in both provinces. In Izmir Province, presence of mycobacteria in lymph node tissue were 56 (24.8z) patients were enrolled from 225 patients conducted in all patients (except 2 patients who were di- with extrapulmonary disease. According to the study in- agnosed on the basis of just clinical and radiological clusion criteria, these patients were classified into two findings). Fine-needle aspiration (FNA) and lymph groups: 48 (21.3z) patients were classified into the node excision and incision were used to investigate su- LNT group, and 8 (3.5z) patients were classified into perficial lymph nodes (i.e., cervical, axillary, or inguinal the LNT-PM group. In Van, 53 (30.8z)LNTpatients

317 Table 2. Demographic data of the patients

LNT patient LNT-PM patient

Characteristic Izmir Van Izmir Van (n ＝ 48) (n ＝ 46) P (n ＝ 8) (n ＝ 7) P no. (z) no. (z) no. (z) no. (z)

Gender Female 13 (27) 28 (60) 0.001 4 4 0.78 Male 35 (73.9) 18 (39.1) 0.001 4 3 Age (y) Range 19–73 4–70 27–64 1–72 Mean±SD 41.7±17.6 31.9±15.1 0.007 48.8±15.9 39±28.3 0.4 TB contact history 13 (27) 13 (28.2) 0.9 2 (25) 3 (42.8) 0.06 BCG status 46 (95.6) 22 (50) 0.0001 8 (100) 2 (22.2) 0.007 No. of TST tested 28 (58.3) 10 (21.7) 0.0004 4 (50) 2(28.5) 0.06 TST1) (＋) 24 (85.7) 4 (40) 0.0001 4 (100) 1(50) 0.33 Predisposing factors HIV 0 0 NA 0 0 NA Diabetes mellitus 2 0 0 0 Alcoholism 0 0 0 0 Malignancy 2 0 1 0 Chronic renal failure 3 1 0 1

1): Number of TST tested cases were used as denominator. LNT, lymph node tuberculosis; LNT-PM, LNT associated pulmonary manifestations; NA, low number of data. were enrolled from 172 patients with extrapulmonary disease; among these, 46 (26.7z) cases were classified into the LNT group and 7 were classified into the LNT- PM group. Demographical aspects, BCG vaccination status, TST status, and predisposing factors of these patients are shown in Table 2. There were significantly higher cases of LNT in women in Van while the reverse was true in Izmir (P ＝ 0.0006). There was no difference in terms of gender in the distribution of LNT-PM cases (P À 0.05). LNT patients in Izmir were significantly older than those in Van (P ＝ 0.005), while the ages of the LNT-PM patients in Izmir and Van were not significantly differ- Fig. 2. Distribution of LNT cases by age and by provinces. ent. Similarly, there was no difference in the ages of LNT and LNT-PM patients from the same region (P À 0.05). No difference in TB contact history between case groups was detected (P À 0.05). PPD-testing rates in (malignancy, thyroid disorder, and chronic renal LNT patients were higher in Izmir than in Van (P ＝ failure). 0.0003), as was the positivity of TST testing (P ＝ 0.01). The most frequent complaint of LNT patients was the TherateofBCGvaccinationinboththeLNTandLNT- occurrence of a palpable mass due to lymphadenopathy PM groups in Izmir was much higher than those in Van (76.6z), followed by night sweats (13.3z), and fatigue (P º 0.0001 and P ＝ 0.0007, respectively). No differ- (7.7z). Although a palpable mass was the most com- ences were detected in terms of predisposing factors be- mon symptom in Izmir patients, fatigue, cough, and tween the two groups. weight loss were also found with remarkable frequency. The distribution of LNT cases according to age is In the Van group, a palpable mass was the major sym- shown in Fig. 2. Cases were more prevalent in the age ptom, and the incidence of this symptom in the Van and range of 21–30 years for both LNT groups (P º 0.05). Izmir groups showed a statistically significant difference Cases were also more prevalent in the early decades in (P º 0.001). Van. A definitive LNT diagnosis was established on the ba- None of the patients had alcohol dependence, sis of histopathological findings in 92 (97.8z)cases. although 10 (34.5z) declared a smoking habit with a The disease was diagnosed in 2 cases by clinico-radio- mean duration of 10 years. Additional disorders were logical and bacteriological methods. Thirteen LNT-PM found in 20 (22.2z) LNT patients. Three patients had cases (86.6z) were diagnosed histopathologically. One chronic renal failure; 2 each had diabetes mellitus, case was diagnosed bacteriologically and another case malignancy, acute rheumatic fever, psychotic disorders, was diagnosed solely on the basis of clinical findings. cardiac disorders, and gastritis; and 1 had rheumatoid Mediastinal lymph node biopsies were performed by arthritis, systemic lupus erythematosus. Three (20z)of VATS in 4 (3.7z)ofLNTcasesinIzmir.Twelve the LNT-PM patients also had additional disorders patients in the Izmir LNT group were also diagnosed

318 Table 3. Clinical symptoms and diagnostic procedures of the LNT patients

LNT patient LNT-PM patient

Izmir Van Izmir Van (n ＝ 48) (n ＝ 46) P (n ＝ 8) (n ＝ 7) P no. (z)no.(z) no. (z)no.(z)

Symptoms Palpable mass 26 (54.1) 44 (95.6) 0.0001 2 (25) 5 (71.4) 0.13 Weakness 5 (10.4) 2 (4.5) 0.43 6 (75) 0 0.007 Night sweat 4 (8.3) 10 (21.7) 0.085 1 (12.5) 2 (28.5) NA Cough 5 (10.4) 1 (2.1) 0.86 4 (50) 2 (28.5) 0.60 Weight loss 4 (8.3) 2 (4.3) 0.67 2 (25) 0 NA Fever 2 (4.1) 5 (10.8) 0.41 1 (12.5) 0 NA Lack of appetite 1 (2.1) 2 (4.3) NA 1 (12.5) 1 (14.2) NA Sputum expectoration 1 (2.1) 1 (2.1) NA 1 (12.5) 0 NA Histopathological diagnosis 47 45 1.0 8 5 Excision 22* 37 6 4 1.0 Incision 2* 3 NA 0 0 Fine needle 12* 5 2 1 Bacteriological tests performed 13 13 6 5 1.0 1.0 Positive 1 0 1 1 Clinico-radiological diagnosis 1 1 NA 0 1 NA

*Total number of cases are unknown. Abbreviations are in Table 2.

Fig. 4. Localizations of lymphadenopathies in total LNT-PM patients. Fig. 3. Localizations of lymphadenopathies in total LNT patients.

these 4 cases. Hilar enlargement was encountered in 10 histopathologically; however, the method of biopsy (66.6z) cases; chronic fibrotic changes, in 2 (13.3z) retrieval was not found in the patient records. Sym- cases, and pulmonary infiltration, in 3 (20z)LNT-PM ptoms and diagnostic features of the cases are shown in cases. Table 3. Significant variables predicting LNT in the study in- A total of 99 lymphadenopathies (51 in Izmir and 48 cluded an age of 20–30 years, palpable cervical node, in Van) were performed in the 94 LNT cases. In 5 cases, BCG vaccination, positive TST, and mediastinal lymph multiple nodes were encountered. Lymphadenopathies node involvement in LNT-PM cases. were most frequently (56.5z) localized to the cervical Variables considered to be indicators of socioeco- region (P º 0.001). There was no significant difference nomic status were not generally associated with TB in- in lymph node localization between the Van and Izmir fection, but prevalence of TB infection tended to be LNT groups (P À 0.05). Cervical and mediastinal higher in wealthier categories. nodes were detected at the same frequency in LNT-PM patients, and there was no significant difference in their DISCUSSION occurrence between the two provinces. The localization, number, and proportions of the lymphadenopathies are Effective treatment regimens and improved living shown in Figs. 3 and 4. standards have helped to decrease the incidence of TB in In addition, 1 case of larynx TB and 1 case of bone most geographic areas in the world. However, the and parotid TB were detected in the Izmir and Van LNT spread of HIV infection and resistance to drugs for groups, respectively. Three cases were associated with treating TB have limited the control of the disease, as a pulmonary TB in the LNT-PM group. result of which TB has reemerged in some regions. Chest radiograms were found to be normal in 90 Although the occurrence of pulmonary TB infection (95.7z) of the LNT cases. Chronic fibrotic pulmonary fluctuates, the incidence of extrapulmonary TB has con- changes were detected in 4 cases, with hilar enlargement tinued to increase (9). being observed in 2 (mediastinal lymphadenopathy) of The incidence of LNT in Turkey ranges from 6.8–

319 43z, and LNT is the second most common form of ex- are those in which there is significant induration but trapulmonary TB after TB pleuritis according to the which are erroneously interpreted as negative by health literature (7,8,11,12). In addition, the incidence of LNT professionals (21). Thus, although TST positivity was has been reported to be between 0.06–5.4z of all TB high in the present study, it was not considered to be a cases in Turkey (13–15). In our study, LNT was found strong indicator for LNT. in 21.3z and 26.7z of the extrapulmonary cases in Iz- There is significant variability in the literature on the mir and Van, respectively. occurrence of clinical signs and symptoms of LNT. Jha In agreement with previous studies, our findings et al. have noted that weakness, night sweats, and cough showed that although in some areas of lower socio- occur in 17.8z,10.3z,and10.3z of the patients, re- economic status, the incidence of TB was higher in spectively (16). The most frequent complaint was cervi- males, LNT was more frequent in females (14,16,17). cal mass (46z). Dundapat et al. reported weight loss in Dundapat et al. have suggested that this phenomenon 85z and fever in 40z of patients (18). The literature occurs as a consequence of male-dominated communi- supports our findings that LNT patients declare their ties, where women experience poorer living conditions, symptoms according to their perception of their own and because young females generally notice differences body and health and their ability to express themselves, in their appearance earlier than males (18). which is based on their socioeconomic and educational In regions of high prevalence, people are more com- levels. monly exposed to TB bacilli and show signs of disease at According to WHO TB guidelines published in 1997, an earlier age. LNT is an early post-primary manifesta- pulmonary parenchymal invasion should be limited to tion of TB. While Van Province represents the charac- extrapulmonary TB cases. Pulmonary TB refers to a teristics of developing countries, Izmir has the socio- disease involving the lung parenchyma. Therefore, economic conditions of more developed countries, and tuberculous intrathoracic lymphadenopathy (mediasti- therefore, it was expected that the patient features in nal and/or hilar) or tuberculous pleural effusion, these two provinces would be different. Thus, poorer without radiographic abnormalities in the lungs, con- socioeconomic conditions could explain the high inci- stitutes a case of extrapulmonary TB. A patient with dence of cases at younger ages in Van Province, while both pulmonary and extrapulmonary TB is considered older age (with associated diseases of old age) promoted to have pulmonary TB (22). Priel et al. have found that reactivation of TB in Izmir. It is also thought that one 28.8z of LNT cases have pulmonary TB (23). In Tur- of the reasons underlying the lower incidence of TB key, particularly in studies originating from hospitals cases in Van is the reporting errors associated with that treat patients with chest diseases, mediastinal LNT issues of compliance to the national TB program (8). together with pulmonary TB is seen at rates as high as Although BCG vaccination is mandatory in Turkey, 7.5–20z (4,5). We found that 3 cases in the LNT-PM it cannot be performed regularly in every district. TST group with mediastinal lymphadenopathy were diag- values are not useful for the diagnosis of TB due to the nosed before pulmonary TB. moderate prevalence of TB and of BCG vaccination. Interpretation of results can be difficult due to the Studies have shown that TST positivity is between 24– two-stage nature of TB, which is characterized by an in- 77z in the worldwide population, while it is 56–69z in fection and a disease stage. Generally, studies do not TB patients in Turkey (19). Therefore, TST is a valua- clearly differentiate between TB infection and TB dis- ble, but non-specific, test for the assessment of TB ease, and it is not clear how socioeconomic conditions patients in Turkey. The BCG vaccination rate was are associated with the risk of infection and the risk of higher in Izmir Province than in Van Province while developing disease, or both (20). TST positivity was similar in the two provinces. While In most previous studies (24–26), data suggest a this could be seen as a normal result of the vaccination strong influence of both household crowding and so- ratio, it could also indicate enhanced immune responses cioeconomic status on the risk of TB infection. Crowd- to TB infection and/or BCG due to better living stand- ing and socioeconomic status perhaps underlie different ards. It is difficult to distinguish between these possibili- causes of TB infection: (i) infections at the household ties. In the literature, correlations between TST positivi- level, which occur through overcrowding in poor house- ty and prior history of contact with TB patients were holds; and (ii) infection at the community level. reported, which could help in the diagnosis of LNT, es- Wealthier households likely reflect a more urban-type pecially in pediatric patients. However, in an adult setting, characterized by a greater population density group, TST has less diagnostic value (13). In areas of and a higher chance of human interaction, which is high prevalence, high rates of BCG vaccination can lead likely to foster TB transmission. This effect has been to a high rate of false-positive TSTs in the healthy popu- demonstrated in previous studies, which show that in lation. False-positive reactions to the TST have also settings with a high prevalence of TB, especially densely been clearly identified in patients previously infected populated settings, extensive TB transmission can occur with nontuberculous mycobacteria. This renders inter- via complex social networks that are likely to be as im- pretation of positive TSTs difficult, especially in situa- portant as household contact in facilitating transmission tion where symptoms of an active TB infection are not (27,28). present (19,20). However, false-negative reactions to the The limitations of the present study that should be ac- TST can also occur since a proportion of individuals knowledged include probable reporting errors in Van that harbor latent TB does not react to the test. This is Province and a relatively low patient number. particularly the case with infants or HIV-infected In summary, LNT occurs as a frequent extrapulmo- patients who have been recently exposed to communica- nary form of TB among females, and young adolescents ble TB. Another notable group of false-negative TSTs have a significantly higher susceptibility, especially in

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