Strana 156 VOJNOSANITETSKI PREGLED Vojnosanit Pregl 2014; 71(2): 156–160. Correspondence to: Natalija Samard?i?, Clinic for Lung Disease, Clinical Center of Serbia, Belgrade, Serbia. E-mail: natalija.samardzic@kcs.ac.rs O R I G I N A L A R T I C L E UDC: 616.234-002.5-07 DOI: 10.2298/VSP1402156S Clinical features of endobronchial tuberculosis Klini?ke karakteristike endobronhijalne tuberkuloze Natalija Samard?iü*, Dragana Jovanoviü*? , Ljiljana Markoviü-Deniü?? , Marina Roksandiü-Milenkoviü*, Spasoje Popeviü*, Vesna ?kodriü-Trifunoviü*? *Clinic for Lung Disease, Clinical Center of Serbia, Belgrade, Serbia, ? Faculty of Medicine, University of Belgrade, Belgrade, Serbia; ? Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Abstract Background/Aim. Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis which often affect the tracheobronchial tree, and can be microbiologically and/or pathohistologically confirmed. The aim of the study was to determine the clinical features and diagnostic aspects of EBTB. Methods. This retrospective study was con- ducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. All patients with EBTB confirmed by bronchoscopy with bi- opsy during a study period were analysed. Data included the patient's medical history, a physical exam, chest X-ray, my- cobacterial analysis of sputum samples, endoscopic types and patohistological confirmation. Results. In the study, 57.6% of the patients were males. The most frequent symptoms were cough (71.2%), malaise (54.2%), fever (49.2%), weight loss (40.7%), and hemoptysis (13.6%). Most of the patients were diagnosed within 30 days of symptoms onset. Sputum examination showed acid-fast bacilli in 31.4% of the patients, while sputum culture for tuberculosis bacilli were positive in 55.9% of the patients. The most common radiographic localization was in the upper lung lobes (63.5%). Cavities were present in 60.4% of the pa- tients. The most common endoscopic subtype determined by bronchoscopy were nonspecific bronchitis (39.9%) and edematous-hyperemic subtype (36.4%). Conclusion. EBTB was more frequent among men, and among people in their fifties in our country. Detailed bronchoscopic examination, correlated with clinical and laboratory findings, will improve diagnostic rate and provide timely therapy. Key words: tuberculosis, pulmonary; diagnosis; signs and symptoms; radiography; bronhoscopy; histological techniques. Apstrakt Uvod/Cilj. Endobronhijalna tuberkuloza (EBTB) je tu- berkuloza traheobronhijalnog stabla, mikrobiolo?ki i/ili patohistolo?ki potvr?ena. Cilj rada bio je da se odrede klini?ke karakteristike i dijagnosti?ki aspekt endobronhi- jalne tuberkuloze. Metode. Ova retrospektivna studija sprovedena je u Klinici za plu?ne bolesti Klini?kog cen- tra Srbije u Beogradu u periodu od januara 1997. do kraja decembra 2007. god. Analizirani su svi bolesnici sa EBTB koja je potvr?ena bronhoskopski i biopsijom u navedenom periodu. Prikupljeni su anamnesti?ki podaci bolesnika, podaci o fizikalnom pregledu i radiografiji plu- ?a, laboratorijske analize sputuma, uz bronhoskopsku i patohistolo?ku potvrdu. Rezultati. U studiji je bilo 57,6% osoba mu?kog pola. Naj?e??i simptomi bolesti bili su ka?alj (71,2%), znojenje (54,2%), povi?ena telesna temperatura (49,2%), gubitak telesne mase (40,7%) i he- moptizije (13,6%). Kod ve?ine bolesnika dijagnoza je po- stavljena unutar 30 dana od po?etka simptoma. U spu- tumu je kod 31,4% bolesnika potvr?en Mycobacterium tu- berculosis, a kultura je bila pozitivna kod 55,9% bolesnika. Na radiografskom nalazu naj?e??e su bili zahva?eni gor- nji re?njevi plu?a (kod 63,5% bolesnika). Kaverne je imalo 60,4% bolesnika. Bronhoskopski nalaz je kod naj- ve?eg broja pokazivao nespecifi?ni bronhitis (39,9%) i edemohiperemi?ni podtip EBTB (36,4%). Zaklju?ak. U na?oj zemlji EBTB je zna?ajno ?e??a kod mu?karaca i osoba u pedesetim godinama ?ivota. Bronhoskopski na- laz koreli?e sa klini?kim i laboratorijskim nalazom i omo- gu?ava lak?e postavljanje dijagnoze i pravovremenu tera- piju. Klju?ne re?i: tuberkuloza plu?a; dijagnoza; znaci i simptomi; radiografija; bronhoskopija; histolo?ke tehnike. Volumen 71, Broj 2 VOJNOSANITETSKI PREGLED Strana 157 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. Introduction Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis (TB) which often injuries the tra- cheobronchial tree, and can be microbiologically and/or pathohistologically confirmed 1 . The diagnosis of EBTB is frequently delayed until the onset of serious bronchial steno- sis with resultant atelectasis and bronchiectasis 2 . EBTB of- ten presents a diagnostic challenge because the clinical pres- entation varies, and some patients can have normal chest ra- diography, even though the acid-fast bacilli (AFB) positive sputum sample is present 3 . EBTB may have a prolonged and insidious course and mimic lung cancer, or an acute course, and imitate bronchial obstruction, aspiration of a foreign body or pneumonia, and sometimes the clinical course can be asymptomatic. Because of the complexity and different prognosis, an endoscopic EBTB classification was adopted based on morphological characteristics of the seven subtypes (actively caseating, edematous hyperemic, fibrostenotic, tu- morous, granular, ulcerative, and nonspecific bronchitic) proposed by Chung and Lee 4 . The course of EBTB differs according to the endoscopic type. Actively caseating, ede- matous hyperemic, and fibrostenotic subtypes most fre- quently lead to the formation of bronchostenosis that is the most serious complication of EBTB 5 . All subtypes can be transformed one into another. The outcome of the treatment for all subtypes is predictable, except for the tumorous form. Fibrostenosis may develop later, after a nine-month doctri- naire treatment (a combination regimen composed of four kinds of anti-tuberculosis drugs – the commonly used drugs include isoniazid, rifampicin, pyrazinamide and ethambutol), which was observed in one third of cases. Endoscopic type can predict bacillar prominence and anticipate the extent and duration of the disease (the edematous hyperemic form, the granulous form, and non-specific bronchitis occur in the early stages, while other forms indicate a widespread dis- ease). The proportion of EBTB in pulmonary TB is about 10–40% 3 . Although the TB incidence has decreased during the last few decades in Serbia 6 , this disease remains an im- portant public health problem especially among patients older than 65 years 7 . The incidence rates being for the last few decades 32–36 per 100,000 inhabitants, up to the last few years when they decreased to 24–26 per 100,000 in- habitants. However, there are a few data about EBTB in our country, and in the region of Balkan and Southern Europe as well, even in the countries with high TB prevalence 8 . The aim of this study was to determine common clinical features and diagnostic aspects of EBTB in our patients. Methods This retrospective study was conducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. A total of 118 consecutive patients with EBTB were hospitalized and treated in our hospital, during the study period. All the cases with EBTB confirmed by bronchoscopy with biopsy during study period were analysed. For each patient we had a questionnaire filled out. Data included the patient's medical history, physical exam, chest X-ray, bronchial examination with bronchial bi- opsies and mycobacterial analysis of sputum samples. Statis- tical Package for Social Sciences (SPSS) program-version 15.0 was used for data entry and analysis. Statistical differ- ences were evaluated using the chi-square test and t-test. The Institutional Ethics Committee approved the study. Results There were 68 (57.6%) men and 50 (42.4%) women, the ratio being 1.4 : 1. The mean age was 44.3 ± 4.32 years (ranged from 16 to 73 years). Twenty four (20.3%) of the patients were older than 60 years. At the time of diagnosis, there was a significant tendency for the women that had EBTB to be younger than 40 years, compared to the men (p = 0.05) (Figure 1). 0 5 10 15 20 25 30 35 < 29 30-39 40-49 50-59 60-69 > 70 Years Fig. 1 – Percentage of patients with endobronchial tuberculosis according to age and sex. Closed bars – men; open bars – women. Nearly half (47.8%) of the patients were diagnosed within 30 days of symptom onset. The clinical presentation of EBTB varied. Five (4.2%) patients were asymptomatic, all the other patients have at least one symptom of TB. Symp- toms and their duration before diagnosis are presented in Ta- ble 1, the dominant being cough 84 (71.2%) and general weakness 64 (54.2%), followed by fever 58 (49.2%), weight loss 48 (40.7%), and hemoptysis 16 (13.6%), respectively. Hemoptysis were significantly more frequent in males than in females (p = 0.04), but without differences according to age. Beside that, other complaints included chest pain (31.4%), sweating (17.8%), and dyspnea (12.4%), and 3.4% patients were hoarse. A predisposing disease or condition was recorded in 43 (36.4%) patients. Forteen (11.9%) pa- tients had diabetes mellitus. A small number of patients, 5 (4.2%) had been previously treated for TB, on average 28.5 years earlier, ranging between 10 and 40 years. In patients with EBTB, a unilateral process was more frequent (59.5%) than bilateral (41.5%). Upper lung fields were the most frequently involved in 63.5% of the patients (Table 2). Cavernous lesions were notified in 60.4% patients. TB was confirmed by direct microscopy and/or culture. Sputum examination for acid-fast bacilli (AFB) was positive in 31.4%, and culture in 55.9% of the patients. The most common bronchoscopic findings were nonspe- cific bronchitis and edematous-hyperemic subtype (Table 3). Strana 158 VOJNOSANITETSKI PREGLED Volumen 71, Broj 2 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. Table 2 Roentgenographic site in 118 patients with endobronchial tuberculosis Localisation Patients, n (%) Right upper lobe 27 (22.9) Left upper lobe 22 (18.6) Both side – upper lobes 26 (22.0) Middle lobe 6 (5.1) Right lower lobe 8 (6.8) Left lower lobe 6 (5.1) Both side – diffusely 23 (19.5) Total 118 (100.0) Table 3 The bronchoscopic findings in 118 patients with endobronchial tuberculosis Bronchoscopic findings Patients, n (%) Actively caseating 10 (8.5) Edematous-hyperemic 43 (36.4) Fibrostenotic 10 (8.5) Tumorous 5 (4.2) Granular 3 (2.5) Nonspecific bronchitis 47 (39.9) Total 118 (100.0) Of the 118 patients, 111 (94.0%) cases presented with chronic tuberculous bronchitis on the pathological findings of biopsy obtained by bronchoscopic procedures while only 6% cases presented tuberculous granuloma. Discussion This research encompassed one of the largest numbers of a series of EBTB cases in the region of Balkan. We found that there were more male than female ETBT patients in the fifth decade of life (sex ratio 1.4 : 1), which is confirmed by papers from different regions (Hong Kong, Korea, China, Japan, Brazil) 9–13 . In contrast, the preponderance of females among patients with EBTB is stated in the works of other authors 14 . Respiratory symptoms in EBTB, according to our re- sults, were nonspecific. Cough and fatigue dominate, fol- lowed by fever, weight loss and hemoptysis. Cough was the most common symptom according to the results of other studies 1, 15 . Thoracic pain was present in almost a third of our patients (31.4%), whereas this symptom was less fre- quently observed (15%) by other authors 3, 9 . In our study group, 13.6% of the patients had hemoptysis, while accord- ing to other papers, 25% to 40.2% of the patients had he- moptysis 9 . General symptoms, such as weakness, fever, and weight loss, were present in a significant number of patients, according to the results of this study and other studies, as well 3, 9 . As for the duration of symptoms prior to diagnosis of TB, according to our results, the interval varies from 1 week to l year, but the severity of symptoms (most com- monly cough and fatigue) most likely contributed to the fact that almost half of patients came for a checkup during the first 30 days of the onset of symptoms. Short average period from disease onset to diagnosis of EBTB, when compared to overall pulmonary TB in the same settings, could be ex- plained by clear clinical symptoms that lead to suspicion to EBTB and faster implementation of diagnostic procedure. Other authors describe precisely this diversity of symptoms and their intensity: with symptoms that mimic asthma 9, 13, 14 , aspiration of a foreign body, and lung cancer 16–18 . An asymptomatic form of the disease is also possible and it was observed in five patients in our study. In terms of the bacilarity of sputum in EBTB, several different results have been published. Thus, some stud- ies 1, 4, 13 confirm the assumption of high infectivity of pa- tients with EBTB by the presence of simple sputum positive for AFB in 51.8–91% patients. On the other hand, some studies 1, 9, 14 report on a significantly lower (9.1–17%) posi- tive sputum for AFB. The results of the present study con- firm AFB in one third of the patients, while the L?wenstein- Jensen culture of sputum samples were positive in over half the cases, which is consistent with the results reported by other authors 4 . Certainly, different histological types EBTB correspond to these contradictory findings. It was noted that the endoscopic ulcerative form and actively caseating type of EBTB have higher sputum positivity, which is not the case with edematous-hyperemic and fibrostenotic type 5 , so that in these cases the histological confirmation of disease fiber- bronchoscopy is required, while negative sputum for AFB does not exclude the diagnosis of EBTB. Radiographic analysis of the lungs of the patients in our study showed that cavernous changes in the lungs were pres- ent in about two-thirds of the patients with EBTB and this finding did not differ significantly from the results in the lit- erature 13 . None of the patients had chest radiography with- out pathological changes, in our study. In contrast to our work, many studies have ascertained the presence of normal chest radiographs in 10–20% of cases 9, 10, 14, 19 . Normal chest radiography is a diagnostic trap for EBTB that is why the di- agnosis of the disease is often delayed 20 . The authors agree Table 1 Symptoms of endobronchial tuberculosis Duration of symptoms (days) Symptoms Patients n (%) ? ± SD median min-max Cough 84 (71.2) 98.6 ± (96.9) 60.0 1–450 Hemoptysis 16 (13.6) 55.7 ± (110.7) 10.0 1–365 Fever 58 (49.2) 47.3 ± (37.8) 30.0 2–150 General weakness 64 (54.2) 87.4 ± (84.9) 60.0 10–450 History of weight loss 48 (40.7) 90.1 ± (91.8) 60.0 20–450 ?The total number of patients is higher than 118 because some of the patients had more than one symptom. Volumen 71, Broj 2 VOJNOSANITETSKI PREGLED Strana 159 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. that the most common radiographic localization of pulmo- nary TB is in the upper lobes which was confirmed by our results, as well (63.5%). The middle and lower lobes, as atypical radiographic presentations, in our work were af- fected in 17% of the patients, while the same results, were found in up to 42–90% of patients, according to the litera- ture 21, 22 . The most common endoscopic forms of EBTB deter- mined by bronchoscopy in our study were nonspecific bron- chitis in 39.8% of the patients, followed by the edematous hyperemic form in 36.4%, while the granular form was re- corded in only 2.5% of the cases, and no patient had ulcera- tive EBTB form. These results differ from those in the study by authors who made a proposal of classification, Chung and Lee 4 and Lee et al. 23 , which showed the most frequent occurrence to be the actively caseating form (43%), while nonspecific bronchitis (7.9%) and ulcerative type (2.7%) were the rarest represented. The differences could most likely be explained by the duration of the disease until bron- choscopy, that is, endoscopic exploration. In our study, in approximately half of the patients the disease was diagnosed by bronchoscopy during the first month, which resulted in the highest frequency of nonspecific bronchitis and edema- tous-hyperemic type, which confirmed the observation that these forms occur in the early stages of EBTB 8 . Bronchos- copy was performed in order to obtain good aspirate sample for bacteriologic analysis, and later to use the same sample to test the susceptibility to antituberculosis (AT) drugs. Con- cerning difficulties of Mycobacterim tuberculosis isolation, it was the case in the past from time to time up to 3–4 years ago, due to the periods when sputum induction could not be performed at all because of a lack of essential equipment (the nineties of 20th century and first few years of new millen- ium). This diagnostic procedure was conducted in the pa- tients with radiological findings which were not enough per- suasive of TB process, and in a certain proportion in the pa- tients without bacteriologic confirmation of TB. They were treated with AT drugs for 3–4 weeks, and when at the first check-up, chest x-ray did not show any initial improvement (initial regression of lesions) and who did not provide good or not at all sputum sample for bacteriologic diagnosis, even after sputum induction, so there was a problem how to con- firm the suspition of TB process. Bronchoscopy was also used to exclude any other underlying or concommitant dis- ease. Due to a serious problem of increasing incidence of lung cancer in our country, in the last decade more than 27% 24 , it is very important to use bronchoscopy as diagnos- tic tool. A histologic confirmation of EBTB is of great impor- tance in the prevention of further spread of TB and to elimi- nate the suspicion of malignancy 25 . It is also useful in dif- ferentiation from the other granulomatosis, mostly sarcoido- sis. We found TB granuloma in 6% of the patients. When EBTB cannot be diagnosed by histologic confirmation find- ings after repetitious examinations, diagnosis should be es- tablished by a combination of clinical, bacteriological and bronchoscopic findings and aggressive treatments must be performed to eradicate Mycobacterium tuberculosis to avoid tracheobronchial stenosis 26 . Conclusion In our patients, EBTB was more frequent among men, and among people in their fifties. Detailed bronchoscopic examination is unavoidable as being a simple and reliable di- agnostic procedure, correlated with clinical and laboratory findings. This procedure alone will improve diagnosis accu- racy rate and provide timely therapy. Acknowledgements This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, Contract No. 175046, 2011–2014. R E F E R E N C E S 1. 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Tuberculosis incidence in elderly in Serbia: key trends in socioeconomic transition. Croat Med J 2008; 49(6): 807– 12. 8. Zuti? H, Dizdarevi? Z, Ustamuji? A, Hadzimurtezi? Z. More than ten years of DOTS in Bosnia and Herzegovina. Bosn J Basic Med Sci 2008; 8(1): 52–7. 9. Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986; 89(5): 727– 30. 10. Hoheisel G, Chan BK, Chan CH, Chan KS, Teschler H, Costabel U. Endobronchial tuberculosis: diagnostic features and therapeu- tic outcome. Resp Med 1994; 88(8): 593–7. 11. Wang SY, Zhang XS. Endobronchial tuberculosis. Report of 102 cases. Chest 1994; 105(6): 1910?1. 12. Kurasawa T, Kuze E, Kawai M, Amitani R, Murayama T, Tanaka E, et al. Diagnosis and management of endobronchial tuber- culosis. Intern Med 1992; 31(5): 593–8. 13. Morrone N, Abe NS. Bronchoscopic findings in patients with pulmonary tuberculosis. J Bronchol 2007; 14(1): 15–8. 14. Lee JH, Park SS, Lee DH, Shin DH, Yang SC, Yoo BM. Endo- bronchial tubeculosis. Clinical and bronchoscopic features in 121 cases. Chest 1992; 102(4): 990–4. Strana 160 VOJNOSANITETSKI PREGLED Volumen 71, Broj 2 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. 15. Sucena M, Amorim A, Machado A Hespanhol V, Magalh?es A. Endobronchial tuberculosis-clinical and bronchoscopic fea- tures. Rev Port Pneumol 2004; 10(5): 383?91. 16. Cordovilla R, Jimenez-Massa A. Endobronchial tuberculosis. a case report and review of the literature. J Bronchol Intervent Pulmonol 2009; 16(2): 121–3. 17. Lohani S, Chadwick PR, Armstrong G, O' Driscoll R, Taggart S. Endo- bronchial Mimics of Lung Cancer. J Bronchol 2005; 121: 56–8. 18. Kreisel D, Arora N, Weisenberg SA, Saqi A, Krupnick A, Demetri- ades A, et al. Tuberculosis presenting as an endobronchial mass. J Thorac Cardiovasc Surg 2007; 133(2): 582–4. 19. Lee JH, Chung HS. Bronchoscopic, radiologic and pulmonary function evaluation of endobronchial tuberculosis. Respirology 2000; 5(4): 411–7. 20. Golshan M. Tuberculous bronchitis with normal chest x ray among a large bronchoscopic population. Ann Saudi Med 2002; 22(1–2): 98?101. 21. Berger HW, Granada MG. Lower lung fields tuberculosis. Chest 1974; 65(5): 522–6. 22. Kim HC, Kim HS, Lee SJ, Jeong YY, Jeon KN, Lee JD, et al. En- dobronchial tuberculosis presenting as right middle lobe syn- droma: clinical characteristics and bronchoscopic findings in 22 cases. Yonsei Med J 2008; 49(4): 615–9. 23. Lee JH, Park SS, Lee DH, Shin DH, Yang SC, Yoo BM. Endo- bronchial tuberculosis. Clinical and bronchoscopic features in 121 cases. Chest 1992; 102(4): 990?4. 24. Markovi?-Deni? L, Vlajinac H, Zivkovi? S, Miljus D. Cancer mor- tality among men in Central Serbia: 1985-2006 survey study. Croat Med J 2008; 49(6): 792–8. 25. Stojsic J, Jovanovic D, Sudjic E. Pathohistological diagnosis of en- dobronchial tuberculosis. Int J Tuberc Lung Dis 2005; 9(Suppl1): 11. 26. Xue Q, Wang N, Xue X, Wang J. Endobronchial tuberculosis: an overview. Eur J Clin Microbiol Infect Dis 2011; 30(9): 1039– 44. Received on April 21, 2012. Revised on July 7, 2012. Accepted on December 11, 2012.
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Strana 156 VOJNOSANITETSKI PREGLED Vojnosanit Pregl 2014; 71(2): 156–160. Correspondence to: Natalija Samard?i?, Clinic for Lung Disease, Clinical Center of Serbia, Belgrade, Serbia. E-mail: natalija.samardzic@kcs.ac.rs O R I G I N A L A R T I C L E UDC: 616.234-002.5-07 DOI: 10.2298/VSP1402156S Clinical features of endobronchial tuberculosis Klini?ke karakteristike endobronhijalne tuberkuloze Natalija Samard?iü*, Dragana Jovanoviü*? , Ljiljana Markoviü-Deniü?? , Marina Roksandiü-Milenkoviü*, Spasoje Popeviü*, Vesna ?kodriü-Trifunoviü*? *Clinic for Lung Disease, Clinical Center of Serbia, Belgrade, Serbia, ? Faculty of Medicine, University of Belgrade, Belgrade, Serbia; ? Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Abstract Background/Aim. Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis which often affect the tracheobronchial tree, and can be microbiologically and/or pathohistologically confirmed. The aim of the study was to determine the clinical features and diagnostic aspects of EBTB. Methods. This retrospective study was con- ducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. All patients with EBTB confirmed by bronchoscopy with bi- opsy during a study period were analysed. Data included the patient's medical history, a physical exam, chest X-ray, my- cobacterial analysis of sputum samples, endoscopic types and patohistological confirmation. Results. In the study, 57.6% of the patients were males. The most frequent symptoms were cough (71.2%), malaise (54.2%), fever (49.2%), weight loss (40.7%), and hemoptysis (13.6%). Most of the patients were diagnosed within 30 days of symptoms onset. Sputum examination showed acid-fast bacilli in 31.4% of the patients, while sputum culture for tuberculosis bacilli were positive in 55.9% of the patients. The most common radiographic localization was in the upper lung lobes (63.5%). Cavities were present in 60.4% of the pa- tients. The most common endoscopic subtype determined by bronchoscopy were nonspecific bronchitis (39.9%) and edematous-hyperemic subtype (36.4%). Conclusion. EBTB was more frequent among men, and among people in their fifties in our country. Detailed bronchoscopic examination, correlated with clinical and laboratory findings, will improve diagnostic rate and provide timely therapy. Key words: tuberculosis, pulmonary; diagnosis; signs and symptoms; radiography; bronhoscopy; histological techniques. Apstrakt Uvod/Cilj. Endobronhijalna tuberkuloza (EBTB) je tu- berkuloza traheobronhijalnog stabla, mikrobiolo?ki i/ili patohistolo?ki potvr?ena. Cilj rada bio je da se odrede klini?ke karakteristike i dijagnosti?ki aspekt endobronhi- jalne tuberkuloze. Metode. Ova retrospektivna studija sprovedena je u Klinici za plu?ne bolesti Klini?kog cen- tra Srbije u Beogradu u periodu od januara 1997. do kraja decembra 2007. god. Analizirani su svi bolesnici sa EBTB koja je potvr?ena bronhoskopski i biopsijom u navedenom periodu. Prikupljeni su anamnesti?ki podaci bolesnika, podaci o fizikalnom pregledu i radiografiji plu- ?a, laboratorijske analize sputuma, uz bronhoskopsku i patohistolo?ku potvrdu. Rezultati. U studiji je bilo 57,6% osoba mu?kog pola. Naj?e??i simptomi bolesti bili su ka?alj (71,2%), znojenje (54,2%), povi?ena telesna temperatura (49,2%), gubitak telesne mase (40,7%) i he- moptizije (13,6%). Kod ve?ine bolesnika dijagnoza je po- stavljena unutar 30 dana od po?etka simptoma. U spu- tumu je kod 31,4% bolesnika potvr?en Mycobacterium tu- berculosis, a kultura je bila pozitivna kod 55,9% bolesnika. Na radiografskom nalazu naj?e??e su bili zahva?eni gor- nji re?njevi plu?a (kod 63,5% bolesnika). Kaverne je imalo 60,4% bolesnika. Bronhoskopski nalaz je kod naj- ve?eg broja pokazivao nespecifi?ni bronhitis (39,9%) i edemohiperemi?ni podtip EBTB (36,4%). Zaklju?ak. U na?oj zemlji EBTB je zna?ajno ?e??a kod mu?karaca i osoba u pedesetim godinama ?ivota. Bronhoskopski na- laz koreli?e sa klini?kim i laboratorijskim nalazom i omo- gu?ava lak?e postavljanje dijagnoze i pravovremenu tera- piju. Klju?ne re?i: tuberkuloza plu?a; dijagnoza; znaci i simptomi; radiografija; bronhoskopija; histolo?ke tehnike. Volumen 71, Broj 2 VOJNOSANITETSKI PREGLED Strana 157 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. Introduction Endobronchial tuberculosis (EBTB) is a specific type of pulmonary tuberculosis (TB) which often injuries the tra- cheobronchial tree, and can be microbiologically and/or pathohistologically confirmed 1 . The diagnosis of EBTB is frequently delayed until the onset of serious bronchial steno- sis with resultant atelectasis and bronchiectasis 2 . EBTB of- ten presents a diagnostic challenge because the clinical pres- entation varies, and some patients can have normal chest ra- diography, even though the acid-fast bacilli (AFB) positive sputum sample is present 3 . EBTB may have a prolonged and insidious course and mimic lung cancer, or an acute course, and imitate bronchial obstruction, aspiration of a foreign body or pneumonia, and sometimes the clinical course can be asymptomatic. Because of the complexity and different prognosis, an endoscopic EBTB classification was adopted based on morphological characteristics of the seven subtypes (actively caseating, edematous hyperemic, fibrostenotic, tu- morous, granular, ulcerative, and nonspecific bronchitic) proposed by Chung and Lee 4 . The course of EBTB differs according to the endoscopic type. Actively caseating, ede- matous hyperemic, and fibrostenotic subtypes most fre- quently lead to the formation of bronchostenosis that is the most serious complication of EBTB 5 . All subtypes can be transformed one into another. The outcome of the treatment for all subtypes is predictable, except for the tumorous form. Fibrostenosis may develop later, after a nine-month doctri- naire treatment (a combination regimen composed of four kinds of anti-tuberculosis drugs – the commonly used drugs include isoniazid, rifampicin, pyrazinamide and ethambutol), which was observed in one third of cases. Endoscopic type can predict bacillar prominence and anticipate the extent and duration of the disease (the edematous hyperemic form, the granulous form, and non-specific bronchitis occur in the early stages, while other forms indicate a widespread dis- ease). The proportion of EBTB in pulmonary TB is about 10–40% 3 . Although the TB incidence has decreased during the last few decades in Serbia 6 , this disease remains an im- portant public health problem especially among patients older than 65 years 7 . The incidence rates being for the last few decades 32–36 per 100,000 inhabitants, up to the last few years when they decreased to 24–26 per 100,000 in- habitants. However, there are a few data about EBTB in our country, and in the region of Balkan and Southern Europe as well, even in the countries with high TB prevalence 8 . The aim of this study was to determine common clinical features and diagnostic aspects of EBTB in our patients. Methods This retrospective study was conducted at the Clinic for Lung Diseases, Clinical Center of Serbia, Belgrade, from January 1997 to December 2007. A total of 118 consecutive patients with EBTB were hospitalized and treated in our hospital, during the study period. All the cases with EBTB confirmed by bronchoscopy with biopsy during study period were analysed. For each patient we had a questionnaire filled out. Data included the patient's medical history, physical exam, chest X-ray, bronchial examination with bronchial bi- opsies and mycobacterial analysis of sputum samples. Statis- tical Package for Social Sciences (SPSS) program-version 15.0 was used for data entry and analysis. Statistical differ- ences were evaluated using the chi-square test and t-test. The Institutional Ethics Committee approved the study. Results There were 68 (57.6%) men and 50 (42.4%) women, the ratio being 1.4 : 1. The mean age was 44.3 ± 4.32 years (ranged from 16 to 73 years). Twenty four (20.3%) of the patients were older than 60 years. At the time of diagnosis, there was a significant tendency for the women that had EBTB to be younger than 40 years, compared to the men (p = 0.05) (Figure 1). 0 5 10 15 20 25 30 35 < 29 30-39 40-49 50-59 60-69 > 70 Years Fig. 1 – Percentage of patients with endobronchial tuberculosis according to age and sex. Closed bars – men; open bars – women. Nearly half (47.8%) of the patients were diagnosed within 30 days of symptom onset. The clinical presentation of EBTB varied. Five (4.2%) patients were asymptomatic, all the other patients have at least one symptom of TB. Symp- toms and their duration before diagnosis are presented in Ta- ble 1, the dominant being cough 84 (71.2%) and general weakness 64 (54.2%), followed by fever 58 (49.2%), weight loss 48 (40.7%), and hemoptysis 16 (13.6%), respectively. Hemoptysis were significantly more frequent in males than in females (p = 0.04), but without differences according to age. Beside that, other complaints included chest pain (31.4%), sweating (17.8%), and dyspnea (12.4%), and 3.4% patients were hoarse. A predisposing disease or condition was recorded in 43 (36.4%) patients. Forteen (11.9%) pa- tients had diabetes mellitus. A small number of patients, 5 (4.2%) had been previously treated for TB, on average 28.5 years earlier, ranging between 10 and 40 years. In patients with EBTB, a unilateral process was more frequent (59.5%) than bilateral (41.5%). Upper lung fields were the most frequently involved in 63.5% of the patients (Table 2). Cavernous lesions were notified in 60.4% patients. TB was confirmed by direct microscopy and/or culture. Sputum examination for acid-fast bacilli (AFB) was positive in 31.4%, and culture in 55.9% of the patients. The most common bronchoscopic findings were nonspe- cific bronchitis and edematous-hyperemic subtype (Table 3). Strana 158 VOJNOSANITETSKI PREGLED Volumen 71, Broj 2 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. Table 2 Roentgenographic site in 118 patients with endobronchial tuberculosis Localisation Patients, n (%) Right upper lobe 27 (22.9) Left upper lobe 22 (18.6) Both side – upper lobes 26 (22.0) Middle lobe 6 (5.1) Right lower lobe 8 (6.8) Left lower lobe 6 (5.1) Both side – diffusely 23 (19.5) Total 118 (100.0) Table 3 The bronchoscopic findings in 118 patients with endobronchial tuberculosis Bronchoscopic findings Patients, n (%) Actively caseating 10 (8.5) Edematous-hyperemic 43 (36.4) Fibrostenotic 10 (8.5) Tumorous 5 (4.2) Granular 3 (2.5) Nonspecific bronchitis 47 (39.9) Total 118 (100.0) Of the 118 patients, 111 (94.0%) cases presented with chronic tuberculous bronchitis on the pathological findings of biopsy obtained by bronchoscopic procedures while only 6% cases presented tuberculous granuloma. Discussion This research encompassed one of the largest numbers of a series of EBTB cases in the region of Balkan. We found that there were more male than female ETBT patients in the fifth decade of life (sex ratio 1.4 : 1), which is confirmed by papers from different regions (Hong Kong, Korea, China, Japan, Brazil) 9–13 . In contrast, the preponderance of females among patients with EBTB is stated in the works of other authors 14 . Respiratory symptoms in EBTB, according to our re- sults, were nonspecific. Cough and fatigue dominate, fol- lowed by fever, weight loss and hemoptysis. Cough was the most common symptom according to the results of other studies 1, 15 . Thoracic pain was present in almost a third of our patients (31.4%), whereas this symptom was less fre- quently observed (15%) by other authors 3, 9 . In our study group, 13.6% of the patients had hemoptysis, while accord- ing to other papers, 25% to 40.2% of the patients had he- moptysis 9 . General symptoms, such as weakness, fever, and weight loss, were present in a significant number of patients, according to the results of this study and other studies, as well 3, 9 . As for the duration of symptoms prior to diagnosis of TB, according to our results, the interval varies from 1 week to l year, but the severity of symptoms (most com- monly cough and fatigue) most likely contributed to the fact that almost half of patients came for a checkup during the first 30 days of the onset of symptoms. Short average period from disease onset to diagnosis of EBTB, when compared to overall pulmonary TB in the same settings, could be ex- plained by clear clinical symptoms that lead to suspicion to EBTB and faster implementation of diagnostic procedure. Other authors describe precisely this diversity of symptoms and their intensity: with symptoms that mimic asthma 9, 13, 14 , aspiration of a foreign body, and lung cancer 16–18 . An asymptomatic form of the disease is also possible and it was observed in five patients in our study. In terms of the bacilarity of sputum in EBTB, several different results have been published. Thus, some stud- ies 1, 4, 13 confirm the assumption of high infectivity of pa- tients with EBTB by the presence of simple sputum positive for AFB in 51.8–91% patients. On the other hand, some studies 1, 9, 14 report on a significantly lower (9.1–17%) posi- tive sputum for AFB. The results of the present study con- firm AFB in one third of the patients, while the L?wenstein- Jensen culture of sputum samples were positive in over half the cases, which is consistent with the results reported by other authors 4 . Certainly, different histological types EBTB correspond to these contradictory findings. It was noted that the endoscopic ulcerative form and actively caseating type of EBTB have higher sputum positivity, which is not the case with edematous-hyperemic and fibrostenotic type 5 , so that in these cases the histological confirmation of disease fiber- bronchoscopy is required, while negative sputum for AFB does not exclude the diagnosis of EBTB. Radiographic analysis of the lungs of the patients in our study showed that cavernous changes in the lungs were pres- ent in about two-thirds of the patients with EBTB and this finding did not differ significantly from the results in the lit- erature 13 . None of the patients had chest radiography with- out pathological changes, in our study. In contrast to our work, many studies have ascertained the presence of normal chest radiographs in 10–20% of cases 9, 10, 14, 19 . Normal chest radiography is a diagnostic trap for EBTB that is why the di- agnosis of the disease is often delayed 20 . The authors agree Table 1 Symptoms of endobronchial tuberculosis Duration of symptoms (days) Symptoms Patients n (%) ? ± SD median min-max Cough 84 (71.2) 98.6 ± (96.9) 60.0 1–450 Hemoptysis 16 (13.6) 55.7 ± (110.7) 10.0 1–365 Fever 58 (49.2) 47.3 ± (37.8) 30.0 2–150 General weakness 64 (54.2) 87.4 ± (84.9) 60.0 10–450 History of weight loss 48 (40.7) 90.1 ± (91.8) 60.0 20–450 ?The total number of patients is higher than 118 because some of the patients had more than one symptom. Volumen 71, Broj 2 VOJNOSANITETSKI PREGLED Strana 159 Samard?i? N, et al. Vojnosanit Pregl 2014; 71(2): 156–160. that the most common radiographic localization of pulmo- nary TB is in the upper lobes which was confirmed by our results, as well (63.5%). The middle and lower lobes, as atypical radiographic presentations, in our work were af- fected in 17% of the patients, while the same results, were found in up to 42–90% of patients, according to the litera- ture 21, 22 . The most common endoscopic forms of EBTB deter- mined by bronchoscopy in our study were nonspecific bron- chitis in 39.8% of the patients, followed by the edematous hyperemic form in 36.4%, while the granular form was re- corded in only 2.5% of the cases, and no patient had ulcera- tive EBTB form. These results differ from those in the study by authors who made a proposal of classification, Chung and Lee 4 and Lee et al. 23 , which showed the most frequent occurrence to be the actively caseating form (43%), while nonspecific bronchitis (7.9%) and ulcerative type (2.7%) were the rarest represented. The differences could most likely be explained by the duration of the disease until bron- choscopy, that is, endoscopic exploration. In our study, in approximately half of the patients the disease was diagnosed by bronchoscopy during the first month, which resulted in the highest frequency of nonspecific bronchitis and edema- tous-hyperemic type, which confirmed the observation that these forms occur in the early stages of EBTB 8 . Bronchos- copy was performed in order to obtain good aspirate sample for bacteriologic analysis, and later to use the same sample to test the susceptibility to antituberculosis (AT) drugs. Con- cerning difficulties of Mycobacterim tuberculosis isolation, it was the case in the past from time to time up to 3–4 years ago, due to the periods when sputum induction could not be performed at all because of a lack of essential equipment (the nineties of 20th century and first few years of new millen- ium). This diagnostic procedure was conducted in the pa- tients with radiological findings which were not enough per- suasive of TB process, and in a certain proportion in the pa- tients without bacteriologic confirmation of TB. They were treated with AT drugs for 3–4 weeks, and when at the first check-up, chest x-ray did not show any initial improvement (initial regression of lesions) and who did not provide good or not at all sputum sample for bacteriologic diagnosis, even after sputum induction, so there was a problem how to con- firm the suspition of TB process. Bronchoscopy was also used to exclude any other underlying or concommitant dis- ease. Due to a serious problem of increasing incidence of lung cancer in our country, in the last decade more than 27% 24 , it is very important to use bronchoscopy as diagnos- tic tool. A histologic confirmation of EBTB is of great impor- tance in the prevention of further spread of TB and to elimi- nate the suspicion of malignancy 25 . It is also useful in dif- ferentiation from the other granulomatosis, mostly sarcoido- sis. We found TB granuloma in 6% of the patients. When EBTB cannot be diagnosed by histologic confirmation find- ings after repetitious examinations, diagnosis should be es- tablished by a combination of clinical, bacteriological and bronchoscopic findings and aggressive treatments must be performed to eradicate Mycobacterium tuberculosis to avoid tracheobronchial stenosis 26 . Conclusion In our patients, EBTB was more frequent among men, and among people in their fifties. Detailed bronchoscopic examination is unavoidable as being a simple and reliable di- agnostic procedure, correlated with clinical and laboratory findings. This procedure alone will improve diagnosis accu- racy rate and provide timely therapy. Acknowledgements This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, Contract No. 175046, 2011–2014. R E F E R E N C E S 1. 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Eur J Clin Microbiol Infect Dis 2011; 30(9): 1039– 44. Received on April 21, 2012. Revised on July 7, 2012. Accepted on December 11, 2012.