Extra-Pulmonary Tuberculosis in Nakhonsawan Province*

Transcription

1 Original Article Extra-Pulmonary Tuberculosis in Nakhonsawan Province* Panithan Santibhavank, M.D. ABSTRACT All out-patient Department cards, registered as extra-pulmonary tuberculosis (EPTB) at 12 hospitals in Nakhonsawan Province, northern Thailand, from January 1 to December 31, 2004, were included in the study. There were 582 patients in total, but 36 were referred from the provincial hospital to the local hospitals. Therefore, there were only 546 patients analyzed. There were 97 patients with abnormal chest radiograph and/or positive acid-fast bacilli (AFB) staining in the sputum, thus this group was categorized as pulmonary tuberculosis (PTS). After follow-up, there were 95 patients who had other or unknown diagnoses. Therefore, only 354 patients were categorized as EPTB according to WHO definitions 1, accounting for the prevalence of cases per 100,000 population. This rate was 3.6 times higher than the national rate. HIV serology was positive in 28.0 percent. Of 546 patients, the lymph node was the most common site of infection (56.0%), and the cervical lymph nodes were involved more than half of the patients (58.1%). The cytological and pathological studies from 312 fine needle aspirates (FNA) or biopsy specimens showed chronic and caseating granulomatous inflammation (42.9% and 40.4%, respectively). Most patients were treated using the category 1 regimen (according to the national guidelines) for 6 to 8.9 months, and 46.9 percent of these patients were improved. HIV serology, chest radiograph, and AFB staining in the sputum should be screened in every EPTB patient. And histopathology of the tissue specimen accompanying with AFB staining and mycobacterial cultures is required for a definite diagnosis. (J Infect Dis Antimicrob Agents 2006;23:67-74.) INTRODUCTION Tuberculosis (TB) is a major health problem in developing countries, especially in Southeast Asia. Thailand ranks seventeen among twenty-two countries in the world with a high burden of TB. 1 In the era of human immunodeficiency virus (HIV) infection, the incidence of TB has markedly increased. 2-3 Extra- pulmonary TB (EPTB) has also increased in these patients with low CD4 lymphocytes, especially TB of the lymph node. 4 From 1994 to 2000, the incidence of pulmonary TB (PTB) in Nakhonsawan Province, northern Thailand, was slightly higher than the national incidence. After 2000, it declined and became lower than the Nakhonsawan Provincial Health Office, Nakhonsawan 60000, Thailand. Received for publication: March 16, Reprint request: Panithan Santibhavank, M.D., Nakhonsawan Provincial Health Office, Nakhonsawan 60000, Thailand. Keywords: tuberculosis (TB), extra-pulmonary tuberculosis (EPTB) *Presented at the 22 nd Annual Scientific Meeting of the Royal College of Physicians of Thailand, April 22-26,

2 68 J INFECT DIS ANTIMICROB AGENTS May-Aug national incidence. The incidence of TB meningitis in Nakhonsawan Province was also slightly higher than the national incidence, but it was much higher after The incidence of other EPTB was higher than the national incidence after 1998, and has been increasing until 2004 where it was approximately five times higher than the national incidence. 5-6 This study aimed to confirm the high incidence of EPTB in Nakhonsawan Province, and to determine the outcome of treatment. MATERIALS AND METHODS All patients registered as having EPTB at 12 hospitals in Nakhonsawan Province from January 1 to December 31, 2004 were included in the study. The out-patient Department card of each patient was carefully reviewed in details regarding the clinical features, laboratory investigations, treatment, and outcome of treatment. If the patient was transferred from one hospital to the other hospital, the information of both hospitals was merged together. The diagnosis of TB meningitis, pleuritis, and peritonitis was based on the analysis of the cerebrospinal fluid (CSF), pleural fluid, and ascitic fluid. These included leukocyte examination, biochemistry, acid-fast bacilli (AFB) staining, and mycobacterial cultures. The diagnosis of TB of the bone and joint included joint fluid examination, bone or synovium biopsy, AFB staining, and mycobacterial cultures. The diagnosis of PTB was based on chest radiograph, sputum AFB staining, and mycobacterial cultures. The diagnosis of TB of the lymph node was based on the cytological and pathological studies of fine-needle aspiration (FNA) and biopsy specimens, in accompanied with AFB staining and mycobacterial cultures. Polymerase chain reaction (PCR) was performed in some patients. The other investigations including ultrasonograph, computed tomograph or magnetic resonance imaging were performed when there was an appropriate indication. Data was processed, using the SPSS/PC computer program. A Chi-square test was used for analysis, and the p value < 0.05 was defined as showing the significant statistical difference. RESULTS Epidemology There were 582 patients from 12 hospitals diagnosed as EPTB. However, there were 36 who were referred from the provincial hospital to the local hospitals for continuing treatment and follow-up. Therefore, there were only 546 patients analyzed. Of these, 316 (57.9%) were male, ranging in age from nine months to 88 years (mean age 41.6 ± years), with most in the years (25.1%) and years (24.9%) age group. Employee was the most common occupation (41.8%), and 66.4 percent of the patients lived in the rural area. There were nine patients (1.6%) who had a family history of TB, and the rest (98.4%) had no available data. The tuberculin skin test was performed in four patients, and the result was reactive (induration cm) in three patients, of which all were children. Pre-existing diseases or conditions were present in 178 patients (32.6%), including 16 diabetes mellitus, 22 cardiovascular diseases, 18 previous history of TB, 12 anemic diseases, 21 anemia with lymphopenia, and 12 HIV infection (Table 1). HIV serology was positive in 150 patients (27.5%), however there were 303 patients (55.5%) who did not have an HIV test (Table 2). Clinical presentations The lymph node was the most common site of infection (56.0%), followed by the leptomeninge (7.9%), the bone and joint (5.7%), and others (pleura, peritoneum, and skin) (26.2%). 4.4 percent of the patients had more than one site of infection. The cervical group was the

3 Vol. 23 No. 2 Extra-pulmonary tuberculosis in Nakhonsawan Province:- Santibhavank P. 69 most common lymph node involvement (58.1%). Eight percent of the patients had more than one group of the lymph node involvement. Laboratory investigations The most common pathological method was a FNA (233 patients, 42.7%), followed by a tissue biopsy (65 patients, 11.9%), and both FNA and tissue biopsy (14 patients, 2.6%). No any diagnostic methods was performed in 114 patients (20.9%). The most common cytological or pathological report from 312 FNA or biopsy specimens showed non-caseating granulomatous inflammation (42.9%), followed by caseating granulomatous inflammation (40.4%), necrotizing granulomatous inflammation (2.9%), suppurative inflammation (2.6%), and nonavailable result (5.4%). Microbiologic results The microbiologic methods used for identifying of TB in 147 clinical specimens included 136 AFB staining which were positive in 62 patients (43 lymph nodes, 17 pleural fluids, and ascetic fluids, and two bone and joint specimens), seven mycobacterial cultures which all were negative (Table 2). On chest radiograph at first visit, 67 patients (12.3%) had pulmonary infiltration compatible with PTB, and 101 patients (18.5%) had no infiltration (Table 2). Chest radiograph was not available in 378 patients (69.2%). Sputum AFB staining was positive in nine patients (1.6%), negative in 107 patients (19.6%), and not available in 430 patients (78.8%) (Table 2). Abnormal chest radiograph was observed in 9.0 percent of patients with positive sputum AFB stainting, and was not present in the patients with negative sputum AFB staining. However, a positive sputum AFB staining was observed in 41.8 percent of patients with normal chest radiograph (Table 3). Table 1. Clinical and demographic data of all 546 patients. Data Number Percent Gender Male Female Age-group (years) < > Occupation Employee Farmer Merchant Government employee Students Others Unknown Residency Nakhonsawan Rural area Urban area Other provinces Family history of TB Yes Unknown Sites of EPTB Lymph nodes Cerebrospinal fluid Bone and joint Others More than one group Group of lymph node Cervical Supraclavicular Submandibular Submental Post-auricular Inguinal Axilla Intra-abdominal Intra-thoracic More than one group Pre-existing disease/condition Opportunistic infection Cardiovascular disease Diabetes mellitus HIV Previous TB Anemia Anemia with lymphopenia Others None EPTB: extra-pulmonary tuberculosis, TB: tuberculosis, HIV: human immunodeficiency virus

4 70 J INFECT DIS ANTIMICROB AGENTS May-Aug Table 2. Laboratory investigations of all 546 patients. Investigations Number Percent HIV serology Positive Negative Not available Investigations for TB A. In tissue and fluid specimens 1. Pathological method (N=327) FNA Biopsy FNA and biopsy Not available AFB staining (N=136) Lymph node (positive/totally available) 43/ CSF (positive/totally available) 0/9 0.0 Pleural effusion and ascites (positive/totally available) 17/ Bone and joint (positive/totally available) 2/ Mycobacterial culture (N=7) CSF (positive/totally available) 0/3 0.0 Bone (positive/totally available) 0/1 0.0 Synovium (positive/totally available) 0/2 0.0 Skin (positive/totally available) 0/ PCR method (N=4) CSF (positive/totally available) 0/2 0.0 Pleural effusion (positive/totally available) 0/ Chest radiograph Abnormal Normal Not available Sputum AFB staining Positive Negative Not available HIV: human immunodeficiency virus, TB: tuberculosis, FNA: fine needle aspiration, AFB: acid-fast bacilli, CSF: cerebrospinal fluid, PCR: polymerase chain reaction, PTB: pulmonary tuberculosis. Table 3. Relationship between chest radiograph and sputum acid-fast bacilli (AFB) staining. Sputum AFB staining N (%) Chest radiograph, N (%) Abnormal Normal Not available Total N (%) Positive 6 (9.0) 28 (41.8) 33 (49.3) 67 (100.0) Negative (17.8) 83 (82.2) 101 (100.0) Not available 3 (7.9) 61 (16.1) 312 (82.5) 378 (100.0) Total 9 (1.6) 107 (19.6) 428 (38.4) 546 (100.0)

5 Vol. 23 No. 2 Extra-pulmonary tuberculosis in Nakhonsawan Province:- Santibhavank P. 71 Treatment and outcome The treatment regimens according to the national guidelines included the category 1 or extended (449 patients, 82.4%), the category 2 or extended (two patients, 0.4%), the category 3 or extended (15 patients, 2.8%), other regimens (79 patients, 14.3%), and no specific treatment (one patient, 0.2%) due to a severe drug allergic reaction (Table 4). The duration of treatment ranged from 0.07 to 26 months (mean 6.85 ± 4.4 months, and median 6.0 months), and most of the patients, (39.6%) were treated for approximately 6 to 8.9 months. The outcome included clinical improvement (256 patients, 46.9%), no improvement (126 patients, 23.1%), worsening (71 patients, 13.0%), death (57 patients, 10.4%), and inability for evaluation (36 patients, 5.7%) (Table 4). During a follow-up period, further investigations in 161 patients who did not respond to anti-tuberculous treatment revealed that 41.0 percent had TB of other sites; 22.4 percent had other diagnoses, and 36.6 percent were still undiagnosed (Table 5). Table 4. Treatment and outcome in 546 patients. Number Percent Regimens Category 1 or extended Category 2 or extended Category 3 or extended Others No treatment Duration of treatment (months) < > Results of treatment Improved Not improved Worsened Dead Undetermined Table 5. Results of further investigations during follow-up in 164 of 546 patients who did not respond to anti-tuberculous treatment or suspected other diagnosis. Results of investigation Number Percent 1. Tuberculosis PTB EPTB PTB + EPTB Disseminated TB MDR-TB Other diagnoses Non-tuberculous mycobacteriosis Carcinoma Hematologic diseases Sepsis Fungal infection Penicilliosis marneffei (lymph node and tonsil) Actinomycosis (lymph node) Unknown diagnosis Total PTB: pulmonary tuberculosis, EPTB: extra-pulmonary tuberculosis, TB: tuberculosis, MDR-TB: multidrug-resistant tuberculosis.

6 72 J INFECT DIS ANTIMICROB AGENTS May-Aug DISCUSSION Of 546 patients with a diagnosis of EPTB, there were six patients with abnormal chest radiograph and positive sputum AFB staining, 61 with positive sputum AFB staining, and three patients with abnormal chest radiograph. After further investigations, there were additional 27 patients with abnormal chest radiograph, as well as 36 and 59 patients with other and unknown diagnoses, respectively. Therefore, only 354 patients were actually categorized as EPTB from January 1 to December 31, 2004, accounting for the prevalence of cases per 100,000 population. This rate is 3.6 times higher than the national rate (8.78/100,000 population). The limitations of this study include the retrospective fashion which the clinical and laboratory, data might not be complete, and no available mycobacterial cultures for a definite diagnosis in most patients. Nakhonsawan Province, lower northern Thailand, is not an endemic area of HIV infection, compared to that in the upper northern provinces. It is interesting that the EPTB incidence in Nakhonsawan Province was 3.6 times higher than the national rate. This finding may be partly due to a higher rate of FNA performed by an active pathologist in this study. Positive HIV serology was observed in 150 and three patients (28.0%) after initial and further investigations, respectively. This number is comparable to that of Ethiopia (27.5%) 7, but is higher than that described in the national survey in Thailand in 1991 (15.8%) 8 and in India (18.8%). 9 Of HIVinfected patients, there were more patients with PTB than EPTB (80% and 20%) when CD4 count of more than 200/mm 3. In contrast, when CD4 count of lower than 200/mm 3, the number of patients with PTB were similar to those with EPTB (50% and 50%). 10 Therefore, HIV counselling and serology should be performed in all patients with TB. Chest radiograph and sputum AFB staining should be performed in every EPTB patient, especially with HIV infection. In this study, there was a high number of patients without available chest radiograph (69.2%) and without sputum AFB staining (78.8%). The sputum AFB staining had a higher sensitivity than chest radiograph in detecting TB (Table 4). The ratio of male-to-female patients in this study (57.9% male) is comparable to the study in India (56.4% male). The age group of the patients in this study (age group of years, 50.0%) is higher than that of India (age group of years, 89.1%) 9, but is comparable to that reported in the United States. 11 Most patients (66.4%) in this study lived in the rural area, in contrast to that described in the national survey in Thailand in 1991 (56.6% lived in urban and Bangkok). 8 This is probably due to the difference in the geographic distribution or the study period. Similar to other studies, TB of the lymph node was the most common form of EPTB. 8,9,11,12 Although FNA has generally a high sensitivity in the diagnosis of TB of the lymph node (88-97%) 13-14, but there is a limitation due to small amount of specimen for evaluation. 15 Therefore, it has a lower diagnostic yield in the range of percent, compared to 85 percent, 88 percent, and 53 percent in histology, cultures, and AFB staining from the biopsy specimen. 16 When comparing cytology from FNA with histopathology from biopsy, the accuracy of TB diagnosis was 61.8 percent. 17 The accuracy in the diagnosis is also influenced by the experience of the cytopathologist. In this study, there is only one pathologist who performed FNA and determined the cytology and histopathology, so there is no interpersonal variation. Most of the cytology and histopathology of TB of the lymph node were granulomatous inflammation with or without caseation. However, it can also be observed in other mycobacterial infection, mycoses,

7 Vol. 23 No. 2 Extra-pulmonary tuberculosis in Nakhonsawan Province:- Santibhavank P. 73 leprosy, sarcoidosis, and carcinoma. In this study, 26 patients with initial diagnosis of TB based on the histopathological results were turned out to be carcinoma during further investigations. It is recommended that the accuracy of TB diagnosis from FNA will increase if AFB staining and mycobacterial cultures are also performed If there is inadequate amount of the FNA specimen and the condition does not improve after an empirical treatment with anti-tb drugs, the lymph node biopsy accompanying with AFB staining and mycobacterial cultures should be performed to exclude other diagnoses. If the patients have HIV co-infection and CD4 count of less than /mm 3, Mycobacterium avium complex (MAC) should also be considered as a differential diagnosis. 20 Thus, the cultures for mycobacteria should be also carried out. 20 In this study, a diagnosis of MAC infection was based on the clinical ground alone when the HIV-infected patient with low CD4 count did not improve after empirical treatment with anti- TB drugs. CONCLUSION Nakhonsawan Province is in the lower northern provinces of Thailand, where the HIV incidence is not as high as the upper northern provinces. It is interesting that the EPTB incidence in Nakhonsawan was 3.6 times higher than the national rate. A definite diagnosis of TB required a high index of suspicion in patients especially with HIV infection who presented with prolonged fever and/or lymphadenopathy or cough. Careful investigations including chest radiograph, sputum AFB staining, cytology of FNA of clinical specimens in accordance with AFB staining and mycobacterial cultures should be performed. HIV serology should also be screened in every TB patient because there is a high rate of coinfection. ACKNOWLEDGEMENT The author would like to thank Dr Chaninya Patanasakpinyo, a pathologist who performed an FNA and determined both cytological and histopathological results, and all health personnel who cared for the patients and gathered the informations. References 1. World Health Organization. WHO report 2005: Global tuberculosis control surveillance, planning and financing. Geneva: WHO, (WHO/HTM/TB/ 2005,349). 2. FitzGerald JM, Grzybowski S, Allen EA. The impact of human immunodeficiency virus infection on tuberculosis and its control. Chest 1991;100: Cantwell MF, Binkin NJ. Tuberculosis in sub-saharan Africa: a regional assessment of the impact of the human immunodeficiency virus and National Tuberculosis Control Program quality. Tuber Lung Dis 1996;77: Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993;148: Bureau of Epidemiology, Department of Disease Control, Ministry of Public Health. Annual epidemiological surveillance report Bangkok: Express Transportation Organization Publishing, Bureau of Epidemiology, Department of Disease Control, Ministry of Public Health. Annual epidemiological surveillance report [cited 2006 Jun 5]. Available from: annual47_index_2.html 7. Kidane D, Olobo JO, Habte A, et al. Identification of

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