Interferon-gamma release assays in patients with Mycobacterium kansasii pulmonary infection: A retrospective survey.

OBJECTIVES: Interferon-gamma release assays (IGRAs) can be positive in patients infected with Mycobacterium kansasii (M. kansasii), which carries some of Mycobacterium tuberculosis specific antigens adopted for IGRAs. Our aim is to evaluate positive rate and factors associated with positive IGRAs in patients with M. kansasii pulmonary infection. METHODS: We retrospectively investigated 105 M. kansasii cases in which IGRAs were performed before or ≦14 days after treatment initiation. Clinical characteristics including a history of tuberculosis, radiographic features and laboratory data were collected from medical records. RESULTS: Positive rate of each IGRA was 25.9% (15/58) in QuantiFERON TB-Gold (QFT-G), 31.8% (7/22) in QuantiFERON-TB Gold In Tube (QFT-GIT), and 33.3% (7/21) in T-SPOT. TB (T-SPOT). After excluding cases having a history of tuberculosis, positive rate of each IGRA decreased to 19% (8/42) in QFT-G, 20% (3/15) in QFT-GIT, and 18.8% (3/16) in T-SPOT. The multivariate analysis revealed that only previous tuberculosis was significantly associated with positive IGRAs (odds ratio, 4.758; 95% confidence interval, 1.73-13.05; p = 0.002). CONCLUSIONS: Positive rates of IGRAs were low in patients with M. kansasii, especially in those without previous tuberculosis. M. kansasii pulmonary infection alone might induce less interferon-gamma production with the antigens.

[Evaluation of tuberculosis treatment including levofloxacin (LVFX) in cases who could not continue standard regimen].

OBJECTIVE: The purpose of this study was to evaluate tuberculosis treatment including levofloxacin (LVFX) and to investigate the effectiveness of changing drug regimens at our hospital. SUBJECTS AND METHODS: A retrospective study was conducted on 331 patients with tuberculosis admitted to Tokyo National Hospital in 2005. Out of these 331 patients, LVFX was used in 48 (14.5%), 41 of which were initial-treatment cases. We studied why and how LVFX was used and compared bacteriological negative conversion rates between the initial-treatment cases in which the initial standard regimen was changed to regimens including LVFX, and those in which the initial standard regimen was either maintained throughout or modified with drugs other than LVFX. Sputum cultures were examined with Mycobacteria Growth Indicator Tube System (BACTEC MGIT 960). RESULTS: LVFX was used in 41 (13.6%) of 302 initial-treatment cases and in 7 (24.1%) of 29 retreatment cases. Out of the 269 initial-treatment cases starting with the standard regimen, LVFX was later used in 26 cases (9.7%). The reasons for using LVFX were adverse reaction to antituberculosis drugs in 23 cases (88.5%) and resistance to antituberculosis drugs in 3 cases (11.5%). We investigated the bacteriological conversion rate in 228 patients who could be followed up for more than five months. The conversion rates in 105 cases under the standard regimen including PZA (PZA+) were 92.4% in three months, 98.1% in four months, and 100% in five months. The rates in 56 cases under the standard regimen without PZA (PZA-) were 92.9 %, 98.2% and 100%,respectively. The rates of 22 cases under the initial regimen modified with LVFX (LVFX +) were 68.2 %, 95.5% and 100%, respectively. In 45 cases under the initial regimen modified with drugs other than LVFX (LVFX-), the rates were 80.0%, 97.8% and 100%, respectively. CONCLUSION: This study showed that LVFX was an effective drug in terms of the bacteriological conversion rate, without adverse reaction. LVFX is not approved as an antituberculosis drug in Japan, but it is often used in cases of MDR-TB or in situations in which the patients cannot continue treatment with the standard regimen. We hope that LVFX will be approved as an antituberculosis drug as soon as possible in Japan.

Mycobacterium shinjukuense sp. nov., a slowly growing, non-chromogenic species isolated from human clinical specimens.

Seven isolates of a slowly growing, non-chromogenic Mycobacterium species were obtained from sputum and bronchial lavage fluid samples from elderly patients in different regions of Japan. These isolates were distinguished from related non-tuberculous species by colony morphology, positive results for Tween hydrolysis, catalase at 68 °C, nitrate reductase and pyrazinamidase and negative results for semi-quantitative catalase, urease and arylsulfatase. The mycolic acid pattern obtained by HPLC revealed a single cluster of late-eluting mycolic acids similar to but different from those of Mycobacterium malmoense ATCC 29571(T). The 16S rRNA gene, 16S-23S internal transcribed spacer (ITS), rpoB and hsp65 sequences were unique in comparison with those of other mycobacteria. Comparison of 16S rRNA gene sequences showed that the isolates were most closely related to Mycobacterium tuberculosis H37Rv(T) (21 base differences in 1508 bp; 98.6 % 16S rRNA gene sequence similarity). A representative strain, GTC 2738(T), showed 91.9 % rpoB sequence similarity with Mycobacterium marinum strain M, 95 % hsp65 sequence similarity with Mycobacterium kansasii CIP 104589(T) and 81.1 % 16S-23S ITS sequence similarity with Mycobacterium gordonae ATCC 14470(T). Phylogenetic analysis of concatenated sequences of the 16S rRNA, rpoB and hsp65 genes showed that strain GTC 2738(T) was located on a distinct clade adjacent to M. tuberculosis, M. ulcerans and M. marinum, with bootstrap values of 81 %. DNA-DNA hybridization demonstrated less than 70 % reassociation with type strains of genetically related species and supported the novel species status of the isolates. On the basis of this evidence, a novel species with the name Mycobacterium shinjukuense sp. nov. is proposed. The type strain, isolated from a sputum sample, is strain GTC 2738(T)( = JCM 14233(T) = CCUG 53584(T)).

Comparison of performance in two diagnostic methods for tuberculosis infection.

Performance of two diagnoses, T-SPOT.TB (T-SPOT) and QuantiFERON-TB Gold (QFT-G), was compared in Japanese subjects. Forty-seven confirmed tuberculosis patients and eighty-four healthy subjects were recruited. All samples were assessed for both T-SPOT and QFT-G, and the sensitivities and the specificities were compared between two methods. The sensitivity was 100% for T-SPOT, and 87.2% for QFT-G. The specificity was 83.3 and 98.8%, respectively. The overall agreement of two tests was substantially high (Kappa coefficient = 0.671). The sensitivity of T-SPOT appeared to be higher than that of QFT-G, whereas the specificity of T-SPOT was significantly lower than that of QFT-G. The difference in the performance between T-SPOT and QFT-G and biological relevance of each system in diagnosing M. tuberculosis infection should be further explored.

Biological and molecular characteristics of Mycobacterium tuberculosis clinical isolates with low-level resistance to isoniazid in Japan.

We reevaluated the BACTEC MGIT 960 antimicrobial susceptibility testing system (MGIT 960 AST) by using 1,112 isolates of Mycobacterium tuberculosis. When the results of MGIT 960 AST were compared with that of the proportion method using Ogawa medium (Ogawa PM), discrepant results were obtained for 30 strains with isoniazid, all resistant by MGIT 960 AST but susceptible by Ogawa PM. For 93% of the strains that produced discrepant results, the MIC was 0.4 or 0.8 microg/ml, showing resistance by the proportion method using Middlebrook agar plates. Furthermore, it was also established by analyses of the katG and inhA genes that strains resistant only by MGIT 960 AST have a low level of isoniazid (INH) resistance, indicating that MGIT 960 AST is a reliable method. Ninety-six strains were resistant to 0.1 microg/ml INH by MGIT 960 AST. When they were divided into three groups, Low-S (susceptible at 0.2 microg/ml), Low-R (resistant at 0.2 microg/ml), and High-R (resistant at 1.0 microg/ml), by Ogawa PM, 43.3% of the Low-S strains had mutations in the promoter region of inhA and no mutations were detected in katG codon 315, while 61.7% of the High-R strains had katG codon 315 mutations or a gross deletion of katG. These results suggest that mutations in inhA are associated with low-level resistance to INH and katG codon 315 mutations are associated with high-level resistance to INH. In addition, the analyses demonstrated some relationship of mutations in the inhA gene with ethionamide resistance for the Low-S strains, but not for the High-R strains.

Comparison of the sensitivity and specificity of two whole blood interferon-gamma assays for M. tuberculosis infection.

OBJECTIVES: To compare the sensitivity and the specificity of the QuantiFERON-TB Gold (QFT-G) and QuantiFERON-TB Gold In Tube (QFT-GIT) diagnostic tests for Mycobacterium tuberculosis infection. METHODS: One-hundred patients with culture and/or PCR confirmed M. tuberculosis infection and 168 volunteers with no risk factors for M. tuberculosis infection were tested to estimate sensitivity and specificity, respectively. RESULTS: Analysis of data from the tuberculosis (TB) patients with valid results found the sensitivity of QFT-GIT (92.6%, 87/94) to be significantly higher than that for the QFT-G test (81.4%, 79/97; p=0.023). The specificity of both QFT-GIT and QFT-G was 98.8% (CI: 95.1%-99.8%) with 2 of the 160 low risk subjects with valid results for both tests being positive. Data analysis confirmed the manufacturer's recommended test cut-off as being optimal, but identified higher sensitivity could be obtained by using a lower cut-off, with only a moderate decrease in specificity. CONCLUSIONS: The QFT-GIT test had enhanced sensitivity for detection of M. tuberculosis infection over the QFT-G test, whilst maintaining equivalent high specificity. The logistic benefits of the QFT-GIT test format, as well as its higher sensitivity, should enable enhanced TB control.

[Drug-induced hepatotoxicity caused by anti-tuberculosis drugs in tuberculosis patients complicated with chronic hepatitis].

OBJECTIVES: To investigate retrospectively the incidence of drug-induced hepatitis (DIH) caused by antituberculosis drugs including isoniazid (INH), rifampicin (RFP), with and without pyrazinamide (PZA), and to evaluate risk factors for DIH in tuberculosis patients complicated with chronic hepatitis (CH). MATERIALS: One hundred and seven tuberculosis patients with CH (M/F= 96/11, mean age +/- SE, 60.8 +/- 1.4 yr) admitted to our hospital during 1998-2006, whose laboratory data had been followed before and at least 2 months after starting antituberculosis chemotherapy, were enrolled in this study. Of these, 58 were being treated with anti-tuberculosis chemotherapy consisting of INH, RFP and PZA (HRZ group) and the remaining 49 with INH and RFP (HR group). For a case-control study, patients admitted to the hospital during the same period and without CH were selected to each CH patient (n=107) of the same gender, the same treatment regimens, and the same age. Clinical diagnosis of CH was based on laboratory data and in some cases pathological findings; etiology of CH was C-CH (CH caused by hepatitis C virus) in 68 patients, B-CH (CH caused by hepatitis B virus) in 23, and alcoholic CH in 16. METHODS: DIH was defined by elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at 1 or 2 months after starting anti-tuberculosis chemotherapy. For patients with serum levels of AST or ALT already abnormally high before starting chemotherapy, an increase of > 1.5 times from the initial serum level was defined to indicate DIH, whereas for patients with AST and ALT within the normal range, and increase of > 3X the normal upper limit was defined to indicate DIH. The incidence of DIH was calculated separately in the groups HRZ and HR for patients with and patients without CH (control). In the HRZ group, the severity of DIH was defined by the maximum serum levels of AST and ALT, and their mean values were compared between CH patients and the control. Risk factors for DIH were examined by comparing patients with and without CH. The clinical course after development of DIH was also followed. [Results] The incidence of DIH in the HRZ group was 13/ 58 (22.4%) for CH patients and 10/36 (27.8%), 2/13 (15.4%) and 1/9 (11.1%) for C-CH, B-CH and alcoholic hepatitis patients, respectively, which was significantly (p < 0.05) higher than that in the control [4/58 (6.9%)]. Confining to the C-CH patients, the incidence of DIH was 10/36 (27.8%) compared with the control 2/36 (5.6%) (p < 0.05). In contrast, the incidence of DIH in the HR group was not significantly different between CH patients and the control, [2/49 (4.1%) vs 2/49 (4.1%)], respectively. The severity of DIH in the HRZ group estimated by the maximum level of serum AST and ALT was not significantly different in CH patients and the control (176.6 +/- 28.1 vs. 311.0 +/- 154.5 IU/L for AST and 187.8 +/- 19.1 vs. 277.8 +/- 72.4 IU/L for ALT). Of the 13 CH patients suffering from DIH caused by antituberculosis chemotherapy containing INH, RFP and PZA, 3 were continued treatment without altering the regimen, and 9 were continued treatment after changing the regimen to INH and RFP, omitting PZA. The one remaining patient was re-treated using INH, RFP and ethambutol (EB), but this again resulted in development of DIH, and he was ultimately treated with INH, EB and levofloxacin, with a successful outcome. Thus, at least 12 out of the 13 CH patients who developed DIH in the HRZ group could be treated by an anti-tuberculosis chemotherapy regimen containing INH and RFP excluding PZA. In C-CH patients who were treated with INH, RFP and PZA, the incidence of DIH was significantly higher when the daily alcohol intake was >20 g [8/18 (44.4%)] compared with those <20 g [0/10 (0%)] (p < 0.05), indicating that alcohol is a risk factor for DIH in C-CH patients treated with INH, RFP and PZA. CONCLUSIONS: In CH patients, anti-tuberculosis chemotherapy containing INH and RFP without PZA can be used safely. The inclusion of PZA in the regimen does substantially increase the incidence of DIH but nonetheless it can be used with caution, especially bearing in mind that daily alcohol intake of >20 g is a significant risk factor for C-CH patients.

[Clinical research on multi-drug resistant and extensive drug-resistant tuberculosis in Japan].

PURPOSE: To know the number of patients with MDR-TB and XDR-TB newly diagnosed annually and the number of those with continuously culture-positive in spite of continued treatment. METHODS: To fill the questionnaire sent to all the TB hospitals in Japan and to investigate the number of beds for TB, MDR-TB cases newly admitted to each hospital in 2006 and chronic bacillary cases in spite of continued treatment. RESULT: We sent the questionnaires to all the TB hospitals in Japan and 81% of 270 hospitals replied. As the result, 93 MDR-TB were newly hospitalized (12 cases were with XDR-TB). 76 cases of them were newly diagnosed MDR-TB. Almost after 1 year treatment, patients with XDR-TB showed lower negative conversion rate than other MDR-TB (42.9% vs 63.8%) and higher fatality rate (42.9% vs 7.2%). Excluding above 93 new MDR-TB cases, 103 cases with chronic MDR-TB including 44 cases with XDR-TB had been treated during the observation period, 84 case had been hospitalized and other 19 cases at OPD. DISCUSSION: Since 2000, extensive multi-resistant (XDR) TB has been a global topic. In Japan, nation-wide survey on 2002 showed the ratio of MDR and XDR were 1.9% and 0.6% respectively out of 3122 TB stains investigated. XDR/MDR rate was higher than those in other countries. Our clinical based investigation showed total XDR/MDR rate was 28.6% (56/196) and it was similar to that of previous bacteriological survey in 2002. CONCLUSION: We investigated the number of patients with MDR-TB and XDR-TB newly diagnosed in 2006 and the number of those who were continuously culture-positive. The survey showed that there were 196 patients with MDR-TB, and 56 patients of them (28.6%) were with XDR-TB. Many of them were in the districts of Kinki area and Kanto-Shinetsu area and 70% of them had been treated in the hospitals belonging to the National Hospital Organization.

[Usefulness of a whole blood interferon gamma assay (QuantiFERON-TB-2G) for detecting tuberculosis infection in HIV-infected persons].

BACKGROUND: New blood test (QuantiFERON-TB-2G: QFT-2G), based on detection of IFN-gamma released by T cells in response to M. tuberculosis specific antigens, has the high sensitivity and specificity for diagnosis of tuberculosis. However, it is essential to evaluate this T cell-based approach in individuals with HIV-associated impairment in T cell immunity. METHODS: We assessed the usefulness of QFT-2G on diagnosis of tuberculosis in 13 HIV-infected patients with tuberculosis and the performance of 25 HIV infected persons under highly active antiretroviral treatment (HAART). QFT-2G, CD4 counts, and tuberculosis skin test and so on were examined. RESULTS: The sensitivity of QFT-2G in HIV-infected patients with tuberculosis was 76.9%, which was significantly higher compared with tuberculin skin test, 15.4%. There was one indeterminate case of which CD4 count was 16/microl, the lowest count among the all patients. CD4 counts of 25 HIV infected persons under HAART were between 100 and 1157/microl. There were 3 QFT-2G positive cases among them, who had past history of tuberculosis. CONCLUSION: Although the very low CD4 counts in HIV-infected patients might adversely affect QFT-2G performance, the sensitivity of QFT-2G in the most of HIV-infected patients with tuberculosis was high, and it was thought that it was useful enough to diagnose tuberculosis infection. Careful observation is required in whether the recurrence of tuberculosis takes place among QFT-2G positive persons who have past history of tuberculosis.

[Features of bronchial tuberculosis--an analysis of 103 cases].

OBJECTIVES: The aim of this study is to clarify the features of bronchial tuberculosis. MATERIALS AND METHODS: We analyzed the clinicopathological data from 103 out of 4467 (2.3%) cases of culture positive tuberculosis admitted to the National Hospital Organization Tokyo National Hospital in the period from 1993 to 2004 in which bronchial tuberculosis was confirmed by bronchofiberscopy. RESULTS: There were 62 women and 41 men, and 53 cases were less than 50 years old. The most common symptom, namely cough was observed in 70 cases, while 79 cases showed III1 to III2 on roentgenographic examination, and 81 cases were smear-positive for acid-fast bacilli in the sputum. Regarding the bronchofiberscopic findings, ulcers were detected in 60 cases, and the major site of bronchial tuberculosis was in the left main bronchus (35 cases). The number of the cases in which the time span from the onset of symptoms to diagnosis took over 3 months was 29, and 26 of them were "doctor's delay" cases which had a history of medical consultation resulting in diagnosis and treatment of other diseases, such as bronchial asthma (7 cases). There were 41 cases in which the second bronchofiberscopic findings have been reviewed, and regardless of the length of the span from the onset to diagnosis, the first bronchofiberscopy mostly revealed ulcer within 1 month after the start of treatment for tuberculosis, and 3 months after the start of treatment, many patients developed fibrous scars. Between 1999 to 2004, the first bronchofiberscopies were usually performed within 2 weeks to 1 month after the start of the treatment in contrast to the cases admitted between 1993 to 1998 in which bronchofribroscopy was mainly performed before the start of the treatment. However, there were no differences in the findings due to the timing of bronchofiberscopy. CONCLUSION: The clinical characteristics of bronchial tuberculosis have not changed, and the delay of diagnosis of bronchial tuberculosis due to doctor's delay also continues to be an important issue today. In patients showing positive sputum smear for mycobacteria, the timing of bronchofiberscopy, although required upon medical examination, is considered to be more appropriately performed from 2 weeks to 1 month after the start of treatment from the view point of nosocomial tuberculosis infection control strategy.

[Examination of administrative dosage of cyclosporine during anti-tuberculosis chemotherapy including rifampicin].

AIMS: In the treatment of tuberculosis with rifampicin in patients treated with prednisolone and cyclosporine, we have to increase the dosage of these drugs. Although prednisolone dosage is recommended to be doubled, there is no established consensus about cyclosporine dosage. Our aim is to review the current situation at our institution regarding the dosage of cyclosporine administered to tuberculous patients after the addition of rifampicin to the treatment regimen. METHODS AND RESULTS: We reviewed patients' clinical status and how dosages of cyclosporine were altered during a course of tuberculosis treatment including rifampicin in 4 patients (2 interstitial pneumonitis, 2 collagen vascular disease) who were being treated with cyclosporine between 2001 and 2003. Prednisolone had been also administrated in all patients and the dosage was doubled from the beginning of the treatment. The appropriate dosage of cyclosporine was found to be 2.5-3.5 (average 3) times that of initial dosage, and it required 5-12 weeks (average 8.3) measurements of trough levels and 6-27 (average 12) weeks until appropriate trough levels were obtained. CONCLUSIONS: The appropriate dosage of cyclosporine was found to be approximately 3 times that of the initial dosage in all patients, but it required a long-term and frequent measurements of trough levels before reaching this goal. It seems that trebling the dosage of cyclosporine from the start of anti-tuberculosis chemotherapy will be an efficient way to achieve good clinical outcome.

[Bone and joint tuberculosis concurrent with tuberculosis of other organs].

OBJECTIVES: To study the characteristics of bone or joint tuberculosis (TB) accompanied by TB in other organs (especially the lung), and to study patients' and doctors' delay in detecting bone or joint TB. SUBJECTS AND METHODS: A retrospective study was conducted on 33 patients with bone or joint TB concurrent with TB of other organs, especially the lung, who were admitted to our hospital between 1981 and 2005. The patients were divided into the following three groups according to the organ of concurrent TB : (1) miliary TB group (N = 10), (2) pulmonary TB group (N = 19), and (3) other TB site group (N = 4). The relationship between bone/joint TB and TB of other organs was studied by comparing the three groups with respect to the time of appearance of musculo-skeletal symptoms or signs such as swelling and pain and that of symptoms or signs originating from other organs, such as cough, sputum, miliary pattern on chest radiograph and superficial lymph node swelling. RESULTS: The mean age (SD) of patients was 50.5 (18.9) yr, and the male to female ratio was 23 : 10. Among 33 patients, bone TB (including 18 spinal TB) was detected in 24 patients, joint TB in 14, and abscess in 3 (concurrent lesions in some patients). The mean intervals from onset of symptoms to consultation (patients' delay), from consultation to diagnosis (doctors' delay) and from symptom onset to diagnosis (total delay) were 5.5 (13.9), 3.4 (5.2) and 8.9 (13.9) months, respectively. (1) Bone/joint TB concurrent with miliary TB (N = 10) In 8 patients with mean age of 61.0 (17.4) yr, musculo-skeletal symptoms/signs preceded respiratory symptoms or appearance of miliary pattern on chest radiograph by 7.8 (7.2) (range; 1-24) months. The patients', doctors' and total delays were 0.4 (0.5), 7.3 (7.8), and 7.7 (7.6) months, respectively. In most cases, bone/joint TB was diagnosed after the onset of miliary pattern on chest radiograph. In one patient with simultaneous onset of musculo-skeletal and respiratory symptoms/signs (age 21 yr), the interval of total delay was 1 month, and in one patient with musculoskeletal symptoms which appeared six months later than respiratory symptoms (age 28 yr), the interval of total delay was 2 months. (2) Bone/joint TB concurrent with active pulmonary TB (N = 19). In this group, the mean age was 52.2 (17.1) yr, and males were predominant (M/F = 15/4). Active pulmonary TB was diagnosed by positive sputum culture in 13 patients, by positive sputum smear or PCR results in 4 patients, and by the clinical course in 2 patients. Ten patients (53%) had a previous TB history. Cavitary lesion was observed in 15 patients, and the upper lobes were predominantly involved on chest radiograph in 19 patients, indicating that the pulmonary TB was probably post-primary (reactivation) in all patients. In 9 patients with mean age of 49.7 (15.7) yr, musculo-skeletal symptoms/signs preceded respiratory symptoms by 14.1 (14.0) (range; 4-48) months. The patients', doctors' and total delays were 13.3 (17.8), 3.8 (6.6), and 17.1 (16.1) months, respectively. On the other hand, in 10 patients with mean age of 54.5 (18.7) yr, musculo-skeletal symptoms/signs and respiratory symptoms/signs appeared simultaneously, and the total delay was 2.7 (1.9) months. Twelve of 19 patients (63%) had complications such as diabetes mellitus, steroid use, and liver diseases. In cases with miliary or pulmonary tuberculosis, the total delay in diagnosis (Y) correlates positively with the time lag from onset of musculo-skeletal symptoms to respiratory symptoms/signs (X), and the regression line (Y = 0.94X + 2.3, r = 0.98, p < 0.001) was almost linear (Y = X), indicating that the diagnosis of bone/joint TB was made just after the diagnosis of miliary or pulmonary TB. (3) Bone/joint TB concurrent with TB of other sites (N = 4) In 2 female cases (21 and 28 yrs) with cervical lymph node TB, musculo-skeletal symptoms/signs and cervical lymph node swelling appeared simultaneously. In a 54-yr male patient, musculo-skeletal symptoms/signs appeared 5 years after appearance of testicular enlargement, and testicular TB was diagnosed by biopsy simultaneously. In a 33 year-old male patient, musculo-skeletal symptoms/signs appeared 7 months after the drainage of pleural and pericardial effusions (TB was not diagnosed initially), and then the diagnosis of bone/joint, pleural, and pericardial tuberculosis was made for the first time. CONCLUSIONS: In middle-aged or elderly patients with active bone/joint TB, miliary TB is sometimes caused by bacillemia originating from the infected bone/joint lesions. In cases with bone/joint TB and concurrent pulmonary TB, bone/joint TB and pulmonary TB are probably reactivated independently as a result of decreased systemic immunocompetence.

[Comparative study of bactec MGIT 960 AST and conventional proportion method using Ogawa medium for the drug susceptibility testing of Mycobacterium tuberculosis to isoniazid].

OBJECTIVE: To evaluate the accuracy of drug susceptibility testing to isoniazid with BACTEC MGIT 960 (MGIT AST) comparing with the standard proportion method using Ogawa medium. METHOD: A total of 1109 M. tuberculosis strains, which were selected from the collection of RYOKEN drug resistance survey in 2002, were selected and subjected to the susceptibility testing to isoniazid using MGIT AST and 1% Ogawa standard methods. The results from MGIT AST were compared with the judicial diagnosis by Ogawa. The sensitivity to detect drug resistance, the specificity for susceptible strain, the efficiency of overall agreement, and kappa coefficient were calculated to evaluate the performance. The treatment process, outcome and prognosis were analysed for the patients on whom the tests showed discrepant results. RESULTS: Compared with the judicial results, the sensitivity, specificity, efficiency, and kappa coefficient of MGIT AST were 100%, 97.1%, 97.3%, and 0.798, respectively. The strains, which showed discrepant results between MGIT AST and Ogawa, were all susceptible by Ogawa and resistant by MGIT AST. A total of 11 out of 30 discrepant cases were followed clinically and no relapse cases were identified, irrespective of the modification of the treatment regimen. As for the proportion of primary INH drug resistance in the present study, it was 5.3% with MGIT AST but was 2.7% with Ogawa, and the difference was statistically significant (p = 0.005). DISCUSSION: The discrepancies on the results of drug susceptibility testing of M. tuberculosis strains to isoniazid between MGIT AST and 1% Ogawa proportion method have been reported. In the present study, the sensitivity, specificity, and overall efficiency of MGIT AST on the prevalent strains in Japan were all beyond 95%, and considered sufficient as the anti-tuberculosis drug susceptibility testing (AST), though 2.7% of discrepancy was observed. Even for the discrepant cases, there was no difference in the treatment outcome and prognosis. Thus, MGIT AST was confirmed as a reliable AST method comparable to Ogawa standard. However, MGIT AST might increase the proportion of INH resistance if it was used as a major AST method, compared with Ogawa.

[Coexisting lung cancer and active pulmonary mycobacteriosis].

We reviewed 72 patients with coexisting lung cancer and pulmonary mycobacteriosis, and discuss the features and transition of these coexistent cases. There were 56 pulmonary tuberculosis (PTB) cases and 16 non-tuberculous mycobacteriosis (PNTM) cases, 62 men and 10 women, with a mean age of 69 years. In 43 cases, both diseases were concurrently detected, lung cancer was first detected in 19 cases, and mycobacteriosis was first detected in 10 cases. The frequency of lung cancer in cases with active pulmonary mycobacteriosis was 1.2%. Pulmonary mycobacteriosis was characterized by Type II (40 cases) and Spread 2 (42 cases) on chest X-rays; the most frequent histologic type of lung cancer was squamous cell carcinoma (32 cases) and most were stage III-IV cases (57 cases). After PTB treatment, the negative conversion rate of sputum cultures in both the concurrently detected group and the group in which lung cancer was initially detected was 56% within one month and 94% within 2 months. For the treatment of lung cancer, 33 cases received supportive care, 13 patients underwent resection and 17 received chemotherapy or chemoradiotherapy. In PNTM cases, both lung cancer and pulmonary mycobacteriosis showed a slight state compared to those in PTB cases, and in the group in which lung cancer was initially detected, both diseases were more advanced or severe than those in the concurrently detected group or in the group in which mycobacteriosis was initially detected. The rate of coexisting lung cancer and pulmonary mycobacteriosis was unchanged at 1-2%, and the incidence of stage IV lung cancer cases has increased recently. Coexisting lung cancer and pulmonary mycobacteriosis is an important condition in respiratory disease in Japan. Physicians should be aware of the possibility of PTB coexisting with lung cancer.

[Application and problems of quantiFERON TB-2G for tuberculosis control programs--(2) clinical use of quantiFERON TB-2G].

BACKGROUND: QuantiFERON TB-2nd Generation (QFT) is an accurate tool for detecting tuberculosis infection regardless of past history of BCG vaccination. In Japan, QFT test was recognized for diagnostic tool on April 2005, and adopted officially on January 2006. Tuberculosis Society issued Guideline for using QFT-2G on May 2006. PURPOSE: This article describe the usefulness and remarks in clinical use on diagnosis and system for detection of tuberculosis infection among staff in NHO Tokyo Hospital that has 100 beds for tuberculosis. METHOD: (1) QFT test for 403 definite diagnosed tuberculosis patient before tuberculosis treatment or within 7 days chemotherapy in NHO Tokyo Hospital. Seventy-four patients have immunosuppressive diseases such as diabetes mellitus, malignant disease, using corticosteroid or immunosuppressor and HIV+ including overlap diseases. QFT result was analyzed by immunosuppressive diseases and by age for 329 patients who have no immunosuppressive diseases. (2) For control of tuberculosis infection of staff, QFT test is used in 3 situation. One is baseline QFT for staff who are shifted to tuberculosis ward from non-tuberculosis ward and new employee, 2nd is following up for staff who work at tuberculosis ward, and 3rd is contact investigation for staff who work at non-tuberculosis ward. Tuberculin skin testing and baseline QFT were done for 92 staff on April 2006, 2 were shifted to tuberculosis ward from non-tuberculosis ward and 90 were new employee. RESULT: (1) Among 403 definite diagnosed tuberculosis patient before tuberculosis treatment or within 7 days chemotherapy, QFT positive rate was 78.7%. Among 74 patients who have immunosuppressive diseases such as diabetes mellitus, malignant disease, using corticosteroid or immunosuppressor and HIV+ including overlap diseases, QFT positive rate was 58-70%. Among 329 patients who have no immunosuppressive diseases, QFT positive rate was 88-89% in thirties and forties, 69% in sixties and 63% in nineties. QFT-2G test for 134 previously treated tuberculosis cases who are not suffered from active tuberculosis, 49 cases (37%) were positive, 27 cases (20%) were intermediate and 58 cases (43%) were negative. Instructive three cases were reviewed. Suspicion of tuberculosis relapse with QFT negative case was M. avium-intracellulare disease. Suspicion of M. avium-intracellulare disease rather than tuberculosis by X-ray and CT with QFT positive case was tuberculosis. A case with small nodule on CT with QFT positive was adenocarcinoma. (2) Tuberculin Skin Testing and baseline QFT for 92 staff, 4 were QFT positive. Compared with Tuberculin Skin Testing more than 29 mm in erythema, QFT positive rate was 9% and more than 9 mm in induration, QFT positive rate was 7%. By following up QFT test for staff working at tuberculosis ward, 2 staff, one nurse and one helper, were diagnosed tuberculosis infection. As to contact investigation, one nurse was diagnosed tuberculosis infection. CONCLUSION: Although QFT is a very excellent tool for detecting tuberculosis infection, on clinical diagnosis, it is important to mind that QFT depends on clinical condition especially immunosuppressive diseases, aging and past infection. We cannot diagnose or exclude active tuberculosis by QFT result. This is a useful assistant tool on clinical diagnosis.

Diagnosis of active tuberculous serositis by antigen-specific interferon-gamma response of cavity fluid cells.

BACKGROUND: To develop a more accurate methodology for diagnosing active tuberculous pleurisy, as well as peritonitis and pericardits of tuberculous origin, we established an antigen-specific interferon gamma (IFN-gamma)-based assay that uses cavity fluid specimens. METHODS: Over a 19-month period, 155 consecutive, nonselected patients with any cavity effusion were evaluated. Study subjects were 28 patients with bacteriologically confirmed active tuberculous serositis and 47 patients with definitive nontuberculous etiology. Culture was performed for 18 h with fluid mononuclear cells in the supernatant of the effusion together with saline or Mycobacterium tuberculosis-specific antigenic peptides, early secretory antigenic target 6 and culture filtrate protein 10. IFN-gamma concentrations in the culture supernatants were measured. RESULTS: In patients with active tuberculous serositis, antigen-specific IFN-gamma responses of cavity fluid samples were significantly higher than those of nontuberculous effusion samples. Area under the receiver operating characteristic (AUROC) curve was significantly greater for cavity fluid IFN-gamma response (AUROC curve, 0.996) than for cavity fluid adenosine deaminase and whole-blood IFN-gamma responses (AUROC curve, 0.882 and 0.719, respectively; P = .037 and P < .001, respectively). Although the AUROC curve was greater for cavity fluid IFN-gamma response than for background cavity fluid IFN-gamma level (AUROC curve, 0.975), the AUROC curves were not statistically significantly different (P = .74). However, multivariate logistic regression analysis revealed that cavity fluid IFN-gamma responses were significantly associated with the diagnosis, even after adjustment for background IFN-gamma level (adjusted odds ratio, 1.21; 95% confidence interval, 1.03-1.42; P < .001). CONCLUSIONS: The cavity fluid IFN-gamma assay could be a method for accurately and promptly diagnosing active tuberculous serositis.

[Tuberculosis complicated with liver cirrhosis].

OBJECTIVES: The aim of this study is to examine the clinical characteristics of tuberculous patients complicated with liver cirrhosis. MATERIALS AND METHODS: 44 patients (39 males and 5 females) admitted to Tokyo National Hospital since 1991 till 2005 were analysed. RESULTS: Eighteen patients died and liver failure was the leading cause of death (N = 10). Hepatitis C viral infection (N = 17), and excessive alcohol consumption (N = 13) were the major causes of liver cirrhosis. Twenty five patients followed-up for more than 3 months were further selected for the detailed analyses. Multi-drug combination chemotherapy including isoniazid, rifampicin and ethambutol was administered in 22 patients. Adverse effects were seen in 20 patients. The numbers of patients with leukopenia, thrombocytopenia and hyperbilirubinemia were 10, 9 and 3, respectively. They recovered following the alteration of chemotherapeutic regimen or drug desensitization. CONCLUSION: Tuberculous patients with liver cirrhosis are characterized with higher mortality rate and higher frequency of adverse effects of antituberculous chemotherapy. Multi-drug combination regimen could be tolerable under adequate surveillance of side effects even in the situation of preexisting liver dysfunction.

Social course patterns of urban dwellers with tuberculosis under fragile living conditions in Tokyo, Japan.

BACKGROUND: People under fragile-living conditions show a high rate of interruption of tuberculosis treatment. We examined the social courses of fragile-living urban dwellers with tuberculosis without customary and regular access to a conventional residence and investigated the factors associated with interruption of treatment. METHODS: One hundred and nineteen tuberculosis patients without customary and regular access to a conventional residence who were discharged from a hospital with the largest number of tuberculosis beds in Tokyo between January 1998 and October 2000 were followed up. The associations between demographic, social, and clinical characteristics and interruption of treatment were examined. RESULTS: The subjects (mean age, 51.2 years) were followed up for a median of 342 days. The percentage of cases of interruption of treatment during inpatient care among patients with alcohol problems (56%) was significantly higher than that among patients without such problems (11%). The proportion of cases of interruption of treatment during outpatient care among patients who were literally homeless before admission (40%) was significantly higher than that in others (5%), and that among those who used transient hostels after the initial inpatient treatment (55%) was significantly higher than that in others (4%). The prevalence of drug resistance was higher in cases with than without a history of tuberculosis treatment (P<0.05). CONCLUSIONS: Factors associated with interruption of tuberculosis treatment in patients under fragile-living conditions were identified. Interruption during inpatient care was significantly associated with alcohol problems, and interruption during outpatient care was significantly associated with the use of transient hostels.

[Case of pulmonary mycobacterium avium complex disease, showing hypersensitivity pneumonitis-like diffuse shadow].

A 59-year-old man who had just completed therapy for tuberculosis, fell down in sauna and was admitted to a hospital. As acid-fast bacilli were positive (Gaffky 2) in sputum and residual cavity was shown in the right upper lobe on chest X-ray, he was transferred to our hospital. In spite of starting antituberculous chemotherapy, small nodular shadows appeared diffusely and were changed into ground-glass appearance on chest X-ray. The trans-bronchial-lung-biopsy revealed alveolitis mainly composed of lymphocyte infiltration with non-caseous epithelioid cell granulomas and organization which are likely to appear in hypersensitivity pneumonitis. As the acid-fast bacilli were identified as Mycobacterium avium, clarithromycin and kanamycin were added to the chemotherapy, but no improvement was observed in clinical feature. Corticosteroid therapy was further added and clinical feature improved immediately. Although we did not examine the presence of Mycobacterium avium in the water of sauna bath, we suspected this case as Hot Tub Lung based on clinical features and the response to treatment.