(Vol.75 No.9 September 2000) <1> Kekkaku Vol.75,No.9:521-526,2000 DESENSITIZATION THERAPY FOR ANTITUBERCULOUS DRUGS 1*Yoshihiro KOBASHI, 1Niro OKIMOTO, 2Toshiharu MATSUSHIMA, 3Takahiro ABE, 3Kazutaka NISHIMURA, 4Shinji SHISHIDO, 5Shin KAWAHARA, 6Eriko SHIGETO, 7Hiroyasu TAKEYAMA, and 8Toshihiko KURAOKA 1*Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School Kawasaki Hospital, 2Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, 3Division of Respiratory Diseases, Department of Medicine, National Ehime Hospital, 4Department of Respiratory Diseases, National Matsue Hospital, 5Department of Medicine, National Minami-Okayama Hospital, 6Department of Respiratory Diseases, National Hiroshima Hospital, 7Department of Medicine, National Sanyo Hospital, 8Department of Medicine, Yoshijima Hospital We retrospectively evaluated the effectiveness of desensitization therapy for antituberculous drugs (Rifampicin and Isoniazid) in 28 cases (29 episodes) with adverse reactions to these drugs. Desensitization therapy for RFP was performed in 23 cases (24 episodes) with administration of a first dose of 1-150mg and a final dose of 300-450mg for 1-29 days. The success rate of this therapy was 79% (19 of 24 episodes). Desensiti- zation therapy for INH was performed in 12 cases with administration of a first dose of 2.5-100mg and a final dose of 200-400mg for 3-25 days. The success rate of this ther- apy was 83% (10 of 12 cases). Based on a comparative study of cases between successful and unsuccessful desensitiza- tion to RFP and INH it was concluded that there were no significant differences with re- gard to allergic history, adverse effects and their periods of appearance, the first dose and final dose of administration and the interval of administration, starting periods of the desensitization therapy and the periods of appearance of adverse effects due to this therapy. We evaluated desensitization therapy for two antituberculous drugs (RFP and INH) for tuberculous patients for whom the use of such drugs was restricted because of adverse effects, and we found it is a usefu treatment, showing a high rate of success (80 %). Key words:Desensitization therapy, Anti- tubercuous drugs, Adverse effect, Rifam- picin, Isoniazid *2-1-80, Nakasange, Okayama-shi, Okayama 700-8505 Japan. (Received 20 Apr. 2000/Accepted 31 May 2000) <2> Kekkaku Vol.75,No.9:527-532,2000 A STUDY OF PATIENT'S AND DOCTOR'S DELAY IN PATIENTS WITH PULMONARY TUBERCUOSIS DISCOVERED BY VISITING DOCTORS WITH SYMPTOMS IN PARTICUAR ON DOCTOR'S DELAY *Yuka SASAKI, Fumio YAMAGISHI, Takenori YAGI, Hideaki YAMATANI, Fuminobu KURODA, and Hideaki SHODA *Division of Thoracic Disease, National Chiba Higashi Hospital Epidemiological trend of tuberculosis in Japan has reversed recently. The incidence of pulmonary tuberculosis (PTB) patients has increased again in Japan, and many outbreaks of PTB including nosocomial outbreaks in health-care facilities have been reported. The purpose of this study is to investigate patient's delay (interval between onset of the disease and first visit to a doctor and doctor's delay (interval between first visit to a doctor and diagnosis as TB) in patients with PTB discovered by visiting doctors with symptoms, and especially, to investigate causes of doctor's delay in details. Of 236 PTB patients who were admitted to our hospital for treatment in 1997, 118 patients (85 males, 33 females) who were detected by their symptomatic visits were en- rolled in to this study. 97 were initial treatment cases and the others were re-treatment cases. Among 34 initial treatment cases who were first seen at a general hospital and diagnosed as PTB by a close medical checkup after admission to our hospital, the 50 percentile of patient's delay was 17.0 days, and the 80 percentile was 36.4 days. The 50 percentile doctor's delay was 19.6 days, and the 80 percentile was 64.2 days. The average hospital stay was 16.2 days, the 50 percentile hospital stay was 7.8 days, and 80 percentile hospital stay was 23.5 days. On the sputum test for acid fact basilli (AFB) performed on admission to our hospital, 26(76%) out of 34 cases were positive for tubercle bacilli, with 18 cases were positive for smear and 8 cases positive for culture. Therefore, risk of nosocomial infection was suspected. Doctor's delay had been attributed mainly to insufficient medical checkup. Among 25 initial treatment cases in whom doctor's delay as more than 4 weeks, 11 cases (44%) showed delay in chest X-ray examination and 8 cases (32%) ordered no sputum examination in spite of recognition of abnormal shadows on chest X-ray. On the sputum test for AFB on admission to our hospital, 22(88%) out of 25 cases were positive for tubercle bacilli. Therefore, it is assumed that the delay in the adequate medical checkup was accountable for the dector's delay. Shortening of the doctor's delay could be possible if hospitals perform the sputum examination for AFB and chest X-ray examinations properly for patients with respiratory symptoms. Key words:Pulmonary tuberculosis, Symptomatic visit, Doctor's delay *673, Nitona-cho, Chuo-ku, Chiba-shi, Chiba 260-8712 Japan. (Received 22 Mar. 2000/Accepted 2 Jun. 2000) <3> Kekkaku Vol.75,No.9:533-544,2000 FACTORS RELATED TO THE SLOWDOWN IN THE REDUCTION OF THE TUBERCULOSIS INCIDENCE RATE IN OSAKA CITY -Structure of the High Incidence Rate of Tuberculosis in Osaka City Analyzed by Administrative-Ward Group, Five-Year Period and Age Group- *Toshio TAKATORIGE, Yoshinori AOKI, Chisato TANIGAKE, Amin RUFUL, and Kozo TATARA *Department of Social and Environmental Health, Osaka University Graduate School of Medicine The tuberculosis incidence rate in Osaka City is the highest in Japan. We analyzed the incidence rate in Osaka City in five-year period from 1978 to 1997, namely, 1978-1982 (period T), 1983-1987(period U), 1988-1992(period V), and 1993-1997 (period W). Until the first half of 1980, the tuberculosis incidence rate in Osaka City had been dropping every year, but the rate of decline has been slowed substantially or even stopped since 1983. The incidence rate ratio of Osaka City compared with the national rate was 2.0 to 2.3 from 1970 to 1975, but it has been increasing from 1983 and is now higher than 3. We divided 24 wards of Osaka City into five groups based on selected employment indicators of population 15 years of age and over of 1995 National Census. Group A consists of two wards characterized by extremely high unemployment rate, Group B of four wards by high unemployment rate and high rate of manufacturing workers, Group C of six wards by high rate of non-manufacturing workers (tertiary industry workers), Group D of five wards by high rate of manufacturing workers, and Group E of seven wards by residential areas. The incidence rate of Group A had been declining during periods T and U but started to rise after period V. The rates of Group B and C had been declining from period T to U but the decline slowed down substantially even for every age class in periods V and W. The incidence rates of Groups D and E have been falling. The incidence rate of the 50-69 year-old age group has been increasing substantially. The proportion of newly registered patients in Group A to all patients of Osaka City increased from 25.2% in period T to 32.7% in period W. The number of newly registered patients of the 40-69 age class in Group A accounted for 45.1% of that in Osaka City in period W. The slowdown in the reduction of the tuberculosis incidence rate has occurred not in all, but in only a few wards and it is a typical phenomenon of the middle-aged in those wards. It would be worth investi- gating whether a substantial decline in the tuberculosis incidence rate in Osaka City cannot be achieved by means of uniform control measures for all wards. Intensified tuberculosis control measures should focus on patients in specific wards and age groups. Key words: Urban city, Regional difference, Middle-aged, Decline rate, Tuberculosis incidence *2-2, Yamadaoka, Suita-shi, Osaka 565-0871 Japan. (Received 31 Jan. 2000/Accepted 7 Jun. 2000) <4> Kekkaku Vol.75,No.9:547-556,2000 The 75th Annual Meeting Lunch-Time Seminar TUBERCULOSIS IN PATIENTS WITH ACQUIRED IMMUNE DEFICIENCY SYNDROME 1Koh NAKATA, 2Yoshihiro HONDA, 3Naohiko TANAKA, 3Michael WEIDEN, and 1Naoto KEICHO 1Department of Respiratory Diseases, Research Institute, The International Medical Center of Japan, 2Department of Medicine, Sendai, Kosei Hospital, 3Division of Pulmonary & Critical Care Medicine and Bellevue Chest Sercvice, NYU Medical Center HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. In Japan, the cumulative number of the patients reported is 131 by the end of 1999 with 10 to 20 an- nual new cases. Most of Japanese cases are advanced AIDS patients with low CD4 number less than 100/ʃ.The peak age of Japanese patient is 40 to 60 years old, whereas that of foreigners is 20-30 years old, suggesting that most Japanese cases are recurrent tuber- culosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found taht, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was re- pressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP- binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16 kDa inhibitory form of C/EBP- after M.tu- berculosis coinfection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16 kDa inhibitory form of C/EBP-. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP- expression. These data suggest that 16 kDa isoform of C/EBP- plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Key words: HIV, AIDS, Tuberculosis, C/EBP-, HIV-LTR *1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655 Japan. (Received 21 Jun. 2000) @ <5> Kekkaku Vol.75,No.9:557-560,2000 The 75th Annual Meeting Symposium V. MECHANISMS OF PATHOGENICITY AND HOST DEFENSE IN INFECTIONS BY INTRACELLULAR PARASITIC MICROBES Chairpersons:1*Masao MITSUYAMA 2Katsuhiro SUZUKI 1*Department of Microbiology, Kyoto University Graduate School of Medicine, 2Kinki Chuo Hospital Mycobacterium tuberculosis is one of the intracellular parasitic bacteria escaping the intracellular killing inside macrophages. The aim of this symposium was to get some insight into the mechanism of pathogenicity and host defense in M.tuberculosis infection, which has not yet been elucidated well, by the presentation of up-to-date knowledge on these aspect in infection with different intracellular parasitic microbes. Dr. Yoshikai (Nagoya Univ.) indicated that TLR is involved in the initial response of host against S. choleraesuis. Among the cytokines contributing to the induction of spe- cific immunity, the importance of IL-15 was emphasized, based on their own experimen- tal data using IL-15 transgenic mice and the application of atni-IL-15 antibody in vivo. Dr. Yoshida (Kyushu Univ.) reviewed the mechanisms of intracellular growth of Legionellae. Several genes so far identified as essential genes in intra-macrophage growth appeared to be similar to those encoding type 3 secretion system observed in Shigellae. There is a significant strain difference in the growth of L.pneumophila inside macrophages and such difference seemed to be under the control of a gene at chromosome 13, Lgn1. The investigation of difference in the mode of escape among various Legionella. spp. may provide a novel mechansim on bacterial invasion and escape. Dr. Kawamura (Kyoto Univ.) summarized some new reports on the molecular mechanism of the inhibition of P-L fusion by M.tuberculosis. He emphasized the importance of the alteration in phagosomal maturation as indicated by the accumulation of TACO protein. The possible involvement of TLR in the recognition of Mycobacterial cells and its LAM was discussed. Dr. Kawakami(Ryukyu Univ.) first discussed the possibility that Cryptococcus neoformans, a fungal pathogen, could be ragarded as one of the intracellular parasitic microbes. His presentation mainly focused on the TH1-TH2 balance in the expression of host defense against C.neoformans in mice. From their experimental infection using attenuated strain TC-13 in various cytokine-knock out mice, the pivotal role of both IL-12 abd IL-18 was clearly indicated. Key words: Intracellular parasitic bacteria, Salmonella, Legionella, Mycobacteria, Cryptococcus *Yoshida Konoe-cho, Sakyo-ku, Kyoto-shi, Kyoto 606-8501 Japan. (Received 21 Jun. 2000)