2 3

Abstract　Nowadays, methods of the diagnosis in infants with suspected tuberculosis and of the treatment are definitely established in Japan, where a number of childhood tuberculo-sis has been falling down (the incidence is less than 2 per 100,000). Still, infants less than one year are considered to be at high risk against tuberculosis. Actually, the number of tu-berculosis among them is three times larger than those of one or two years old children. One of major reasons of difficulties in the treatment is the rapid progress of the disease because of underdeveloped cell-mediated immunity among them. Alveo-lar macrophage and lymphocyte and their cooperation in im-munological functions do not develop enough to kill or con-fine Mycobacterium tuberculosis. As a result, the infection may progress to disease quickly, and then may spread system-ically before the starting treatment. Anatomical underdevelop-ment of cranial arteries and narrow cerebrospinal passages easily cause cerebral infarction and hydrocephalus following meningeal inflammation due to tuberculosis. These neurologi-cal disorders may result in poor prognosis despite of adminis-tration of effective anti-tuberculosis medicines. Delay in the diagnosis also makes the treatment difficult in some infants whose tuberculin skin test shows false negative and radio-

graphic manifestation of chest is not clear. During the treat-ment, systemic and enteric viral infections occur frequently among infants with tuberculosis, and liver functional disorders caused by these infections sometimes disturbs the treatment for tuberculosis. Recurrence of tuberculosis is very rare among infants who complete the full treatment at the age of more than one year. Finally, it is important for the early start of treatment for tuberculosis to recognize both susceptibility to tuberculosis and difficulties in the diagnosis in some infants less than one year.

Key words : Infants less than one year, Tuberculosis, Cell-mediated immunity, Delayed-type hypersensitivity, Tubercu-lous meningitis, Paradoxical worsening

Division of Respiratory Diseases, Tokyo Metropolitan Kiyose Children’s Hospital

Correspondence to : Shinya Kondo, Division of Respiratory Diseases, Tokyo Metropolitan Kiyose Children’s Hospital, 1_3_1 Umezono, Kiyose-shi, Tokyo 204_0024 Japan. (E-mail : shykondo＠chp-kiyose-tokyo. jp)

3

－－－－－－－－ Issue－－－－－－－－

DIFFICULTIES IN THE TREATMENT OF TUBERCULOSIS IN INFANTS

Shinya KONDO and Masaki ITO

Treatment of TB in Infants/S. Kondo et al.

12 13

13TB Incidence Rate with Fibrotic Lesions/A. Shimouchi et al.

Abstract　The incidence rate of “active” pulmonary tubercu-losis (TB) cases with bacteriological confirmation or cavitary lesions on chest radiographs was studied among population screened with mass miniature radiography in Funai-Gun, Kyoto Prefecture from 1982 to 1993. The results were as follows : Among population of 40 and over, prevalence rate of all fibrotic lesions on chest radiographs among male (8.3％) was twice as high as that of female (3.8％). The rate of mod-erate or extensive fibrotic lesions among male (3.3％) was three times as high as that of female (1％). The higher the age of the population, the higher the prevalence rate of radiologi-cal fibrotic lesions both in male and female. In male, in partic-ular, prevalence rate of moderate or extensive fibrotic lesions started to rise after 40 years of age, became much higher after 70 years of age and reached 8.1％ after 80 years of age. In fe-male, however, it started to rise at 50s (0.3％) gradually and reached only 2.3％ after 80 years of age. The incidence rate of “active” pulmonary TB among male of 40 years and over with moderate or extensive fibrotic lesions (4.2 per 1000 per-son-years) was 16 times as high as male of 40 years and over with normal chest X-ray finding (0.26 per 1000 person-years).

Similarly, the incidence rate of “active” pulmonary TB in female of 40 years and over with moderate or extensive fibro-tic lesions was 24 times as high as among female with normal finding, and the difference was statistically significant (p<0.001). From the data obtained and bibliographical review, benefits of INH prophylaxis were discussed.

Key words : Pulmonary tuberculosis, Incidence of tuberculo-sis, X-ray mass screening, Fibrotic lesions

1Department of Infectious Disease Control, Bureau of Health & Welfare, Osaka City Government, 2Department of Social Medicine and Cultural Sciences, Research Institute for Neuro-logical Diseases and Geriatrics, Kyoto Prefectural University of Medicine

Correspondence to : Akira Shimouchi, Department of Infec-tious Disease Control, Bureau of Health & Welfare, Osaka City Government, 1_3_20, Nakanoshima, Kita-ku, Osaka-shi, Osaka 530_8201 Japan. (E-mail : shimouchi＠sannet.ne.jp)

－－－－－－－－ Original article－－－－－－－－

THE INCIDENCE RATE OF ACTIVE PULMONARY TUBERCULOSISAMONG ADULT POPULATION WITH FIBROTIC LESIONS

1Akira SHIMOUCHI and 2Kotaro OZASA

18 19

Abstract　In cases in which hepatotoxicity developed during anti-tuberculosis chemotherapy, the rapid recovery of liver function is essential for the completion of the anti-tuberculosis chemotherapy protocol. Glycyrrhizin (Stronger Neo-Minopha-gen C : SNMC) is widely used in Japan for the treatment of patients with drug eruption or chronic hepatitis. However, a consensus on the clinical effects of glycyrrhizin for the treat-ment of anti-tuberculosis drug-induced hepatitis has not yet been reached. We studied 24 cases who showed abnormal liv-er function test results while undergoing anti-tuberculosis chemotherapy and who were treated with or without glycyr-rhizin. We then compared recovery periods of liver function among both groups. The time required for liver function nor-malization in the patients who received glycyrrhizin (SNMC, 40 ml daily, intravenously) was 15.1±4.5 days and the time required for normalization in the non-glycyrrhizin group was

15.2 ± 5.2 days. The difference was not significant and the fact indicated that glycyrrhizin is not useful for the treatment of anti-tuberculosis drug-induced hepatitis.

Key words : Anti-tuberculosis drug, Liver dysfunction, Drug-induced hepatitis, Glycyrrhizin, Hepatoprotective agent

Department of Respiratory Medicine, Kanagawa Cardiovas-cular and Respiratory Center

Correspondence to : Naoki Miyazawa, Department of Respi-ratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6_16_1 Tomiokahigashi, Kanazawa-ku, Yokohama-shi, Kanagawa 236_0051, Japan. (E-mail : nmiyazawa＠dream.com)

19

－－－－－－－－ Original Article－－－－－－－－

EFFECT OF GLYCYRRHIZIN ON ANTI-TUBERCULOSISDRUG-INDUCED HEPATITIS

Naoki MIYAZAWA, Hiroshi TAKAHASHI, Yasuhiro YOSHIIKE, Takashi OGURA,Yuji WATANUKI, Masamichi SATO, Nobumasa KAKEMIZU, Yasushi YAMAKAWA,

Chol-han U, Hideto GOTO, and Shigeki ODAGIRI

Therapy for TB Drug Hepatitis/N. Miyazawa et al.

30 31

する可能性があるという点で注意を払うべきであり報告

した。肺結核症例で低ナトリウム血症を認めた場合に

SIADHを考慮すべきだけでなく，逆に SIADHの病因と

して軽症の肺結核も念頭において診療を行うべきである

と考えられた。

文　　　献

1） Schwartz WB, Bennett W, Curelop S : A syndrome of renal sodium loss and hyponatremia probably resulting from in-appropriate secretion of antidiuretic hormone. Am J Med. 1957 ; 23 : 529_542.

2） 山本恭平，内田大学，吉田尚志：「SIADH」. 領域別症候群シリーズ No.1.日本臨牀社，東京，1993 ; 142_144.

3） Weiss H, Katz S : Hyponatremia resulting from apparently inappropriate secretion of antidiuretic hormone in patients with pulmonary tuberculosis. Am Rev Resp Dis. 1965 ; 92 : 609.

4） Chung DK, Hubbard WW : Hyponatremia in untreated active pulmonary tuberculosis. Am Rev Respir Dis. 1969 ;

99 : 595_597.5） Cockcroft DW, Donevan RE, Copland GM, et al. : Miliary

tuberculosis presenting with hyponatremia and thrombo-cytopenia. Can Med Assoc J. 1976 ; 115 : 871_873.

6） Smith J, Godwin-Austen R : Hypersecretion of anti-diuretic

hormone due to tuberculous meningitis. Postgrad Med J. 1980 ; 56 : 41_44.

7） Vorherr H, Massry SG, Fallet R, et al. : Antidiuretic princi-ple in tuberculous lung tissue of a patient with pulmonary tuberculosis and hyponatremia. Ann Intern Med. 1970 ; 72 : 383_387.

8） 山田幸寛：肺結核と SIADH. 臨床医. 1981 ; 7 : 1725.9） 吉田尚義：抗利尿ホルモン分泌異常症（SIADH）. 日本臨床. 1985 ; 41（臨時増刊号）: 715.

10） 中俣正美，月岡一治，近藤有好，他：肺結核における抗利尿ホルモン（ADH）について. 結核. 1987 ; 62 : 635_639.

11） Rosenow EC, Segar WE, Zehr JE : Inappropriate antidiuretic hormone secretion in pneumonia. Mayo Clin Proc. 1972 ; 47 : 169_173.

12） 宮地厚雄，杉浦芳樹，吉川公章，他：肺結核に合併した SIADHの 1例. 結核. 1988 ; 63 : 181_184.

13） 菅原　斉，平沢邦彦，吉岡　礼，他：SIADHをきたした粟粒結核の 2例. 結核. 1989 ; 64 : 413_419.

14） 安藤隆之，田中稔彦，佐伯　篤，他：甲状腺癌術後経過中栗粒結核を発症し，SIADHを合併した 1例. 結核. 1997 ; 72 : 161_165.

15） 高原　誠：SIADHおよび脳内結核腫・結核性髄膜炎を合併した粟粒結核の 1例. 結核. 2002 ; 77 : 67_72.

31Pulmonary Tuberculosis and SIADH/Y. Nishizawa et al.

Abstract　A 90-year old man was admitted to a hospital because of consciousness loss with hyponatremia. Although his symptom promptly improved with Na supply, his chest X-ray film showed pulmonary infiltration and direct microscopy of sputum smear was positive for acid-fast bacilli, then he was referred our hospital and was admitted. We made a clinical diagnosis of pulmonary tuberculosis with SIADH based on detailed examinations. But he should neither respiratory symptoms nor fever. He was medicated with the standard antituberculosis drugs with fluid restriction, and his tuberculo-sis and hyponatremia were improved gradually.　We should be more careful about pulmonary tuberculosis irrespective of its severity as a cause of SIADH.

Key words : Pulmonary tuberculosis, Syndrome of inappro-priate secretion of antidiuretic hormone (SIADH), Hypo-natremia

1Department of Respiratory Medicine, National Kanazawa Wakamatsu Hospital, 2Department of Geriatric Medicine, Kanazawa Medical University, 3Department of Respiratory Medicine, Kanazawa University School of Medicine

Correspondence to : Yoriko Nishizawa, Department of Respi-ratory Medicine, National Kanazawa Wakamatsu Hospital, Se 103-1, Wakamatsu-machi, Kanazawa-shi, Ishikawa 920_1183, Japan. (E-mail : nisizawa＠wakamatu.hosp.go.jp)

－－－－－－－－ Case Report－－－－－－－－

A CASE OF PULMONARY TUBERCULOSIS INITIALLY PRESENTED WITHSYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (SIADH)

1Yoriko NISHIZAWA, 1Chihiro YAMAMORI, 2Yukiharu NISHIMURA, 2Kunimitsu IWAI, 2Kouya OKAISHI, 2Shigeto MORIMOTO,

2Masayuki MATSUMOTO, 3Masahide YASUI, and 3Masaki FUJIMURA

34 35

らない種々の課題が山積みしていることを示しており，

今後の研究の進展に期待したい。

　CAMを分与頂いた大正製薬に深謝します。

文　　　献

1） Tomioka H : Prospects for development of new antimyco-bacterial drugs. J Infect Chemother. 2000 ; 6 : 8_20.

2） Cole ST, Brosch R, Parkhill J, et al. : Deciphering the biolo-gy of Mycobacterium tuberculosis from the complete ge-nome sequence. Nature. 1998 ; 393 : 537_544.

3） 冨岡治明：肺結核，細菌学の進歩. カレントテラピー. 2000 ; 18 : 22_27.

4） Glickman MS, Jacobs WR: Microbial pathogenesis of My-cobacterium tuberculosis : dawn of a discipline. Cell. 2001; 104 : 477_485.

5） Harth G, Zamecnik PC, Tang JY, et al. : Treatment of My-cobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-L-glutamate/glutamine cell

wall structure, and bacterial replication. Proc Natl Acad Sci USA. 2000 ; 97 : 418_423.

6） Hingley-Wilson SM, Sly LM, Reiner NE, et al. : The immu-nology of the mycobacterial infected macrophage. Mod Asp Immunobiol. 2000 ; 1 : 96_101.

7） 冨岡治明：非結核性抗酸菌の細菌学と感染宿主応答.「結核」，光山正雄編，医薬ジャーナル社，東京，2001, 322_333.

8） Sherman DR, Sabo PJ, Hickey MJ, et al. : Disparate responses to oxidative stress in saprophytic and pathogenic mycobacteria. Proc Natl Acad Sci USA. 1995 ; 92 : 6625_

6629.9） Wilson T, de Lisle GW, Marcinkeviciene JA, et al. :

Antisense RNA to ahpC, an oxidative stress defence gene involved in isoniazid resistance, indicates that AhpC of Mycobacterium bovis has virulence properties. Microbiol-ogy. 1998 ; 144 : 2687_2695.

10） Bryk R, Lima CD, Erdjument-Bromage H, et al. : Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 ; 295 : 1073_1077.

Effects of AsDNAs against oxyR and ahpC /T. Shimizu et al. 35

Abstract　There has not yet been systematic studies which attempt to elucidate detailed profiles of the interaction be-tween antimicrobial drugs and macrophage microbicidal mechanisms. We examined the effects of antisense oligo DNAs (AsDNAs) against oxyR and ahpC on the susceptibility of Mycobacterium avium complex (MAC) to the H2O2-halogenation system and combined antimycobacterial drugs 〔clarithromycin (CAM) ＋ rifampicin (RFP) 〕, both separate-ly and in combination. It was found that AsDNA treatment of MAC did not affect the susceptibility of the organisms to any of the antimicrobial systems tested. Since the present AsDNAs did not efficiently reduce the expression of AhpC mRNA, attempts to increase bacterial uptake of AsDNAs are

necessary to achieve significant increase in the drug suscepti-bility of MAC organisms due to AsDNA treatment.

Key words : Mycobacterium avium complex, Antisense oligo DNA, H2O2-halogenation system, Clarithromycin, Rifampicin

1Department of Microbiology and Immunology and 2Depart-ment of Otorhinolaryngology, Shimane Medical University

Correspondence to : Haruaki Tomioka, Department of Micro-biology and Immunology, Shimane Medical University, 89_1, Enya-cho, Izumo-shi, Shimane 693_8501 Japan. (E-mail :tomioka＠shimane-med.ac.jp)

－－－－－－－－ Short Report－－－－－－－－

EFFECTS OF ANTISENSE OLIGO DNA ON THE ANTIMICROBIAL ACTIVITY OFREACTIVE OXYGEN INTERMEDIATES AND ANTIMYCOBACTERIAL AGENTS

AGAINST MYCOBACTERIUM AVIUM COMPLEX

1Toshiaki SHIMIZU, 1Katsumasa SATO, 1Chiaki SANO, 1,2Keisuke SANO, and 1Haruaki TOMIOKA

44

Abstract　The unprecedented and rapid changes at the global level posed a big challenge to public health. The tuberculosis disease as one of major health problems today should be viewed from this context. These global challenges include 1) population issue particularly on growth and ageing ; 2) epide-miological issue such as health transition ; and, 3) social and environmental issues such as rapid urbanization and global warming. Furthermore, we should also take into account other changes such as the role of the government in the health ser-vice delivery, clinical or cure-oriented approach to prevention, increasing consumer demand and health financing.　The burden of tuberculosis is devastating. Everyday in the Western Pacific Region (WPR), about 1000 people lose their life due to tuberculosis. Most of them are between the ages 14_54, which are the so-called economically productive age group. The economic impact, therefore, is significant. In ad-dition TB is a disease of poverty of which the risk of getting TB is higer in poor who have less access to TB services due to

financial barrier and lack of knowledge. Despite this devastat-ing situation, TB has a significant and cost effective tool called DOTS. WPRO put highest priority in TB control pro-gramme not only because of the facts mentioned above but I also consider TB as an agenda carried over from the last cen-tury. I would like, then, to commit myself to this cause for the betterment of the future of the next generation.

Key words : Tuberculosis Control, Western Pacific Region, DOTS strategy

Regional Office for the Western Pacific Region, World Health Organization

Correspondence to : Shigeru Omi, Regional Office for the Western Pacific Region, World Health Organization, United Nations Avenue, P.O. Box 2932, 1000 Manila, Philippines.

結核 第78巻 第 1号 2003年 1月

－－－－－－－－ The 77th Annual Meeting Invited Lecture－－－－－－－－

TUBERCULOSIS CONTROL STRATEGY IN ASIA FOR THE 21ST CENTURY─ Tuberculosis Control in the Western Pacific Region of World Health Organization─

Shigeru OMI

44

48 49

Abstract　The number of people infected with human immu-nodeficiency virus (HIV) is gradually increasing in Japan, and the morbidity rate from tuberculosis in the Japanese people is high. Accordingly, the number of cases with both infections is considered to increase in the future. Our hospital has already encountered 31 cases of HIV associated tuberculosis. 　HIV infects mainly CD4-positive cells. The extreme de-crease in the cell count results in serious cellular immunologi-cal disorder. CD4-positive cell disorder induces disorders of B lymphocytes, cytotoxic T cells, natural killer cells, and macro-phage functions. These destructive conditions show the state of immunodeficiency including macrophage that are most im-portant for defense of acid-fast bacterial infection. Migration and activation of macrophages with cytokines derived from T cells are impaired to induce the following phenomena: hypo-plasia of granuloma, failure of tubercule bacillus suppression, the spread to regional lymph nodes (hilar or mediastinal lymph nodes), and hematogenous dissemination. On this oc-casion, caseous necrosis and cavitation are unlikely to occur, and false-negative tuberculin reaction is often observed.　The incidence of severe cases, which include miliary tuber-culosis, tuberculous meningitis, etc., and extrapulmonary tu-berculosis, are high among acquired immunodeficiency syn-drome (AIDS)- associated tuberculosis cases. HIV-infected tuberculosis cases are generally regarded as endogenous exac-erbation, but they include primary infection and reinfection as well. Even during the treatment for drug-sensitive strains par-ticularly, some cases may have reinfection with multidrug-resistant bacteria, suggesting that caution should be taken against this point. Conversely, the association of tuberculosis is a factor for the poor prognosis of HIV infection, since it facilitates the development of HIV infection. If the bacteria belong to a drug-sensitive strain, the infection with them responds well to antituberculous drugs, the same as in tuber-culosis cases without HIV infection, showing a favorable prognosis. However, the mortality rate of infection with multi-drug-resistant tuberculosis is extremely high.　The combined use of a protease inhibitor, i.e., anti-HIV drug, with rifampicin is regarded as contraindication for the treatment because rifampicin strongly induces hepatic cyto-chrome P-450 and increases the metabolism of protease inhib-itors and nonnucleoside reverse transcriptases to markedly de-crease the blood concentrations. Accordingly, the treatment

for tuberculosis should take priority over that for HIV infec-tion in HIV-infected tuberculosis, and highly active antiretro-viral therapy (HAART) may be administered after the treat-ment of tuberculosis. When HAART is necessary for the treatment during the tuberculosis treatment, rifampicin had better be exchanged to rifabutin because the effect of rifabutin to induce cytochrome P-450 is less potent than that of rifam-picin.　A report has recently shown that the exacerbation of pyrex-ia and chest X-ray findings was transiently observed approxi-mately 2 weeks after potent anti-HIV therapy for HIV- infect-ed tuberculosis, which included a protease inhibitor. The reason for the exacerbation has been believed to be that the impaired function of CD4-positive cells is improved by the administration of anti-HIV drugs to raise temporarily the reaction of the vital part to M. tuberculosis.　A tuberculin skin test (TST) reaction size of ≧5 mm of in-duration is considered positive (i.e., indicative of M. tubercu-losis infection) in persons who are infected with HIV. Persons with a TST reaction size ≧5 mm who have not previously re-ceived treatment for M. tuberculosis infection should receive tuberculosis preventive treatment. Prevention by BCG vacci-nation is regarded as contraindications for HIV-infected pa-tients, because disseminated M. bovis infection may be associ-ated with them.　Many HIV-positive patients infected with tuberculosis show uneventful healing, when M. tuberculosis is the sensitive strain. However, since some patients show the rapid course of tuberculosis, clinical physicians keep the early detection of tuberculosis for HIV-infected patients and the association of HIV infection for tuberculosis patients in their mind, respec-tively.

Key words : Tuberculosis, Human immunodeficiency virus, Acquired immunodeficiency syndrome, Protease inhibitor, Immune reconstitution syndrome

Department of Pulmonary Diseases, National Tokyo Hospital

Correspondence to : Hideaki Nagai, Department of Pulmonary Diseases, National Tokyo Hospital, 3_1_1, Takeoka, Kiyose-shi, Tokyo, 204_8585 Japan. (E-mail : hnagai＠tokyo.hosp.go.jp)

49

－－－－－－－－ The 77th Annual Meeting Educational Lecture－－－－－－－－

HIV INFECTION AND TUBERCULOSIS

Hideaki NAGAI

Educational Lecture/HIV Infection and Tuberculosis/H. Nagai

54 55

Abstract　This symposium was organized to provide the up-to-date knowledge on tuberculosis immunity, especially on the understanding of cytokines or Th1 cells involved in pathophysiology/protective immunity and vaccine develop-ment.　Dr. Kazuo Kobayashi (Osaka City Univ.) reported their findings on the immune response to bioactive lipid component from M. tuberculosis, trehalose-dimycolate (TDM) and sulfo-lipid (SL) in mice. Their unique and novel finding was that TDM is capable of inducing T-dependent immune response in euthymic mice. The specific immune response in TDM-immune mice was consisting of CD4＋ cell response and expression of chemokines, inflammatory cytokines and then TH1-related cytokines. In contrast, SL did not show such an activity. TDM may be one of the protective antigens and may modulate the specific immune response of the host.　Dr. Isamu Sugawara’s group (JATA) has examined the in-volvement of various cytokines in the host response to aero-solic infection with virulent strain of M. tuberculosis by using cytokine-knockout mice. The single deletion of IFN-γ or TNFα resulted in a severe lesion of multiple necrosis with-out granuloma, and cytokine mRNA level other than knocked out cytokine was normal, suggesting that IFN-γ and TNFα are principally important cytokines. In knockout mice for IL-12 or IL-18, necrotic lesion was not induced after infection and the pathological change was not so significant as in IFN-γ / TNFα knockout mice. By using IFN-γ knockout mice, it became possible to generate a granulomatous lesion with central necrosis and cavity resembling the lesion in humans. These mouse model appeared to be useful in the analysis of pathophysiology of human tuberculosis.　Dr. Kazuyoshi Kawakami (Ryukyu Univ.) reported the im-portance of TH1 cytokines in anti-tuberculous immunity. By using IL-12，IL-18 knockout mice or double knockout mice, it was shown that IL-12 exhibits more important role than IL-18 in the protection. A possible contribution of IL-23 was also suggested. In most of the clinical cases of tuberculosis, the production of IL-12, IL-18 and IFN-γ is increased, how-ever, the group of relatively lower cytokine production did not respond well to the treatment. In addition, the plasma lev-el of one of the chemokines, IP-10, was shown to be an indi-cator for the severity of the disease. Thus, some cytokines

appear to be employable for the novel treatment in the near future.　Dr. Saburo Yamamoto (NIH) summarized the recent ad-vance in the understanding of biological function of CpG motifs. Immunostimulatory DNA is effective in the modula-tion of TH1/TH2 polarity and the enhancement of protective immunity to M. tuberulosis in animals. CpG motif (immuno-stimulatory DNA) appears to exert its activity by signaling cascade via TLR9 resulting in NF-κB activation and cytokine gene expression. Analysis of basic mechanism of action by CpG motif should pave the way to the clinical application in the future.　Dr. Masaji Okada (Kinki Chuo Hospital) reported the cur-rent situation in the development of novel vaccines against tuberculosis. They have extensively constructed and exam-ined the efficacy of various types of vaccines including sub-unit, DNA and recombinant BCG vaccines. Various vector systems have been tested for DNA vaccine. As immunizing antigens, a-Ag, ESAT-6, HSP65, 38kD-lipoprotein and so on have been employed. A large body of experimental data are accumulating for final evaluation, and among them, it is note-worthy to mention that HSP65DNA+IL-12DNA was 100 times more effective than conventional BCG in animal model. Among subunit vaccines, Mtb72f vaccine appears to be one of the promising candidates. In addition to the trial with various candidates, they have established a new mouse model, SCID/human PBL. This model animal has been employed for the development of vaccine effective for the induction of ESAT-6-specific human T cells.

Key words : Anti-tuberculous immunity, TH1, Cytokine, Vaccine

1Department of Microbiology, Kyoto University Graduate School of Medicine, 2Department of Immunology, National Institute of Infectious Diseases

Correspondence to : Masao Mitsuyama, Department of Mi-crobiology, Kyoto University Graduate School of Medicine, Yoshida-Konoecho, Sakyo-ku, Kyoto-shi, Kyoto 606_8501 Japan. (E-mail : mituyama＠mb.med.kyoto-u.ac.jp)

55

－－－－－－－－ The 77th Annual Meeting Symposium－－－－－－－－

UP-TO-DATE UNDERSTANDING OF TUBERCULOSIS IMMUNITY

Chairpersons : 1Masao MITSUYAMA and 2Kiyoko AKAGAWA

Symposium/Anti-Tuberculous Immunity

58 59

ち寄り，記入漏れのチェック，服薬支援困難な事例には

お互いに助言をし，支援のポイントや工夫などの共有化

を図っている。さらにコホート観察簿に服薬支援のポイ

ントを加え，初回面接時，各月ごとに要点を明確にし服

薬手帳を活用するなど均等化して質の高い患者支援を試

みている。

　 4 . 白井千香医師（神戸市保健所）は，行政は治療の

徹底と治療成績の判定を行い結核対策を評価する必要が

あると述べた。神戸市の目標を治療成功率85%・中断と

失敗合わせて 5%未満・本人面接 2週以内90%・菌所見

の把握（培養・同定・感受性）100%・接触者健診100%

に設定し，「コホート検討会」を積極的に実施した。治

療成績の改善について，平成 3～ 8年の中断率と失敗率

は11%であったが，平成12年には 4%に減少し改善が

見られたと報告した。

　今後の課題として，①発生動向調査上のコホート観察

との連動，②服薬支援の強化（DOTS），③記録の効率化，

④医療機関への標準治療の徹底，⑤患者支援における関

係機関の連携，⑥結核診査協議会の機能強化，⑦医療機

関との連携，などについてさらに改善を要すると強調さ

れた。

　 5 . 追加発言①で，木村もりよ医師（結核研究所）が

わが国における DOTSの費用対効果分析を大阪市住所不

定者を 1モデル集団として解析し，1993年より1995年

までに登録された，あいりん地区の塗抹陽性新登録患者

529名を非 DOTS群とし，2000年に登録された大阪市の

住所不定者（DOTS実施）で，塗抹陽性新登録患者209名

を DOTS群として，費用対効果分析を行った。結果，非

DOTS群の治療失敗中断率は25.7%に比し，DOTS群は

4.8%と低下している。費用対効果を見ると，非 DOTS

群は 2305万円 /QALY/人で，DOTS群は 113万 7000円

/QALT/人と，DOTS群がはるかに費用対効果が良い。

効果については，非 DOTS群が0.84（QALY）で，DOTS

群が0.93（QALY）と DOTS群が優れているが，2者の

費用対効果比の差は主に経費の差からきている。つまり

DOTSを導入することによって 1人あたり年額90万円，

209人全体で約 1億8810万円の経費を節約することがで

きたといえる。一方 DOTSの費用が 1人約240万円を超

えると費用対効果はなくなる。

　しかしこの結果をもたらしたのは，大阪市の取り組み

である住所不定者に対する DOTS事業が病院と保健所，

福祉の密なる連携のもとに患者の住居確保などの働きが

あったからであり，その意義は大きい。今後わが国の結

核対策は DOTSを徹底し，DOTSによって節約された費

用を社会下層構造の改善に寄与させるべきである，との

発表は印象深いものがあった。

　 6 . 追加発言②は，黒須功医師（国立療養所兵庫中央

病院）から，当院での院内 DOTS実施について報告があ

り，患者間での不平等をなくし，「DOTSは標準治療で

ある」ことを強調し直接服薬することを確認することに

患者全員の理解を得ることが重要であると発表があっ

た。また，入院早期より患者との信頼関係を作る必要が

あり，看護師は患者との信頼を深める努力が必要である。

また，患者情報を提供し保健師，看護師，福祉との連携

が必要。保健師・看護師連絡会や DOTSカンファレンス，

コホート検討会など定期的な会を持つことが DOTS成功

の鍵と思われる，と院内 DOTSの重要性について述べら

れた。

58

Abstract　The most important aim of tuberculosis control is to increase treatment success rates. Therefore, it is necessary to prevent unfavourable outcomes and multi-drug resistant tu-berculosis to achieve the goal. Our national average figure of tuberculosis success rates between 1991 and 1996 has been 79.9 percent, which did not reach the WHO recommended success rate of 85 percent. The geographical discrepancy be-came bigger by years and the high death rate among the elder-ly owes very much the low success rates. There are two major factors that contribute the relatively low success rates in Japan. One factor is age and another is high incidence rate in urban area. Our previous study showed that 30.2 percent of

the total tuberculosis patients were over 70 of age with the higher death rate and lower success rate than those younger than 70. High default rates in urban area have greatly contrib-uted to the low success rates. There was huge difference of highest success rate and lowest one, 86.7 and 53.4 percent, respectively.　Lively discussion towards tuberculosis elimination was done in this symposium. The major topics were unique re-gional activities and cost-effective analysis of DOTS in urban setting.

　1. Hospital DOTS was presented by Ms. Yukiko Saito,

－－－－－－－－ The 77th Annual Meeting Symposium－－－－－－－－

TOWARDS SUCCESS OF TUBERCULOSIS TREATMENT

Chairpersons : 1Toyoo SAKURAYAMA and 2Takeko YAMASHITA

結核 第78巻 第 1号 2003年 1月

58 59

59Symposium/Towards Success of TB Treatment

RN. She shared the experience of her DOTS practice and evaluation method of hospital DOTS in the Fukujuji hospital. Their questionnaire results showed that DOTS group had low-er percentage of imperfect pill taking and indicated the impor-tance of hospital DOTS for the smooth transition to outpatient DOTS.　2. Ms. Kazuyo Arima, RN presented her health center DOTS strategy (Fureai DOTS) in Osaka city. Osaka city has the highest tuberculosis incidence rate that is equivalent to that of Nepal due to the high incidence among street persons. Tuberculosis control has been the city’s rolling cry. The com-ponents of Osaka tuberculosis control are ; (1) indiscriminate DOTS for street people and smear positive patients (Airin DOTS and Fureai DOTS) and (2) the patients follow up meet-ing (Cohort Kaigi). The number of health care providers who adopted DOTS has been increasing because of their active campaign of DOTS. This also stimulates the motivation of public health nurse to involve tuberculosis control.　3. The patient management using follow up chart (Cohort Kansatsubo) was presented by Ms. Yoko Nagata, RN in Itabashi Ward Health Center. The results of follow-up obser-vation in 2000 revealed low success rate (72.3 percent), high proportion of bacteriological non-confirmation, and low pub-lic health nurse involvement rate. These figures ameliorated in accordance with the introduction of their unique follow-up method. The better outcome may be because of better collabo-ration among public health nurses according to Ms. Nagata. Their next ambition is to establish the standardized care for tuberculosis patients throughout the Itabashi ward.　4. The endeavour of Kobe city was presented by Dr. Chika Shirai, MD. Kobe city set up their goals by conducting follow up meeting (Cohort Kentoukai) ; 85 percent of success rate, less than 5 percent of default and failure, 90 percent of pa-tients with the public health nurse encounter, 100 percent in bacteriological confirmation and indiscriminate contact inves-tigation. The default/failure rates reduced from 11 to 4 per- cent. She also emphasized on the prospective plan, e.g., com-bination of their cohort based follow up chart and tuberculosis surveillance system, DOTS, reporting and recording system up date, expansion of standardized tuberculosis treatment, col-laboration with other organization for patients follow-up, and

integration of tuberculosis diagnosis committee.　5. The cost-effectiveness analysis of Japanese DOTS among homeless persons in Osaka city was presented by Dr. Moriyo Kimura, MD in the Research Institute of Tuberculo-sis. The results showed that DOTS was more cost-effective than non DOTS mainly due to low default rate and short hos-pitalization. However, the success of DOTS is not simply be-cause of implementation of DOTS strategy but the person to person relationship between public health nurses and tubercu-losis patients is the most important issue. In other words, DOTS would be highly cost-effective only if public health nurse involvement existed. This presentation also suggests that DOTS in slum area may reduce the burdens of poverty that is an important factor of tuberculosis.　6. Final presenter, Dr. Isao Kurosu, MD, shared his experi-ence in his hospital. He emphasized the importance of DOTS implementation as the standardized treatment. The most im-portant point for the DOTS introduction is that each patient understands that DOTS equalizes patients opportunities and confirms their pull taking, according to him. His presentation was concluded with that the collaboration with other health personnel such as nurses and public health nurses should be the key for the success of hospital DOTS.

　In summary, DOTS is an important and highly cost-effec-tive strategy for tuberculosis control in Japan. The establish-ment of human relationship between patients and health care providers is the key issue. Doctors should collaborate with other health personnel to make the Japanese DOTS success-ful.

Key words : Hospital DOTS, Outpatient DOTS, Cohort chart, Cohort meeting, Cost-effective analysis

1Director, Hachioji Public Health Center, 2Head, Department of Program Support, Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association

Correspondence to : Toyoo Sakurayama, Director, Hachioji Public Health Center, 13_18, Asahicho, Hachioji-shi, Tokyo 192_0083 Japan.