(Vol.76. No.1 January 2001)

<1>
Kekkaku Vol.76, No.1: 1-8, 2001

THE CAUSES OF DEATH IN PATIENTS WITH NON-MDR PULMONARY 
TUBERCULOSIS IN OUR HOSPITAL 

*Naohiro NAGAYAMA, Kimihiko MASUDA, Wakana TAKADA, Motoo BABA, 
Akihiro HORI, Atsuhisa TAMURA, Hideaki NAGAI, Shinobu AKAGAWA, 
Yoshiko KAWABE, Kazuko MACHIDA, and Atsuyuki KURASHIMA 

*Department of Respiratory Disease, Tokyo National Chest Hospital 

  We studied the causes of death in 295 patients (mean (}SD) age 70.5}13.2 y.o.) with 
active non-MDR pulmonary tuberculosis who died in our hospital between 1991 and 1999.
A hundred and twenty eight patients (43.4%, group A) died of tuberculosis, while 167 
patients (56.6%) of other accompanying diseases. In 46 patients of the latter (15.6%, 
group B), pulmonary tuberculosis gave an unfavorable impact on their clinical course. In 
these patients the extent of pulmonary tuberculosis on chest roentgenograph was similar 
with the remaining 121 patients who also died of the accompanying diseases (41.0%, 
group C) and was less severe than those of the group A patients. Their nutritional 
conditions measured by serum albumin and choline-esterase level on admission, however, 
were as low as those of the group A patients and distinctly worse than those of the 
group C patients. Most patients of groups A and B died within 3 months after admission, 
while less than half patients of group C died during the same period. The age frequency 
distribution of the patients in groups B and C had a single peak in the age group 70 to 
89, while that in group A showed two peaks, one similar peak as in groups B and C, and 
another peak in the age group 50 to 59. The numbers of homeless patients, of the 
patients with extensive cavitary lesions, and of the patients who died of ARDS (Adult 
Respiratory Distress Syndrome) or severe pneumothorax in group A were the most also 
in the age group 50 to 59, indicating that the patients' delay in admitting to hospitals 
was the major cause of high motality in this age group. 
  As to detailed causes of death in group A, patients died of respiratory failure (32 
cases), emaciation (28 cases), progression of pulmonary tuberculosis (20 cases), ARDS 
(15 cases), tuberculosis-related diseases such as pneumothorax, hemoptysis, and DIC (24 
cases). In groups B and C patients died of organ failure (36 cases), infectious diseases 
(33 cases) and malignancy (30 cases). The total number of died patients has increased, 
and the proportion of cases dying of ARDS and infectious diseases has increased statisti- 
cally significantly recently. 

Key words :Tuberculous death, Non-tuberculous death, ARDS, Frequency distribution 
of age, Temporal change 

* 3-1-1, Takeoka, Kiyose-shi, Tokyo 204-8585 Japan. 
(Received 14 Jul. 2000/Accepted 11 Oct. 2000)





<2>
Kekkaku Vol.76, No.1: 9-18, 2001

USEFULNESS OF SELF LIGATION MEDIATED POLYMERASE CHAIN 
REACTION:A RAPID METHOD FOR FINGERPRINTING IN MOLECULAR 
EPIDEMIOLOGY OF TUBERCULOSIS 

1Amin RUHUL, 2*Yasuhiko SUZUKI, 3Toshio TAKATORIGE, 3Kozo TATARA, 
and 1Ryota SHIRAKURA 

1Division of Organ Transplantation, Biomedical Research Center, 
Osaka University Graduate School of Medicine, 
2*Department of Pathology, Osaka Prefectural Institute of Public Health, 
3Department of Social and Environmental Medicine, 
Osaka University Graduate School of Medicine 

  Restriction fragment length polymorphism (RFLP) analysis based on the insertion 
sequence IS6110 has been used as one of the powerful tools for epidemiological study of 
tuberculosis. However this technique requires more than 1 micro-gram of DNA and two 
days for completion. To overcome these inconvenience, we have modified a PCR-based 
method, self ligation mediated PCR (SL-PCR) on the molecular epidemiological study. 
This method uses a pair of primers whose orientations are from inside to outside of 
IS6110. The DNA fragments flanking IS6110 are amplified by the PCR by using the 
Sau3A I digested and ligated chromosomal DNA of Mycobacterum tuberculosis strains. 
By using this method, M.tuberculosis strains can be differentiated within 8 hours. 

Key words :Mycobacterium tuberculosis,
RFLP, SL-PCR, Molecular epidemiology 

*1-3-69, Nakamichi, Higashinari-ku, Osaka-shi, Osaka 
537-0025 Japan. 
(Received 26 Jul. 2000/Accepted 30 Oct. 2000)






<3>
Kekkaku Vol.76, No.1: 19-27, 2001

A STUDY ON CHEST RADIOGRAPHS IN MEDICAL CHECK-UPS 
FOR OVER-STAYING FOREIGNERS 

*Jumpei YAMAMURA 

*Minatomachi Medical Center 

  During the past nine years from 1991 to 1999, Minatomachi Medical Center and other 
organizations have provided free medical check-ups for foreigners in Kanagawa, Tokyo 
and Chiba. Eighty-five percent of the total of the 2370 examined were over-staying 
foreigners who were not covered by national health insurance system. The ratio of male 
to female was two to one and the most of them were in the twenties and thirties. As for 
their ethnic origins from forty-three countries, the Filipinos were the largest numbers, 
followed by Koreans, Iranians, Bangladeshi, and Chinese/Taiwanese. 
  As a result of chest radiographs, 82% were normal, 8.3% mostly normal, 9.6% tuber- 
culosis shadow (TBS) including active, non active and previous, 0.09% suspected pneumo- 
nia, 0.05% suspected cardiac disease, and 0.05% suspected sarcoidosis. 
  The TBS and active tuberculosis (ATB) rates of all examined were 9.6% and 0.69% 
respectively. There was no significant difference in each TBS and ATB rate between the 
two sexes. Seen from the age group, it was found that the more aged they were, the 
higher the TBS and the ATB rates were. The TBS and the ATB rates were 24.6% and 2.73 
% in the Koreans, 10.7% and 0% in the Chinese/Taiwanese, 10.2% and 0.65% in the 
Filipinos, 11.3% and 1.44% in the South-East Asians, 6.3% and 0.25% in the South 
Asians, 2.3% and 0% in the Iranians, 3.7% and 0% in the sub-Saharan Africans, 8.5% 
and 0.61% in the Latin Americans, and 0% in the Europeans/North Americans. 
  Based on a presumed ATB rate of 0.75%, approximately two thousand cases with ATB 
could be calculated to exist among the estimated 270000 over-staying foreigners. It is, 
therefore, important to give them more frequent medical check-ups for early detection of 
latent cases with ATB. 

Key words :Tuberculosis, Over-staying foreigners, Free 
medical check-ups, Chest radiograph 

*7-6, Kinko-cho, Kanagawa-ku, Yokohama-shi, Kana- 
gawa 221-0056 Japan. 
(Received 19 Jul. 2000/Accepted 15 Nov. 2000) 






<4>
Kekkaku Vol.76, No.1: 29-31, 2001

IN VITRO ANTIMYCOBACTERIAL ACTIVITIES OF A NEW 
QUINOLONE, BALOFLOXACIN 

1*Shin KAWAHARA, 1Atsuhiko TADA, and 2Hitoshi NAGARE 

1*Department of Internal Medicine, National Minami-Okayama Hospital, 
2Department of Clinical Laboratory, National Minami-Okayama Hospital 

  Balofloxacin (BLFX), a newly developed fluoroquinolone, was studied for its in vitro 
antimycobacterial activity by the agar dilution method with 7H11 agar medium. The 
MIC(90)s were as follows:0.39ƒĘg/ml for M.tuberculosis, >50ƒĘg/ml for M.avium, >50 
ƒĘg/ml for M.intracellulare, 0.39ƒĘg/ml for M.kansasii, 0.39ƒĘg/ml for M.fortuitum, > 
50ƒĘg/ml for M.abscessus, and 50ƒĘg/ml for M.chelonae, The antimycobacterial activity 
of BLFX was comparable or slightly inferior to that of levofloxacin (LVFX). Considering 
the present findings and pharmacokinetics of BFLX, it appears that BFLX may achieve 
favorable outcome in the treatment of patients with infection due to M.tuberculosis, M. 
kansasii, or M.fortuitum similar to that of ofloxacin or LVFX.

Key words : New quinolones, Balofloxacin, 
In vitro antimycobacterial activity, Various mycobacteria 

* 4066, Hayashima, Hayashima-cho, Tsukubo-gun, 
Okayama 701-0304 Japan. 
(Received 31 Aug. 2000/Accepted 7 Nov. 2000) 






<5>
Kekkaku Vol.76, No.1: 33-43, 2001

The 75th Annual Meeting Lunch-Time Seminar 

EFFECTIVENESS AND PROBLEMS OF PZA-CONTAINING 6-MONTH REGIMEN 
FOR THE TREATMENT OF NEW PULMONARY TUBERCULOSIS PATIENTS 

*Masako WADA 

*Department of Applied Research, The Research Institute of Tuberculosis, 
Japan Anti-Tuberculosis Association 
  
  One third of the world population has been infected with Mycobacterium tuberculosis, 
and the number of tuberculosis will increase worldwide without more effective programs 
of tuberculosis control. Despite of the presence of very potent anti-tuberculosis drugs the 
global tuberculosis situation is still very serious, and such gloomy feature are caused, at 
least partly, by the failures in the treatment of tuberculosis. The most important factor 
for the failure in chemotherapy is incompliance of the patients to the regimens. History 
of the chemotherapy of tuberculosis can be said as the history of the efforts to reduce 
such defaulters. 
  Modern chemotherapy of tuberculosis has started from the discovery of streptomycin. 
Streptomycin monotherapy could improve temporally symptoms and bacteriological 
status, but could not cure the patients with moderately advanced pulmonary tuberculosis 
because of the emerge of drug-resistant tuberculosis. This problem was overcome by com- 
bining use of para-aminosalicylate and/or isoniazid developed later on. About 97% of 
patients with pulmonary tuberuclosis became bacteriologically quiescent by the 12 months 
of streptomycin, para-aminosalicylate and isoniazid. Since 1950s through 1970s three 
drug combination of streptomycin, para-aminosalicylate and isoniazid had been the stan- 
dard regimen for the treatment of tuberculosis. By the introduction of rifampicin, the 
duration of chemotherapy could be shortened to 9 months. 
  Subsequent to the successful animal experiments carried out by Grosset which demon- 
strated that the addition of pyrazinamide for initial 2 months to the standard two-drug 
combination (isoniazid and rifampicin) could remarkably shorten the duration of chemo-
therapy, many clinical trials have been done all over the world to compare the efficacy 
and safety of pyrazinamide-containing intensified short-course regimen with those of 
standard regimen without pyrazinamide. Sputum negative conversion rates after 2 months 
of treatment with PZA-regimen was 70`95%, and the relapse rates after the completion 
of the treatment course were less than 4%, The incidence of adverse events was less than 
4%. The pyrazinamide-containing 6 months short-course regimens has been established 
as a new standard regimen for the initial treatment of pulmonary tuberculosis world- 
wide. 
  But, in Japan, this regimen had not been adapted as the standard untill April 1996 
because of undue fear for high incidence of liver toxicity induced by pyrazinamide. How- 
ever, in many clinical trials carried out in various parts of the world did not show any 
causative relationship between the higher incidence of liver toxicity and pyrazinamide. 
According to our own experience in Fukujuji Hospital, Japan Anti- tuberculosis Associa- 
tion, the frequency of drug induced hepatitis among 632 patients with normal liver func- 
tion at the onset of chemotherapy was 7.9 percent (50/632) when treated with 
pyrazinamide-containing regimens, and was similar to that among 412 patients treated 
with other regimens without pyrazinamide (7.3 percent 30/412). These figures were higher 
than tohse reported in the literatures. The risk factors of drug-induced hepatitis so far 
reported included elderly, positive hepatitis C virus antibody, low serum albumin and so 
on. Such known risk factors could not wholly explain the higher rate of liver dysfunction 
observed among our Japanese patients. We have examined additional factors affecting 
the frequency of drug-induced hepatitis in our hospital, and noticed that the past history 
of gastrectomy and over-dosing of isoniazid (†7.5mg/kg) and/or pyrazinamide (†30mg) 
were relating to the higher incidence of drug-induced hepatitis. Another important find- 
ing is that the relapse rate among patients complicated with diabetes mellitus is signifi- 
cantly higher than that of the patients without diabetes mellitus (6.31/100 person-years 
vs 0.90/100 person-years, Pƒ0.001). Further research will need whether the patients com- 
plicated with diabetes mellitus have any immunological deficient to kill Mycobacterium 
tuberculosis. 
  WHO, CDC and ATS recommended that 4-drug regimen including pyrazinamide for the 
initial treatment of all cases of tuberculosis. Considering that the incidence of initial 
resistance to isoniazid is 4.4% in Japan, we should start to treat all cases of newly 
diagnosed tuberculosis with pyrazinamide-containing regimen (isoniazid, rifampicin, 
pyrazinamide, plus streptomycin or ethambutol). To do this, further studies on the risk 
factors of drug-induced hepatitis are urgently needed. 

Key words :Pulmonary tuberculosis, Short-
course chemotherapy, Pyrazinamide, Drug- 
induced hepatitis 
  
*3-1-24, Matsuyama, Kiyose-shi, Tokyo 204-8533 
Japan. 
(Received 19 Oct. 2000)