Waning of the specific interferon-gamma response after years of tuberculosis infection.

HYPOTHESIS: Memory T-cell responses to specific antigens wane over time in subjects with tuberculosis (TB) infection. SETTING: Accumulated evidence indicates that QuantiFERON-TB Gold (QFT-G), a specific whole-blood interferon-gamma (IFN-gamma) based assay, can detect recent TB infections with superior sensitivity and specificity. OBJECTIVE: We applied this technique to the adult population of a Japanese community to determine its epidemiological usefulness. METHOD: A total of 1559 subjects attending periodic health screening volunteered to participate in the study. RESULTS: The QFT-G positive rates were 3.1% for those aged 40-49 years, 5.9% for those aged 50-59 and 9.8% for those aged 60-69. The expected infection prevalence estimated by the authors from a series of studies was 11.1%, 29.6% and 53.1% for those aged 40-49, 50-59 and 60-69 years, respectively. This wide gap between the expected and observed positivity suggests that the IFN-gamma response waned substantially with time after infection. Those with X-rays suggestive of old TB lesions exhibited positivity rates well below 100%. CONCLUSION: The specific IFN-gamma response may wane considerably with time after infection. Longitudinal studies are required to investigate long-term dynamics of cell-mediated immunity in infected donors.

[Fifty years of research on tuberculosis. Lessons I have learnt during 50 years and topics to be investigated in the future].

I have engaged in the research on tuberculosis for 50 years, and lessons I have learnt during this period could be summarized in the following ten topics. First is great research achievements by our predecessors on the establishment of so-called primary infection theory on the pathogenesis of TB, planning of TB control principles based on the theory and development of new technologies used for TB control, such as mass miniature X-ray examination and BCG vaccination in 1920s and 1930s. TB control law was enforced in 1951, and the modern TB programme was initiated. Second, the field is a treasure house of interesting data. Several interesting data on TB soon after the World War II in Tokyo and a rural area were collected and analyzed from the mass health examination. Third, looking at the increase of tuberculin positivity with age, it was found that the tuberculin negativity decreased as the exponential function of age, and the current concept of the annual risk of TB infection was already developed in late 1940s. It was 18.1% in male and 11.6% in female in Tokyo in late 1940s. Based on this concept, age specific TB mortality was analyzed by the type of TB, and the rates of miliary TB and TB meningitis were similar to the rate of newly infected to the total population, while the rate of all forms could be divided into early and late death as shown in Fig. 1. Fourth, I suffered from TB by myself from 1951 to 1953, receiving first thoracoplasty in two stages under local anaesthesia, then right upper lobectomy and segmentectomy of superior segment of right lower lobe. From this experience, I learnt a lot about the psychology and suffering of TB patients. Fifth, the importance of recognition of real magnitude of the problem in such a disease as TB in which many TB cases did not aware of their disease. The answer to this was the first TB prevalence survey in 1953 using stratified random sampling method, and based on the results of the survey, the mass health examination originally focussed on youth was expanded to the total adult population of Japan. Sixth, TB could be reduced rapidly by applying appropriately planned control programme. In big enterprises, the application of intensive case-finding programme brought about the rapid decline of severe TB cases, contributed to the increase of the productivity of the enterprises, thus to the rapid increase of GDP of whole Japan, and the growing spiral between the improvement of health and the economic development was formed by successful TB control. In addition to the mass health examination, BCG vaccination and spread of appropriate treatment in the original TB control law, the registration and case management system and the more extensive application of hospitalization for infectious cases were introduced in early 1960s. Observing the proportion of TB care expenditure to the national medical expenditure, it was 28% in 1954, and it dropped down to 0.4% in recently as shown in Fig. 2. The decline of TB in Japan during 1950s and 1960s was one of fastest in the world. Seventh, there had been marked differences in the prevalence of TB as well as the coverage and quality of TB programmes in several areas of Japan though it was often said that Japan is homogeneous country. To know the real status in various areas of Japan, a chart to express graphically the magnitude of TB and coverage and quality of TB programmes was developed (Fig. 3), and it was finally refined to the current form. Eighth difficulty in changing existing programmes, and we are grateful for kind cooperation of Niigata Prefecture for making several new attempts. Ninth, it has been needed to observe TB problems from global standpoint, and it was actually done through participation to the bilateral cooperation projects on TB control and conducting the international training courses sponsored by JICA. Tenth, TB is a pertinacious disease. As shown in Fig. (ABSTRACT TRUNCATED)

[Global situation of TB and its control].

Tuberculosis occupies 4th place among major causes of death, and the number of new cases is estimated at 7.25 million in 1997, and 99% of TB deaths and 95% of new TB cases are seen in developing countries. TB had been brought under control in developed countries by applying modern TB control programme including chemotherapy, as basic health infrastructure was already well developed, and their economy can afford cost of control programme including TB drugs. The rapid decline of TB due to the success of TB control in developed countries had lowered the concern on TB, thus bought about the reduction in research grant for TB and difficulty in bringing up successors engaging in TB control. Similar trend was seen also in developing countries, where TB still remains one of most important health problems due to poor quality of the programme caused by poorly developed health infrastructure including man-power, budget and institutions. New obstacles which hinder the smooth implementation of TB control programme have appeared, and they are the rapid expansion of global population, the move of population, the impact of HIV epidemic on TB and the multi-drug-resistant TB (MDRTB). The growth of population automatically increases the number of TB cases and gives heavier burden for TB control. TB has moved from developing to developed countries with the move of the population, and currently approximately half of new TB cases in developed countries is occupied by foreign born patients. Among several opportunistic infections seen in AIDS cases, TB comes out first as the virulence of tubercle bacilli is much higher than the other germs causing opportunistic infections. The pathogenesis of TB changes markedly among HIV positives, and the incidence becomes much higher, and the time interval from the primary infection to the disease, and that from the detection of the disease to death without any effective treatment are shortened, and the fatality rate becomes much higher. Because of the atypical clinical picture, attenuated tuberculin sensitivity and high incidence of side-effects of TB drugs, in particular thiacetazone, clinical management of HIV positive TB is much more difficult than ordinary TB. MDRTB is produce by the bad quality of TB control, and by improving treatment completion rate as well as the cure rate, decline in the prevalence of drug resistance, both primary and acquired, could be expected together with the decline of TB itself. WHO has made a great challenge with TB after the nomination of Dr Kochi to chief medical officer, TUB in 1989. Currently, Global TB Programme (GTB) is promoting so-called DOTS strategy of TB control, consisting of the commitment of the government to give high priority to TB control, passive case-finding with sputum smear examination by microscopy, directly observed treatment by standardized short-course regimen of chemotherapy, well-organized logistics for TB drugs, and the provision of reporting and monitoring system of TB including the evaluation of treatment outcome by cohort analysis. Marked achievements have been obtained in several countries introduced DOTS strategy. Japan is asked to intensify its efforts in international cooperation in TB control.

[The first-three year report of the Tuberculosis Control Project, Lumbini, Rupandehi].

The Tuberculosis Control Project, Lumbini, Rupandehi (TCPLR) is a bilateral cooperative venture between two NGO's, the Nepal Anti-Tuberculosis Association (NATA) and the Japan Anti-Tuberculosis Association (JATA), which consists of planning and implementing pilot tuberculosis control activities in Lumbini, Rupandehi district in Nepal, aiming at achieving high cure rate of newly detected smear-positive pulmonary tuberculosis patients before introducing DOTS strategies. Between December 1993 and July 1996, 349 tuberculosis (TB) cases were enrolled in the TCPLR. The categories of cases were as follows: 138 cases (40%) of new smear-positive pulmonary TB [new Sm(+) PTB], and 54 cases (15%) of smear positive pulmonary TB other than new Sm(+) PTB [other Sm(+) PTB] including such cases as continued treatment and relapse, 106 cases (30%) of new smear-negative TB [new Sm(-) TB], and 51 cases (15%) of other smear-negative TB other than New Sm(-) PTB [other Sm(-) TB]. The number and proportion of new Sm(+) PTB cases enrolled in the project have been increasing [6 cases (23%) for the first year, 102 cases (54%) for the third year] although the proportion is still low (40% overall). The regimens of chemotherapy in the initial intensive and the continuation phases of treatment according to the categories of TB were as follows: New Sm(+) PTB; 2HRZE(S)/6HE, other Sm(+) PTB; 2HRZES/1HRZE/5HRE, and Sm(-) TB; 2HRZ/6HE. The proportion of cases treated by the appropriate regimen of chemotherapy has increased. The cohort analysis of the treatment outcome of the cases enrolled in the project showed the following. The proportion of cured cases plus smear-unconfirmed cases completing treatment among new Sm(+) PTB was 74% overall, however, the proportion of defaulters increased in the third year. The proportion of cured cases plus smear-unconfirmed cases completing treatment among other Sm(+) PTB cases was 66% overall, which is slightly lower than that of new Sm(+) PTB cases, however, the difference was not so marked. The proportion of treatment completed cases among smear-negative pulmonary TB cases was 77% overall, however, proportion of defaulters increased in the third year. The treatment outcome in this report was obtained before the adoption of DOTS strategies: However, it showed that cure and treatment completion rates were comparable to those obtained in the SEARO countries which adopt DOTS strategies. The treatment outcome could be improved after the introduction of DOTS strategies in 1997.

Disaster awaits Asia.

PIP: The World Health Organization (WHO) and the Japanese Anti-Tuberculosis Association estimate that tuberculosis (TB) will be responsible for more than 20 million premature deaths in Asia because governments worldwide have stopped fighting TB. About 66% of all TB cases in the world are in Asia. HIV infection is spreading more rapidly in Asia than anywhere else in the world. In the next 10 years, TB and AIDS will probably be responsible for the deaths of more Asians than the combined populations of the cities of Singapore, Beijing, Yokohama, and Tokyo. People with HIV infection are 30 times more likely to develop TB than people with no HIV infection. In fact, an HIV-positive person has a 10% chance of developing TB each year, while an HIV-negative person has a 10% chance of developing TB in his/her lifetime. Just breathing the same air as people infected with TB places the immuno-comprised person at risk of TB. A few weeks after beginning TB treatment, most TB patients, regardless of HIV status, are no longer contagious. Yet, governments' unwillingness to fight TB results in less than 50% of all TB cases being cured of TB. Some poor countries (Tanzania, Mozambique, China, and Peru) have invested in effective TB control programs, resulting in a cure rate as high as 90%. WHO estimates that annual expenditures geared towards HIV control in developing countries need to increase between $1500 million and $2900 million. They must increase between $100 million and $150 million for TB control activities. Yet, funding for WHO's Global Programme on AIDS is decreasing and its TB program operated on $7 million in 1994. The Japanese government provides more foreign aid to WHO's TB Programme than any other developed country. As of 1992, Japan had about 11,000 HIV-infected persons compared to about 30 million persons with TB. More than 32,000 Japanese will probably die from TB during the 1990s.^ieng

The impact of intensified supervisory activities on tuberculosis treatment.

A Health Subcentre-based randomized controlled trial was conducted in order to determine the importance of the motivation of the tuberculosis personnel in improving the results of a treatment programme. A total of 1300 newly detected tuberculosis patients from 7 Health Centres were divided into study and control groups using the Health Subcentre areas as sampling units. In the study group, worker motivation was intensified through special regular sessions and closer supervision, while in the control group the usual procedures were followed. Treatment performance was remarkably improved in the study areas: treatment completion rate was 78.8% in the study group, compared with 65.2% in the control group. Bacteriological conversions among those having completed the treatment were 91.9% and 62.2% respectively, and overall efficacy was 75.2% and 45.8%, respectively. In addition to improved treatment, the follow-up case examinations also showed markedly increased performance. Although this study was done in facilities using conventional regimens which have been replaced with short-course regimens more recently, the study results still clearly indicate the importance of motivating personnel in the field to attain better case management.

Analysis of case-finding process of tuberculosis in Korea.

A total of 630 pulmonary tuberculosis patients newly registered with the health centres in the Republic of Korea were interviewed to determine their process of case-finding. One-quarter of the cases had a previous history of tuberculosis. About 70% of these retreatment cases had been treated for less than 1 year, indicating the importance of more thorough follow-through during treatment. Almost all of the cases had at least one standard symptom, with fatigue being most frequent, followed by cough and sputum. On developing the illness, about 40% of the cases were motivated to seek medical help after seeking advice from people other than family members such as friends or health workers. Half of the patients first went to the health centre, and one-third to a private clinic. The average time between the onset of symptoms and the initial medical consultation was 1.8 months (patient's delay). This delay is longer in the rural areas; besides location no other patient characteristics had any correlation with patient's delay. Nearly 80% of all cases were diagnosed as tuberculous within the first 2 weeks. Health centres diagnosed cases faster than private clinics and thus had a shorter doctor's delay. Mean total delay (patient's delay plus doctor's delay) was 2 months, with 80% of this being patient's delay.

[Situation of tuberculosis in the world and the role expected of Japan in the global fight against tuberculosis].

The whole world is divided into 3 groups by the magnitude of tuberculosis problem: namely, developed countries in which tuberculosis is already a minor health problem and continues to decline; NIES and some oil-producing countries in which tuberculosis started to decline significantly; and most developing countries in which tuberculosis is still highly prevalent and no or only a slow decline. Number of new smear positive pulmonary tuberculosis in the whole world in a year is estimated at about 4.5 million, and adding smear negative pulmonary tuberculosis and extra-pulmonary tuberculosis, total number of new tuberculosis patients amounts to 9 to 10 million, and nearly 3 million persons die every year from tuberculosis, and 97% of these cases occur in developing countries. Failure of tuberculosis control in most developing countries could be explained by slow economic development of financial crisis, which caused poor allocation of budget for health including tuberculosis programme and slow development of primary health care. Activities of tuberculosis supervisory teams are weak. Tuberculosis programmes succeeded in developed countries could not be implemented easily in developing countries. New obstacles to the rapid decline of tuberculosis are the epidemic of AIDS, movement of population and lowering concern on tuberculosis problems, and tuberculosis will remain as one of serious global health problems at least for coming several decades. Maintenance of research and training facilities for tuberculosis is needed, however, they have been disappearing in developed countries. Facilities in developing countries might have difficulties to maintain unless financial and technical support is given from developed countries. Japan is the second biggest economic power in the world, and it is our duty to increase ODA for developing countries. In the field of health, Dr. Nakajima started to work as the director-general of WHO since 1988. We have to intensify our technical cooperation in health. As we succeeded to control tuberculosis in the past 40 years and still maintain research and training facilities for tuberculosis, they should be used for the sake of developing countries. Multi-and bi-lateral cooperation in tuberculosis control should also be intensified. The author would like to urge members of the Japanese Society for Tuberculosis to talk about the importance of tuberculosis problem and role expected to Japan in the global fight against tuberculosis to people outside the society so as to have appropriate understanding on global tuberculosis problems.