(Vol.77. No.1 January 2002) <5> Kekkaku Vol.77, No.1: 37-40, 2002 The 76th Annual Meeting Educational Lecture PULMONARY COMPLICATIONS IN PATIENTS WITH AIDS Shinichi OKA Abstract HIV infection was first reported in 1981 in USA. It has been 20 years since then. Owing to understandings of pathogenesis of this disease and development of new drugs such as the HIV-specific protease inhibitor(PI), prognosis of disease has been tremendously improved. Especially after 1997 in Japan, the strategy of anti-HIV treatment shifted from two drugs combination to three drugs comvination, which is called highly active antiretoviral therapy (HAART). HAART was so effective that prevalence of HIV associated opportunistic infections were decreased dramatically. Mortality among hospitalized HIV-infected patients was decreased from 6.7% in 1996 to 2.6% since then in ACC. However, 80% of patients receiving HAART suffered from side effects and 15% of them had to be changed their treatment due to side effects. Furthermore, an unexpected side effect, namely lipodystrophy syndrome (LDS), was emerged among patients who were receiving HAART more than one year. LDS was furst reported as re-distribution of lipid such as central obesity with or without lipo- atrophy from extremities and/or face. Now only cosmetic change, but also it is associated with elevation of lipid and glucose level. Therefore, those patients who have LDS are in face of the risk for the ischemic heart diseases. Our survey indicated that the rate of LDS in Japanese patients were almost same as that of Caucasian patients reported elsewhere. Opportunistic infections associated with HIV infection. Treatment for HIV infection consists of two major arms;one is use of anti-HIV drugs to prevent development of AIDS described above and the other is diagnosis, treatment, and prophylaxis of opportunistic infections. There are five very important ooportunistic infections;Pneumocystis carinii pneumonia (PCP), cryptococcus meningitis, toxoplasma encephalitis, cytomegalovirus(CMV) infeciton, and Mycobacterium avium complex(MAC) bacteremia. Because if these five were able to diagnose, a patient can survive under appropriate treatment. On the other hand, if these were not diagnosed, patient must be AIDS death. After introducing HAART, number of CMV retinitis, MAC bacteremia, and AIDS dementia complex were decreasing. However, number of PCP sustained high because PCP is the first indicator disease of AIDS if the patient did not know his HIV status. The first choice of drug is sulfamethoxazole/trimethoprim(ST) for PCP treatment. If the patient were in severe respiratory failure, corticosteroid is used concomitantly. Treatment is usually continued for 3 weeks. We have successfully treated 45 out of 47 cases of PCP for 4 years. However, those patients treated with ST for 3 weeks were linited only 35% because of very high rate of side effects of ST. If the patient was intolerant to ST, treatment was switched to pentamidine. After finishing the treatment, the patient is to be treated with a 5-day course of oral desensitization to ST. More than 80% of patients who were previously intolerant to ST became successfully getting tolerance by this method. Key words:AIDS, Highly active antiretoviral therapy, Pulmonary complication, Pneumocystis carinii pneumonia, Mycobacterial infection AIDS Clinical Center, International Medical Center of Japan Correspondence to:Shinichi Oka, AIDS Clinical Center, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655 Japan. (E-mail:oka@imcj.hosp.go.jp) <6> Kekkaku Vol.77, No.1: 41-45, 2002 The 76th Annual Meeting Symposium TUBERCULOSIS IN MEDICAL WORKERS Chairpersons:1Eriko SHIGETO and 2Kiminori SUZUKI Abstract In Japan there still are tuberculosis outbreaks in the hospitals and nursing homes. The incidence of tuberculosis is higher in medical workers than that in general population. In 1999, guidelines for prevention of nosocomial infection of tuberculosis were release. Since around then, many hospitals have been practicing tuberculosis infection control, but it has been pointed out that there are many problems on the practical point of view. 1. Tuberculosis infeciton control and health management of hospital workers in a general hospital:Kazuo ENDO(Okinawa Prefectural Chubu Hospital) The important factors for tuberculosis infection control are (1)early case detection, (2)proper isolation of infectious patients, (3)reliable chemotherapy, (4)health management of hospital workers. Educationof tuberculosis, especially to young doctors, is essential for early diagnosis. As airflow controlled room is available only in small number of hospitals, use of N95 respirator masks is useful. Data of two- step tuberculin skin test(TST) should be recorded as the baseline reaction to be compared with TST after contact with tuberculosis patients. I considered the contacts as infected if there was 10 mm or more increase in the diameter of indurations or 20 mm or more increase in erythema, after exposure to infectious patient. Following things are necessary for tuberculosis infection control in Japan;(1)guidelines based on evidence and scientific analysis, (2)education of medical workers, (3)regulations to protect safety of medical workers, (4)construction of surveillance systems in clinical settings, (5)staffs, time, budgets to guarantee infection control measures, (6)collaboration with public health centers. 2. Tuberculosis in medical workers and their tuberculin skin test(TST) reactiouns: Yoshiko KAWABE(National Tokyo Hospital) We conducted a questionnaire survey of tuberculosis contraction in nursing school graduates. Thirty-two tuberculosis patients were reported in 756 graduates from 1957 to 1998. They contracted tuberculosis mainly in the age of twenties. Three out of 88 BCG vaccinated after admission to nursing school and 29 out of 664 unvaccinated contracted tuberculosis. Since 1990, there were 17 tuberculosis patients from the staffs of our hospital. Mean diameter of TST of them before and after the onset were 24.8}10.1 and 42.7}15.7 mm by erythema and 10.3}7.1 and 19.9}5.4 mm by induration. I recommend criteria of being infected to be more than 20mm increase from baseline TST and more than 30mm in erythema or 15mm increase in induration. 3. The role of two-step tuberculin skin test in hospital employee and possibility of cytokines for the diagnosis of tuberculosis infection:Hidetoshi IGARI(Department of Respirology(B2), Graduate School of Medicine, Chiba University) TST in 331 medical staffs and students in Chiba University were analyzed. Diameter of erythema was 40mm or more in 93(28.1%). Second TST was done in 173 whose diameter of erythema was less than 40mm. In 78 of them, the increase of diameter of erythema was more than 10mm. Mean diameter was 20.8mm in the first test and 30.5mm in the second test. Twenty-one were BCG vaccinated and in 7 of them, Koch's phenomenon was observed. Intracellular expression of INF in peripheral lymphocytes were stronger in those with Koch's phenomenon than in those without Koch's phenomenon. Diagnosis of infection by cytokines may be possible in the future. But at present, TST is the essential tool for diagnosing infection of tuberculosis and baseline reaction should be recorded in medical workers. 4. Tuberculin skin test and BCG vaccination in staffs of national hospitals and students of attached nursing schools:Mitsunori SAKATANI(National Kinki-Chuo Hospital) We started a project to analyze the effectiveness of BCG revaccination and TST in the workers of National Hospitals and students of attached nursing schools in Kinki District. The numbers of non-reactors were 31/226(13.7%) in 1999 and 25/189(13.2%) in 2000 in newly employed nurses, 113/506 (22.3%) in 1999 and 71/486(14.6%) in 2000 in students by single TST. The numbers of non-reactors by two-step TST were 19/205(9.3%) in 1999 and 15/186(8.1%) in 2000 in nurses, 28/365 (7.7%) in 1999 and 26/379(6.9%) in 2000 in students. The number of nurses and students who were vaccinated by BCG was 43. None of them contracted tuberculosis till the end of 2000. In 2000, only one contracted tuberculosis in 4279 nurses in the National Hospitals in Kinki District. This rate was much lower than in 1999. If the rate of tuberculosis in nurses remains low, it may be hard to analyze the effectiveness of BCG vaccination but I would say that our project itself succeeded to decrease tuberuclosis from the point of education of infection control. 5. Tuberculosis infection control and medical education:Shuji KURANE(Department of Internal Medicine IV, Nippon Medical School) Now in Japan, less than 30% of medical schools have room(s) for tuberculosis patients. This lack of experience in young doctors to see tuberculosis patients may be one of the causes of doctor's delay in diagnosis and nosocomial infection of tuberculosis. In Nippon Medical School, two air-flow-controlled rooms for tuberculosis patients are available since 1998. These rooms have been very useful not only for medical practice but also for the education of medical students. In medical students, the understanding of tuberculosis as an infectious disease surveyed by questionnaire in the lectures wa very poor. The significance of experience of seeing tuberculosis in the early stage of medical education is far beyond the cost for installation and maintenance of airflow controlled room(s). There were many questions form the audience about the tuberculin skin test in medical workers. It is celar that there is only a limited evidence for usefulness of two-step TST in medical personnel in Japan almost all of whom are vaccinated with BCG. We have to continue to elaborate to find the better answer. The most important point is that the education to all the medical workers is essential for infecton control of tuberculosis. Understanding for the necessity of education to reduce nosocomial infection of tuberculosis is of great importance. Key words:Nosocomial infection, Health management, Two-step tuberculin skin test, Medical education 1Department of Respiratory Diseases, National Hiroshima Hospital, 2Chiba Branch, Japan Anti-Tuberculosis Association Correspondence to:Eriko Shigeto, Department of Respiratory Diseases, National Hiroshima Hospital, 513, Jike, Saijo-cho, Higashihiroshima-shi, Hiroshima, 739-0041 Japan. <7> Kekkaku Vol.77, No.1: 47-50, 2002 The 76th Annual Meeting Symposium EVALUATION OF STANDARDIZED TREATMENT REGIMENS FOR TUBERCULOSIS IN JAPAN Chairpersons:1Atsuyuki KURASHIMA, 2Hideo OGATA Abstract Symposium Topics and Presenters: 1. Evaluation of pyrazinamide-containing six-month short course chemotherapy in Japan: Masako WADA(Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) 2. Evaluation of pyrazinamide-containing short course chemotherapy-Analysis of discontinued and recurrent cases:Kazuko MACHIDA (Department of Internal Medicine, Tokyo National Hospital) 3. Evaluation of INH-RFP chemotherapy for Tuberculosis:Kenji KAWAKAMI(Department of Respiratory Medicine, National Kawatana Hospital) 4. Assessment of anti-tuberculosis therapy in patients with Diabetes mellitus: Katsuhiko TSUKAGUCHI et al.(Second Department of Internal Medicine, Nara Medical College) 5. Study of the duration of required treatment in the standard short course chemotherapy containing Pyrazinamide:Yasuhiro YAMAZAKI (Department of Pulmonary Medicine, National Dohoku Hospital) 6. Special Speech:Influence of the standard anti-tuberculosis chemotherapy including Pyrazinamide on liver function:Takefumi SAITO(Department of Internal Medicine, National Seiranso Hospital) No new anti-tuberculosis drugs have been introduced since the launch of RFP almost 30 years ago. The critical success factor to control tuberculosis today is reliable practive of multidrug combination chemotherapy. In 1991, the World Health Organization recommended a six-month short-course chemotherapy starting with four drugs, including PZA, as the standard treatment for tuberculosis. This treatment regimen was subsequently introduced into many countries. Drug-resistant bacilli surveillance by WHO/IUATLD has shown an inverse correlation between the level of adoption of the WHO standard regimen and the frequency of the development of drug-resistant bacilli. Japan adopted the fifth revision of its tuberculosis treatment standards in April 1996. The new standards were largely identical with those of the WHO recommendations. One year after the adoption of the fifth revision of the treatment standards, the Treatment Committee of the Japanese Society for Tuberculosis analyzed the results to date. They showed that the new short-course chemotherapy with PZA was given as the initial treatment to 38.3%. Of those 25.7% reported liver complications. The new standard course with PZA was discontinued for 33.5% of the patients in whom liver failures developed. The short-course chemotherapy with PZA is known to be superior form theoretical as well as clinical standpoints. Nonetheless, it has failed to win widespread recongnition in Japan. One of the primary reasons behind this is insufficient data on PZA-related liver failures, which in certain cases can be quite serious. TB-patient trends in Japan differ from those in the developed as well as the developing countries. In Japan, the occurrence of tuberculosis seems to fall very heavily on the elderly. Statistics for 1998 show that 56% of the new TB-patient detected in 1998 were over 60 years old. This also means that a standard safe and certain chemotherapy for elderly patints must be developed in order to popularize a short-course chemotherapy with PZA. An investigation to evaluate the initial standard treatment for bacilli-positive pulmonary tuberculosis patients was conducted for this symposium. A questionnaire was sent to 206 tuberculosis treatment facilities across Japan, centering on those where the board of trustees of the Japanese Society for Tuberculosis works. Replies were received from 65 facilities. Clinical data on 3,858 patients from those was used for analysis. The results showed that the standard treatment (A) was selected as the initial treatment for pulmonary tuberculosis in 54.4% of the cases, standard treatment (B) in 42.6% and standard treatment (C) in 2.9% of the cases. Dr. Wada of the Research Institute of Tuberculosis concluded that PZA dosage should be adjusted for patient's weight. This conclusion was based on consideration of the fact that among the 1,306 patients who received the initial pulmonary tuberculosis treatment, the negative conversion rate was relatively high for those receiving the standard (A) treatment. Liver complications were reported in 7.9% of the patients, a figure marginally higher than those receiving standard treatment (B), but no significance was recognized. According to the Chemotherapy Research Committee of National Hospitals, Dr. Machida of the Tokyo National Hospital, analyzed data on 169 randomly selected patients who were treated with standard treatment (A) and 159 patients who underwent standard treatment (B). The results showed that, after three months, the negative conversion rate was relatively higher in patients receiving standard treatment (A). The number of patients who discontinued treatment due to side effects was also significantly higher for the standard treatment (A), suggesting that the treatment poses serious side effects for the liver. Dr. Kawakami of Kawatana National Hospital seemed to prefer the standard treatment (C) as the primary treatment for the elderly. In this case, the increase in rate of detection of initial INH durg resitance showed that there was a danger of RFP resistance developing. Dr. Tsukaguchi, of the Second Internal Medicine of Nara Medical College, analyzed data on peripheral blood CD4{cell's IFN- production. The analysis revealed that the IFN- production was significantly low even in patients with advanced diabetic complications after six months standard treatment(A), suggesting that the period of treatment needs to be extended in cases where diabetic complications are involved. Dr. Yamazaki of Dohoku National Hospital, reported results of the extension of the treatment period. The analysis was based on responses to a national questionnaire and his own data. The results showed that treatment was extended for a larger number of patients receiving the standard treatment (A). The primary reasons for such extension were that the number of more serious patients was higher and the number of smear positive culture negative (SPCN) patinets was higher. The treatment was clearly longer in patients with diabetic complications and those on steroid treatment. It was also pointed out that, although small, there were cases in which there was a lack of proper reasons for treatment extension. Dr. Saito at Seiranso National Hospital reported that 7.3% of the patients receiving standard treatment (A) and 5.1% of those receiving standard treatment(B) were forced to stop treatment due to liver complications, based on data from a national poll. The complications were more serious in patients receiving standard treatment (A) and complicatons developed in most cases within two months of starting the treatment. The frequency of such complications developing in the first two weeks was high and was unrelated to advanced age. From the report received from the above doctors, it is evident that standard treatment (A) is an advanced chemotherapy treatment and it was selected for 54.4% of the patietns, a fugure much higher than the 38.8% reported for 1997 by the Japanese Society for Tuberculosis, (the Tuberculosis Treatment committee). Although more patients received this (A) treatment, the rate of liver complications was found to be identical. The results indicate that current tuberculosis treatment guideline need practical reform in several respects, including clarification of dosage per unit of body weight, attaching importance of closer monitoring in the early stages of treatment, and the extension of the treatment course in cases of patients suffering from other ailments such as diabetes. In August 2001, the U.S. CDC reproted five fatal liver failures in patients on a two-month RFP-PZA preventive chemotherapy course. Further research on the mechanism, prevention and treatment of PZA's side effects on the liver is required. In closing, we would like to thank all the medical facilities responding to our complicated questionnaire for preparing for this symposium. Key words:Tuberculosis, Chemotherapy, Standard treatment, Pyrazinamide, Liver failure 1Department of Respiratory Medicine, Tokyo National Hospital, 2Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association Correspondence to:Atsuyuki Kurashima, Department of Respiratory Medicine, Tokyo National Hospital, 3-1-1, Takeoka, Kiyose-shi, Tokyo 204-8585 Japan. (E-mail:krsm@tokyo.hosp.go.jp)