The Incidence and Risk Factors of Hyponatremia in Pulmonary Tuberculosis.

Context: The syndrome of inappropriate antidiuresis (SIAD) with euvolemic hyponatremia may occur in patients with pulmonary tuberculosis (PTB), but little is known about the clinical characteristics of SIAD-associated hyponatremia in PTB patients. Objective: This study aimed to investigate the frequency and risk factors of hyponatremia in PTB patients. Methods: In this retrospective chart review, we examined the incidence and severity of hyponatremia in PTB patients. Multivariate analysis was conducted to identify risk factors for hyponatremia in PTB patients. Results: Of the 161 patients who were screened, after excluding patients with hyperglycemia and renal failure, we enrolled and analyzed data from 113 participants. Hyponatremia occurred in 40.7% patients (<135 mEq/L). Univariate analysis revealed that the presence of hyponatremia was associated with old age, female sex, low body mass index, high glycosylated hemoglobin, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide. Multivariable analysis indicated that hyponatremia was strongly associated with old age (odds ratio, 1.06; 95% CI, 1.03-1.09 for every 1-year age increase) and CRP values (odds ratio, 1.15; 95% CI, 1.03-1.30 for every 1-mg/dL increase in CRP). For 86 patients with blood cortisol measurements, the cortisol level was significantly high in the hyponatremia group. Conclusions: Hyponatremia was less frequently associated with hyperglycemia, heart failure, renal failure, and other diseases that cause euvolemic hyponatremia; thus, PTB patients may have euvolemic hyponatremia due to SIAD. Administration of hypertonic saline or fluid restriction should be considered in PTB patients with hyponatremia.

Retrospective investigation of combination therapy with clarithromycin and levofloxacin for pulmonary Mycobacterium avium complex disease.

BACKGROUND: Fluoroquinolones are often used for the treatment of refractory Mycobacterium avium complex (MAC) disease when the clinical efficacy of the recommended regimen, which includes clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB), is insufficient. However, recent in vitro and in vivo studies have suggested that fluoroquinolones decreased the antibacterial activity of CAM when they were administered in combination. In this study, we retrospectively investigated the influence of the combination of CAM and levofloxacin (LVFX) on clinical outcomes for pulmonary MAC disease patients. METHODS: Pulmonary MAC disease patients from 2010 to 2012 were divided into two groups, those who received LVFX together with CAM (LVFX group) and those who received CAM without LVFX (control group). The number of patients who showed improvement was evaluated at 1, 3, 6 and 12 months after the start of therapy based on bacteriological examination (culture and smear examination) and the bacilli negative conversion rate. RESULTS: There were no significant differences between the LVFX group (n = 18, 64.5 ± 6.5 years old) and the control group (n = 57, 71.0 ± 7.0 years old) in terms of gender, age, etiologic agent, baseline culture examination score, concomitant medication, and dosage of each drug. The clinical outcomes in the LVFX group were inferior to those in the control group at all endpoints and observational periods, and we found a significant difference in the percent improvement of the smear examination by fluorescence microscopy method (38 % vs. 83 %) and the bacilli negative conversion rate (38 % vs. 79 %) at 3 months. Our study suggests that the combination of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment. There was no significant difference between both groups in terms of frequency of adverse events. CONCLUSION: The possibility that combined administration of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment was suggested.

Serum concentrations of clarithromycin and rifampicin in pulmonary Mycobacterium avium complex disease: long-term changes due to drug interactions and their association with clinical outcomes.

BACKGROUND: Concomitant use of clarithromycin (CAM) and rifampicin (RFP) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease affects the systemic concentrations of both drugs due to CYP3A4-related interactions. To date, however, there has been no report that investigates the long-term relationship between the drug concentrations, CYP3A4 activity, and clinical outcomes. Our aim was to investigate the time course of the drug levels in long-term treatment of subjects with pulmonary MAC disease, and examine the correlation of these concentrations with CYP3A4 activity and clinical outcomes. METHODS: Urine and blood samples from nine outpatients with pulmonary MAC disease were collected on days 1, 15, and 29 (for four subjects, sample collections were continued on days 57, 85, 113, 141, 169, 225, 281, 337, and 365). Serum drug concentrations and urinary levels of endogenous cortisol (F) and 6 beta-hydroxycortisol (6ßOHF), the metabolite of F by CYP3A4, were measured, and evaluated 6ßOHF/F ratio as a CYP3A4 activity marker. In addition, the clinical outcomes of 4 subjects were evaluated based on examination of sputum cultures and chest images. RESULTS: The mean 6ßOHF/F ratio increased from 2.63 ± 0.85 (n = 9) on the first day to 6.96 ± 1.35 on day 15 and maintained a level more than double initial value thereafter. The serum CAM concentration decreased dramatically from an initial 2.28 ± 0.61 µg/mL to 0.73 ± 0.23 µg/mL on day 15. In contrast, the serum concentration of 14-hydroxy-CAM (M-5), the major metabolite of CAM, increased 2.4-fold by day 15. Thereafter, both CAM and M-5 concentrations remained constant until day 365. The explanation for the low levels of serum CAM in pulmonary MAC disease patients is that RFP-mediated CYP3A4 induction reached a maximum by day 15 and remained high thereafter. Sputum cultures of three of four subjects converted to negative, but relapse occurred in all three cases. CONCLUSIONS: Our study demonstrated that serum CAM concentrations in pulmonary MAC disease patients were continuously low because of RFP-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes.

[Reconsideration of the admission and discharge criteria of tuberculosis patients in Japan].

Japanese Ministry of Health, Labour and Welfare issued new criteria for admission and discharge of tuberculosis patients in 2007. The criteria for admission are extended for the patients of the risk of Mycobacterium tuberculosis transmission and of the possible risk of treatment failure. The criteria for discharge are consisted of the 3 factors, (1) symptoms (cough, fever, etc.) are free after the standard chemotherapy of more than 2 weeks, (2) three different sputum smears are negative for acid-fast bacilli after the standard chemotherapy of more than 2 weeks, (3) patients are estimated to adhere to the chemotherapy after discharge and understand the infection control of M. tuberculosis. Although the criteria were simple, the goal was to treat tuberculosis patients successfully and improve treatment outcomes. For the effective operation of these criteria, the network of primary care facilities for early diagnosis and treatment after discharge, tuberculosis treatment facilities for hospitalization and local government including health care center is important. Four speakers proposed the problems and revealed their own resolutions. Three speakers from tuberculosis treatment facilities were positive for the shortening of hospitalization length by modifying the discharging criteria, however 1 speaker from the Tokyo Metropolitan Government emphasized that the regional medical system should be established for the treatment of discharged tuberculosis patient. 1. Reconsideration of admission and discharge criteria for tuberculosis patients: Kazunari TSUYUGUCHI (Department of Infectious Diseases, Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center) According to the present guideline in Japan, three consecutive negative sputum results for smear or culture are required for discharge of tuberculosis (TB) patients, making their duration of hospitalization extremely long. On the other hand, most of the TB ward in Japan consists of big rooms without air conditioning which carries a potential risk of nosocomial transmission and reinfection. In order to establish effective TB control, suspected or confirmed TB patient should be isolated in a single room equipped with the capacity for airborne infection isolation during hospitalization, as long as sputum smear or culture remains positive. It is reasonable to discharge patients to home before sputum conversion if effective chemotherapy is provided and all household members have been previously exposed. Rapid drug sensitivity testing will be helpful in assuring the effectiveness of chemotherapy for prompt discharge and detecting multidrug-resistance immediately. 2. Reconsideration of admission and discharge criteria for tuberculosis patient in Japan : Taku NAKAGAWA, Kenji OGAWA (Department of Pulmonary Medicine, National Hospital Organization Higashi Nagoya National Hospital) Admission criteria for tuberculosis patient are based on the positive result of sputum AFB smear test in principle. But admission criteria should be applied flexibly depending on the extent and severity of illness, socioeconomic background of the patient, and adherence to treatment in cooperation with the public health center. The Japanese Tuberculosis Society published "Guidelines for Admission and Discharge of Tuberculosis Patient" in January 2005. This guideline was consistent with the notice from Ministry of Health, Labour and Welfare. Improvement of management of patients with tuberculosis is most important, but bacteriological conversion is not necessary to release isolation from the hospital. The patients treated with standard regimen over two weeks and having improvement of clinical symptoms may be able to go home back in the absence of compromised person. As a result of putting this guideline into practice, there were no problems about infectiousness for tuberculosis. But the modified notice from Ministry of Health, Labour and Welfare based on bacteriological conversion was made public in September 2007. This modified notice brought in a prolonged period of hospitalization and created confusion in clinical practice. Based on the result of our study for infectiousness, it is appropriate to use the guideline in January 2005. 3. Consideration of the standard for leaving TB hospital: Masako WADA (Chemotherapy Research Institute, Kaken Hospital) In Japan, infectious pulmonary tuberculosis patients are ordered to receive chemotherapy in admission to tuberculosis treatment facilities according to Infectious Diseases Control Law. Infectious pulmonary tuberculosis is defined as sputum smear positive for acid-fast bacilli (AFB) even it is questionable. And there consecutive negative sputum smear for AFB is needed as a criteria for discharge. In this study we defined our own admission criteria as follows, medical service is needs owing to serious pulmonary tuberculosis, meningitis and other complications. We simulated the cost for hospitalization. During study period 170 patients were admitted and only 36 patients (21%) were needed hospitalization on our own criteria. The other 134 patients were admitted because of infectiousness. The average hospital stay was 63.0 days and 64.8 days, respectively. Total cost of patients cares were 26 million yen and 100 million yen respectively. On the points of saving medical costs, Infectious Diseases Control Law should be revised. 4. Recent problems in tuberculosis hospitalization and countermeasures related to patients support in urban area: Michihiko YOSHIDA (Infectious Control Section, Health and Safety Division, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Govenment) Standard treatment for tuberculosis led to a shortening of hospitalization days. After discharge most patients are treated as outpatient. In the outpatient, the decreased numbers and the bias in the geographical distribution of tuberculosis hospitals impair patients' accessibility and may lead to increase of drop out cases. And there is possible poor adherence to treatment in such as foreign-born patients from high burden countries, so intensive intervention will,be needed for successful treatment. On the other hand, in the tuberculosis hospitals, there are noninfectious tuberculosis patients with chronic complications such as psychiatric disorders and dialysis. In most cases, these patients cannot be transferred to other hospitals or welfare facilities. To resolve these problems, it is necessary to build community DOTS system including the public health centers, tuberculosis hospitals and related community resources such as clinics and welfare facilities. Also, in the near future, it is necessary to review and rebuild tuberculosis medical system comprehensively at the national level.

[Adverse effect other than liver dysfunction in treatment of latent tuberculous infection by isoniazid].

PURPOSE: To study the frequency and degree of adverse effect, other than liver dysfunction, of isoniazid (INH) preventive therapy in Japanese people. OBJECT AND METHOD: Chart review of Japanese persons who started isoniazid preventive chemotherapy in the two clinics in Tokyo, from 2003/1/1 to 2004/12/31. RESULT: There were 779 cases who did not transiently or completely stop INH preventive therapy because of adverse effect, and 20 cases who stopped INH transiently or completely because of adverse effect other than liver damage (total 799 cases). Of those cases, 153 cases (153/799=19.1%) experienced one or more adverse effect other than liver damage, and 20 cases (20/799=2.5%) of these 153 cases stopped INH transiently (12 cases) or completely (8 cases). For each category of adverse effect, digestive system symptoms were most frequent (5.9%), and then in frequency order, lethargy or easy-fatigability (4.6%), central nervous symptoms (4.5%), skin eruptions (2.6%), acne (2.5%), alcohol intolerance-like symptoms (2.5%), peripheral neuropathy (0.4%), arthralgia or limb pain (0.3%). Adverse effect requiring stopping INH transiently or completely were skin eruption (1.3%), digestive system symptoms (1.1%), central nervous symptoms (0.6%), acne (0.1%). Most of the adverse effect were not serious, and not required hospitalization. In isoniazid (INH) preventive therapy in Japanese people, adverse effect other than liver damage were not infrequent, but most of them are not serious, and do not disturb continuation of preventive therapy in most cases.

[Liver damage in treatment of latent tuberculous infection by isoniazid].

PURPOSE: To study the frequency and degree of liver damage as adverse effect of isoniazid (INH) preventive therapy in Japanese people. OBJECT AND METHOD: Chart review of Japanese persons who started isoniazid preventive chemotherapy in the two clinics in Tokyo, from 2003/1/1 to 2004/12/31. RESULT: There were 779 cases who did not transiently or completely stop INH preventive therapy because of adverse effect, and 26 cases who stopped INH transiently or completely because of liver damage as adverse effect (total 805 cases). In 371 cases, of those 779 cases, AST (asparate aminotransferase) and ALT (alanine aminotransferase) was measured after starting INH at least once. In 14.9% (59/397) of these 391 cases (= 371 + 26), liver damage as adverse effect was found. In 1.51% (6/397), liver damage with AST and/or ALT higher than 400 IU/L was found. Clinical hepatitis, associated with clinical symptom of hepatitis, was seen in 0.37% (3/805). Hepatitis with liver failure was seen in 0.12%. There was no death due to liver damage. CONCLUSION: Liver damage as adverse effect of isoniazid (INH) preventive therapy in Japanese people is not rare.

[Tuberculosis and human rights].

Tuberculosis (TB) patients must be hospitalized while the smear of sputum is positive because TB spreads through air. Cooperation of a patient is important in order to complete the treatment of TB. However, a small number of patients are noncooperative for the treatment and may sometimes refuse it. At this symposium, we discussed about whether we could restrict the human rights of noncooperative TB patients. Although the patients' human rights must be protected, we also have to protect the human rights of people who may receive TB infection. The balance of the both people's rights is fully considered in the TB control policy. It is epoch-making that the TB society took up the theme about the human rights' restriction of TB patients. Five speakers presented their papers from each position. There were presentations about the scientific evidence of isolation, the actual cases, the situation of the United States, and the legal view on the human rights' restriction of TB patients. The present situation and the legal problems in Japan became clear at this symposium. We need further discussion about the human rights' restriction of TB patients for the revision of the Tuberculosis Protection Act and have to obtain the national consensus on it. 1. The evidence for isolation: Emiko TOYODA (International Medical Center of Japan) To determine appropriate periods of respiratory isolation, available biological, clinical, and epidemiological issues and data were studied. Although absolute lack of infectiousness requires consecutive culture negative and it takes too long and impractical periods. There seems to be no established evidence for noncontagiousness after 2 to 3 weeks effective treatment. Practically conversion to 3 negative consecutive smear results may used as a surrogate for noninfectiousness, even though a small risk of transmission still be present. Chemical isolation has been more important and administration with DOT should be indicated to keep compliance. 2. Discontinued hospitalization in tuberculosis patient: Yoshiko KAWABE (National Hospital Organization Tokyo National Hospital) We investigated the background of tuberculosis patients who entered our hospital in 11 years from 1993 to 2003 and discontinued hospitalization. Out of 4,126 cases 76 cases (1.8 %) discontinued hospitalization. We classify three groups. One is self discharged group who leaved hospital without permission. Second is obligatory discharged group who were displaced for some trouble. Third is transferred group who were transferred to another hospital including mental hospital that have ward for tuberculosis. Major reasons were drinking during hospitalization, violence, roam because of dementia and major backgrounds were repeatedly noncompliant patients, homeless people, and suffering from senile dementia. We concluded we need some legal intervention for few cases who cannot continue hospitalization. 3. Tuberculosis control policy and human rights in public health center: Keiko FUJIWARA (Infection Diseases Control Division, Public Health Bureau, City of Yokohama) It is required for a success of the tuberculosis control policy to consider human rights. Patients' human rights should be respected, and surrounding people's human rights should also be respected. We sometimes see a tuberculosis patient who cannot continue tuberculosis treatment. A society as a whole has to share the recognition of tuberculosis as a social illness. The completion of tuberculosis treatment is not only the benefit of individual, but also it is very important as social defense. When we revise the tuberculosis control policy, we should think about both protecting a society from tuberculosis and protecting tuberculosis patients' human rights and obtain national consensus. 4. The mandatory TB control policy in the US: Hidenori MASUYAMA (Shibuya Dispensary, Japan Anti-TB Association) The mandatory TB control policy in the US was discussed. If the mandatory health policy would be applied, the following three criteria of human rights must be satisfied. 1. The health of others will be adversely affected without a mandatory program. 2. The mandatory program is the least restrictive alternative. 3. The mandatory program is implemented equitably without purposeful bias. For example, the mandatory DOT could not satisfy these criteria. Before applying the mandatory TB control policy in Japan, the TB patient's autonomy and social cooperation of TB therapy need to be considered. 5. Tuberculosis and guarantee of human rights: Shigeru TAKAHASHI (Graduate School of Law, Hitotsubashi University) In modern administrative Law the relations between Governments and peoples are regarded not as the facing relationships between Governments and the peoples, who submit to the interventions by Government, but as the triangle relationships between Governments, the peoples who submit to the interventions by Governments and the peoples who enjoy benefits from the interventions by Governments. When we make a new design of the Tuberculosis Protection Act, we must at first take considerations of the human rights of the tuberculosis patients from the view points of due Process of Law. And we must also take considerations of the human rights of the peoples who are threatened with the risks of tuberculosis infection.

[Preventive therapy in middle-aged and elderly persons selected from the population-based screening by mass miniature radiography--methodological aspect and adverse reactions].

The notification rate of tuberculosis in Japan was 31.0 per 100,000 in 2000. The rate was especially high among the elderly population, reaching 85.5 per 100,000 among those over 65 years of age. We conducted a study of preventive therapy in middle-aged and elderly persons selected from the population-based screening by the mass miniature radiography. The eligible criteria were 50-79 years of age, fibrous lesion which were compatible with healed tuberculosis and showed no change for at least one year, no previous treatment for tuberculosis, normal liver function tests, and no serious disease at the time of study. The eligible criteria for liver function tests in this study was less than 50 IU/L of AST and ALT value, and less than 1.5 mg/dl of T-bil level. A total of 13,219 people underwent TB screening in 4 cities in 1997 and 2 cities in 1998. Among them, 440 persons fulfilled the above criteria based on the screening records and chest X-ray films. The municipal offices sent letters to 418 people, except 22 whose addresses were unknown, to obtain permission to use their addresses and results of screening in our study. Permission was obtained from 137 persons and we sent them invitation letters for cost-free physical checkup service. Ninety-five persons visited us, and we offered them physical checkup and explained about our study. After obtaining the informed consent, we performed chest X-ray and sputum examination for 3 consecutive days. Finally 29 people were enrolled in the study. They were divided into 4 groups by sex and age, and were randomly assigned to one of two treatment groups. One group took 300 mg of INH per day for 6 months and the other group was only followed up by chest X-ray. Fourteen out of 29 persons began to take INH and received monthly liver function test. All the subjects were scheduled to follow by medical checkup every 6 months for 5 years. The proportion of taking INH tablets was estimated to range from 94% to 100%, based on the calendar for record of taking medication and the number of remaining tablets each month. Six (42.9%) of 14 persons reported adverse reactions. Two of 6 persons complained some of diarrhea, vomiting and gastrointestinal disturbance within 2 weeks, and discontinued taking INH, although none of them showed abnormal liver function tests. Two of 6 persons who reported some kinds of symptoms and 2 of 8 persons who did not complain of any symptoms showed abnormal liver function tests. The abnormal liver function tests had developed from 2 months after the beginning of INH taking in most of the persons and the abnormality improved after the completion of 6-month treatment. We have followed them for a maximum duration of 2.5 years, and 3 cases dropped out from the study. These defaulted cases had completed 6 months of INH. One person (69 y.o. male) was diagnosed as active TB by his chest X-ray film at the 6th month medical checkup, although it was not confirmed bacteriologically. One person (62 y.o. female) had the mastectomy for breast cancer 7 months before the entry to this study and relapsed at the 8th month after the entry. One person (73 y.o. female) was diagnosed as lung cancer at the medical checkup on 2.5 years. Besides them, 4 persons were suspected of worsening the abnormal shadows on chest X-ray films; one was from the INH group and three were from the follow-up group. However none of them was diagnosed clinically and bacteriologically as active tuberculosis.