Effects of long-term low-dose oxygen supplementation on the epithelial function, collagen metabolism and interstitial fibrogenesis in the guinea pig lung.

BACKGROUND: The patient population receiving long-term oxygen therapy has increased with the rising morbidity of COPD. Although high-dose oxygen induces pulmonary edema and interstitial fibrosis, potential lung injury caused by long-term exposure to low-dose oxygen has not been fully analyzed. This study was designed to clarify the effects of long-term low-dose oxygen inhalation on pulmonary epithelial function, edema formation, collagen metabolism, and alveolar fibrosis. METHODS: Guinea pigs (n = 159) were exposed to either 21% or 40% oxygen for a maximum of 16 weeks, and to 90% oxygen for a maximum of 120 hours. Clearance of inhaled technetium-labeled diethylene triamine pentaacetate (Tc-DTPA) and bronchoalveolar lavage fluid-to-serum ratio (BAL/Serum) of albumin (ALB) were used as markers of epithelial permeability. Lung wet-to-dry weight ratio (W/D) was measured to evaluate pulmonary edema, and types I and III collagenolytic activities and hydroxyproline content in the lung were analyzed as indices of collagen metabolism. Pulmonary fibrotic state was evaluated by histological quantification of fibrous tissue area stained with aniline blue. RESULTS: The clearance of Tc-DTPA was higher with 2 week exposure to 40% oxygen, while BAL/Serum Alb and W/D did not differ between the 40% and 21% groups. In the 40% oxygen group, type I collagenolytic activities at 2 and 4 weeks and type III collagenolytic activity at 2 weeks were increased. Hydroxyproline and fibrous tissue area were also increased at 2 weeks. No discernible injury was histologically observed in the 40% group, while progressive alveolar damage was observed in the 90% group. CONCLUSION: These results indicate that epithelial function is damaged, collagen metabolism is affected, and both breakdown of collagen fibrils and fibrogenesis are transiently induced even with low-dose 40% oxygen exposure. However, these changes are successfully compensated even with continuous exposure to low-dose oxygen. We conclude that long-term low-dose oxygen exposure does not significantly induce permanent lung injury in guinea pigs.

[Comparative study of bactec MGIT 960 AST and conventional proportion method using Ogawa medium for the drug susceptibility testing of Mycobacterium tuberculosis to isoniazid].

OBJECTIVE: To evaluate the accuracy of drug susceptibility testing to isoniazid with BACTEC MGIT 960 (MGIT AST) comparing with the standard proportion method using Ogawa medium. METHOD: A total of 1109 M. tuberculosis strains, which were selected from the collection of RYOKEN drug resistance survey in 2002, were selected and subjected to the susceptibility testing to isoniazid using MGIT AST and 1% Ogawa standard methods. The results from MGIT AST were compared with the judicial diagnosis by Ogawa. The sensitivity to detect drug resistance, the specificity for susceptible strain, the efficiency of overall agreement, and kappa coefficient were calculated to evaluate the performance. The treatment process, outcome and prognosis were analysed for the patients on whom the tests showed discrepant results. RESULTS: Compared with the judicial results, the sensitivity, specificity, efficiency, and kappa coefficient of MGIT AST were 100%, 97.1%, 97.3%, and 0.798, respectively. The strains, which showed discrepant results between MGIT AST and Ogawa, were all susceptible by Ogawa and resistant by MGIT AST. A total of 11 out of 30 discrepant cases were followed clinically and no relapse cases were identified, irrespective of the modification of the treatment regimen. As for the proportion of primary INH drug resistance in the present study, it was 5.3% with MGIT AST but was 2.7% with Ogawa, and the difference was statistically significant (p = 0.005). DISCUSSION: The discrepancies on the results of drug susceptibility testing of M. tuberculosis strains to isoniazid between MGIT AST and 1% Ogawa proportion method have been reported. In the present study, the sensitivity, specificity, and overall efficiency of MGIT AST on the prevalent strains in Japan were all beyond 95%, and considered sufficient as the anti-tuberculosis drug susceptibility testing (AST), though 2.7% of discrepancy was observed. Even for the discrepant cases, there was no difference in the treatment outcome and prognosis. Thus, MGIT AST was confirmed as a reliable AST method comparable to Ogawa standard. However, MGIT AST might increase the proportion of INH resistance if it was used as a major AST method, compared with Ogawa.

[Clinical analysis of patients with sequelae of pulmonary tuberculosis undergoing home oxygen therapy].

PURPOSE: To clarify the clinical characteristics of patients with sequelae of pulmonary tuberculosis undergoing home oxygen therapy. OBJECTS AND METHODS: We conducted a cross-sectional survey of those with newly-introduced home oxygen therapy for the sequelae of pulmonary tuberculosis from 1998 through 2001, using national hospital network of respiratory diseases. RESULTS: The study subjects were 402 in total (271 men and 131 women), who started the home oxygen therapy at the age ranging between 33 and 100 years (72.2 +/- 8.1 years, mean +/- S.D.). They suffered from pulmonary tuberculosis at the mean age of 37.7 +/- 19.4 years, and the interval leading to oxygen therapy averaged 33.1 +/- 19.1 years. Sixty-eight percent of these patients demonstrated body mass index (BMI) less than 20. Pulmonary function studies revealed the markedly-decreased vital capacity (46.2 +/- 15.0%) as well as reduced FEV1/FVC (68.5 +/- 18.8%). Arterial blood gases measured when home oxygen therapy was introduced showed hypoxemia (Pa(O2), 60.4 +/- 10.7 Torr) with hypercapnea (Pa(CO2), 50.5 +/- 9.4 Torr). The average flow rate of oxygen was 0.94 +/- 0.64 L/min at rest and 1.51 +/- 0.70 L/min on exertion. The patients were divided into two groups; those with surgical intervention including thoracoplasty or lung resection (126 cases, group 1) and those without surgery (148 cases, group 2). The mean age of the patients in the group 1 when home oxygen therapy was started was 72.3 +/- 6.4 years and 71.6 +/- 9.1 years in the group 2, respectively. Subjects in group 1 were more likely suffered from TB in younger age than those in group 2 (28.2 +/- 9.7 vs. 45.4 +/- 21.5 years, p < 0.01), and had the longer duration to initiate domiciliary oxygen therapy (43.0 +/- 10.9 vs. 25.3 +/- 20.3years, p<0.01). The former was also more likely to have lower % VC (p < 0.01), more elevated Pa(CO2) (p<0.05), and lower inspired flow rate of oxygen (p<0.01). There was no significant difference between the two groups with respect to BMI, FEV1/FVC, or CONCLUSION: Our investigation demonstrated that patients with sequelae of pulmonary tuberculosis under oxygen therapy revealed the different clinical course and characteristics regarding the presence or absence of previous surgical intervention.

[Evaluation of respiratory failure due to sequelae of tuberculosis].

Though the mortality of tuberculosis in Japan has been extremely rapidly depressed from about 150 deaths per 100,000 in 1950 down to about 4 in 1985 during the period of a couple of decades after the World War II. However, the declining trend of the mortality and the morbidity seem to be leveling off now and the morbidity of the tuberculosis remain on the almost same level which are much higher than that of the developed countries. We have to make the progress in the field of the new diagnostic technique and the creation of the new drugs applying the most frontier science and the social system supporting the completion of the treatment for every patient. On the other hand, it is also very important to take care of those who have been suffering from the sequelae of the pulmonary tuberculosis, which include chronic respiratory failure, cor pulmonale, and non-TB chronic pulmonary secondary infections. Among the sequelae we focus to the respiratory failure. Among the patients with various chronic respiratory diseases, there are many who are not hypoxic at rest but are hypoxic during physical exercise in the daily life. The pulmonary exercise test by treadmill or ergometer which needs a lot of work is the standard method to detect the exercise hypoxia. But this test is too complicated to come into wide use in the daily clinical study in Japan. Another exercise test has been eagerly expected for a long period. We newly developed a method to detect the exercise hypoxia in the patients' daily life without burdening the additional physical activities. The device of the new method consists of a portable pulse oxymeter with a built-in accelerometer which measures the oxygen saturation percutaneously and also measures simultaneously the vertical acceleration of the subject's physical movement by the accelerometer. The appropriate evaluation of exercise hypoxia of the patients with respiratory disturbances due to pulmonary tuberculosis sequelae, especially exercise hypoxia, should be performed widely all over the daily clinical examination by such a method as described in this report. Further the system of the evaluation of the exercise respiratory disturbances should be introduced in the various social regimen which concern with the disability due to the respiratory disturbances. We wish our society will be more matured society in which the patients with respiratory disturbances can afford to fully enjoy their lives. Both the frontier science against the tuberculosis and the measures against the sequelae of the pulmonary tuberculosis are one of our important challenges today.

[Pulmonary infection in immunocompromised hosts].

While typical pulmonary infections can be cured with antimicrobial agents, three types require surgical lung resection: those in immunocompromised patients; those with acquired resistance to medication; and those caused by microorganisms against which there are no effective drugs. We discuss these three types from the viewpoint of physicians. With the development of chemotherapy for malignant disease, patients with leukemia can be cured with bone marrow transplantation. During the leukopenia accompanying chemotherapy, Aspergillus sp. can infect the lungs. Aspergillus infections are resistant to antimicrobial agents, and thus surgical resection is necessary. Aspergillus infections may occur in previous sites of pulmonary tuberculosis lesions after the tuberculosis is cured producing massive hemoptysis. In this case, surgical resection is also needed. When patients who are immunocompromised due to various underlying diseases become infected with multidrug-resistant tuberculosis, they require surgical resection. Finally, when lesions of nontubercular mycobacterial infection are found, these patients also require surgical lung resection.

[A clinical study on tuberculosis among young adults in Japan: analysis on patients admitted to national hospitals in Kanto- and Kinki-areas in the year 2000].

Considering the high social activity, the trend of tuberculosis among young adults appears to be one of the key factors that influence the future morbidity rate of tuberculosis in Japan. To investigate its current characteristics, we analyzed new cases of tuberculosis aged 20 to 29 who were admitted to 7 national hospitals in Kanto- and Kinki-areas during the period of January 1st to December 31st, 2000. Data on the following items were compiled: sex, age, body height and weight, nationality; background factors such as life style, complications; course of the disease before the diagnosis; result of PPD skin test; severity of the disease estimated by the amount of M. tuberculosis in sputum and the grade of chest X-ray findings; therapeutic regimens and the response rate. Data were collected from 234 patients (129 males and 105 females) and the results were as follows: 1) about 80% of the patients were symptomatic and in 50% of patients who presented with cough, more than one month was needed before establishing the diagnosis as TB, 2) the disease was found in advanced stage in more than half of the patients, 3) foreigner patients, most of them were from Kanto-area, accounted for 11%, and were in advanced stage, some with drug-resistant tuberculosis, 4) INH resistance was noted in 7.7%, 5) pyrazinamide was included in the therapeutic regimens in 84.0% of the smear positive patients, 6) the admission period was within 90 days in 63.7% of the patients, however, the duration of treatment was 6 months in only 48.0% of patients who were treated with regimens containing pyrazinamide. More efforts for early detection of patients is needed to prevent the transmission of the disease, and more extensive use of directly observed therapy is essential for the prevention of dropout. We also argued about the shortening of the admission and duration of treatment in these patients.

[Trends in drug-resistant tuberculosis in National Higashisaitama Hospital, 1994-2001].

To know the prevalence of resistance to four first-line anti-tuberculosis drugs, we reviewed the results of drug-susceptibility tests of patients with tuberculosis who were admitted to our hospital from 1994 to 2001. Among patients with no prior chemotherapy against tuberculosis, the complete resistance rate was 1.9% for INH, 0.81% for RFP, 5.1% for SM, 0.81% for EB, and 0.32% for multiple drug-resistance (MDR). The acquired resistance rate was 9.7% for INH, 11.5% for RFP, 7.3% for SM, 2.4% for EB, and 6.1% for MDR. There was no significant increase in the prevalence of drug resistance between the first half (1994-1997) and the latter half (1998-2001) of the investigation periods. Compared with the previous reports, our results indicated no increase in the prevalence of drug resistance in tuberculosis patients with no prior treatment and the decrease of prevalence in patients with prior treatment of tuberculosis. A multi-drug regimen consisted of INH, RFP, PZA and EB or SM, which is currently considered as a standard regimen of tuberculosis chemotherapy and used quite widely, does not seem to induce the increase of drug-resistant tuberculosis.

[Superior sensitivity of MGIT method in identification of specimens culture-positive for acid-fast bacilli (AFB) and individuals with positive AFB cultures].

To investigate the superiority of the Mycobacteria Growth Indicator Tube (MGIT) over Ogawa medium in the detection of acid-fast bacilli (AFB), we surveyed all specimens for AFB culture using Ogawa medium in 1999 and MGIT in 2000. The MGIT method increased the culture-positive rate from 23.1% (Ogawa medium) to 34.5% (p < 0.01). The culture-positive rate in smear-negative specimens was greatly increased (from 9.5% to 16.9%) (p < 0.01). The culture-negative rate in smear-positive specimens was decreased to 19.5% from 27.7% (p < 0.01). More individuals with positive M. tuberculosis cultures were found by the MGIT method than with Ogawa medium. Many more individuals with nontuberculous mycobacteria (NTM), notably those with NTM other than M. avium complex, were detected by the MGIT method than with Ogawa medium. The use of the MGIT method in the clinical laboratory will improve sensitivity in the detection of AFB.