Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan.

BACKGROUND: Though various clinical conditions of aspergillosis can occur, depending essentially on the host's immunological status, the focus of research in North American and European countries has mainly been on invasive pulmonary aspergillosis in immunocompromised patients. There are, however, also many problems to overcome in chronic forms of aspergillosis. One of those problems is that there are no codified treatment guidelines for chronic pulmonary aspergillosis (CPA). Especially in Japan, this issue is more serious, because there are more cases with CPA due to the many aged people with past history of tuberculosis. Several clinical cases and case series have reported the usefulness of the various antifungal agents that are available. The new triazole, voriconazole, in particular, seems to be effective in the treatment of CPA. The aim of the present study is to evaluate the efficacy and safety of voriconazole in the treatment of CPA in non-immunocompromised patients. PATIENTS AND METHODS: We conducted a prospective, open-label, non-comparative, multicenter study over a 2-year period. For inclusion in the study, patients with confirmed or probable CPA were recruited in 11 hospitals of the National Hospital Organization in Japan. Clinical, radiological, serological, and mycological data were collected at baseline and 12 weeks after treatment or at the end of treatment. RESULTS: Among 77 patients enrolled in the study, 71 patients (mean age 65.9 years, 56 males and 15 females) were eligible for the study. All of the eligible patients presented with underlying lung diseases, including sequelae of tuberculosis (n = 35), non-tuberculous mycobacterial lung disease (n = 8), chronic obstructive pulmonary disease (COPD) (n = 8), interstitial pneumonia (n = 7), cystic lung disease (n = 4), pneumothorax (n = 3), bronchial cancer (n = 1), and others (n = 5). Voriconazole was indicated in 48 cases (68 %) as the first-line treatment for CPA and 23 patients previously received other antifungal therapies. Based on a composite of clinical, radiologic, serological, and mycologic criteria, good response was seen in 43 patients (60.6 %), no response was observed in 19 patients (26.8 %), and 4 cases (5.6 %) got worse. Five patients (7.0 %) were unassessable for efficacy. The common adverse events were visual disturbances (17 patients, 23.9 %), abnormal liver function test results (12 patients, 16.9 %), adverse psychological effects (3 patients, 4.2 %), and others (10 patients, 14.0 %). Treatment with voriconazole had to be stopped in 2 cases (2.8 %) because of serious adverse events (abnormal liver function test results). There was no association between adverse effects and trough voriconazole levels in serum. CONCLUSIONS: In Japan, voriconazole provides effective therapy of CPA in non-immunocompromised patients with an acceptable level of toxicity.

Clinical evaluation of Amplicor Mycobacterium detection system for the diagnosis of pulmonary mycobacterial infection using sputum.

SETTING: The Amplicor Mycobacterium detection kit was evaluated for the diagnosis of active pulmonary mycobacterial infection using sputum. OBJECTIVE: To assess the clinical usefulness of the Amplicor Mycobacterium kit for the diagnosis of pulmonary tuberculosis and non-tuberculous mycobacterial infection in the country of medium prevalence. DESIGN: All the patients were diagnosed with bacterial, histopathological, and clinical 'gold standard'. The sensitivity and specificity for diagnosing clinically active pulmonary tuberculosis and Mycobacterium avium and Mycobacterium intracellulare infections were evaluated comparing Amplicor results and clinical diagnosis. RESULTS: A total of 1088 sputum specimens were collected from 780 in and out patients. Mycobacteria were recovered from 339 specimens by culture. The sensitivity and specificity of conventional culture method for the diagnosis of pulmonary tuberculosis were 60.2% and 99.8% respectively based on the number of patients. The figures for Amplicor were 61.8% and 97.4% respectively. There was no statistical significant difference between these methods. In rapidity, the Amplicor was significantly superior to the microscopy method in sensitivity. CONCLUSION: Patients with Amplicor positive and conventional negative result had mostly mycobacteria related diseases. The Amplicor positive result indicated mostly active mycobacterial infection and was clinically useful for rapid diagnosis.

Is thrombomodulin useful as a tumor marker of a lung cancer?

To evaluate whether thrombomodulin (TM) can be considered a tumor marker of lung cancer, we examined serum TM levels in 179 lung cancer patients by an enzyme immunoassay. Further, in 91 resected cases, we also investigated the TM presence in lung cancer tissue by an immunohistochemical method. Our findings revealed that 58 (32%) of 179 lung cancer patients had higher serum TM levels than our cutoff levels. No difference was seen in the serum TM-positive ratio between histologic types, but patients with Stage IV disseminated cancer showed a higher serum TM-positive ratio than those with Stage I-IIIB localized cancer, especially cases of adenocarcinoma. Immunostaining results showed a TM presence in the cancer cells of 32 (35%) of 91 lung cancer cases. The TM presence in cancer cells was higher in cases with squamous cell carcinoma than with adenocarcinoma; no differences were seen among the disease stages. No correlation was found between the serum TM and the presence of TM in cancer cells. Further, serum TM status appears to have little clinical significance as a method to detect early lung cancer or for predicting the recurrence after the surgical excision of a lung cancer. Thus, we have concluded that, although serum TM levels are elevated in some lung cancer patients, it is doubtful that the TM status is useful as a tumor marker of lung cancer.

Prognostic significance of thrombomodulin expression and vascular invasion in stage I squamous cell carcinoma of the lung.

Thrombomodulin (TM) is an important modulator of intravascular coagulation. TM exists on endothelial cells and on several types of tumor cells, especially squamous cell carcinoma cells. Tumor cell TM is thought to be associated with progression and metastasis of the tumor. To evaluate the prognostic significance of TM in lung cancer, we examined TM expression and vascular invasion in surgical specimens obtained from 90 patients with completely resected stage I non-small cell lung cancer (NSCLC). In addition, we correlate these pathologic data to other clinicopathologic data, including the outcome of the patients. Squamous cell carcinomas had a significantly higher incidence (P<0.0001) of TM expression (22/36 cases, 61%) than adenocarcinomas (9/54 cases, 17%). In 36 squamous cell carcinoma patients, both vascular invasion (P=0.0153; risk ratio 6.507) and TM non-expression (P=0.0282; risk ratio 3.584) were significant for a poor prognosis. Univariate analysis of patient survival rates also revealed that vascular invasion and TM expression were significant prognostic factors (P=0.0036 and 0.012, respectively). Further, combination analysis of vascular invasion and TM expression in the squamous cell carcinoma patients showed that the 5-year survival rate was 90% in patients with TM expression and without vascular invasion, but 21% in patients with vascular invasion and without TM expression (P=0.0004). Since our results suggest that vascular invasion and TM expression are independent prognostic factors of stage I squamous cell carcinoma of the lung, and since the two factors play different roles in the metastatic process of cancers (promotion of metastasis by vascular invasion and inhibition of metastasis by TM expression), the combination evaluation of vascular invasion and TM expression may be very significant in evaluating the prognosis of patients with completely resected stage I squamous cell carcinoma.

Early pulmonary resection for localized Mycobacterium avium complex disease.

BACKGROUND: Results of antituberculous chemotherapy for Mycobacterium avium complex disease remain disappointing. Pulmonary resection during an early stage of the disease, therefore, may be beneficial to patients whose disease is localized and who can tolerate a resectional operation. METHODS: Thirty-three patients with localized M avium complex disease underwent 33 pulmonary resections between 1979 and 1996. There were 17 males and 16 females, with a mean age of 50 years (range, 30 to 69 years). Lobectomy was performed in 26 patients, pleuropneumonectomy in 1, segmentectomy in 5, and wedge resection in 1. RESULTS: There was no operative mortality. After pulmonary resection, 31 (94%) patients attained sputum-negative status. Bronchopleural fistula occurred in one patient who underwent a right upper lobectomy. There were two late deaths. A patient with bronchopleural fistula died of respiratory failure two years postoperatively. Another patient died of an unknown cause 12 years postoperatively. Of the 31 patients with negative sputum status postoperatively, only 2 patients (6%) had relapse at 1 and 9 years after operation. CONCLUSIONS: We recommend that patients with this disease be considered for pulmonary resection as early as possible.

Comparative study of amplicor Mycobacterium PCR and conventional methods for the diagnosis of pleuritis caused by mycobacterial infection.

OBJECTIVE: To assess the clinical significance of the Amplicor Mycobacterium system for the diagnosis of mycobacterial infection in patients with pleural fluid, and to compare its usefulness with that of conventional smear and culture methods. DESIGN: Pleural fluid specimens were obtained randomly from in-patients admitted to National Tokyo Hospital between January and December 1996. All the patients were diagnosed with bacterial, histopathological and clinical gold standard. The sensitivity and specificity for diagnosis of mycobacterial infection were evaluated. RESULTS: Seventy-five pleural fluid specimens were obtained. Conventional methods demonstrated a sensitivity of 30.6% and a specificity of 100%, while the Amplicor Mycobacterium demonstrated a sensitivity and specificity of 27.3% and 97.6% respectively. Lactic dehydrogenase, carcinoembryonic antigen, red blood cell, protein, glucose and types of inflammatory cells were not different in Amplicor positive and negative pleural fluid with mycobacterial infection. CONCLUSION: There was not much improvement in the accuracy of diagnosis when Amplicor Mycobacterium was used to diagnose mycobacterial pleuritis among various diseases with pleural fluid; however, the assay time was dramatically reduced with the use of Amplicor Mycobacterium.

Potential use of Amplicor PCR kit in diagnosing pulmonary tuberculosis from gastric aspirate.

Polymerase chain reaction (PCR) detection of mycobacteria from gastric aspirate for the diagnosis of tuberculosis is not fully evaluated up to now. A total of 116 gastric aspirate specimens were collected from patients with suspected pulmonary tuberculosis. The breakdown of diagnosis was 67 pulmonary tuberculosis, 16 nontuberculous mycobacterial infection, 5 extra pulmonary tuberculosis, and 28 other lung diseases. The conventional methods were shown to have a sensitivity of 47.8% and a specificity of 79.6%; on the other hand, Amplicor had 34.9% and 97.0%, respectively. The Amplicor provided a more rapid and specific method for diagnosing tuberculosis and was more useful than the conventional.

Non-Hodgkin's lymphoma with pulmonary infiltrates mimicking miliary tuberculosis.

Miliary infiltrates observed on chest films in non-Hodgkin's lymphoma are extremely rare. We report a case with pulmonary infiltrates mimicking miliary tuberculosis associated with prominent eosinophilia and elevated IgE levels. The levels of circulating eosinophils correlated with disease activity as they transiently returned to normal after effective chemotherapy in a short period. However, the patient developed acute respiratory failure due to the rapid progression of the disease even with intensive chemotherapy. We emphasize that small nodular shadows appear to be a sign of the rapid progression of the disease and a poor prognosis.

The use of bronchofiberscopy for diagnosis of allergic bronchopulmonary aspergillosis.

To assess the use of bronchofiberscopy for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA), we retrospectively analyzed bronchofiberscopic and pathologic findings of specimens obtained by bronchofiberscopy in 8 patients who met the British criteria for ABPA. Two of the 8 patients completely met Rosenberg's primary criteria for ABPA, while the remaining 6 lacked only 1 or 2 immunologic and radiographic conditions of the criteria. Bronchofiberscopic inspection revealed the presence of mucus plugs in all patients. Pathologic examination of plug specimens obtained by suction from 6 of 7 of these patients showed that the plugs consisted of allergic mucin containing fungal hyphae, diagnostic of ABPA. Bronchofiberscopy appears to be a useful tool in the diagnosis of ABPA, if immunologic and radiographic findings are not typical of ABPA. This bronchofiberscopic method is easily applicable for diagnosing allergic bronchopulmonary fungal disease (ABPFD) in addition to ABPA.

[A study on in vitro antibacterial activity and clinical usefulness in respiratory tract infections of panipenem/betamipron, a newly synthesized carbapenem antibiotic].

Panipenem/betamipron (PAPM/BP) is a combination drug of PAPM, a new parenteral carbapenem antibiotic and BP, an amino acid derivative at a weight ratio of 1:1. Its in vitro antibacterial activities against clinically isolated respiratory pathogenic bacteria were determined. It was superior to imipenem (IPM) in the in vitro antibacterial activities against Haemophilus influenzae, Haemophilus parainfluenzae, Branhamella catarrhalis, Staphylococcus aureus including MRSA, Klebsiella pneumoniae, Serratia marcescens and Escherichia coli. PAPM had antibacterial activities almost equal to those of IPM against Streptococcus pneumoniae and Enterococcus spp. Against Pseudomonas aeruginosa, however, its antibacterial activity was about 1/4 that of IPM. The clinical usefulness of PAPM/BP was studied by dissolving it in a solution containing lactate and administering the solution by intravenous drip infusion to 12 cases of respiratory tract infections. Out of 11 cases with respiratory tract infections excluding cytomegalovirus pneumonia, the efficacy rate was 90.9%, with 4 cases of excellent and 6 cases of good responses. In terms of its bacteriological efficacies, eradication of pathogenic bacteria including super-infection were observed in 2 out of 4 strains, but 2 strains of P. aeruginosa remained unchanged. Six strains appeared as superinfected bacteria during and after administration of this preparation substituting original pathogens. Side-effects were not observed in the 12 cases, and in laboratory tests, slight transient increases of S-GOT and S-GPT were found in 1 case. In conclusion, PAPM/BP is a very useful parenteral antibiotic against respiratory tract infections and can be one of the drugs of the first choice.

[Clinical studies on ceftriaxone in respiratory tract infections. CTRX Study Group].

We report that the results of clinical studies on ceftriaxone (CTRX) in respiratory tract infections (RTIs). Clinical efficacies and side effects of CTRX were as follows; 1. Clinical efficacies of CTRX in a total of 61 cases with RTIs were excellent in 11 cases, good in 23, fair in 11, poor in 12 and unknown in 4. Thus the overall clinical efficacy rate was 59.6%. In cases of patients with lung cancers, the efficacy rate was 42.9%. 2. Clinical efficacy rates with once daily dosage were 50.0% with a dose level of 1 g CTRX and 54.8% with that of 2 g CTRX. 3. Side effects were observed in 2 cases (3.1%) and laboratory abnormalities were observed in 1 case (1.6%). They were not serious, however. These data suggest that CTRX is one of the useful cephalosporins in treatment of RTIs.

[The short-term effects of multidrug chemotherapy for pulmonary Mycobacterium avium-intracellulare complex (MAC) infection].

In performing MAC chemotherapy, we are faced with the following two problems: first, unlike for Mycobacterium tuberculosis, we have neither any suitable bacteriocidal drugs nor bacteriocidal regimens for MAC treatment; secondly, in case of MAC, unlike in the case of Mycobacterium tuberculosis, in vitro sensitivity does not correlate with in vivo sensitivity. For these reasons, we find difficulty in planning a rational protocol for MAC treatment, and thus depend on previous experiences of other physicians in MAC chemotherapy. Here, we have tried to evaluate such previous experiences objectively, and studied retrospectively the effects of previous combination chemotherapy cases of pulmonary MAC infections at National Tokyo Hospital. We selected 170 cases which had received the same chemotherapy continuously over a period of six months. Concentration of bacilli cultured, 8 weeks in Ogawa solid egg containing medium was translated semi-quantitatively to colony forming units (CFU) according to the Japanese guideline for acid fast bacilli test. Having set a mean CFU of 3 times sputum culture before treatment as 100%, we calculated a six month sequential bacillary response to a regimen and plotted the bacillary response curves. The response curve of the total 170 MAC treatment cases exhibits a minimum point of 42.9% at 2 months, and subsequently rises to 71.1% after six months compared to the state before treatment. The response curves of various regimens of multidrug chemotherapy indicate that combinations of more than 3 drugs including aminoglycoside and clarithromycin are most effective. However, although some effectiveness is indicated, neither the present drugs nor regimens are capable to achieve a bacteriocidal effect in MAC treatment.

[Diagnostic role of fiberoptic bronchoscopy for mycobacterial diseases].

From 1981 to 1991, 5,572 patients underwent bronchoscopic examination, in this series 3,754 patient's samples were sent for determination of mycobacterial isolation. In the 506 samples, mycobacterial bacilli were detected with smear or culture. In the low tuberculous incidence area like northern part of America, many reporters supported the opinion that routine bronchial aspirate detection for tuberculosis was not cost-effective. Inversely, in the high tuberculous incidence area like Hong Kong, M. lp et al. claimed the usefulness of routine bronchial aspirate examination for mycobacterial bacilli. Japan was regarded as moderate tuberculous incidence area. We review a ten-year experience with fiberoptic bronchoscopy for mycobacterial isolation. Our results suggest that in an area with a moderate prevalence of tuberculosis, bronchoscopic examination for mycobacterial disease is useful in the selected hospitals for the selected cases. In Japan, the smear positive prevalence has been on the increase from 1982. We estimate that the Japanese popularization of fiberoptic bronchoscopy may influence a part of the Japanese epidemic statistical analysis of mycobacteriosis.

[Parameters relating to the development of residual pleural thickening in tuberculous pleurisy].

To identify predictive parameters for the development of residual pleural thickening in tuberculous pleurisy, we investigated 58 tuberculous pleurisy patients retrospectively who could be followed up until their chest roentgenogram no longer changed. The patients were divided into the following three groups according to the final configuration of pleural space: group I costphrenic angle (C-P angle) of the affected side was completely or almost completely recovered (20 cases), group II C-P angle became dull (20 cases), group III pleural thickening of > 2 mm remained in the lateral chest wall above the diaphragmatic dome level (18 cases). Differences of the clinical, chest roentgenographic and laboratory data were compared between these three groups. There were no differences between groups I and II in all of the parameters compared, while there were some differences between groups I and/or II and group III. The mean age of group III (51.1 +/- 18.1 y.o.) was significantly higher than that of group I (40.7 +/- 18.6 y.o.) and group II (34.7 +/- 14.7 y.o.) (p < 0.05 and p < 0.005 respectively). Glucose level in pleural fluid of group III (32 +/- 31 mg/dl) was lower than that of group I (96 +/- 13 mg/dl) and group II (86 +/- 21 mg/dl) (p < 0.001, respectively), while the levels of LDH, TP and ADA in pleural fluid were not different significantly among three groups. BSR (blood sedimentation rate) and CRP (C-reactive protein) were higher in group III (77 +/- 30 mm/hr and 8.5 +/- 4.3 mg/dl) than those in group I (45 +/- 23 mm/hr and 4.1 +/- 5.4 mg/dl) (p < 0.01 and p < 0.05, respectively). The level of albumin in serum was lower and that of globulin was higher, and consequently that of A/G ratio in group III (0.78 +/- 0.17) was lower than that of group I (1.15 +/- 0.16) and group II (1.10 +/- 0.22) (p < 0.001, respectively). It should be emphasized that the level of gamma-globulin was higher in group III irrespective of the presence or absence of accompanying pulmonary tuberculosis. Most patients more than 40 years old with serum A/G ratio less than 0.95 belonged to group III (13/15 (87%)) while most of those with serum A/G ratio more than 0.95 belonged to group I or II (10/11 (91%)). Thus hyper (gamma-) globulinemia and the intensity of inflammatory reaction in the whole body and in the pleural space are the predictive factors for the development of residual pleural thickening in tuberculous pleurisy.

[The present situation, treatment and prognosis of drug-resistant pulmonary tuberculosis. Cooperative Study Unit of Chemotherapy of Tuberculosis of the National Sanitoria in Japan].

We studied 266 patients with drug-resistant pulmonary tuberculosis at national sanatoria in Japan. The patients included 218 men (mean age, 58 years) and 48 women (mean age, 62 years). The levels of isoniazid and rifampicin resistance were determined at 1 mcg/mL and 50 mcg/mL, respectively. The results were as follows. (1) Most patients with drug-resistant pulmonary tuberculosis were middle-aged or past middle-aged. (2) There were many cases of drug-resistant pulmonary tuberculosis in previously treated tuberculosis patients with active disease and several cases in previously untreated pulmonary tuberculosis patients. However, in some previously untreated patients active tuberculosis was convert relatively easily to inactive tuberculosis. (3) Concerning life style, bachelors who drank heavily were more likely to develop drug-resistant pulmonary tuberculosis. (4) Most cases of drug-resistant pulmonary tuberculosis had at least one cavity on chest radiographs. (5) Several patients with drug-resistant tuberculosis left the hospital against the advice of their attending doctors; therefore, it was difficult to treat their illnesses. (6) In more than half the cases in which Mycobacterium tuberculosis was resistant to isoniazid and rifampicin, tolerance to streptomycin and ethanbutol was also seen. (7) When patients with drug-resistant pulmonary tuberculosis continued to have tuberculous bacilli in their sputum after 3 months of chemotherapy, there was a tendency for them to expectorate tuberculous bacilli in their sputum. For these drug-resistant tuberculosis patients, we must pay attention not only to the medical aspects but also to the social aspects of their disease.

[Tuberculosis sequelae: secondary bacterial infections].

Bacterial infections is one of the most important complications in the patients with pulmonary tuberculosis. We reported the causative microorganisms in these cases with special reference to various clinical features and presented the recommended treatment and prophylaxis against respiratory bacterial infections in the patients with pulmonary tuberculosis sequelae. In 1988 and 1989, 63 patients with tuberculosis sequela were demonstrated to have been infected with respiratory pathogenic bacteria by the quantitative sputum culture method (greater than or equal to 10(7)/ml) in Tokyo National Chest Hospital. The male/female ratio of these patients was 3.5, and their average age was 62.5 years. Causative microorganisms of the secondary infections in the patients with tuberculosis sequela were essentially similar in those with other lower respiratory tract infections, i.e., chronic bronchitis, bronchiectasis, diffuse panbonchiolitis, chronic pulmonary emphysema, etc. Pseudomonas aeruginosa, other glucose-nonfermentative Gram-negative bacilli (GNF-GNB), and glucose-fermentative Gram-negative bacilli (GF-GNB) were the major pathogenic bacteria responsible for the chronic respiratory failure and/or fatal outcome in the post-tuberculous patients. Patients with complications, including aspergillosis, atypical mycobacteriosis, bronchial asthma, and so forth, showed no specific causative microorganism for the secondary infections except frequent isolation of Haemophilus influenzae. Our clinical observations clearly demonstrated that there were differences between the causative microorganisms in patients hospitalized during 1988 to 1989 and those in patients without admission. Gram-negative bacilli, including P. aeruginosa, GNF-GNB and GF-GNB, and Staphylococcus aureus were predominant in hospitalized patients. On the contrary, Streptococcus pneumoniae, H. influenzae, and Branhamella catarrhalis were major pathogenic bacteria in patients without hospitalization.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of inflammatory bronchial polyp associated with pulmonary and bronchial tuberculosis].

A 67-year-old man was admitted to our hospital because of cough and sputum. Chest X-ray revealed cavity and consolidation in the right upper lobe. Microscopical examination of stained specimens of sputum disclosed acid-fast bacilli (Mycobacterium tuberculosis). Cough and sputum resolved and cultures of sputum did not yield M. tuberculosis a month after administration of antituberculosis agents. However, a mass shadow in the right upper lobe was found 3 months later. Bronchofiberscopy revealed a polyp with a stalk at the orifice of right upper bronchus, which was elastic, soft in consistency, smooth surfaced, and movable. The pathological findings of the polyp showed non-specific inflammatory granulation which suggested to be inflammatory bronchial polyp. It was appeared in the healing process of bronchial tuberculosis.

[Pathology of bronchopulmonary aspergillosis].

This paper concerns the morphology of 3 types of bronchopulmonary aspergillosis: saprophytic aspergillosis (SPA), invasive aspergillosis (IVA) and allergic bronchopulmonary aspergillosis (ABPA)/allergic bronchopulmonary mycosis (ABPM). To know whether Aspergillus (ASP) in SPA only colonizes in preexisting cavities or presents significant pathogenecity, we examined 38 surgical specimens of SPA and 10 post-tuberculous open cavities (PT-OC). Macroscopically, SPA cavities had macroscopic ulcers (81.6%) and bronchi originating from the cavities (68.4%), in contrary to PT-OC that had neither of them. Microscopically, SPA cavities showed shallow ulcers (100%), coagulation necrosis (42.1%) and granulomatous reaction (52.6%), although ASP invasion to the viable lung tissue couldn't be discovered. The lung tissue around the SPA cavities showed various inflammation caused by transbronchial ASP dissemination from the cavities. We concluded that (1) SPA should be considered chronic destructive infection by ASP, but not colonization, (2) SPA couldn't be differentiated in quality from semi-invasive/chronic necrotizing pulmonary aspergillosis, and both should be categorized into secondary bronchopulmonary aspergillosis. Respecting IVA, we investigated 10 autopsy cases. In those cases, the disease was brought about in the lungs having no preexisting lesions. Three forms were distinguished; (1) 5 cases in that coagulation necrosis was a main feature (CN-IVA). (2) 2 cases having lung balls in cavitary lesions (LB-IVA), and (3) 3 cases showing suppurative lesions (SP-IVA). In CN-IVA and LB-IVA cases, ASP invaded to the viable lung tissue. But in 2 cases of SP-IVA, fungal hyphae were identified only in necrotic lesions but not in the viable tissue. Because the "invasive" was vague in definition, we should categorized these cases into primary bronchopulmonary aspergillosis. To determine the primary lesion of ABPA/ABPM, 5 lobectomy specimen were examined. All cases had hard or firm mucous plugs in the proximal bronchi, peripheral to which we found inflammation with tissue eosinophilia (bronchocentric granulomatosis with tissue eosinophilia : 5 cases, xanthogranuloma-like lesions : 2 cases, eosinophilic pneumonia : 2 cases and organizing pneumonia : 4 cases). Conglomerates of degenerated eosinophils, sometimes showing fir-structure, and fungal hyphae were recognized in both of mucous plugs and the peripheral lesions. We concluded that the mucous plug was the primary lesion of ABPA/ABPM.

[Acute respiratory failure caused by tuberculosis requiring mechanical ventilation].

The patients with active tuberculosis in whom respiratory failure requiring mechanical ventilation developed were studied retrospectively. Nine patients (M 8, F 1) were identified at the National Tokyo Hospital during 5 years from January, 1993 to December, 1997. Seven of 9 patients were single men, and the duration of symptoms before admission was over 1 month in all patients, while the time from first visit to diagnosis was less than 7 days. All patients were identified as malnourished, and 7 patients suffered from another underlying diseases. The patients were classified into two groups. Six of 9 patients had pulmonary tuberculosis and the other three had miliary disease. The proportion of cases requiring mechanical ventilation was 0.3% and 8.6%, respectively, in pulmonary tuberculosis and miliary tuberculosis. At the start of mechanical ventilation, PaO2/FIO2 was lower than 200 in all 9 patients, and 6 patients were probably ARDS. Steroids (methylprednisolone 250-1000 mg/day) were used in all 9 patients. Despite the use of mechanical ventilation and antituberculous therapy, 8 out of 9 patients died. Only one patient with miliary tuberculosis survived. The establishment of the therapy for acute respiratory failure is needed so as to improve prognosis of such cases. At the same time, the delay in consulting a doctor led to acute respiratory failure in most cases, so it is also important to encourage tuberculosis patients to visit a doctor as soon as possible, after the appearance of symptoms.

[Detection of Mycobacterium tuberculosis in clinical specimens other than sputum by the Mycobacterium Tuberculosis Direct Test (MTD)--assessment of sample preparation methods and clinical evaluation].

The Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test (MTD) has been widely used as a rapid test for the identification of Mycobacterium tuberculosis complex in clinical samples, and several research groups have verified its clinical usefulness. However, most of the specimens they tested were sputum, and there have been few reports on other specimens. In particular, there have been no reports on assessments of methods of preparing samples other than sputum for the MTD. We assessed methods of preparing samples other than sputum and the influence of a local anesthetic and an anticoagulant that may be present in samples, and also evaluated the MTD as a means of detecting M. tuberculosis in pleural fluid, bronchial lavage cerebrospinal fluid, urine and ascitic fluid. 1. Assessment of three sample preparation methods, i.e., the NALC-NaOH method GuSCN-Diatom nucleic acid extraction method, and the ultrasonication method, revealed that the combination of the NALC-NaOH method and the ultrasonication method, widely used to prepare sputum samples, is also a valid method of preparing other samples. 2. The local anesthetic and the anticoagulant used clinically and remained in specimens did not affect the results of the MTD. 3. Seven (36.8%) of 19 pleural fluid samples from patients diagnosed as tuberculous pleurisy were positive of M. tuberculosis by the MTD, while five (27.8%) of 18 pleural fluid samples cultured for bacteria were positive for M. tuberculosis complex. None of the 20 pleural fluid samples from patients diagnosed as non-tuberculous pleurisy were positive for M. tuberculosis complex either by MTD or culture. 4. Eight (32.0%) of 25 bronchial lavage samples from patients diagnosed as pulmonary tuberculosis were positive for M. tuberculosis complex by the MTD, while 3 (12.0%) were positive by culture. None of the 18 bronchial lavage samples from patients diagnosed as non-tuberculous disease were positive for M. tuberculosis complex either by the MTD or culture. Based on these results, it is concluded that the MTD is a very useful method of detecting M. tuberculosis in clinical samples other than sputum because it is more sensitive than culture on Ogawa's egg medium in detecting M. tuberculosis complex in pleural fluid samples, bronchial lavage samples, and so on, with the same preparation method as used for sputum.