Molecular Epidemiology of Drug-Resistant Mycobacterium Tuberculosis in Japan.

Clinical isolates of drug-resistant (isoniazid and/or rifampicin-resistant) Mycobacterium tuberculosis were obtained from 254 patients diagnosed with drug-resistant tuberculosis in Japan from April 2015 to March 2017 in National Hospital Organization hospitals. The 254 patients were approximately 32% of all 795 patients who were diagnosed with culture-confirmed drug-resistant tuberculosis from 2015 to 2016 nationwide in Japan. The whole-genome sequences of all the isolates from the 254 patients and the lineages of these isolates were determined, and phylogenetic trees were constructed based on single nucleotide polymorphism concatemers. Of these patients, 202 (79.5%) were born in Japan and 52 (20.5%) were born elsewhere. Of the 254 drug-resistant isolates, 54 (21.3%) were multidrug resistant, being resistant to both isoniazid and rifampicin. The percentages of multidrug-resistant isolates were significantly higher in foreign-born (38.5% [20/52]) than Japanese-born patients (16.8% [34/202]). Of the 54 multidrug-resistant isolates, nine were extensively drug resistant, which were all obtained from Japanese-born patients. Five extensively drug-resistant isolates were obtained from patients with incipient tuberculosis. A significant number of multidrug-resistant M. tuberculosis strains were isolated from foreign-born patients from Asian countries that have a high tuberculosis burden. Foreign-derived isolates affect the nationwide genetic diversity of drug-resistant M. tuberculosis in Japan. Extensively drug-resistant M. tuberculosis isolates were transmitted among the Japanese population. IMPORTANCE The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis. Of the tuberculosis patients in the present study, 5.4% and 1.0% showed resistance to isoniazid and rifampicin, respectively, and 0.7% were multidrug resistant. The objective of this study was to clarify the molecular epidemiological properties of drug-resistant tuberculosis in Japan. Molecular epidemiology provides several clues to inform potential measures to control drug-resistant tuberculosis in Japan.

Cathepsin S, a new serum biomarker of sarcoidosis discovered by transcriptome analysis of alveolar macrophages.

BACKGROUND: Development of reliable new biomarkers remains crucial to improve diagnosis and assessing disease activity in sarcoidosis. The objective of this study was to seek such markers from the gene expression signature of alveolar macrophages by transcriptome analysis. METHODS: Pooled RNA extracted from alveolar macrophages from patients with active sarcoidosis and control patients was subjected to transcriptome analysis using microarrays. Expressed gene intensity in sarcoidosis relative to that in control was calculated. We measured serum cathepsin S (CTSS) concentrations in 89 healthy volunteers, 107 patients with sarcoidosis, 26 with interstitial pneumonia, 150 with pneumoconiosis, and 76 with pulmonary mycobacteriosis by the enzyme-linked immunosorbent assay. RESULTS: Among 12 genes with ratios higher than that of a housekeeping gene, we selected CTSS for scrutinizing protein expression in serum because of the feasibility of the protein assay. CTSS concentrations were significantly increased in sarcoidosis compared with not only controls but also all the other lung diseases. Receiver operating characteristics curve for sarcoidosis and parenchymal lung diseases revealed an area under the curve of 0.800 (95% confidence interval, 0.751-0.850; p=1.4 x 10-18) with 70% sensitivity and 78% specificity at a CTSS concentration of 15.5 ng/ml. A significant trend was identified between CTSS concentrations and the number of affected organs. Serum CTSS concentrations varied in parallel with clinical courses both spontaneously and in response to corticosteroid therapy. Epithelioid cells in granulomas were positive for immunohistochemical staining with CTSS. CONCLUSIONS: CTSS has the potential to be a useful biomarker in sarcoidosis.

[CHANGES IN MAC ANTIBODY LEVELS BEFORE AND AFTER SURGERY AND AT THE TIME OF RELAPSE/RECURRENCE IN MAC LUNG DISEASE--Can MAC Antibodies Be an Indicator of Postoperative Relapse/Recurrence?].

BACKGROUND: Patients receiving surgical treatment for Mycobacterium avium complex (MAC), lung disease should be followed up with careful attention paid to relapse/recurrence, but there is some debate regarding the findings based on which relapse/recurrence should be diagnosed. PURPOSE AND METHODS: We hypothesized that we might be able to use anti-GPL core IgA antibodies (MAC antibodies), which have been attracting attention as a factor that may support diagnosis of MAC lung disease, to diagnose postoperative relapse/recurrence. Therefore, we compared the levels of these antibodies before and at the time of relapse/recurrence, and also compared antibody titers before and after surgery. RESULT: MAC antibody titers were elevated by an average of about 50% at the time of relapse/recurrence compared to those before relapse/recurrence for 6 patients. In contrast, MAC antibody titers were about 30% lower after surgery compared to those before surgery for 37 patients. CONCLUSION: It may be possible to use MAC antibodies as an indicator of postoperative relapse/recurrence for MAC lung disease.

Bronchial occlusion with Endobronchial Watanabe Spigots for massive hemoptysis in a patient with pulmonary Mycobacterium avium complex infection.

The safety of occlusion with Endobronchial Watanabe Spigots (EWS) for the management of hemoptysis associated with chronic respiratory tract infection has not yet been established. A 57-year-old woman diagnosed as having pulmonary Mycobacterium avium complex (MAC) infection presented to our hospital with hemoptysis. She underwent bronchoscopy for bronchial occlusion with EWS, which resulted in the resolution of hemoptysis. Subsequently, she underwent bronchial artery embolization and then EWS were removed. During placement of EWS, no worsening of infection was observed. After removal of EWS, there was no recurrence of hemoptysis. Bronchial occlusion with EWS for hemoptysis associated with pulmonary MAC infection can be performed safely.

[A STUDY OF SURGICAL TREATMENT FOR PATIENTS WITH MYCOBACTERIUM ABSCESSUS PULMONARY DISEASE AND A COMPARATIVE EXAMINATION OF MYCOBACTERIUM AVIUM COMPLEX DISEASE].

OBJECTIVE: This is a retrospective study on six surgical cases of Mycobacterium abscessus pulmonary disease, including a comparison with M. avium complex (MAC) disease. SUBJECTS AND METHODS: We performed surgery for six cases of M. abscessus pulmonary disease between July 2012 and June 2014. In all the cases, video-assisted thoracic surgery alone was performed. Age, sex, bacillus identification method, disease type, preoperative anti-glycopeptidolipid core immunoglobulin A antibody value, preoperative chemotherapy, preoperative chemotherapy period, adaptation of the operation, surgical method, result of the bacillus culture of an organization that was extracted at operation, postoperative hospitalization period, surgical complications, and postoperative relapse were examined for the six cases of M. abscessus pulmonary disease. In addition, the cases were compared with 36 cases of MAC disease for which operation was performed during the same period. RESULT: None of the patients had major surgical complications or in-hospital death. Although three patients survived for more than 1 postoperative year and completed chemotherapy, relapses are not accepted in all cases at present. In the comparison with MAC disease, the mean preoperative chemotherapy period for M. abscessus pulmonary disease was 5.5 months, which was 18.9 months shorter than that for MAC disease, with a statistically significant difference. CONCLUSION AND CONSIDERATION: Surgery for M. abscessus pulmonary disease may be considered a safe and effective therapeutic procedure. Moreover, some physicians believe that surgical treatment is required at an earlier stage of M. abscessus pulmonary disease compared with MAC disease.

[A study of relapse/recurrence cases after surgical treatment for patients with pulmonary nontuberculous mycobacteriosis].

PURPOSE: This is a retrospective study on relapse/recurrence of surgical cases of pulmonary nontuberculous mycobacteriosis (NTM). Surgical treatment was performed at one hospital and by one surgeon. METHOD: Fifty patients had undergone surgical treatment from August 2004 to July 2011 in hospital. From this group, 37 patients were selected after one year, and of these, 9 patients had a relapse/recurrence (group A) and the others (28 patients without relapse/recurrence, group B). Data was recorded about their age, gender, pre-operative image score, cavernous lesions, residual lesions after operation, drugs of pre-operative chemotherapy, the duration of pre-operative chemotherapy, the duration of any follow-up after operation, type of mycobacteria, the results of bacterial cultivation of surgical specimens, type of mycobacterium and operative procedure. RESULT: Three factors, the result of bacterial cultivation of surgical specimens, duration of chemotherapy before operation and existence of residual lesions, showed a significant difference statistically. No case with major surgical complication and hospital death was recognized. CONCLUSION: The visible foci should be removed as thoroughly as possible. Pre-operative chemotherapy should not be continued unnecessarily, and surgical treatment should be chosen at an early stage. The results of bacterial cultures of surgical specimens could be very useful for predicting the possibility of relapse/recurrence after operation. Surgical treatments of our patients were carried out safely. However, as the patients have a risk of relapse/recurrence, they require careful monitoring and post-operative chemotherapy over along period.

[Clinical analysis of drug interaction between rifampicin and clarithromycin which are used for treating pulmonary Mycobacterium avium complex infection].

PURPOSE: We reviewed the interaction between rifampicin (RFP) and clarithromycin (CAM) during treatment of pulmonary Mycobacterium avium complex infection. SUBJECTS AND METHODS: The subjects were patients with pulmonary non-tuberculous acid-fast bacillus infection during the period from September 2004 to January 2006 who consented to this study. Drug blood concentrations were compared with the minimum inhibitory concentrations for M. avium isolated from sputum and blood levels of CAM were assessed when the time of administration was changed for RFP. RESULTS: The blood concentration of CAM showed a marked decrease in all cases (n = 6) when administered together with RFP, but there was no significant difference in the blood concentration of 14-R-hydroxy-clarithromycin (M-5), the active metabolite of CAM. However, the total blood concentration of CAM and M-5 showed a significant fall, similar to the blood concentration of CAM alone. When the blood concentration and bacterial MIC were compared for RFP, the blood concentration exceeded five MIC(s) in six samples as did the CAM+M-5 level in four out of six samples. There was no significant difference in the blood concentration of CAM (n = 5) when the time of RFP administration was altered. CONCLUSION; Because the total blood concentration of CAM+M-5 fell markedly by co-administration of RFP, this might have an influence on the antibacterial effect of CAM. In addition, examination of the administration of RFP and CAM at different times showed that the blood concentration of CAM did not increase and the influence of induction of hepatic drug-metabolizing enzymes by RFP could not be avoided.

[A case of pulmonary tuberculosis complicated with tuberculosis of bilateral cervical lymph nodes and exacerbated pericostal abscess].

A 23-year-old man was admitted to our hospital because of cough and sputum in April 2001. A chest roentgenogram revealed infiltrative shadow with cavity formation in the bilateral lung fields. He was treated with sensitive antituberculous drugs. After starting the antituberculous therapy with INH, RFP, EB and PZA, bilateral cervical lymphadenopathy developed. Three months later, pericostal abscess appeared in the left anterior chest wall. Microscopic examination of the specimen obtained by needle aspiration biopsy disclosed positive for acid-fast bacilli. Smears of the pus showed acidfast bacilli identified as Mycobacterium tuberculosis by DNA-DNA PCR method. He developed tuberculous bilateral cervical lymphadenopathy and pericostal abscess during the course of antituberculosis chemotherapy. Drug sensitivity test revealed that tubercle bacilli in this case were sensitive. One year after the administration of chemotherapy, cervical lymphadenopathy and pericostal abscess were improved. Both masses were discontinuous with pulmonary tuberculosis and the possibility of lymphogenous spread of organism was speculated as its etiology. We assumed that both masses were due to paradoxical response to the antituberculosis chemotherapy.

[A case of multidrug-resistant tuberculosis (MDR-TB) in young female complicated with acute respiratory distress syndrome and developing multiple giant cysts and pneumothorax in both lung].

A 20-year-old woman was admitted to our hospital because of cough and dyspnea in April 2001. On admission, laboratory data showed positive inflammatory signs. A chest roentogenogram revealed infiltrated shadow in the bilateral lung fields. Sputum smear examination showed acid-fast bacilli identified as Mycobacterium tuberculosis by DNA-DNA PCR method. Four days after admission, she had an acute respiratory distress syndrome (ARDS) and serious liver dysfunction. Moreover, drug sensitivity test revealed that this case was multidrug-resistant tuberculosis (MDR-TB), and she was treated with sensitive anti-tuberculous drugs (PZA, SM, LVFX). Three months later, her sputa converted to negative for tubercle bacillis, however, a chest computed tomogram (CT) revealed multiple giant cysts in the bilateral lung fields, which developed during treatment. Pneumothorax of both sides was repeatedly observed, and it was difficult to treat. At present (1 year after admission), multiple giant cysts stopped its progression and treatment for tuberculosis is being continued.

[An autopsy case with subacute spinal cord disease showing progressive paraplegia].

We report a 72-year-old woman who died of respitory failure. History included onset of diabetes mellitus at the age of 67 years and hypertension at the age of 72 years. The patient had been in good health otherwise until 2000, when she had onset of numbness or tingling of the bilateral lower limbs. On December 3, 2000, she was admitted to a hospital in the vicinity of her home because of the above-mentioned complaints. Neurological examinations revealed progressive paraplegia. Symptoms and signs suggested Guillain-Barré syndrome. Examinations of cerebrospinal fluids revealed cell count of 338/3 (mono 72%, poly 18%) and protein value of 100 mg/dl. Later the patient course deteriorated. On December 15, 2000, she was admitted to Hakujikai Memorial Hospital for the second time. Ten days later, MRI examination showed diffuse swelling of the spinal cord from the cervical (C 3/4) level to the thoracic level. Gd-enhanced T 1-weighted MRI performed 22 days later showed a partially enhanced lesion at the thoracic (Th 5/6) level of the spinal cord. The patient was treated with steroid therapy (methylprednisolone 500 mg/dl). She died of respiratory failure on January 6, 2001. The patient was presented in a neurological CPC. Neurological and imaging findings suggested a transverse myelopathy. However, there were several points in this case that were unusual for a typical transverse myelopathy, such as total sensory loss below spinal segments of thoracic level (Th 5) and motor weakness of the upper limbs of upper segment of the same level. A clinical neurologist concluded that the patient had subacute transverse myelopathy with fused multiple pathy pathologic lesions. We discussed whether this case was a transverse myelopathy or multiple sclerosis. Post mortem examination revealed acute necrotic myelopathy affecting the spinal cord from the second cervical to the tenth thoracic vertebrae, with conspicuous infiltration of CD 68-positive macrophages involving both gray and white matter, partially necrotic associated with scattered UCHL-1 dominants lymphocytic infiltration of T cells around vessels. There were relatively older lesions with demyelinating features in the spinal roots that were particularly dominant in the anterior roots. No demyelinated plaques in the optic chiasm, tracts and nerves, or in the cerebero-cerebellar white matter were found. Systemic pathological diagnosis was lung edema with fresh hemorrhage, pancreatic atrophy consistent with diabetes mellitus and choleductlithiasis.