Kekkaku : [Tuberculosis]

[Objective] To contribute to countermeasures against pulmonary tuberculosis in patients with HIV infection through analyzing and evaluating its treatment outcomes and patient management. [Methods] The 'subjects were pulmonary tuberculosis patients newly registered between 2008 and 2014 in whom concomitant HIV infection was detected. For the control, sex- and generation-matched pulmonary tuberculosis patients newly registered in Osaka City -between 2012 and 2014 were adopted. On analysis, the X² test and Fisher's exact test were used, and a significance level below 5% was regarded as significant. [Results] 1) There were 25 pulmonary tuberculosis patients complicated by HIV. All were male -and the mean age was 43.2 years old. 2) The sputum smear positivity rate was 76.0% in the pulmonary tuberculosis patients complicated by HIV and 50.8 % in 250 control pulmonary tuberculosis patients, showing a significantly higher rate in the former. 3) Risk factors for the discontinuation of medication for tuberculosis: In the patients complicated by HIV, the follow- ing risks of the discontinuation of medication were noted in the order of a decreasing frequency: 'Lack of medication helpers' in 68.0%, 'Side effects' in 48.0%, 'Financial prob- lems' in 32.0%, and 'Liver damage' in 28.0%. Those in the control pulmonary tuberculosis patients were 33.2%, 22.8 %, 16.0%, and 11.6%, respectively, showing a significant difference in each factor. 4) The DOTS executing rates were 68.0% and 94.8% in the patients complicated by HIV and control patients, respectively, showing that it was significantly lower in the patients complicated by HIV. On comparison of the treatment outcomes excluding died, on treatment, transferred out, not evaluated, treatment succeeded in 72.7% in the patients complicated by HIV and 92.9% in the control patients, showing a significantly lower success rate in the patients complicated by HIV. The numbers of risk factors of discon- tinuation in. 16 and 6 patients complicated by HIV in whom treatment succeeded and treatment failed/defaulted were 3.8 and 2.8, respectively, showing that the number was higher in patients with successful treatment, and the DOTS execution rates were 75.0% and 33.3%, respectively, showing a higher rate in the successful treatment cases. [Conclusion] The treatment outcome was significantly poorer in pulmonary tuberculosis patients complicated by HIV than in the control pulmonary tuberculosis patients. More risk factors for the discontinuation of medication were observed and the DOTS execution rate was lower in the patients complicated by HIV, suggesting that risk assess- fient for the discontinuation of medication should be appro- priately performed, and support for medication should be strengthened.

[Objectives] To investigate the adverse reactions of antimicrobial drugs in multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR- TB) patients. [Results] Sixty-six patients with MDR-TB who have been treated from 2010 through 2014 were evaluated in the retro- spective analysis. Variety of adverse reactions including psychological reaction, central nervous system toxicity, ophthalmic toxicity, peripheral neurotoxicity, gastrointestinal reactions, hematologic abnormalities, musculoskeletal adverse effects, and endocrine disorder, were observed. However, there was no fatal case due to the adverse reactions of the anti-tubercu- losis drugs in this observation. [Conclusions] Drugs for MDR-TB and XDR-TB treatment are limited and the adverse reactions of drugs for MDR-TB and XDR-TB are not well-known. Therefore, the treatment may fail due to inappropriate management of adverse events. MDR-TB and XDR-TB should be treated by the experts of the adverse reactions of all anti-tuberculosis drugs.

[Methods] We retrospectively studied 115 con- secutive pulmonary tuberculosis patients whose sputum smear was .negative, diagnosed by positive culture and/or PCR of various samples, or positive QFT. [Results] The culture positive rate of tuberculosis by spu- tum, gastric aspirate, bronchoscopy, and computed tomogra- phy (CT)-guided needle biopsy samples was 55.7%, 45.6%, 73.2%, and 71.4%, respectively. In multivariate analysis, negative or unknown sputum PCR, negative or unknown gastric aspirate, and minimal spread of tuberculosis were risk factors for negative culture from both sputum and gas- tric aspirate. Sputum culture was positive in only one of the four patients with multi-drug resistant Mycobacterium tuberculosis. [Conclusion] Invasive diagnostic procedures such as fiber- optic bronchoscopy should be considered in patients with negative sputum PCR and minimal spread of tuberculosis.

[Objectives and Materials] Based on the tuber- culosis (TB) surveillance database, the incidence rates of TB infection and active disease among healthcare workers were observed for female nurses and male doctors in 2010 in comparison with those of the general population. [Results] The relative risk (RR) of active TB among female nurses aged 20-69 years was 4.86 (95% confidence interval: 4.31-5.45) for 2010, which has increased from 2.30 observed in 1987-1997. The RR was highest for nurses aged 20-29 years at 8.84 and declined with age until 3.60 for those aged 50-59 years that was still significantly higher than 1. For male doctors the RR was significantly higher than 1 only for those aged 39 years or younger. The rates of those who were -indicated for treatment of latent TB infection (LTBI) were clearly higher among healthcare workers; for female nurses the RR was 32.7 (95% CI: 30.5-35.0), ranging from the highest level of 62.8 among those aged 20-29 years down to 11.6 for those aged 60-69 years. For male doctors also, the RR was high at 9.7 (7.9- 11.7) for 20-69 years, ranging from 14.5 for those aged 20- 29 years down to 5.3 for those aged 60-69 years. [Discussion] TB cases of nurses and doctors were more likely to be detected by the active case finding measures such as periodic screening and contact investigations than cases in the general population, which indicates the current effort of addressing the occupational exposure in the healthcare set- tings. The high level of risk of TB disease as Iwell as LTBI among healthcare professions and its possibly increasing trend as. seen in female nurses warrants further strengthening of monitoring of the problem and overall countermeasures in their workplaces.

We present a case of a 59-year-old man with pulmonary tuberculosis and esophago-bronchial fistulas after chemoradiotherapy (CRT) for esophageal cancer. A lung nodule was detected in the right upper lobe and diagnosed as an inactive old inflammatory tumor by several examinations, including bronchoscopy. He was admitted to our hospital because of dysphagia 3 months later. The esophagoscopy showed advanced, stage IVa esophageal cancer. He received CRT at the university hospital and experienced partial remission. Two months later, he called an ambulance for dyspnea and chest roentgenography showed pneumonia in the right lung fields. The respiratory failure was severe and required mechanical ventilation. The intubation and bronchoscopy were performed in the emergency room. The bronchoscopy showed the esophago-bronchial fistulas due to recurrent esophageal cancer and backward flow of digestive juice. Mycobacterium tuberculosis was isolated from aspi- rated sputum several days later. Administrations of isoniazid/ levofloxacin and intramuscular injection of streptomycin were started. The patient moved to a medical center with a tuberculosis ward while on the respirator. The tuberculosis was not detected in the ward for 2 months. The patient returned to our hospital, but his esophageal cancer had progressed with distant metastases, he died 3 weeks later. When performing CRT, we should be careful for relapse of tuberculosis.

[Background] Interferon-gamma release assay (IGRA) is necessary for evaluating Mycobacteriun tuber- culosis infection in Japan. Application of IGRA for contact surveys has been extended for the aged population; how- ever, there is little information on positive rates with Quanti- FERON® in Tube (QFT-3G) and T-SPOT.®TB (T-SPOT), which sometimes makes it difficult to interpret the results of IGRA performed in contact investigation including the aged population. [Objective] To estimate the positive rate of IGRAs by age group in the general population as well as among healthcare workers. [Methods] We requested all public health centers in Japan to provide contact investigation data for which the risk of infection is limited. Collected data included results of IGRAs in the target group, sputum bacteriological examinations and chest-image findings, and symptoms of the index cases as well as closeness and duration of contact between the index case and the target group. We scrutinized all the cases and exclude data that were not eligible for this study. Positive rates by age group were calculated by summing the number of contacts who were "positive" and dividing by the number of examinees. [Results] In spite of our effort to exclude newly infected persons from the index case, a small portion (probably 3%) may be due to those newly infected by a source case, as it is difficult to exclude those who get infected by casual contact. It is sometimes difficult to collect information on the close- ness and overall duration of contact with the index case, which is a limitation in the questionnaire. Positive rates of IGRA by age group in the general popula- tion were one third to one fifth of the predicted prevalence of infection, which is consistent with findings in the study using QFT Gold (QFT-2G) that IGRA wanes after infection. There were no differences of IGRA positive rate between the general population and health care workers. It may be because the risk of infection for health care workers is similar, as the number of infectious TB patients has been decreasing and infection control in hospitals has generally improved. It may be also because targets for IGRA in contact examina- tion among health care workers tend to be broad including a certain number of low risk staff. [Conclusion] With reference to past studies, we estimated that IGRA positive rates were 5% in the 60's and 15% in the 70's. It will be useful in assessing the possibility or spread of infection for aged groups in contact investigation.

[Objective] To compare the tuberculosis (TB) surveillance systems of Japan and low TB-incidence western countries in terms of institutional design. [Method] We conducted a descriptive comparative study for TB surveillance systems in Japan, the Netherlands, the United Kingdom, and the United States. The following information was collected from self-administrated question- naires and relevant published data: 1) TB notification, 2) TB registration, 3) quality assurance and data protection mechanisms, 4) linkage with other surveillance, and 5) data disclosure. [Result] The basic structure common to all countries sur- veyed was that TB notifications were reported quickly through an online system, as required by law. TB registration data, which included detailed demographic and clinical informa- tion, was shared via the database and available to all admin- istrative levels. In addition, aggregated data reports were published periodically. Information related to TB genotype and data quality assurance, for example, detection of duplication of records, was available in surveillance systems in countries other than Japan. [Conclusion] We propose that developing a sharing mechanism for TB genotype and ensuring better quality assurance would strengthen the Japanese TB surveillance system.

Rifampicin can induce hypothyroidism. We report a case of pulmonary tuberculosis and tuberculous pleurisy that was complicated by rifampicin-induced hypothyroidism. The patient received rifampicin-based tuberculosis treatment and experienced persistent appetite loss, which led us to pro- vide concomitant hypothyroidism treatment. An 85-year-old woman with no underlying thyroid-related disease presented to her local hospital with a 3-month history of appetite and weight loss. A chest radiograph revealed pleural effusions and infiltrative shadows in the lower fields of both lungs, and we also detected high levels of lympho- cytes and adenosine deaminase levels (49.6 IU/1) in the pleu- ral effusion, with positive results from a polymerase chain reaction assay of a sputum sample. Thus, we diagnosed the patient with pulmonary tuberculosis and tuberculous pleurisy, and initiated treatment using isoniazid, rifampicin, etham- butol, and pyrazinamide. Her clinical course was good and her anorexia was improved. However, she subsequently experienced recurrent appetite loss, malaise, and bilateral lower-leg edema. Follow-up laboratory testing revealed that she had developed hypothyroidism. We started treatment using levothyroxine without interrupting the tuberculosis treatment. The loss of appetite and other thyroid-related symptoms were improved. The patient's thyroid function had been normal at her admission, and there were no findings of Hashimoto's thyroiditis or other thyroid conditions. Based on the clinical course, we conclude that the rifampicin induced the hypothyroidism. Therefore, rifampicin-induced hypothyroidism should be considered in cases with persistent appetite loss, even if the patient appears to be experiencing anorexia as an adverse drug reaction.

A 40-year-old woman was admitted to our hos- pital with cough and sputum production. A chest computed tomography (CT) scan revealed a diffuse nodular shadow in the upper lung. The patient was diagnosed with pulmonary tuberculosis, based on a positive T-SPOT®.TB test result of peripheral blood and a positive polymerase chain reaction (PCR) test result for Mycobacterium tuberculosis in gastric aspirates. M.tuberculosis was subsequently isolated from the gastric aspirate specimen. After 2 months of treatment with antituberculous medication, the patient developed a low grade fever and left-sided chest pain. A CT scan revealed a left pleural effusion and a right subphrenic abscess. Tuber- culous pleurisy with paradoxical response was diagnosed on the basis of an increased lymphocyte count and increased adenosine deaminase activity in the pleural fluid exudate. A percutaneous ultrasound-guided needle biopsy of the sub- phrenic abscess was performed. Histological analysis revealed epithelioid cell granulomas with necrosis and PCR for M. tuberculosis using puncture needle washing fluid returned positive results. Based on these findings, a diagnosis of subphrenic abscess with paradoxical response, caused by M. tuberculosis, was made. Subphrenic abscess caused by M. tuberculosis is an important consideration during antituber- culous therapy.

[Aim] To explore the possible role of social network analysis (SNA) in identifying infected contacts and visualizing data in a tuberculosis (TB) contact investigation. [Method] We analyzed TB contact investigation data from an outbreak in a Japanese language school in Tokyo, Japan, in 20XX. Information on places which the index case and his contacts commonly shared was collected in line with the data collected routinely in contact investigation. Average hours of exposure to the index case were calculated for each contact by using SNA software, and the relationship to the index case via commonly shared places was visualized as a sociogram. Statistical analysis was performed to. compare the exposure hours and TB infection statuses, between those . infected, including active TB and latent TB infection (LTBI), and non- infected contacts. [Result] The data on the index TB case and 41 contacts, of whom 5 and 10 were diagnosed with active TB and LTBI, were analyzed. Contacts with active TB and LTBI had 12.5 and 11.5 times longer median hours of exposure, which were significantly longer compared to non-infected contacts. The sociogram summarized the network of index TB case, contacts characterized by exposure hours and infection statuses, and the places shared by the index case and the contacts. [Discussion] SNA analysis was considered to be useful in prioritizing contacts in a TB contact investigation, in assisting interpretation of indeterminate Interferon-Gamma release assay test results, in estimating places where transmission occurred, and visualizing data accrued in TB contact inves- tigations.

[Objective] To determine whether three sputum examinations with fluorescent staining are necessary to diag- nose tuberculosis (TB) in our hospital. [Patients] From April 2005 to December 2012, 379 TB patients were admitted and received anti-TB therapy in our hospital. [Methods] A retrospective study was conducted to assess the positivity rates of sputum smears based on three exami- nations. The positivity rate of first sputum smear and the cumulative smear-positive rates in the second and third were determined. Then, we also determined difference of positivity rates in sputum properties, sampling procedures and cavity formation. [Results] Of the 379 patients who met the screening criteria, 300 tested positive based on the first sputum smear (79.2%). The positivity rate of the first sputum smears was higher in the purulent sputum group than in the mucous sputum group (91.2% vs. 72.3%). Cavity formation, and sputum extraction procedures were not related to the positivity rate of the first sputum smears. In the mucous sputum group, the cumulative smear-positive rate in the second test significantly rose, but did not rise in the third test. [Conclusions] Three sputum smear examinations were necessary in patients who submitted mucous sputum samples. It is important to get purulent sputum.

The prevalence of nontuberculous mycobacterial (NTM) pulmonary disease is increasing in Japan and worldwide, and the importance of proper diagnosis and management of the disease has been recently recognized. Mycobacterium aviun complex (MAC) is the most common and important causative agent of pulmonary disease among nontuberculous mycobacteria. I have described the latest epidemiology of NTM lung disease, clinical feature, disease type, disease progression, diagnosis including serodiagnosis, and treatment strategy of MAC lung disease in this report. There are a lot of unsolved problems in the field of NTM lung disease, therefore, further investigations are required.

BACKGROUND:T-SPOT.TB (T-SPOT), an interferon-gamma release assay, has shown promise as a diagnostic tool for active tuberculosis (TB), and its use is expanding. Addition of the T-Cell Xtend (TCX) reagent may allow delayed processing, and this characteristic is important for using this test in the field. However, limited data is available on the usefulness of T-SPOT with TCX as a field test for diagnosing active TB.PURPOSE:To investigate the clinical utility of T-SPOT with TCX and the risk factors for a false-negative result in patients with active TB.METHODS:A total of 57 patients with active TB who underwent the T-SPOT test with TCX prior to treatment were enrolled between May 2013 and May 2015. One patient with an indeterminate result for T-SPOT was excluded; therefore, the data of 56 patients were eventually included in the final analysis. The basic characteristics and clinical findings were compared between the true-positive and false-negative T-SPOT groups.RESULTS:Of the 56 patients, 40 (71.4%), 13 (23.2%), 3 (5.4%) had true-positive, false-negative, and borderline T-SPOT results, respectively. This study did not reveal any significant risk factors for a false-negative T-SPOT result.CONCLUSION:In this clinical study, the proportion of patients with a false-negative result for T-SPOT with TCX for active TB was higher than that reported previously. Therefore, careful interpretation of a negative result for T-SPOT with TCX is necessary, regardless of the patient's background.

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.

In this article, we reviewed data regarding the previous treatment history, regimen types, and hospitalization status of tuberculosis (TB) patients newly notified in 2014. The duration of treatment and hospitalization, and the treat- ment outcomes of TB patients notified in 2013 were also eval- uated by using a cohort analysis. Of the 19,615 newly notified TB patients in 2014, 1,179 had a previous history of TB treatment. Approximately 90% of all TB patients aged 15-49 years were treated with isoniazid, rifampicin, pyrazinamide, and ethambutol (or strepto- mycin), which is the globally recommended regimen for initial treatment. However, the proportion of patients receiv- ing the standard regimen decreased with their increasing age, and sharply dropped for those aged ≥80 years. Of 15,149 patients with pulmonary TB (PTB), more than 50% of those aged 50 years were hospitalized at the beginning of the TB treatment; the proportion of those hospitalized in each age group increased with the increasing age of the patients. At the end of 2014, the median durations of hospitalization and treatment for all forms of TB notified in 2013 were 62 and 273 days, respectively. For cases notified in 2013, the rates of treatment success for patients with new sputum smear-positive PTB (n=7,600) and for those on re-treatment (n= 529) were 49.6% and 41.8%, respectively. In addition, the treatment success rates for foreign-born patients with new sputum smear-positive PTB (n=289), and those on re- treatment (n= 19) were 59.5% and 36.8%, respectively. The rates lost to follow-up for patients with new sputum smear- positive PTB and those undergoing re-treatment were well below 5% when considering the total number of patients (both foreign-born and Japan-born), as well as only the foreign-born patients. The death rate among all new sputum smear-positive PTB patients was 21.6%, and the rates were relatively higher in the age groups 60-69, 70-79, 80-89, and ≥90 years (13.1%, 21.6%, 33.0%, and 46.7%, respectively).

The occurrence of pulmonary tuberculosis (PTB) and lung cancer as comorbidities has been extensively discussed in many studies. In the past, it was well known that lung cancer is a specific epidemiological successor of PTB and that lung cancer often develops in scars caused by PTB. In recent years, the relevance of the two diseases has drawn attention in terms of the close epidemiological connection and chronic inflammation-associated carcinogenesis. In Japanese case series studies, most lung cancer patients with tuberculous sequelae received supportive care alone in the past, but more recently, the use of aggressive lung cancer treatment is increasing. Many studies on PTB and lung cancer as comorbidities have revealed that active PTB is noted in 2-5% of lung cancer cases, whereas lung cancer is noted in 1-2% of active PTB cases. In such instances of comorbidity, many active PTB cases showed Type II (non-extensively cavitary disease) and Spread 2-3 (intermediate-extensive diseases) on chest X-rays, but standard anti-tuberculosis treatment easily eradicates negative conversion of sputum culture for M. tuberculosis; lung cancer cases were often stage III- IV and squamous cell carcinoma predominant, and the administration of aggressive treatment for lung cancer is increasing. The major clinical problems associated with PTB and lung cancer as comorbidities include delay in diagnosis (doctor's delay) and therapeutic limitations. The former involves two factors of radiographic interpretation: the principles of parsimony (Occam's razor) and visual search; the latter involves three factors of lung cancer treatment: infectivity of M.tuberculosis, anatomical limitation due to lung damage by tuberculosis, and drug-drug interactions between rifampicin and anti-cancer drugs, especially molecularly targeted drugs. The comorbidity of these two diseases is an important health-related issue in Japan. In the treatment of PTB, the possibility of concurrent lung cancer should be kept in mind, while in the treatment of lung cancer, the possibility of concurrent PTB should also be considered.

BACKGROUNDPulmonary disease caused by nontuberculous mycobacteria has a variable clinical course. Although this is possibly the result of not only host factors, but also bacterial factors, many questions remain to be answered regarding these manifestations.METHODSTo assess the relationship between the progression of pulmonary Mycobacterium avium disease and bacterial factors we performed variable number tandem repeats (VNTR) typing analysis of M. avium tandem repeats (MATR) in M. avium isolates from 46 patients with different clinical courses, and furthermore, examined the association between disease progression and a pMAH135 plasmid derived from M. avium.RESULTSIn patients whose treatment was initiated because of worsenedchest radiograph findings and/or clinical symptoms within 18 months after being diagnosed with pulmonary M. avium disease, the detection rate of 6 genes located in pMAH135 was 35.3-47.1% for 17 isolates. However, in untreated patients with a stable condition, these rates were 10.3-13.8% in 29 isolates. MATR-VNTR typing analysis showed that isolates from patients with worsened disease and those with stable disease are clustered differently. In cluster III, the number of isolates from patients with worsened disease was higher than that from patients with stable disease (p = 0.019), and furthermore, the number of isolates carrying pMAH135 genes was higher than that not carrying pMAH135 genes (p ≤ 0.001).CONCLUSIONThese results indicate an association between the progression of pulmonary M. avium disease and pMAH135. The presence of pMAH135 genes might be a useful prognostic indicator for pulmonary M. avium disease and may serve as one criterion for treatment initiation.

OBJECTIVEThe incidence rate of nontuberculous mycobacterial (NTM) infection has been increasing globally in recent years. However, reports of osteoarticular NTM infection are relatively rare. We report the characteristic clinical features of patients with osteoarticular NTM infection.PATIENTS AND METHODSWe examined 14 patients with osteoarticular NTM infection (mean age, 68 years) were treated in our hospital in the 20 years between 1995 and 2015.RESULTSThe rate of osteoarticular NTM infection in whole osteoarticular infection during the same period in our hospital was 2.7%. The NTM species. isolated from the 14 patients included Mycobacterium avium (n = 7), M. intracellulare (n = 5), M. fortuitum (n = 1), and M. kansasii (n = 1). Twelve patients had spinal involvements, and their levels were categorized as thoracic (n = 3), lumbar (n = 4), thoracolumbar (n = 1), and cervicothoracic (n = 4), with an average number of affected vertebra of 4.4. Nine patients had pulmonary lesions, including fibrocavitary (n = 5) and nodular/ bronchiectatic types (n = 4). Nine patients had lesions in sites other than the spinal and pulmonary regions, including the skin (n = 6), rib (n = 2), ilium (n = 2), humerus (n = 2), ulna (n = 1), wrist (n = 1), knee joint (n = 1), femur (n = 2), tibia (n = 1), toe (n = 1), and kidney (n = 1). In the initial examination, 11 patients were misdiagnosed, which delayed the final diagnosis in 7 patients. Six patients received chemotherapy with rifampicin, ethambutol, and clarithromycin, and 8 patients received other macrolide-based therapy. Five patients underwent surgical treatments in former hospitals, and 8 patients underwent surgical treatments (including salvage surgeries) in our hospital. With regard to outcome, 9 patients achieved healing, 2 patients with relapse were healed after retreatment, 1 patient was undergoing treatment, 1 patient had interrupted treatment, and 1 patient died during the treatment period.DISCUSSIONOsteoarticular NTM infection presented widely spread lesions in the spine and other various locations, mostly developed as a part of disseminated infection. Most patients were aged or immunosuppressed, but some patients were healthy individuals with no relevant medical history. Thus, if a patient is diagnosed with disseminated NTM infection, examination for possible lesions in other sites, including the bone and joint, should be performed. Cutaneous lesions, including subcutaneous abscess, were also characteristic. It is worth mentioning that such lesions can develop even under chemotherapy. Given the increasing trend in the overall incidence of NTM infection, awareness that NTM is a causative organism of osteoarticular infection is important.