A retrospective study of pulse steroid therapy for acute respiratory failure associated with tuberculosis.

BACKGROUND: Tuberculosis can cause acute respiratory failure, which is associated with a high mortality rate, even in patients receiving effective anti-tuberculosis therapy. We retrospectively analyzed patients with acute respiratory failure associated with tuberculosis who underwent pulse steroid therapy to describe the clinical characteristics and effectiveness of pulse steroid therapy in this condition. METHODS: The medical records of patients admitted to our hospital for culture-proven tuberculosis treatment from April 1, 2017, to March 31, 2022, who received pulse steroid therapy for acute respiratory failure associated with tuberculosis were reviewed. RESULTS: In total, 10 patients were included in this study. Chest computed tomography (CT) revealed diffuse ground-glass opacities and consolidation in these patients. Overall, 70% of the patients (7/10) showed an adjudicated response to pulse steroid therapy, with improved respiratory condition and radiological findings. Three patients died without response to pulse steroid therapy. One patient died of pancreatic cancer after recovering from respiratory failure. The remaining six patients were discharged without supplemental oxygen and completed anti-tuberculosis therapy. CONCLUSIONS: Pulse steroid therapy can lead to dramatic improvements in some patients with acute respiratory failure associated with tuberculosis.

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial.

BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

Performance evaluation of Xpert MTB/RIF in a moderate tuberculosis incidence compared with TaqMan MTB and TRCRapid M.TB.

Xpert MTB/RIF is an automated nucleic acid amplification test (NAT) that can detect the presence of Mycobacterium tuberculosis complex (MTC) in clinical specimens as well as rifampicin (RIF) resistance resulting from rpoB mutation. Despite its high sensitivity and specificity for diagnosing tuberculosis (TB) with or without RIF resistance, the clinical performance of the test is variable. In this study, we evaluated the performance of Xpert MTB/RIF in a setting of moderate TB burden and high medical resources. A total of 427 sputum specimens were obtained from 237 suspected TB cases. Of these, 159 were identified as active TB, while the other 78 were non-TB diseases. The overall sensitivity and specificity of MTC detection by Xpert MTB/RIF using culture results as a reference were 86.8% [95% confidence interval (CI): 81.8%-90.6%] and 96.8% (95% CI: 93.1%-98.5%), respectively. Among MTC-positive culture specimens, Xpert MTB/RIF positivity was 95.2% (95% CI: 91.2%-97.5%) in smear-positive and 44.7% (95% CI 30.1-60.3) in smear-negative specimens. Xpert MTB/RIF was similar to other NATs (TaqMan MTB and TRCRapid M.TB) in terms of performance. Xpert MTB/RIF detected 25 RIF-resistant isolates as compared to 22 with the mycobacterial growth indicator tube antimicrobial susceptibility testing system, yielding a sensitivity of 100% (95% CI: 85.1%-100%) and specificity of 98.3% (95% CI: 95.1%-99.4%). These results indicate that although sensitivity in smear-negative/culture-positive specimens was relatively low, Xpert MTB/RIF is a useful diagnostic tool for detecting TB and RIF resistance even in settings of moderate TB burden.

[ANTI-TUBERCULOSIS THERAPY AND PARADOXICAL RESPONSE WHEN TUBERCULOSIS DEVELOPS UNDER THE INFLUENCE OF BIOLOGICS FOR RHEUMATOID ARTHRITIS].

A paradoxical response is designated as the clinical or radiological worsening of pre-existing TB lesions or the development of new lesions during appropriate anti-TB treatment. Tuberculosis bacilli have no toxin and the organism apparently does not produce any toxins, so the virulence depends on a response to the host immune reaction. According to our report, the annual reported numbers of tuberculosis cases and death did not decrease during biologics treatment in Japan. We have been monitoring and analyzing all the TB cases activated during adalimumab treatments in Japan. According to the analysis, there was no TB related death and severe sequelae in patients with lung tuberculosis without extra pulmonary TB; TB related deaths were caused not by delays of diagnosis and therapy but by the paradoxical response following miliary TB. Paradoxical response after abrupt cessation of anti-TB treatment is caused by immune activation to cell components despite TB bacilli are alive or dead. So, we concluded that the abrupt cessation of anti-TNF agents after TB development could activate immune response causing paradoxical response, which lead to severe sequelae and death, and that continuation of anti-TNF therapy for rheumatoid arthritis in patients with active tuberculosis reactivated during anti-TNF medication is more beneficial than its cessation concerning not only clinical and radiological but also bacteriological outcomes.

[The evaluation of the utility of QuantiFERON TB-Gold In-Tube; QFT-GIT].

Four years has passed since QuantiFERON TB-Gold In-Tube (QFT-GIT), the third generation test, has replaced QuantiFERON-Gold in Japan. The QFT-GIT test detects interferon-gamma (IFN-γ), which is released from lymphocytes present in blood after exposure to the M. tuberculosis complex antigens ESAT-6, CFP-10 and TB7.7. These proteins are absent from all Bacille-Calmette-Guérin (BCG) strains and from most non-tuberculosis mycobacteria, resulting in fewer false positive reactions as seen with the tuberculin skin test (TST). We had various experiences with QFT-GIT during these four years. So, we discussed the usefulness and its limitation of QFT-GIT as follows: 1. Development of the principle of QuantiFERON-GIT: Nobuyuki HARADA (Research Institute of Immune Diagnosis (RIID)). QuantiFERON (QFT) was originated from diagnostic system for bovine in Australia. Although the first generation of QFT, in which PPD had been used as stimulating antigens, was approved in USA, its diagnostic value was not recognized in Japan where most of Japanese are vaccinated with BCG. By combining M. tuberculosis-specific antigens with QFT system, the second generation of QFT, QFT-Gold, was developed, and approved in Japan in 2005. QFT-Gold was soon incorporated in several guidelines such as contact investigations and nosocomial infection measures. Now, QFT-Gold was superseded by the improved QFT-Gold, the current QFT-GIT. However, since QFT-GIT may contain unstable factors including blood volume and shaking methods of blood collection tubes, development of the more improved version is strongly expected. 2. Evaluating the result of QFT-GIT in patients treated with dialysis and immunosuppressive agents: Hidetoshi IGARI (National Hospital Organization Chiba-East National Hospital) The effectiveness of QuantiFERON TB-Gold In-Tube was analyzed in the patients with chronic kidney disease (CKD) and rheumatoid arthritis (RA). QFT positive was 7% and 11% respectively, and indeterminate was 5% and 2% respectively. QFT positive was 2% in hemodialysis patients, significantly lower than that of CKD. QFT positive after biological drug was administered was 8% in RA patients, significantly lower than 15% of RA without biological drug. The rate of latent tuberculosis patients in CKD was as well as health care workers (HCWs) of 8% of QFT positive. On the other hand that of RA might be higher than HCWs. Hemodialysis and biological drug administration might attenuate QFT result with lower rate of positive. The rate of indeterminate was less than 5%. This results was improved in compared with former generation QFT. 3. QFT in Vietnam: Naoto KEICHO (Research Institute of Tuberculosis, JATA). We have promoted collaborative research on tuberculosis with Vietnamese institutes since 2002. NCGM-BMH Medical Collaboration Center plays an important role in the clinical research projects. We report 1) quality assessment of QFT for tuberculosis infection, 2) prevalence and risk factors for tuberculosis infection among hospital workers, and 3) analysis of factors lowering sensitivity of QFT for active tuberculosis. We also discuss significance of QFT in developing countries. 4. Comparison of diagnostic performances using QFT Gold and Gold In-Tube in patients with active tuberculosis: Tetsuya YAGI (Department of Infectious Diseases, Center of National University Hospital for Infection Control, Nagoya University Hospital). The goal of this study was to assess the diagnostic performances of QFT-GIT compared with QFT-Gold in patients with active tuberculosis in Nagoya University Hospital, in Japan. The sensitivity of QFT-Gold was 87.2%, the specificity of that was 77.5%. The sensitivity of QFT-GIT was 88.8%, specificity 73.2%. The performance of QFT-GIT was the same as that of QFT-Gold. The QFT-GIT tended to show higher concentration values of IFN-γ than that of QFT-Gold especially in patients with extra pulmonary tuberculosis, smear positive pulmonary tuberculosis, both lung lesion and using immunosuppressive medications. 5. Simultaneous and longitudinal comparison between QFT Gold and Gold In-Tube among health care workers; Tomoshige MATSUMOTO (Department of Clinical Laboratory Medicine, Osaka Anti-Tuberculosis Association Osaka Hospital. ex-Osaka Prefectural Medical Center for Respiratory and Allergic Diseases). The aim of this study was to compare the indeterminate rates between QFT-GIT and QFT-Gold tests. And to make longitudinal comparison by QFT-Gold assay to the same HCW. We collected blood samples by simultaneously QFT-Gold and QFT-GIT from 120 staff members in the institute who participated in this prospective comparison study. Moreover, the latest QFT-Gold test was longitudinally compared for the same 55 staff members who have received QFT-Gold before. The statistically significant difference was observed in the results of indeterminate rate between QFT-Gold and QFT-GIT using the same blood samples. It is concluded that QFT-Gold and QFT-GIT are different assays therefore it is difficult to compare QFT-Gold with QFT-GIT data on the same level. Concerning the follow-up test of the 55 people by QFT-Gold, 5 turned from positive to negative and 4 turned from indeterminate to negative. From this analysis, QFT-Gold positive subjects in the previous time have not been always positive. 6. Interpreting QFT "equivocal" results: Kenji MATSUMOTO (Osaka City Public Health Office). The participants were examined QFT-GIT test after two months to four months from last contact of smear-positive tuberculosis cases in contact investigations. We enrolled 79 contacts whose tests of QFT-GIT were equivocal results. The second QFT-GIT results were 42 negative (53.2%), 28 equivocal (35.4%) and nine positive (11.4%). 64% of the second QFT-GIT tests result in negative or positive among the first QFT-GIT equivocal contacts. When the second QFT-GIT tests were positive, it is highly probable that the contacts were infected tuberculosis and we adequately could treat latent tuberculosis infected contacts.

[Considerations on uses of newly developed anti-tuberculosis drugs for multi-drug resistant tuberculosis].

We, group of tuberculosis experts, made discussions over how to improve the quality of treatment of multidrug resistant tuberculosis using a newly developed anti-tuberculosis drug, and at the same time, how to prevent the disadvantages of the treated patients and also that of persons who would be infected with newly produced drug-resistant bacilli, by preventing the emergence of resistance to the new drug. A series of proposals are made.

[Biologics and mycobacterial diseases].

Various biologics such as TNF-alpha inhibitor or IL-6 inhibitor are now widely used for treatment of rheumatoid arthritis. Many reports suggested that one of the major issues is high risk of developing tuberculosis (TB) associated with using these agents, which is especially important in Japan where tuberculosis still remains endemic. Another concern is the risk of development of nontuberculous mycobacterial (NTM) diseases and we have only scanty information about it. The purpose of this symposium is to elucidate the role of biologics in the development of mycobacterial diseases and to establish the strategy to control them. First, Dr. Tohma showed the epidemiologic data of TB risks associated with using biologics calculated from the clinical database on National Database of Rheumatic Diseases by iR-net in Japan. He estimated TB risks in rheumatoid arthritis (RA) patients to be about four times higher compared with general populations and to become even higher by using biologics. He also pointed out a low rate of implementation of QuantiFERON test (QFT) as screening test for TB infection. Next, Dr. Tokuda discussed the issue of NTM disease associated with using biologics. He suggested the airway disease in RA patients might play some role in the development of NTM disease, which may conversely lead to overdiagnosis of NTM disease in RA patients. He suggested that NTM disease should not be uniformly considered a contraindication to treatment with biologics, considering from the results of recent multicenter study showing relatively favorable outcome of NTM patients receiving biologics. Patients with latent tuberculosis infection (LTBI) should receive LTBI treatment before starting biologics. Dr. Kato, a chairperson of the Prevention Committee of the Japanese Society for Tuberculosis, proposed a new LTBI guideline including active implementation of LTBI treatment, introducing interferon gamma release assay, and appropriate selection of persons at high risk for developing TB. Lastly, Dr. Matsumoto stressed the risk of discontinuing TNF-alpha inhibitor during treatment for tuberculosis. He showed from his clinical experience that TNF-alpha inhibitor can be safely used in active TB patient receiving effective antituberculosis chemotherapy and it is even more effective for prevention of paradoxical response. Active discussion was done about the four topics, including the matter beyond present guidelines. We hope these discussions will form the basis for the establishment of new guideline for the management of mycobacterial disease when using immunosuppressive agents including biologics. 1. The risk of developing tuberculosis (TB) and situations of screening for TB risk at administration of biologics-the case of rheumatoid arthritis: Shigeto TOHMA (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital) We calculated the standardized incidence ratio (SIR) of TB from the clinical data on National Database of Rheumatic Diseases by iR-net in Japan (NinJa) and compared with the SIR of TB from the data of the post-marketing surveillances of five biologics. Among 43584 patient-years, forty patients developed TB. The SIR of TB in NinJa was 4.34 (95%CI: 3.00-5.69). According to the post-marketing surveillances of 5 biologics, the SIR of TB were 3.62-34.4. The incidence of TB in patients with RA was higher than general population in Japan, and was increased more by some biologics. We have to recognize the risk of TB when we start biologics therapy to patients with RA. Although the frequency of implementation of QuantiFERON test (QFT) had gradually increased, it was still limited to 41%. In order to predict the risk of developing TB and to prevent TB, it might be better to check all RA patients by QFT at time time of biologics administration. 2. Biologics and nontuberculous mycobacterial diseases: Hitoshi TOKUDA (Social Insurance Central General Hospital) Several topics about the relationship between RA and nontuberculous mycobacterial (NTM) diseases were discussed, which is still poorly understood. It is well known that airway diseases often accompany RA, which may be considered as a possible etiology for development of NTM diseases, but conversely it may lead to overdiagnosis of NTM disease. Next, we evaluated justification for the contraindication of biologics in patients with NTM diseases. Recent multicenter study showed that prognosis of patients developing NTM diseases during treatment with biologics were not always poor, which throws doubt on uniform prohibition of biologics in NTM diseases. 3. Future guideline for treating latent tuberculosis infection: Seiya KATO (Research Institute of Tuberculosis, Japan AntiTuberculosis Association) The Japanese Society for Tuberculosis issued a joint statement on chemoprophylaxis with the Japan College of Rheumatology in 2004. However, issues and challenges due to changing circumstance indicate application of interferon gamma release assay (IGRA), increased variety and indication of biologics, dissemination of knowledge on strategy and system for latent tuberculosis infection (LTBI), etc. Future guideline should include 1) promoting LTBI treatment to achieve low incidence, 2) updated information on IGRAs, 3) treatment strategy and target: contact to infectious cases, immunosuppressive cases (especially HIV and patients treated with biologics), high risk groups, etc. 4) fundamental information on tuberculosis control strategies, especially DOTS. 4. Therapy for RA and tuberculosis in patients with RA and TB activated by anti-TNF treatment: Tomoshige MATSUMOTO (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) Biologics targeting TNF, including infliximab, have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). In 2001, tuberculosis, an ancient and also modem scourge, became spotlighted again, because Keane reported in the New England Journal of Medicine that infliximab administration induced reactivation of tuberculosis. How should we treat RA after we successfully treated tuberculosis? Decisions regarding the treatment of patients with refractory RA in the setting of active tuberculosis remain difficult. We successfully treated RA in patients with tuberculosis by anti-TNF therapy. These demonstrate that anti-TNF therapy can be considered for patients with refractory RA who have tuberculosis and in whom antituberculosis therapy can be maintained.

[Clinical evaluation of a line probe assay kit for the identification of Mycobacterium species and detection of drug-resistant Mycobacterium tuberculosis].

BACKGROUND: Multidrug resistance (MDR) involves resistance to both isoniazid and rifampicin, which makes the treatment of tuberculosis very difficult. Extensive drug resistance (XDR) occurs when, in addition to isoniazid and rifampicin resistance, the microorganisms are resistant to a fluoroquinolone and an injectable agent (e.g., kanamycin, amikacin, or capreomycin). Generally, drug susceptibility testing takes more than 3-4 weeks after the initial cultivation. There is an urgent need to identify methods that can rapidly detect both the presence of Mycobacterium tuberculosis and the status of drug resistance. PURPOSE: This study was aimed at evaluating the line probe assay (LiPA; Nipro Co.), for the identification of Mycobacterium species and detection of mutations associated with antituberculous drugs. RESULTS: We found that LiPA enabled the rapid identification of M. tuberculosis, M. avium, M. intracellulare, and M. kansasii. When the results of the LiPA and conventional drug susceptibility tests were compared, there was no difference in the susceptibility to rifampicin, pyrazinamide, and levofloxacin; however, there was a difference in the susceptibility to isoniazid. CONCLUSION: Thus, LiPA can be used for the rapid identification of Mycobacterium species and the determination of susceptibility to drugs, which can help in the early initiation of appropriate treatment, leading to a reduction in infectiousness.

Comprehensive multicenter evaluation of a new line probe assay kit for identification of Mycobacterium species and detection of drug-resistant Mycobacterium tuberculosis.

We evaluated a new line probe assay (LiPA) kit to identify Mycobacterium species and to detect mutations related to drug resistance in Mycobacterium tuberculosis. A total of 554 clinical isolates of Mycobacterium tuberculosis (n = 316), Mycobacterium avium (n = 71), Mycobacterium intracellulare (n = 51), Mycobacterium kansasii (n = 54), and other Mycobacterium species (n = 62) were tested with the LiPA kit in six hospitals. The LiPA kit was also used to directly test 163 sputum specimens. The results of LiPA identification of Mycobacterium species in clinical isolates were almost identical to those of conventional methods. Compared with standard drug susceptibility testing results for the clinical isolates, LiPA showed a sensitivity and specificity of 98.9% and 97.3%, respectively, for detecting rifampin (RIF)-resistant clinical isolates; 90.6% and 100%, respectively, for isoniazid (INH) resistance; 89.7% and 96.0%, respectively, for pyrazinamide (PZA) resistance; and 93.0% and 100%, respectively, for levofloxacin (LVX) resistance. The LiPA kit could detect target species directly in sputum specimens, with a sensitivity of 85.6%. Its sensitivity and specificity for detecting RIF-, PZA-, and LVX-resistant isolates in the sputum specimens were both 100%, and those for detecting INH-resistant isolates were 75.0% and 92.9%, respectively. The kit was able to identify mycobacterial bacilli at the species level, as well as drug-resistant phenotypes, with a high sensitivity and specificity.

Effectiveness of omalizumab in a patient with severe asthma, low serum IgE level, and lack of sensitized allergens induced by oral steroid therapy: the usefulness of impulse oscillation for assessment of omalizumab therapy.

BACKGROUND: Omalizumab is a humanized monoclonal anti-IgE antibody that was recently approved for the treatment of severe allergic asthma. However, omalizumab is not licensed for allergic asthma in patients with a low serum IgE level (<30 IU/mL) or negative results for specific allergen tests. CASE HISTORY: We present a patient with severe asthma and low serum IgE levels who had negative results for specific allergens induced by oral steroid therapy. Omalizumab administration improved asthma exacerbated forced expiratory volume in 1 s (FEV(1)) and respiratory resistance measurements based on the impulse oscillation technique (Mostgraph-01). The response to omalizumab therapy was evidenced by a decrease in airway resistance at 1 month. CONCLUSIONS: The findings of this case report indicate that omalizumab treatment had beneficial effects in a patient with severe asthma and low total serum IgE levels with negative results for specific IgE, which may have been induced by long-term corticosteroid administration.

Poncet's Disease (Reactive Arthritis Associated with Tuberculosis).

An 82-year-old man with miliary tuberculosis was admitted to our hospital. Approximately six weeks after starting anti-tuberculosis treatment, he complained of pain in the fingers, wrists, and ankles. A histopathological examination of the synovial biopsy revealed nonspecific chronic inflammation with no granulomas. Culture of the biopsy specimen yielded no acid-fast bacilli. Poncet's disease was diagnosed based on the clinical presentation, with no findings suggestive of other diseases. His joint pain rapidly improved with steroid therapy. Tuberculosis can cause arthritis through immune-mediated mechanisms without direct invasion in an entity known as Poncet's disease.

Tuberculosis infection among homeless persons and caregivers in a high-tuberculosis-prevalence area in Japan: a cross-sectional study.

BACKGROUND: Tuberculosis (TB) is a major public health problem. The Airin district of Osaka City has a large population of homeless persons and caregivers and is estimated to be the largest TB-endemic area in the intermediate-prevalence country, Japan. However, there have been few studies of homeless persons and caregivers. The objective of this study is to detect active TB and to assess the prevalence and risk factors for latent TB infection among homeless persons and caregivers. METHODS: We conducted a cross-sectional study for screening TB infection (active and latent TB infections) using questionnaire, chest X-ray (CXR), newly available assay for latent TB infection (QuantiFERON-TB Gold In-Tube; QFT) and clinical evaluation by physicians at the Osaka Socio-Medical Center Hospital between July 2007 and March 2008. Homeless persons and caregivers, aged 30-74 years old, who had not received CXR examination within one year, were recruited. As for risk factors of latent TB infection, the odds ratios (OR) and 95% confidence intervals (95% CI) for QFT-positivity were calculated using logistic regression model. RESULTS: Complete responses were available from 436 individuals (263 homeless persons and 173 caregivers). Four active TB cases (1.5%) among homeless persons were found, while there were no cases among caregivers. Out of these four, three had positive QFT results. One hundred and thirty-three (50.6%) homeless persons and 42 (24.3%) caregivers had positive QFT results. In multivariate analysis, QFT-positivity was independently associated with a long time spent in the Airin district: ≥10 years versus <10 years for homeless (OR = 2.53; 95% CI, 1.39-4.61) and for caregivers (OR = 2.32; 95% CI, 1.05-5.13), and the past exposure to TB patients for caregivers (OR = 3.21; 95% CI, 1.30-7.91) but not for homeless persons (OR = 1.51; 95% CI, 0.71-3.21). CONCLUSIONS: Although no active TB was found for caregivers, one-quarter of them had latent TB infection. In addition to homeless persons, caregivers need examinations for latent TB infection as well as active TB and careful follow-up, especially when they have spent a long time in a TB-endemic area and/or have been exposed to TB patients.

Prediction of the duration needed to achieve culture negativity in patients with active pulmonary tuberculosis using convolutional neural networks and chest radiography.

BACKGROUND: We aimed to predict the duration needed to achieve culture negativity in patients with active pulmonary tuberculosis using convolutional neural networks (CNNs) and chest radiography. METHODS: Medical records were searched for eligible patients with culture-confirmed active pulmonary tuberculosis. The eligible patients were randomly assigned to the training dataset group (N = 180) and the validation dataset group (N = 59). Posteroanterior X-ray radiographs in the standing position were obtained at diagnosis. The image data were augmented by a factor of 10 by randomly shifting and rotating the original image. Thus, 1800 images (112 × 112 pixels, 8-bit grayscale) from 180 patients in the training dataset group were used for training the CNN model. The model performance was evaluated on the validation dataset. RESULTS: The values predicted by the CNN model were significantly associated with the actual values (Pearson's correlation coefficient 0.392, p = 0.002). The mean absolute error was 18.0. The visualization of the layer outputs suggested that the CNN model recognized some of the chest radiographic findings that were useful in predicting the duration needed to achieve culture negativity. CONCLUSIONS: The CNN model was useful for predicting the duration needed to achieve culture negativity in active pulmonary tuberculosis, although the accuracy was unsatisfactory. This study suggests that chest radiography findings are as important as other clinical factors for prediction and could be learned by the machine.

Abatacept for rheumatoid arthritis complicated by disseminated cryptococcosis: a case report.

A 78-year-old man developed disseminated cryptococcosis with central nervous system involvement as encapsulated yeast cells were detected in transbronchial biopsy and skin biopsy specimens, and cerebrospinal fluid. Cryptococcus neoformans was confirmed by culture. He had been treated with low-dose prednisolone and methotrexate for rheumatoid arthritis. He started receiving antifungal therapy with intravenous liposomal amphotericin B followed by oral fluconazole. Methotrexate was discontinued. Approximately 4 months after the course of intravenous liposomal amphotericin B was completed, he complained of pain and swelling of the right wrist, which suggested that rheumatoid arthritis was worsening. Abatacept therapy was initiated along with antifungal therapy, and his symptoms relieved. After 24 months of antifungal therapy, although he was still receiving oral fluconazole, he was doing well and the serum cryptococcal antigen had become negative. Disseminated cryptococcosis is an important opportunistic infection associated with low-dose methotrexate for rheumatoid arthritis. Abatacept therapy may be feasible in strictly selected patients with rheumatoid arthritis complicated with cryptococcosis concomitantly with intensive anti-fungal therapy.

Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB.

Very short gastroesophageal acid reflux during the upright position could be associated with asthma in children.

BACKGROUND: Gastroesophageal reflux disease (GERD) is diagnosed by the reflux index of 24-hour pH monitoring (pH monitoring). In our previous study, GER episodes during the upright position were more frequent than those during the supine position in asthmatic children. In this study, we investigated the clinical usefulness of the mean hourly number of acid refluxes, designated as the mean number of acid refluxes/hour (h) during the upright position in addition to the pH index for the diagnosis of GERD. METHODS: The subjects were 22 preschool asthmatic children. When the reflux index was over 4% or the mean number of acid refluxes/h during the upright position were three times more frequent than those during the supine position even if the reflux index was below 4%, we prescribed famotidine. Children whose asthmatic symptoms improved with famotidine were included in a GERD group. Children who did not meet the criteria by pH monitoring were included in a non-GERD group in asthmatic children. RESULTS: The GERD group was comprised of 9 children. In 2 out of 9 GERD group children, the reflux index was below 4%. The median of the mean number of acid refluxes/h during the upright position was 12.9 in the GERD group, and 3.15 in the non-GERD group. The mean number of acid refluxes/h during the upright position were associated with asthmatic symptoms (p < 0.05). CONCLUSIONS: Reflux during the upright position was associated with asthmatic symptoms. The mean number of acid refluxes/h during the upright position in addition to the reflux index could be useful in the diagnosis of GERD when associated with asthma.

[Future prospects of molecular epidemiology in tuberculosis].

Before the availability of high-resolution genotyping tools in 1990s, there was a prevailing dogma of little genomic sequence diversity in Mycobacterium tuberculosis. Due to the low levels of genetic variation, it was assumed that M. tuberculosis exhibit very little phenotypic variation in immunologic and virulence factors. The fingerprinting method based on restriction fragment length polymorphisms (RFLP) of IS6110 insertion sequences had unveiled the underestimation of the sequence variation in M. tuberculosis and the importance of strain-to-strain variation for understanding pathogenesis, immune mechanisms, bacterial evolution, and host adaptation. This method became a gold standard for strain differentiation in the molecular epidemiological study. It had lead to a profusion of studies in molecular epidemiology such as the detection of unsuspected transmission, the estimation of the extent of recent transmission, the identification of laboratory cross-contamination, the identification of outbreaks, and distinction between reinfection and relapse. This, in 1990s, is the opening of the molecular epidemiology of tuberculosis. After the completion of genome project of the M. tuberculosis laboratory strain H37Rv, some of the clinical isolates were completely sequenced. This prompted the in silico genome comparison and identified various genomic markers which can give a unifying framework for both epidemiology and evolutionary analysis of M. tuberculosis population. Of them, variable numbers of tandem repeats (VNTR) was found as the most promising PCR-based method which can provide adequate discrimination of M. tuberculosis strains in many cases, including the estimation of M. tuberculosis transmission and the identification of genetic lineages. PCR-based VNTR analysis is easy, rapid, and highly specific and can generate portable digit-based data, unlike the analog information obtained from IS6110 RFLP which is labor intensive. In this regards, investigators can easily compare the genotypic data of independent studies between different laboratories. With the advantages, VNTR surpassed IS6110 RFLP and became the first line genotyping method in molecular epidemiology. One of the most attractive potentials on this method is its applicability for establishment of the database of M. tuberculosis genotype which covers not only local area but also world wide scale. This would open the door to "in silico epidemiology" which brings a breakthrough on the current TB control program. The optimization and standardization of the combination of VNTR loci for strain genotyping is the only but hard issue for the development of global database system. Road to the global Mtb genotype database is hard, but we believe, "Yes, We Can!". Another attractive potential of VNTR is its use for phylogenetic analysis, although more intensive research on this with using comprehensive marker sets, such as large sequence polymorphisms and single-nucleotide polymorphisms are required. Again, with the advantages of VNTR analysis, i.e., easy, rapid, specific, and digit-based data, VNTR became the first line method in molecular epidemiology. Molecular epidemiology of tuberculosis is expanding its research field from the investigation of TB transmission to more basic science such as evolution and phylogeographic distribution. In this symposium, we have invited four opinion leaders in molecular epidemiology of TB in Japan who are talking about each title as followed. 1. Establishment of the standard VNTR analysis systems for Tuberculosis (TB) and preparation of databases for TB genotyping: Shinji MAEDA and Yoshiro MURASE (Department of Mycobacterium Reference and Research, Research Institute of Tuberculosis, JATA). We have already reported the JATA (12)-VNTR system for TB genotyping in Japan. However, by comparison of cluster formation rate, the discrimination power of JATA (12)-VNTR was lower than that of IS6110 RFLP analysis. Therefore, we improved the JATA (12)-VNTR system for developing discrimination power. By addition of 3 loci (ETR-A, VNTR-1982 and VNTR-2163 a) to JATA (12)-VNTR, we established new JATA (15)-VNTR. We found that the discrimination power of JATA (15)-VNTR was almost the same as that of RFLP analysis. 2. Molecular epidemiology of Mycobacterium tuberculosis reviewed by molecular epidemiology of other pathogenic bacteria: Eiji YOKOYAMA (Division of Bacteriology, Chiba Prefectural Institute of Public Health). Molecular epidemiology of M. tuberculosis should be progressed to two goals. First is the short-term goal that intends to elucidate the unapparent route of transmission of the organism. Second is the long-term goal that intends to ascertain the phylogeny of the organism. The combination of VNTR loci should be changed according to the goals of molecular epidemiology of the organism. 3. Progress of the research in molecular epidemiology of Mycobacterium tuberculosis: Tomotada IWAMOTO (Department of Microbiology, Kobe Institute of Health). In the past decade, molecular epidemiology of tuberculosis brought significant insights into the transmission of tuberculosis, genetic diversity of M. tuberculosis, population structure and geographical distribution of M. tuberculosis, etc. In the advanced stage of the molecular epidemiological study, we expect to change the current geno-typing based molecular epidemiology to whole genome-typing based molecular epidemiology on the basis of the rapid innovation of next-generation sequencing technology. 4. Clinical application of molecular epidemiology of tuberculosis: Tomoshige MATSUMOTO (Department of Clinical Research and Development, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases). The molecular epidemiology can be applied in clinical practice. We showed some examples about usefulness of the clinical application of molecular epidemiology, especially using variable number of tandem repeats (VNTR) analysis. One example we showed: using VNTR, we can know whether two tuberculosis bacilli which developed from the patients, who have close contact, are the same or not in a few days; Especially, when one patient suffers from multidrug-resistant (MDR) strain of or extensively drug resistant (XDR) of tuberculosis, we can easily know whether the other suffers from MDR/XDR tuberculosis or not. The other example we showed: we can know relapse, reinfection, or laboratory contamination by using VNTR in a few days when a patient shows bacteriological relapse during the treatment. By introducing VNTR to clinical practice, we can diminish days of inappropriate hospitalization. Because VNTR data are numerical, we can easily construct VNTR database, compare data, and survey emergence of MDR/XDR-tuberculosis.

A meta-analysis of laninamivir octanoate for treatment and prophylaxis of influenza.

BACKGROUND: Laninamivir octanoate is a recently developed inhaled neuraminidase inhibitor for treating influenza virus infection. We performed meta-analyses to clarify the efficacy of laninamivir octanoate on influenza treatment and prevention. METHODS: MEDLINE and CENTRAL were searched to identify eligible studies. The log median time to event ratios (logMRs) and log odds ratios (logORs) were combined with meta-analysis. RESULTS: Nine studies in treatment settings and three studies in prophylaxis settings were eligible for this meta-analysis. There was no significant difference between laninamivir octanoate and oseltamivir (8 studies, logMR 0.04, 95% CI [-0.05, 0.14]; P=0.36) or zanamivir (4 studies, logMR -0.01, 95% CI [-0.12, 0.11]; P=0.93) in alleviating fever. However, laninamivir octanoate was associated with significantly longer fever duration in treating H3N2 influenza as compared to oseltamivir (4 studies, logMR 0.29, 95% CI [0.00, 0.59]; P=0.047). Laninamivir octanoate was associated with significantly longer duration of fever as compared to peramivir (4 studies, logMR 0.46, 95% CI [0.14, 0.77]; P=0.004). Laninamivir octanoate significantly reduced the incidence of clinical influenza in post-exposure settings (3 studies, logOR -1.17, 95% CI [-1.72, -0.62]; P<0.001). CONCLUSIONS: Overall, the efficacy of laninamivir octanoate in treating influenza was comparable to that of oseltamivir or zanamivir, but it should be noted that laninamivir octanoate was associated with significantly longer fever duration in treating influenza H3N2 as compared to oseltamivir and oseltamivir-resistant mutations in seasonal influenza H1N1 might have affected the results. Peramivir may be superior to laninamivir in treating influenza. Laninamivir octanoate is effective in preventing influenza in post-exposure settings as compared to placebo.

Foreign body-associated endobronchial inflammatory polyps.

Endobronchial polypoid lesions can be observed after removal of a foreign body and usually regress without treatment. Bronchial obstruction with a foreign body can cause atelectasis in nonelderly adults without history of an episode of aspiration.