Search

Background In a previous retrospective observational study, a 3-day regimen of oseltamivir as post-exposure prophylaxis (PEP) for preventing transmission of influenza in wards was shown to be comparable to 7- to 10-day regimens provided index cases were immediately separated from close contacts. In order to confirm the efficacy of a 3-day regimen, we started to conduct a prospective, multi-center, single-arm trial. Methods This study is a prospective, multi-center, single-arm study designed by the Sectional Meeting of Clinical Study, Japan Infection Prevention and Control Conference for National and Public University Hospitals. Index patients with influenza are prescribed a neuraminidase inhibitor and are discharged immediately or transferred to isolation rooms. The close contacts are given oseltamivir as 75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children for 3 days as PEP. All close contacts are monitored for development of influenza for 7 days after starting PEP. Discussion A 3-day regimen of oseltamivir as PEP has advantages over 7- to 10-day regimens in terms of costs, medication adherence and adverse effects. Trial registration The Institutional Review Board of Hokkaido University Hospital for Clinical Research, 015-0518, registered on November 11, 2016. UMIN Clinical Trials Registry, UMIN000024458, disclosed on October 31, 2016. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000027881. Japan Registry of Clinical Trials, jRCTs011180015, disclosed on March 14, 2019. https://jrct.niph.go.jp/latest-detail/jRCTs011180015

OBJECTIVE Japan is an aging society, and pneumonia is the leading cause of death, but the suitability of antibiotics for treating community-acquired pneumonia (CAP) in Japan is not clear. The purpose of this study was to investigate antibacterial drugs for treating CAP according to age. MATERIALS AND METHODS Using the Japanese national database from 2011 to 2014, we analyzed the usage of antibiotics for CAP according to age. RESULTS The numbers of claim information were 9,386, and 70% of the patients were aged ≥ 75 years. Sulbactam/ampicillin (SBT/ABPC) or ceftriaxone (CTRX) was used in 60%, but broad-spectrum antibiotics, combination therapy, and anti-mycoplasma antibiotics were used in 15 - 28% of all age groups. The 30-day survival rate did not differ between SBT/ABPC or CTRX vs. others. There was no difference in 30-day mortality and risk in any group between the ages of 15 and 64 years. On the other hand, the use of anti-mycoplasma antibiotics reduced the 30-day mortality by 0.50 times (p

The Macrolides (MLs), clarithromycin and azithromycin, are key drugs for non-tuberculous mycobacteria (NTM) diseases treatment. A three antibiotics regimen including MLs, rifampicin (RFP) and ethambutol (EB) has been recommended for the treatment of NTM diseases in ATS/IDSA guideline. However, anti-biotics are not necessarily prescribed in compliance with the guideline. Inappropriate regimens are risk of introducing MLs resistance. Therefore, we planned this study to evaluate the current Japanese NTM diseases treatment conditions. We used the national database (NDB) from 2011 to 2014. A total of 183 patients were entered into the study. The patients number increased at an accelerating rate in patients aged ≥55 years. Patients aged ≥55 years made up 91.3% of the total NTM diseases. Male and female patients were 61 and 122, respectively, a female/male ratio of 2.00. Clarithromycin, RFP, EB and fluoroquinolones were frequently prescribed, with the numbers of prescriptions being 125, 66, 57 and 45, respectively. The regimen of MLs, RFP and EB recommend by ATS/IDSA guideline 2007 was only followed by 25.1% of the patients. MLs monotherapy was as high as 30.6% of NTM diseases and would be a risk factor leading to an increase of MLs resistance and poor treatment outcome. Without effective NTM disease therapy, the increase of MLs-resistant NTM diseases would be a burden for Japanese health care facilities.

A 55-year-old Japanese man was hospitalized with the novel coronavirus disease 2019 (COVID-19). On the 14th day after the start of favipiravir administration, the patient developed a fever with a temperature of 38.1°C. His pulse rate also became elevated to 128 bpm, so relative bradycardia was not suspected. Since he was in good overall health and no concomitant symptoms and signs were apparent, we considered it to be drug fever due to favipiravir. After the completion of favipiravir treatment, the patient's temperature normalized within 24 hours. We herein report this case of drug fever caused by favipiravir.

Favipiravir is an antiviral drug that is expected to have a therapeutic effect on SARS-CoV2 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects. This report describes a case of cholestatic liver injury induced by favipiravir. A 73-year-old Japanese with a history of alcoholic hepatitis was infected with SARS-CoV2. Drug therapy was instituted with lopinavir/ritonavir combined with interferon β-1b. However, his condition worsened despite additional support with continuous hemodiafiltration and veno-venous extracorporeal membrane oxygenation. We suspected complications of bacterial pneumonia and started favipiravir in addition to antimicrobial therapy. Favipiravir was administered at 6000 mg/day on the first day and 2400 mg/day for the second and subsequent days for 14 days. After the initiation of antibiotics, transaminase and total bilirubin were elevated, suggesting a transient cholestasic liver dysfunction. The liver dysfunction in this case may have been triggered by antibacterial treatment, and high dose of favipiravir may have promoted the deterioration of liver function. Monitoring of liver function is vital and close attention should be paid when using favipiravir at high doses or in patients with impaired liver function.

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and developing active tuberculosis. QuantiFERON®-TB Gold Plus (QFT-Plus) has two TB-specific antigens tubes (TB1 and TB2). TB1 elicits CD4 T-cell response, and TB2 elicits both CD4 and CD8 T-cells responses, with expected increased sensitivity. The aim of this study was to estimate the prevalence of LTBI in renal transplant recipients in Japan. We conducted a cross-sectional study by using two interferon-γ release assays (IGRAs), QFT-Plus and T-SPOT®.TB (TSPOT). One hundred thirty-five recipients were prospectively enrolled. The median age was 49 years (range: 20 to 79). The positivity rates of QFT-Plus and TSPOT were 5.9% (95%CI 3.0-11.3) and 3.7% (95%CI 1.6-8.4), respectively, with no significant difference. The concordance rate was 95.5% (κ coefficient, 0.76). Age of 60 years and higher was related to the higher positivity rate in both QFT-Plus and TSPOT. The positivity rates of TB1 and TB2 were 5.1% (95%CI 2.5-10.2) and 5.9% (95%CI 3.0-11.2), respectively, with no significant difference. The concordance rate was 99.3% (κ coefficient, 0.93). TB2 did not show a higher positivity rate compared with TB1. The estimated prevalence of LTBI by using the both IGRAs was 3.7-5.9% in renal transplant recipients. These results were equivalent to the IGRAs positivity rate in the general Japanese population, even under the condition of immunosuppressive therapy. In consideration of the higher risk of developing active TB from LTBI, we can use both IGRAs as acceptable tools for LTBI diagnosis in renal transplant recipients.

Cured or completed cases in newly diagnosed sputum smear-positive pulmonary tuberculosis (TB) is 47.7% in Japan in 2016. Aging of TB patients and their underlying conditions could affect treatment outcome. We analyzed the association between the isolation of microorganisms from sputum at admission and the 180-day mortality rate of the sputum smear-positive pulmonary TB patients in Chiba-East Hospital in Japan. Total subjects were 761 (median age: 63 years). Sputum test for microorganisms was conducted in 708 patients. Microorganisms other than the normal oral flora were isolated in 128 cases (18.1%). Details of the isolated microorganisms were as follows: methicillin-resistant Staphylococcus aureus 23 cases, Klebsiella pneumoniae 17 cases, Pseudomonas aeruginosa 16 cases. Mortality was significantly elevated in the patients with those microorganisms than the others (39.8% vs. 10.2%) (P 0.01). Fifty-one of 128 patients with those microorganisms died, and 10 of them died of infectious disease, which is the most frequent cause of deaths. The factors associated with the isolation of those microorganisms were as follows: respiratory failure (adjusted odds ratio (aOR):2.5 [95% confidence interval (CI) 1.3-4.7]), performance status 3 or 4 (aOR:2.9 [95% CI 1.6-5.4]), serum albumin3.0 mg/dL (aOR:2.1 [95% CI 1.3-3.6], age of 65 years or older (aOR:2.0 [95% CI 1.2-3.4]). Those strains were isolated from one of sixth patients. Patients with those microorganisms did not always develop infectious diseases; however, treatment outcomes were poor, with higher mortality. The isolations of microorganisms were associated with various underlying conditions, leading to death. Thus, attention should be paid to TB patients with the above factors.

We analyzed peripheral blood mononuclear cells (PBMCs) of each 20 individuals with a high anti-SARS-CoV-2 antibody titer and a low antibody titer out of 1,774 healthcare workers who received BNT162b2 mRNA vaccine. A higher antibody titer was associated with the frequencies of naïve and transitional B cells before vaccination. In addition, fold changes in the frequency of activated CD8+ T cells upon vaccination were correlated with the antibody titers.

Objectives This study aimed to determine antibody responses in healthcare workers who receive the BNT162b2 mRNA COVID-19 vaccine and identify factors that predict the response. Methods We recruited healthcare workers receiving the BNT162b2 mRNA COVID-19 vaccine at the Chiba University Hospital COVID-19 Vaccine Center. Blood samples were obtained before the 1st dose and after the 2nd dose vaccination, and serum antibody titers were determined using Elecsys® Anti-SARS-CoV-2S, an electrochemiluminescence immunoassay. We established a model to identify the baseline factors predicting post-vaccine antibody titers using univariate and multivariate linear regression analyses. Results Two thousand fifteen individuals (median age 37-year-old, 64.3% female) were enrolled in this study, of which 10 had a history of COVID-19. Before vaccination, 21 participants (1.1%) had a detectable antibody titer (≥0.4 U/mL) with a median titer of 35.9 U/mL (interquartile range [IQR] 7.8 – 65.7). After vaccination, serum anti-SARS-CoV-2S antibodies (≥0.4 U/mL) were detected in all 1,774 participants who received the 2nd dose with a median titer of 2,060.0 U/mL (IQR 1,250.0 – 2,650.0). Immunosuppressive medication (p

We measured antibody responses in 2,015 healthcare workers who were receiving 2 doses of BNT162b2 mRNA vaccine against SARS-CoV-2. The vast majority (99.9%) had either seroconversion or a substantial increase in antibody titer. A multivariate linear regression model identified predictive factors for antibody responses which may have clinical implications.

Objective We aimed to test our hypothesis that traditional Japanese (Kampo) medicine, hochuekkito (Hochu-ekki-to: HET) has a preventive effect for the symptoms on COVID-19. Trial design The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator sponsored, two-arm study. Participants Six thousand participants will be recruited from healthy hospital workers in 7 Japanese University Hospitals. Inclusion criteria: 1. Age from 20 to 75 years old at the time of registration 2. Asymptomatic and body temperature below 37°C at the time of registration 3. Capable of eating orally Exclusion criteria: 1. Previous upper respiratory inflammation due to viral infection (including suspected COVID-19) 2. Taking immunosuppressants 3. Allergic to the Kampo medicines used in this study 4. History of hypokalaemia, severe hypertension, severe liver dysfunction, and interstitial pneumonia 5. Regularly taking other Kampo medicines 6. Pregnant or possibly pregnant 7. Participating in other research 8. Judged to be unsuitable for this study by the doctor in charge Intervention and comparator Kampo group: participants receive HET in 9 tablets 2 times per day for 8 weeks. Control group: participants receive placebo in the same dosage as the Intervention group - 9 tablets 2 times per day for 8 weeks. Placebo tablets are identical in appearance and package to HET. Taste of placebo is different from that of HET. The Ohsugi Pharmaceutical Co. Ltd, Osaka, Japan manufactured the placebo and HET. Main outcomes Primary outcome: Number of patients with a SARS-CoV-2 RNA by ploymerase chain reaction (PCR) positive result with at least one symptom (fever, cough, sputum, malaise, shortness of breath) during the 12-week study period (including the 4-week observation period after oral administration). Secondary outcomes: 1. Period from infection to onset 2. Period from the appearance of symptoms to the disappearance of PCR positive 3. Number of days until the appearance or improvement of symptoms 4. Severe stage: presence of hospitalization 5. Shock stage: ICU management required for mechanical ventilation, shock vitals or failure of organ(s) other than lungs Safety endpoints include numbness in the hands and/or feet, edema, skin rash or other allergic symptoms, and gastric discomfort. Randomisation Patients are randomized (1:1 ratio) to each group using minimization implemented with the Electric data capture system (DATATRAK Enterprise Cloud), with balancing of the arms with age range (under 50 years of age or not) and having a history of risk factors for COVID-19 (cardiovascular disease, hypertension, diabetes, respiratory diseases). Blinding (masking) Only participants will be randomized. Numbers to be randomised (sample size) The main research hypothesis of this study is that Kampo medicines significantly prevent the onset of COVID-19. It is assumed that the infection rate before the administration of the drug under consideration will be 0% and that the incidence of COVID-19 thereafter will be 2- 3%, of which 70%-80% will show symptoms of COVID-19. Assuming that the pharmaceutical effect of the drug will be effective in 50% of patients and that the incidence rates in the placebo and drug groups will be 1.4%-2.4% and 0.7%-1.2%, respectively, the placebo is calculated at 2%, and the study drug at 1%. Since the frequency of verification is low and the number of cases will be large, we set a total of 10 analyses (9 interim analyses and a final analysis). Since the number of cases at the time of the final analysis will be 4,986 under the conditions of α = 0.05 and a power of 80% by the Peto method. We set at 600 cases in each interim analysis with an estimated dropout rate of 16.9%. Finally, the total number of cases is set to 6,000 with 3,000 in the placebo group and 3,000 in the HET group. Trial status Protocol version 1.3 of October 23rd , 2020. Recruitment start (expected): December 1st, 2020. Recruitment finish (expected): December 31st, 2022. Trial registration This trial is registered in the Japan Registry of Clinical Trials (jRCT) (jRCTs031200150) on 14 October 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Introduction Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Although most patients with COVID-19 develop asymptomatic or mild disease, some patients develop severe disease. The effectiveness of various therapeutic agents, including antiviral drugs, steroids, and anti-inflammatories for COVID-19, have been being confirmed. The effect of administering steroids in early disease is unclear. This study therefore aimed to evaluate the effectiveness and risk of exacerbation of steroids administered preceding antiviral drugs in patients with COVID-19 pneumonia. Methods This retrospective, single-center, observational study included consecutive patients with COVID-19 between March 2020 and March 2021. Patients were divided into a steroids-first group and antiviral-drugs-first group. Mortality, duration of hospitalization, incidence rate and duration of intensive care unit (ICU) admission, intubation, and extracorporeal membrane oxygenation (ECMO) induction of the two groups were compared. Results A total of 258 patients were admitted during the study period. After excluding patients who received symptomatic treatment only, who were taking immunosuppressive drugs, or who were administered antiviral drugs only, 68 patients were included in the analysis, 16 in the steroids-first group and 52 in the antiviral-drugs-first group. The rate of intubation, ICU admission and ECMO induction were significantly higher in the steroids-first group than in the antiviral-drugs-first group (81.3% vs. 33.3, pp = 0.001, and 31.3% vs. 7.8%, p = 0.017, respectively). Furthermore, patients who received steroids within ten days after starting antiviral drugs had significantly lower rates of ICU admission, intubation, and ECMO induction. (81.3% vs. 42.9% p = 0.011, 75.0% vs. 37.1% p = 0.012, and 31.3% vs. 8.6% p = 0.039, respectively). Conclusions Administering steroids prior to antiviral drugs soon after symptom onset can aggravate disease severity. When administration of steroids is considered soon after symptom onset, it may be safer to initiate antiviral drugs first.

Background: Reactogenicity of vaccines can derive from different immunological processes and is composed of a range of symptoms with varying time courses. This study aimed to decompose complex adverse reactions against the BNT162b2 SARS-CoV-2 vaccine into spatiotemporal patterns and clarify their associations with external information. Methods: We recruited healthcare workers who were receiving the BNT162b2 mRNA SARS-CoV-2 vaccine in the Chiba University Hospital vaccination program. We collected information on adverse reactions every day after each dose using a smartphone/web-based platform. Information for immediate reactions was collected specifically on the vaccination day. We determined the serum anti-SARS-CoV-2S antibody titers after the 2nd dose. We employed non-negative tensor factorization to decompose the serial reactogenicity information into components. Associations of these tensor components with external information were analyzed using a generalized linear model and a generalized additive model. Findings: We analyzed 1,774 participants who received two doses of vaccine. Tensor decomposition revealed four components that represented spatiotemporal patterns of adverse reactions. The original reactogenicity data were well explained by these four tensor components with minimal errors. One component, which represented diverse and severe symptoms that occurred early after the 2nd dose, was significantly associated with post-vaccination antibody titers, suggesting the involvement of acquired immunity. On the other hand, the other three components were not significantly associated with antibody titers. These four components were differently associated with immediate reactions and background factors such as demographics, habits, comorbidities, and medications. Interpretation: Complex adverse reactions against vaccines can be explained by a limited number of spatiotemporal components identified by tensor decomposition. Our data indicate that these components reflect distinct underlying immunological processes. Funding: This study was supported by a donation to Chiba University Hospital, the Future Medicine Founds at Chiba University, a JST Moonshot R&D Grant, a JST CREST Grant, and Japan AMED Grants. Declaration of Interest: None to declare. Ethical Approval: The study procedures for sample collection and those for analyses were approved by Chiba University Ethics Committee on February 24th, 2021 (No. HS202101-03) and April 21st, 2021 (No. HS202104-01), respectively.

Introduction Human immunodeficiency virus (HIV) infected individuals are at increased risk of developing active tuberculosis (TB). TB incidence remains higher than in non-HIV subjects after antiretroviral therapy (ART) initiation. This study was conducted to estimate the prevalence of positive IGRA, reflecting latent tuberculosis infection and/or a history of active TB, in HIV-infected individuals after ART initiation in Japan. Methods Two IGRAs (Interferon (IFN)-γ release assays), QuantiFERON®-TB Gold Plus (QFT-Plus) and T-Spot®.TB (TSPOT), were used. We also analyzed the TB associated risk factors for the IGRAs results and the role of CD4+ T-cells, CD8+ T-cells and NK cells for producing IFN-γ. We also analyzed the risk factors for positive IGRA responses and the role of CD4+ T-cells, CD8+ T-cells and NK cells for producing IFN-γ. Results One hundred eight-four subjects were prospectively enrolled. Median age was 49 years. The positivity rates of QFT-Plus and TSPOT were 7.6% [95%CI 4.6–12.4] and 2.7% [95%CI 1.2–6.2], respectively, with significant difference. TB-associated risk factors and NK cells ≥300/μL were selected as independently significant factors by multivariate logistic regression. The NK cell count revealed significant linear regression with IFN-γ production responding to TB-specific antigens. Conclusions The prevalence of positive IGRAs was 2.7%–7.6%. QFT-Plus would be practical for a higher positivity rate and reflect TB risk factors. The innate immune system, referring to IFN-γ production, plays an important role in the immune response to TB-specific antigens even after initiating ART.

Community-acquired pneumonia (CAP) is one of the most common causes of pediatric infection requiring hospitalization. Antimicrobial resistance due to the inappropriate use poses a threat worldwide. Our objective is to analyze and optimize the trends of antibiotics used for pediatric inpatients with CAP in a claims database provided by the Ministry of Health, Labour and Welfare.Our database randomly sampled 10% of the hospitalized patients every October from 2011 to 2014. Patients aged15 years in whom antibiotic therapy was initiated within two days of admission were listed. Subsequently, we investigated the antibiotics administered on the first day of prescription.A total of 4,831 antibiotics were prescribed for 3,909 patients. Many patients aged ≤ five years were treated with β-lactams alone whereas many patients aged ≥ six years were treated with a single antibiotic, such as a macrolide, tetracycline, and quinolone, which covers atypical bacteria. Combination therapy was primarily used in children aged ≥ six years (nearly 30%); the main combination was a β-lactam and non-β-lactam covering atypical bacteria. Ampicillin-sulbactam was the most frequently prescribed β-lactam in children of all ages other than infants. Ampicillin, however, was most often prescribed in infants, but its usage rate was low at other ages.Antibiotics were appropriately prescribed and were similar to that recommended in the 2011 guidelines for pediatric inpatients with CAP. However, combination therapy was frequently prescribed in children aged ≥ six years. According to the revised guidelines in 2017, ampicillin should be used more frequently for patients hospitalized with CAP.

Survival Sepsis Campaign (SSC) guidelines have recommended broad-spectrum antibiotics prescriptions to cover the possible pathogenic microorganisms. However, mortality from sepsis is still high, as about one quarter of cases are thought to result in death. We analyzed nationwide health claims data of universal health insurance systems in Japan. Our aim was to describe the antibiotics prescriptions and underlying conditions of Japanese sepsis patients. In addition, we analyzed the factors associated with 30-day mortality. A total of 1188 patients aged ≥15 years were entered, of which 80.1% were ≥65 years old. Broad-spectrum antibiotics were prescribed for 53.8%. Carbapenem, Piperacillin Tazobactam and Anti-pseudomonas Cephalosporin were prescribed for 30.8%, 13.0% and 12.2% of the patients, respectively. (Some patients were counted twice) The overall 30-day mortality rate was 21.3%. Risk factors associated with 30-day mortality were examined by Cox proportional hazards regression analysis. Age of ≥85 years, malignancy, chronic kidney disease (CKD), shock and respiratory failure were selected as risk factors, but broad-spectrum antibiotics was not included. Sepsis is mostly observed in those aged 65 years and over. The rates of broad-spectrum antibiotics were restricted, and antibiotics were also not necessarily prescribed on the basis of SSC guidelines. However, broad-spectrum antibiotics did not improve the treatment outcome. Aging and underlying conditions like malignancy, CKD, shock and respiratory failure were poor prognostic factors.

Rheumatoid arthritis (RA) is an immune mediated inflammatory disorder, and immune suppressive drugs are prescribed. RA patients receiving treatments are in a kind of immunosuppressive condition that presents increased risk of developing active tuberculosis. Accurate diagnosis of latent tuberculosis infection (LTBI) is recommended for RA. QuantiFERON®-TB Gold Plus (QFT-Plus), a novel IGRA, has two tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses, with expected increased sensitivity. We conducted a cross-sectional study to compare two IGRAs, QFT-Plus and T-SPOT®.TB (TSPOT), in RA. One hundred fifty-two RA patients (median age: 66.5 yrs) were enrolled. QFT-Plus and TSPOT were concurrently conducted. Lymphocyte subsets (CD4 T-cell and CD8 T-cell) were also measured. The positivity rates of QFT-Plus and TSPOT were 9.7% and 4.5%, respectively, with the difference being significant (P

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to

Renal transplant recipients are at increased risk of reactivating latent tuberculosis infection (LTBI) and progressing to active tuberculosis (TB). This study was conducted in National hospital for tuberculosis and renal transplantation (RT) in Japan. The purpose is to compare two interferon-γ release assays (IGRAs), QuantiFERON®-TB Gold in Tube (QFT) and T-SPOT®.TB (TSPOT), in patients after renal transplantation for detecting latent TB infection (LTBI). Total 92 renal transplant recipients (median age 46 years, range 17-75) were prospectively enrolled, and QFT and TSPOT were concurrently examined. Total subjects were 92 patients (median age 46 years, range 17-75). The positive rate in QFT and TSPOT were 6.5% (95% confidence interval (CI) 3.0-13.5) and 2.2% (95% CI 1.0-7.6), respectively. There was a significant difference in IGRAs positivity (P

Recent contacts with active TB (tuberculosis) patients were screened for latent tuberculosis infection (LTBI) because of their greater relative risk for developing active TB. QuantiFERON®-TB Gold Plus (QFT-Plus) offers two TB-specific antigen tubes (TB1 and TB2). TB1 elicits CD4 T-cell responses, and TB2 is designed to elicit both CD4 and CD8 T-cell responses. These mechanisms could be useful for estimating the role of CD8 T-cell immune responses to TB-specific antigens. To estimate the QFT-Plus capability to diagnose LTBI, a prospective cross-sectional study was conducted. A total of 412 TB contacts (median age 44 years) were enrolled. The positivity rates of QFT-Plus, TB1 and TB2 were 7.5%, 6.3% and 7.2%, respectively. TB2 showed a higher positivity rate compared to TB1, but without significant difference. The interferon (IFN)-γ productions of TB1 and TB2 were well correlated (r = 0.934, P 0.001). The ratio of IFN-γ production between TB1 and TB2 showed a median (interquartile range) of IFN-γ

Background Individuals with recent contact with active tuberculosis (TB) patients were screened for latent tuberculosis infection (LTBI) considering their greater relative risk for developing active TB. QuantiFERON®-TB Gold Plus (QFT-Plus) assay offers two TB-specific antigen tubes (TB1 and TB2). TB2 is designed to elicit both CD4 and CD8 T-cell responses. This mechanism could lead to increased sensitivity as compared to the QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay. Our objective was to compare the LTBI diagnostic capability of QFT-Plus with that of QFT-GIT. Methods A total of 412 TB contacts (median age 44 years) were prospectively enrolled. We conducted both QFT-Plus and QFT-GIT assays concurrently. We also analyzed production of interferon-γ (IFN-γ) in response to TB-specific antigens. Results The positivity rates in QFT-Plus and QFT-GIT were 7.5% (95% confidence interval (CI), 5.4–10.5) and 5.8% (CI, 3.9–8.5), respectively, showing a significant difference (P Conclusions QFT-Plus revealed significantly higher positivity rate compared with QFT-GIT, which might be attributed to increased IFN-γ production. The cut-off in both QFT-Plus and QFT-GIT was 0.35 IU/mL. These effects might resulted in the higher positivity rate in QFT-Plus.

Inactivated quadrivalent influenza vaccine (IIV4) has been used as seasonal influenza vaccine since 2016 in Japan. This study examined the safety of IIV4 in comparison with the AH1pdm monovalent vaccine used for novel influenza in 2009. Questionnaire surveillance associated with adverse events (AEs) was conducted at Chiba University Hospital, Japan. After being vaccinated, all health care workers (HCWs) were given a daily AEs check sheet on which they recorded solicited events, the same surveillance program used after AH1pdm vaccination in 2009. The frequency of injection site AEs with IIV4 was significantly higher than with the monovalent vaccine, but there was no significant difference with systemic AEs. Injection site and systemic AEs were reported as 83.7% and 25.5%, respectively, with IIV4. The grades of AE, mild, moderate and severe, were 67.2%, 16.4% and 0.1% with IIV4, respectively, indicating that almost all of the AEs reported with IIV4 were mild or moderate. Systemic AEs with IIV4 and monovalent vaccine were reported to be 25.5% and 23.1%, respectively, with the difference not being significant. The grade of AEs with IIV4, mild, moderate and severe, was 19.1%, 5.6% and 0.9%, respectively. The ratio of HCWs reporting AEs peaked at around 80% on day 1, then decreasing to less than 5% by day 7. AEs with IIV4 were reported more frequently compared with the AH1pdm monovalent vaccine. However, in consideration of the grade and duration of AEs, IIV4 was a well-tolerated, safe vaccine.

SETTING National hospital for tuberculosis (TB) and rheumatoid arthritis (RA) in Japan. OBJECTIVE To compare two interferon-γ release assays (IGRAs), QuantiFERON®-TB Gold In-Tube (QFT) and T-SPOT®.TB (T-SPOT), in RA patients for detecting latent tuberculous infection (LTBI). DESIGN QFT and T-SPOT were conducted concurrently in 230 prospectively enrolled RA patients. RESULTS There were no active TB patients. The percentage of QFT- and T-SPOT-positive patients was respectively 8.3% and 5.7%. In patients aged ⩾60 years, these proportions were respectively 12.3% and 7.2%. The percentage of QFT positivity and T-SPOT positivity at age

OBJECTIVE We aimed to investigate the incidence and clinical characteristics of nontuberculous mycobacterial (NTM) pulmonary disease as a complication of chronic thromboembolic pulmonary hypertension (CTEPH). METHODS We conducted a retrospective study of 10 cases (5.6%) complicated by NTM pulmonary disease among 180 CTEPH patients. RESULTS Isolated species of avium (n=5), kansasii (n=2), intracellulare (n=1), abscessus (n=1) and fortuitum (n=1) were detected. NTM-infected lesions were observed in 33 of 180 (18.3%) lung segments obtained from the 10 patients, and complete obstruction due to chronic pulmonary thromboembolism was detected in 65 of the 180 segmental pulmonary arteries (36.1%). The NTM-infected segments in the CTEPH patients were significantly associated with obstructed rather than unobstructed pulmonary artery segments [25 of 65 (38.5%) vs. 8 of 115 (6.9%), p

QuantiFERON-TB gold in-tube has been used for screening latent tuberculosis infection in newly employed health care workers in Japan. There have been a few studies concerning quality control. We retrospectively analysed QuantiFERON-TB gold in-tube results in a hospital in Japan. Interferon-γ values in three blood collection tubes for QuantiFERON-TB gold in-tube were analysed in association with the positivity rate. The data set consisted of health care workers aged 20-29 years during the 7 years between 2010 and 2016. The yearly QuantiFERON-TB gold in-tube positivity rate was 0.9%, 16.4%, 3.0%, 39.3%, 2.8%, 0.9% and 1.5%, and was extremely high in 2011 and 2013. The interferon-γ values in the tuberculosis antigen tube were elevated in these two years, as indicated by higher median and wider interquartile range. The interferon-γ value in the negative control tube was also higher in 2011. The higher interferon-γ values in collection tubes (tuberculosis antigen tube and/or negative control tube) resulted in higher QuantiFERON-TB gold in-tube positivity rate. The distribution of interferon-γ in tuberculosis antigen tube and negative control tube, as evaluated by median and interquartile range, proved to be an effective index for the quality control of QuantiFERON-TB gold in-tube.

Background Corynebacterium striatum was recently recognized as a potential pathogen of various infectious diseases. However, the clinical entity of this microorganism has not been clearly identified. Therefore, we analyzed C. striatum isolates from blood culture and explored their clinical determinants. Methods We reviewed the medical records of all patients from whom C. striatum isolates were recovered from blood culture for analysis of the patients' backgrounds and clinical course including response to antimicrobial therapy and prognosis. Results During the 5-year study period (January 2010 to December 2014), 24 C. striatum strains were isolated from blood samples, and the frequency of C. striatum bacteremia increased. The majority of the strains were multidrug resistant. All of the tested strains were susceptible to only vancomycin. The age at onset of C. striatum bacteremia encompassed all adult age groups, and at least one underlying condition was documented in all patients. Thirteen of the 24 patients were cured using appropriate antibiotics (true infection group); however, 11 of the 24 patients were cured using inappropriate antibiotic therapy or no antibiotics (contamination group). Malignancy and neutropenia significantly increased the odds of true C. striatum bloodstream infection. Conclusions The Corynebacterium species is often considered a contaminant when isolated in culture. Instead, particularly when the strain is isolated from blood, the species should be considered clinically relevant and identified to the species level; in addition, antimicrobial susceptibility testing is recommended.

The track records of the use of anti-methicillin-resistant Staphylococcus aureus agents (anti-MRSA agents) in a 5-year period (2001.4-2006.3) were collected, and cases in which anti-MRSA agents were used for >4 days were selected. In each case, the results of laboratory data and bacterial examination before and after administering the anti-MRSA agents were investigated retrospectively. In addition, it was also investigated in each case whether therapeutic drug monitoring (TDM) was carried out. It was observed that the number of patients treated with anti-MRSA agents and the total dose of anti-MRSA agents used tended to increase over time, except for arbekacin sulfate. It was, however, shown that treatment with anti-MRSA agents resulted in significant decreases in body temperature, C-reactive protein, and white blood cell counts. Bacterial examination was conducted in 75.6% of the patients treated with anti-MRSA agents, with MRSA being detected in 72.4% of the cases examined. On the other hand, TDM was also conducted in 60% of the cases, but this was at a lower percentage than that of the other examinations. Quantitative bacterial examination after treatment with anti-MRSA agents indicates that TDM can be considered important for the appropriate use of anti-MRSA agents.

Chronic kidney disease (CKD) is an increased risk for the development of active tuberculosis, but few studies have analyzed the treatment outcome of pulmonary tuberculosis among CKD patients. A retrospective cohort study was conducted at Chiba-East Hospital in Chiba, Japan. Our study estimated the treatment outcomes in smear-positive pulmonary tuberculosis in relation to CKD and its stages. Total subjects were 759 patients (12-99 years) hospitalized between 2007 and 2012. Patients suffering from multi-drug-resistant tuberculosis were excluded. Patients with CKD were 19.3% aged65 years (n = 384), and 49.6% aged ≥ 65 years, respectively (P 0.001). Successful treatment was 52.7% in CKD (n = 260) and 67.3% in non-CKD (n = 499) (P 0.001). Death was 25.4% in CKD and 12.4% in non-CKD (P 0.001). Treatment outcome was especially poor in patients with low estimated glomerular filtration rate (eGFR) of30 ml/min/1.73 m(2), as successful treatment was 20.0%, and death was 50.0%, significantly lower than in other CKD and non-CKD patients. After multivariate logistic regression analysis, eGFR30 ml/min/1.73 m(2) was an independent factor affecting successful treatment and death, and its adjusted odds ratios (aOR) were 0.20 (95% confidence interval (CI) 0.07-0.50) and 2.99 (95%CI 1.20-7.51), respectively. Other factors affecting successful treatment were serum albumin3.0 mg/dl, steroid therapy for underlying disease and cardiovascular disease, with aOR (95%CI) of 0.28 (0.20-0.39), 0.32 (0.16-0.63) and 0.49 (0.28-0.86), respectively. Several factors were associated with poor treatment outcome of smear-positive pulmonary tuberculosis. Advanced stage of CKD with eGFR of30 ml/min/1.73 m(2) was a risk factor for poor treatment outcome.

Patients with toxic epidermal necrolysis (TEN) have been known to have various complications. Though pulmonary complications are often observed, they usually show an acute form; however, chronic complications are quite rare and little is known about either their incidences or clinical manifestations. We herein report a 33-year-old man who presented with chronic pulmonary complications after a recovery from TEN. At the onset of TEN, he had severe respiratory failure and artificial ventilation was instituted. Despite being extubated successfully, respiratory failure reappeared 1 month later. A diagnosis of chronic bronchitis with severe obstructive ventilatory impairment and bronchiectasis was made and he was treated with steroids, bronchodilators and antibiotics, however, he died 1.5 years after the onset of TEN. There have been 13 reported cases of chronic pulmonary complications with TEN or Stevens-Johnson syndrome (SJS) in the English published work. Such cases are usually classified into chronic bronchitis/bronchiolitis with obstructive change (including bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia), respiratory tract obstruction and bronchiectasis. Approximately 40% of all such patients die while the surviving continue to suffer from these complications because no curative therapy yet exists. As a result, the prognosis seems to be poor. The relationship between TEN and these chronic pulmonary complications remains to be elucidated. Interestingly, our patient was asymptomatically anti-Ro/SS-A positive at the onset of TEN. In addition, eccrine gland involvement and an extremely high level of serum salivary amylase were observed at the onset of TEN, furthermore, Sjögren-like symptoms occurred after recovery from TEN. These findings suggested that the Sjögren-like autoimmune abnormalities induced by anti-Ro/SS-A correlated with the development of chronic pulmonary complications in our patient.

Study objectives: Vascular endothelial growth factor (VEGF) signaling may be required for maintenance of the alveolar structures, and alveolar septal cell apoptosis could contribute to the pathogenesis of COPD presenting emphysematous changes; however, the common mutation at position 936 in the 3 untranslated region of the VEGF gene, a C to T substitution (the C allele was denoted as 1, and the T allele as 2), VEGF936*2, has been reported to be associated with significantly lower VEGF plasma levels. Based on these concepts, we hypothesized that VEGF936*1/2 polymorphism may be linked to the development of COPD. Design: The differences in VEGF936*1/2 allele frequency were examined in 113 patients with smoking-related COPD and two control groups (101 smoker/ex-smoker control subjects and 102 population control subjects) using the polymerase chain reaction-restriction fragment length polymorphism technique. Results: VEGF936*1/2 allele frequencies did not differ among the groups: 0.792/0.208 in COPD patients, 0.822/0.178 in smoker/ex-smoker control subjects, and 0.842/0.152 in population control subjects. Conclusion: The 936 C/T polymorphism of the VEGF gene (including both homozygous and heterozygous) was not associated with the development of COPD (odds ratio, 1.23; 95% confidence interval, 0.760 to 1.995). (CHEST 2003; 124:323–327)

We compared the specificities of two interferon-gamma release assays (IGRAs), T-SPOT®.TB (T-SPOT) and the QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay, in strictly selected subjects with a low risk of tuberculosis (TB) infection in a Japanese population. Of 111 subjects who were mostly bacille Calmette-Guerin vaccinated, one was positive using both assays and 110 were negative, using international cut-off values. Although several meta-analyses report that QFT-GIT has higher specificity than T-SPOT, our study demonstrates that the specificity of both assays is equally high in a population with a truly low risk of TB infection.

The immunogenicity of pandemic influenza A H1N1 virus (A/H1pdm) vaccine might be modified by prior seasonal trivalent influenza vaccine (sTIV) administration. We conducted a retrospective analysis of immunogenicity of 243 health care workers (number of sTIV-positive [sTIV+] subjects, 216; number of sTIV−subjects, 27) by hemagglutination inhibition. There was no significant difference in the ratios of antibody titers of ≥40 (41.2% versus 48.1%;P= 0.49) and fold increases in geometric mean titer (3.8 versus 4.5;P= 0.37). sTIV injected 7 to 10 days prior to A/H1pdm vaccine administration did not interfere with the immunogenicity of the latter.

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

A 50-year-old man with chronic renal failure (hemodialysis treatment) and interstitial pneumonia (IP) was referred to our hospital for exacerbation of IP. We immediately administered a mechanical ventilation, broad spectrum antibiotics, steroid pulse therapy, and endoxan pulse therapy in the intensive care unit, but alveolar opacities became worse. Subsequently, an intrapulmonary cavity appeared in the left middle lung field on the chest X-ray and we also administered amphotericin B. However he died of tension pneumothorax on the tenth day of hospitalization. In an autopsy the rupture of the intrapulmonary cavity of the left S3 region was detected and we diagnosed as invasive pulmonary mucormycosis by Grocott stain of the cavitary lesion. We report a rare case that complicated by fatal tension pneumothorax during treatment with a ventilator in invasive pulmonary mucormycosis and review the literature.

A phase III observational study evaluating a single-dose of an inactivated, split-virus, unadjuvanted AH1pdm vaccine in HCW was conducted. A safe and effective vaccine was needed after the emergence of AH1pdm in April 2009. We analyzed the immunogenicity and safety of the vaccine. A total of 409 subjects were enrolled and given 15 μg hemagglutinin antigen by s.c. injection. Antibody titers were measured using hemagglutination-inhibition antibody assays before vaccination and 28 days after. The co-primary immunogenicity end-points were the proportion of subjects with antibody titers of 1:40 or more, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in geometric mean titer. We collected 389 pair samples. Antibody titers of 1:40 or more were observed in 148 of 389 subjects (38.0%, 95% CI: 33.2-42.9). The immunogenicity was also confirmed in other end-points, but was not sufficient and was lower than in previous reports. A total of 96 of adverse events was reported: 51 local events and 57 systemic events. There were 12 subjects with both local and systemic events. Nearly all events were mild to moderate except in four subjects. A single 15-μg dose of AH1pdm vaccine did not induce sufficient immunogenicity in HCW, with mild-to-moderate vaccine-associated adverse events. We need to consider further improvement of the AH1pdm vaccine program in HCW for the prevention of nosocomial infection, as well as for the benefit of HCW.

SummaryGenerally, the primary lesion of a mold infection is in the airway, an extravascular site. Therefore, the antifungal drug concentration at the actual tissue lesion of a mold infection is as important as in the blood compartment. Although our antifungal armamentarium has expanded recently, polyenes are still often needed in clinical practice because of their potent fungicidal activity and the rarity of resistance. Nevertheless, the distribution of amphotericin B (AmB) in infected lung tissue has not yet been evaluated. Using high-performance liquid chromatography analysis, we determined the concentrations of AmB in plasma and infected and uninfected tissues of resected lung simultaneously, in a patient with pulmonary aspergillosis treated with liposomal amphotericin B (L-AmB). The AmB concentration in the infected lesion of the lung was approximately 5.2 times higher than that in plasma and 3.7 times higher than in uninfected lung tissue. L-AmB accumulated in the infected lesion of the lung at a higher concentration. Although our data are from only one patient, they may be useful in helping to develop better strategies for the use of L-AmB against pulmonary fungal infections.

e19504 Background: Primary central nervous system lymphoma (PCNSL) is one of the life-threatening diseases in patients (pts) with acquired immunodeficiency syndrome (AIDS). We previously reported t...

A case of lung adenocarcinoma and extensive deep vein thrombosis in a patient with Peutz-Jeghers syndrome (PJS) is presented. A 31-year-old Chinese man complained of shoulder pain and swelling of the right arm. A series of diagnostic procedures revealed a primary adenocarcinoma in the left upper lobe with cervical and supraclavicular lymph node metastases accompanied by deep vein thrombosis in the superior vena cava and right jugular vein. In addition, typical pigmentation of the lips and oral mucosa and multiple hamartomas in the stomach, duodenum and colon led to the diagnosis of PJS. PJS is known to be associated with increased risk of malignancies, especially in the gastrointestinal tract, breast, genitals and pancreas. As bronchoscopic examination showed no hamartomatous lesions in the bronchi, the development of primary lung cancer in this young patient might be independent of any hamartomatous lesion and might be associated with some genetic factors relating to PJS.

Alveolar septal cell apoptosis may contribute to the pathogenesis of emphysema. Because tumor necrosis factor (TNF)-alpha is assumed to play an important role in the induction of apoptosis, and allele 2 of the polymorphism at position--308 in the promoter of the TNF-alpha gene has been associated with alteration of TNF-alpha secretion in vitro, we hypothesized that genotypes containing this allele would show more destructive emphysematous changes of the lung.The percentage ratio of the low attenuation area to the corresponding lung area was evaluated using a visual scoring system for CT findings in patients with COPD (n = 84), and these patients were classified into two groups: those with a visual score11 and those with a visual scoreor = 11. A polymerase chain reaction-based assay was developed to determine the TNF-alpha genotype (TNF-alpha-308*1/2) between subjects with high and low visual scores on chest CT scans.The TNF-alpha-308*1/2 allele frequency tended to differ between patients with a visual score11 (0.90/0.10) and those with a visual scoreor = 11 (0.81/0.19) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30; p = 0.09].These results indicate that the TNF-alpha-308 allele 2 may be partly associated with the extent of emphysematous changes in patients with COPD.

Tumor necrosis factor alpha (TNF-alpha), a potent proinflammatory cytokine, may be involved in the development of chronic obstructive pulmonary disease (COPD). The production of TNF-alpha is elevated in the airways of these patients. A polymorphism at position -308 of the TNF-alpha gene promoter (TNF-alpha-308*1/2) is known to be associated with alteration of TNF-alpha secretion in vitro. In this study we examined the differences in TNF-alpha-308*1/2 allele frequency to investigate the association of this polymorphism with the presence of smoking-related COPD. TNF-alpha-308*1/2 allele frequency in 106 patients (73 men and 33 women) was compared with 110 asymptomatic smoker/ex-smoker control subjects matched for sex and age and population control subjects consisting of 129 blood donors. Genotype was analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic DNA isolated from peripheral blood lymphocytes. TNF-alpha-308*1/2 allele frequencies were significantly different among the groups: 0.835/0.165 in patients with COPD, 0.918/0.082 in smoker/ex-smoker control subjects, and 0.922/0.078 in population control subjects. These results indicate that TNF-alpha-308*1/2 alleles are significantly associated with the presence of smoking-related COPD.

We investigated how signals arising from peripheral chemoreceptors could affect pulmonary vasculature in rats. Effects of the hypoxic exposure (10%) on mean pulmonary arterial pressure (mPAP), abdominal aortic flow (Q) and the estimated total pulmonary vascular resistance (mPAP/Q) were determined in anesthetized, artificially ventilated, carotid sinus nerve intact or chemodenervated rats. The pressor response of PAP to hypoxia seen in intact rats changed to the depressor response after chemodenervation. Hypoxia elicited a decrease in Q and an increase in mPAP/Q in both intact and chemodenervated rats. Selective carotid body stimulation by the intra-carotid injection of sodium cyanide (NaCN) in normoxia elicited an immediate but transient increase in PAP and Q before and after bilateral vagotomy. The peak change in PAP slightly preceded that in Q. These responses to NaCN were completely abolished by chemodenervation. These results indicate that the immediate chemoreflex contributes to the short-term regulation of pulmonary vasculature in rats.