Abstract Subjects exposed to non-tuberculous mycobacterium (NTM) species do not always develop an active disease, which likely reflects underlying host susceptibility factors. Recent reports have ...shown that anti interferon gamma (IFN-γ) neutralizing autoantibodies (IFN-γ Ab) are associated with the development of disseminated NTM in patients without known evidence of immunodeficiency. The purpose of this study is to establish the screening method if subjects have IFN-γ Ab. Whole blood was obtained from patients with disseminated NTM, those with pulmonary NTM, and healthy controls. The neutralizing capacity to IFN-γ activity was assessed as an inhibition of Signal Transducer and Activation of Transcription 1 (STAT-1) phosphorylation in leukocyte after stimulation with exogenous IFN-γ by flow cytometer. The strength of phosphorylation was described as STAT1 phosphorylation index. Antigen capture assay was performed to measure the relative titer of Immunoglobulin-G fraction of IFN-γ Ab. STAT1 phosphorylation by IFN-γ was significantly inhibited in the leukocytes from patients with disseminated NTM compared to that in healthy subjects, while this inhibition was not observed in patients with pulmonary NTM. All subjects with inhibited STAT1 phosphorylation had high titer of Immunoglobulin-G that reacted with IFN-γ in the antigen capture assay. The measurement of STAT1 phosphorylation index in whole blood leukocytes and antigen capture assay are simple and useful method for detection of anti-IFN-γ neutralizing autoantibodies, and is valuable in the pathophysiological diagnosis of disseminated NTM patients without obvious immunodeficiency.
Enhanced surveillance of invasive pneumococcal disease (IPD) in adults was conducted during April 2013-March 2018 in 10 of 47 prefectures in Japan, and a total of 1277 IPD patients were enrolled. An ...emergence of IPD caused by serotype 12F was identified during May 2015-March 2018 through this surveillance. 12F isolates were composed of four related sequence types. In total, 120 patients with 12F IPD were reported during this period. To characterize the clinical features of 12F IPD, the disease characteristics of these patients were compared with those of 1157 patients with non-12F IPD. Compared with the non-12F IPD patients, a significantly lower proportion of 12F IPD patients was aged 65 years or older (55% vs. 70%), vaccinated with 23-valent pneumococcal polysaccharide (4% vs. 14%), had comorbid illness (65% vs. 77%), or were immunocompromised (19% vs. 30%; all P < 0.05). No significant difference in the proportion of case fatalities was found between the two groups. The proportions of those aged 65 years or older (53% vs. 69%) and with bacteremic pneumonia (35% vs. 69%) were significantly lower in 17 patients who died from 12F IPD than in 205 patients who died from non-12F IPD (all P < 0.05). Differences in clinical features were similarly found between 12F IPD patients and patients in low- or intermediate-level invasive potential serogroups. Our data demonstrated that serotype 12F was associated with IPD in younger adults and a lower proportion of comorbid illness, including immunocompromised conditions, in adult IPD, suggesting the high invasive potential of the serotype 12F. In addition, patients who died from 12F IPD were younger and had proportionately more bacteremia without focus. These findings may provide new insight into the pathogenesis of IPD in adults caused by 12F serotype with a high invasive potential.
In Japan, the clinical characteristics and recent serotype distribution among adult patients of invasive pneumococcal disease (IPD) have not been fully investigated since the introduction of the ...pneumococcal conjugate vaccine (PCV) in children. From November 2010, PCV7 was encouraged by an official program, funded by government, subsequently included in the routine schedule in April 2013, and replaced with a PCV13 in November 2013.
Between April 2013 and March 2015, patients with IPD older than 15 years were evaluated based on the enhanced national surveillance in ten prefectures of Japan. The serotype distribution of the isolates was analyzed in these patients.
The analysis included 291 patients: 107 patients (37%) were female and the median age was 70 years. Of 281 patients with available data, 202 (72%) had underlying diseases, including 107 patients (38%) with immunocompromised status. The case fatality proportion for all case was 20%. In subgroup analysis, the case fatality proportion (29%) in immunocompromised patients was much higher than that (0-16%) in each age group of nonimmunocompromised patients (15-39 years, 40-64 years, and ≥ 65 years). While the proportion of bacteremia without any focus (27%) was higher than that (8-10%) in nonimmunocompromised patients, the proportions of vaccine types (PCV13, 32%; PPSV23, 51%) of the causative isolates were lower than those in each age group of nonimmunocompromised patients. Among 291 isolates, the most frequent serotypes were 3 (17%), 19A (13%), and 22F (10%). Twelve percent of the isolates were PCV7 serotypes, 46% were PCV13 serotypes, and 66% were PPSV23 serotypes.
The majority of adult patients of IPD had underlying diseases, including immunocompromised conditions. A low proportion (12%) of PCV7-type IPD was observed in this population where PCV7 for children had been included in the routine immunization schedule.
Pneumococcal surface protein A (PspA) is a surface protein of
that may be a candidate antigen for new pneumococcal vaccines. This study investigates the distribution of PspA clades of the causative ...strains of adult invasive pneumococcal disease (IPD) in Japan. Of the 1,939 strains isolated from cases of adult IPD during 2014-2019, the PspA clades of 1,932 (99.6%) strains were determined, and no
was detected in the remaining 7 strains (0.4%). PspA clades 1-6 were detected in 786 (40.5%), 291 (15.0%), 443 (22.8%), 369 (19.0%), 33 (1.7%), and 6 (0.3%) strains, respectively. New PspA clades (0.2%) were identified in two non-typeable and two serotype 35B pneumococci. The proportions of clade 1 and clade 2 showed significantly decreased and increased trends, respectively. Furthermore, the PspA clade of pneumococcal strains was partially serotype- and sequence type-dependent. The majority of strains belonging to serotypes contained in both the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) belonged to PspA clades 1 or 3. In contrast, the distribution of clades in non-vaccine serotypes was wider than that of vaccine serotype pneumococci. Our findings demonstrate that almost all pneumococcal strains from adult IPD express PspA clades 1-4, especially for non-vaccine serotypes. These results may be useful for the development of a new pneumococcal vaccine with PspA.
A-DROP system for prognostication of NHCAP inpatients Koizumi, Takeshi; Tsukada, Hiroki; Ito, Kazuhiko ...
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy,
08/2017, Letnik:
23, Številka:
8
Journal Article
Recenzirano
Abstract Nursing and healthcare-associated pneumonia (NHCAP) is a category of healthcare-associated pneumonia that was modified for the healthcare system of Japan. The NHCAP guidelines stated the ...difficulty in assessing the severity classifications, for instance, A-DROP. We compared the usefulness of different severity classifications (A-DROP, CURB-65, PSI, and I-ROAD) in predicting the prognosis of nursing and healthcare-associated pneumonia. We conducted a retrospective analysis on 303 adult patients hospitalized for nursing healthcare-associated pneumonia and community-acquired pneumonia, which were diagnosed at the Department of Respiratory Medicine of Niigata General City Hospital between January 2012 and December 2014. We evaluated 159 patients with community-acquired pneumonia and 144 with nursing and healthcare-associated pneumonia. In the nursing and healthcare-associated pneumonia group, 30-days mortality and in-hospital mortality rates were 6.5% and 8.7%, respectively, in severe cases and 16.1% and 25.0%, respectively, in the most severe cases, based on A-DROP. With I-ROAD, these rates were 11.1% and 11.1%, respectively, in group B and 14.9% and 20.7%, respectively, in group C. With PSI, the rates were 2.3% and 6.8%, respectively, in class IV and 14.3% and 19.8%, respectively, in class V. Despite some variability due to the small sample size, both the 30-days and in-hospital mortality rates increased as the severity increased. In this study, both the 30-days mortality and in-hospital mortality rates in the nursing and healthcare-associated pneumonia group tended to increase in severity with the A-DROP. We found that A-DROP was useful in predicting the prognosis of nursing and healthcare-associated pneumonia.
Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in ...patients with suppressed viral load.
This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation.
58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD).
Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load.
ClinicalTrials.gov NCT01294761 http://clinicaltrials.gov/ct2/show/NCT01294761?term=SPARE&rank=2, Umin Clinical Trials Registry UMIN000005116 http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J).
The current guidelines recommend 21-day adjunctive corticosteroid therapy for HIV-1-infected pneumocystis pneumonia patients (HIV-PCP) with moderate-to-severe disease. Whether shorter adjunctive ...corticosteroid therapy is feasible in such patients is unknown.
We conducted a retrospective study to elucidate the proportion of patients with moderate and severe HIV-PCP who required adjunctive corticosteroid therapy for 21 days. The enrollment criteria included HIV-PCP that fulfilled the current criteria for 21-day corticosteroid therapy; PaO2 on room air of <70mmHg or A-aDO2 ≥35 mmHg.
The median duration of corticosteroid therapy in the 73 study patients was 13 days (IQR 9-21). Adjunctive corticosteroid therapy was effective and discontinued within 10 and 14 days in 30% and 60% of the patients, respectively. Only 9% of the patients with moderate HIV-PCP (n = 22, A-aDO2 35-45 mmHg) received steroids for >14 days, whereas 35% of the patients with severe HIV-PCP (n = 51, A-aDO2 ≥45 mmHg) required corticosteroid therapy for ≥21 days. Four (13%) of the severe cases died, whereas no patient with moderate disease died. Among patients with severe HIV-PCP, discontinuation of corticosteroid therapy within 14 days correlated significantly with higher baseline CD4 (p = 0.049).
Shorter adjunctive corticosteroid therapy was clinically effective and adjunctive corticosteroid could be discontinued within 14 days in 60% of moderate-to-severe HIV-PCP and 90% of moderate cases.
Abstract We report the case of a 44-year-old woman with disseminated Mycobacterium avium complex (MAC) infection involving multiple bone lesions despite a normal healthy status until 6 months ...previously. Because she was suspected to have acquired immunodeficiency, we tested interferon (IFN)-γ production by peripheral blood mononuclear cells (PBMC) after phytohemagglutinin (PHA) or anti-CD3 stimulation, and found that these cells produced no, or undetectable, levels of IFN-γ in the presence of the patient’s plasma, but produced nearly normal levels of IFN-γ in the presence of healthy donor plasma. Since the IgG fraction of the patient’s plasma was capable of blocking in vitro responses to IFN-γ, the cause of disseminated MAC infection in this case appeared to be anti-IFN-γ autoantibodies. To reduce the titer of anti-IFN-γ autoantibodies, the patient received intravenous immunoglobulin (IVIG). However, titer of autoantibodies changed little compared to that before IVIG administration. According to our literature search, this is only the second case of disseminated MAC infection associated with anti-IFN-γ autoantibodies in Japan.
STAT1 is an essential part of interferon signaling, and STAT1-deficiency results in heightened susceptibility to infections or autoimmunity in both mice and humans. Here we report that mice lacking ...the IFNα/β-receptor (IFNAR1) or STAT1 display impaired deletion of autoreactive CD4(+)CD8(+)-T-cells. Strikingly, co-existence of WT T cells restored thymic elimination of self-reactive STAT1-deficient CD4(+)CD8(+)-T cells. Analysis of STAT1-deficient thymocytes further revealed reduced Bim expression, which was restored in the presence of WT T cells. These results indicate that type I interferons and STAT1 play an important role in the survival of MHC class I-restricted T cells in a T cell intrinsic and non-cell intrinsic manner that involves regulation of Bim expression through feedback provided by mature STAT1-competent T cells.
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