Clinical characteristics and genome epidemiology of Stenotrophomonas maltophilia in Japan.

BACKGROUND: Stenotrophomonas maltophilia is a carbapenem-resistant Gram-negative pathogen increasingly responsible for difficult-to-treat nosocomial infections. OBJECTIVES: To describe the contemporary clinical characteristics and genome epidemiology of patients colonized or infected by S. maltophilia in a multicentre, prospective cohort. METHODS: All patients with a clinical culture growing S. maltophilia were enrolled at six tertiary hospitals across Japan between April 2019 and March 2022. The clinical characteristics, outcomes, antimicrobial susceptibility and genomic epidemiology of cases with S. maltophilia were investigated. RESULTS: In total, 78 patients were included representing 34 infection and 44 colonization cases. The median age was 72.5 years (IQR, 61-78), and males accounted for 53 cases (68%). The most common comorbidity was localized solid malignancy (39%). Nearly half of the patients (44%) were immunosuppressed, with antineoplastic chemotherapy accounting for 31%. The respiratory tract was the most common site of colonization (86%), whereas bacteraemia accounted for most infection cases (56%). The 30 day all-cause mortality rate was 21%, which was significantly higher in infection cases than colonization cases (35% versus 9%; adjusted HR, 3.81; 95% CI, 1.22-11.96). Susceptibility rates to ceftazidime, levofloxacin, minocycline and sulfamethoxazole/trimethoprim were 14%, 65%, 87% and 100%, respectively. The percentage of infection ranged from 13% in the unclassified group to 86% in genomic group 6A. The percentage of non-susceptibility to ceftazidime ranged from 33% in genomic group C to 100% in genomic groups 6 and 7 and genomic group geniculate. CONCLUSIONS: In this contemporary multicentre cohort, S. maltophilia primarily colonized the respiratory tract, whereas patients with bacteraemia had the highest the mortality from this pathogen. Sulfamethoxazole/trimethoprim remained consistently active, but susceptibility to levofloxacin was relatively low. The proportions of cases representing infection and susceptibility to ceftazidime differed significantly based on genomic groups.

Interstitial lung disease with prolonged fever that occurred during long-term administration of olaparib in a 74-year-old ovarian cancer patient: Radiological features and considerations for preventing delayed diagnosis.

A 74-year-old woman, who had been receiving olaparib for the treatment of ovarian cancer for more than a year, visited the emergency department complaining of a fever that had lasted for 1 month. She had been taking antipyretics and antibiotics for her fever, but without any effect. Although she had no symptoms other than fever, she had stopped taking olaparib for 1 week before her visit because she had developed anemia caused by myelosuppression from olaparib. After discontinuing olaparib, her maximum body temperature decreased. On admission, chest X-ray revealed no abnormalities, but chest CT showed diffuse ground-glass opacities. Chest CT taken 5 days later showed partial improvement; therefore, we diagnosed her with interstitial lung disease (ILD) associated with olaparib. After short-term steroid treatment, the ground-glass opacities disappeared, and the patient became afebrile. The CT scan taken for tumor evaluation 2 days before the onset of fever showed a few centrilobular nodular opacities and small patchy ground-glass opacities. These findings could indicate early lesions of ILD, but they seemed inconspicuous and nonspecific, and it might have been difficult to diagnose ILD then. To date, few cases of ILD associated with olaparib have been reported. However, based on previous reports, fever is often seen, and CT findings mainly comprise diffuse ground-glass opacities, and in some cases, centrilobular nodular shadows. Thus, in conjunction with the findings of the present case, these characteristics may be representative of olaparib-induced ILD.

Successful immunosuppressant-free treatment of a drug-induced sarcoidosis-like reaction caused by dupilumab.

We present a case of a drug-induced sarcoidosis-like reaction (DISR) in a 34-year-old female patient who had been receiving dupilumab for eosinophilic rhinosinusitis, for seven months. Computerized tomography scans revealed multiple lymphadenopathies, and biopsies performed on the lung and skin lesions showed the presence of non-caseating granulomas. The patient's serum levels of soluble interleukin-2 receptor and angiotensin-converting enzyme were elevated. There were no findings of Mycobacterium spp, or any other bacterial infections. Based on these findings, it was suspected that the sarcoidosis-like reaction observed in this patient was caused by dupilumab. Switching the patient's treatment from dupilumab to mepolizumab improved the DISR.

Isolation of human monoclonal antibodies with neutralizing activity to a broad spectrum of SARS-CoV-2 viruses including the Omicron variants.

Monoclonal antibody therapy is a promising option for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and a cocktail of antibodies (REGN-COV) has been administered to infected patients with a favorable outcome. However, it is necessary to continue generating novel sets of monoclonal antibodies with neutralizing activity because viral variants can emerge that show resistance to the currently utilized antibodies. Here, we isolated a new cocktail of antibodies, EV053273 and EV053286, from peripheral blood mononuclear cells derived from convalescent patients infected with wild-type SARS-CoV-2. EV053273 exerted potent antiviral activity against the Wuhan wild-type virus as well as the Alpha and Delta variants in vitro, whereas the antiviral activity of EV053286 was moderate, but it had a wide-range of suppressive activity on the wild-type virus as well as the Alpha, Beta, Delta, Kappa, Omicron BA.1, and BA.2 variants. With the combined use of EV053273 and EV053286, we observed similar inhibitory effects on viral replication as with REGN-COV in vitro. We further assessed their activity in vivo by using a mouse model infected with a recently established viral strain with adopted infectious activity in mice. Independent experiments revealed that the combined use of EV053273 and EV053286 or the single use of each monoclonal antibody efficiently blocked infection in vivo. Together with data showing that these two monoclonal antibodies could neutralize REGN-COV escape variants and the Omicron variant, our findings suggest that the EV053273 and EV053286 monoclonal antibody cocktail is a novel clinically applicable therapeutic candidate for SARS-CoV-2 infection.

Effectiveness of remdesivir in hospitalized nonsevere patients with COVID-19 in Japan: A large observational study using the COVID-19 Registry Japan.

OBJECTIVES: To evaluate the effectiveness of remdesivir in the early stage of nonsevere COVID-19. Although several randomized controlled trials have compared the effectiveness of remdesivir with that of a placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. METHODS: We evaluated the effectiveness of remdesivir in the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalized patients with COVID-19 in Japan. Two regimens ("start remdesivir" therapy within 4 days from admission versus no remdesivir during hospitalization) among patients without the need for supplementary oxygen therapy were compared by a 3-step processing (cloning, censoring, and weighting) method. The primary outcome was a supplementary oxygen requirement during hospitalization. Secondary outcomes were 30-day in-hospital mortality and the risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). The data of 12,487 cases met our inclusion criteria. The "start remdesivir" regimen showed a lower risk of supplementary oxygen requirement (hazard ratio [HR]: 0.850, 95% confidence interval [CI]: 0.798-0.906, p value < 0.001). Both 30-day in-hospital mortality and risk of IMV/ECMO introduction were not significantly different between the 2 regimens (HRs: 1.04 and 0.983, 95% CI: 0.980-1.09 and 0.906-1.07, p values: 0.210 and 0.678, respectively). CONCLUSIONS: Remdesivir might reduce the risk of oxygen requirement during hospitalization in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction in IMV/ECMO requirement.

Risk factors associated with asymptomatic hypoxemia among COVID-19 patients: a retrospective study using the nationwide Japanese registry, COVIREGI-JP.

Deaths of home-care patients with coronavirus disease (COVID-19) have become a social problem. One of their causes is hypoxemia without dyspnea which delays seeking medical attention. This was a retrospective study including patients registered in the COVID-19 Registry Japan, in which hospitalized patients with COVID-19 in 227 participating healthcare facilities were enrolled. The enrolled patients were divided into two groups: non-dyspneic patients with a peripheral capillary oxygen saturation (SpO2) ≤ 93% on admission (the hypoxemia without dyspnea group) and non-dyspneic patients with an SpO2> 93% (the control group). We conducted a multivariate logistic regression analysis to identify the factors associated with hypoxemia without dyspnea. 21544 patients were enrolled, 1035 (4.8%) patients were in the hypoxemia without dyspnea group, and 20509 (95.2%) patients were in the control group. The median respiratory rate (RR) of the hypoxemia without dyspnea group was higher than that of the control group (31/min vs. 18/min, p < 0.001). Age> 65, male, body mass index> 25, smoking, chronic obstructive pulmonary disease, other chronic lung disease, and diabetes mellitus were the independent factors associated with hypoxemia without dyspnea. Patients with those background should be closely monitored. RR is an important indicator of hypoxemia, even in the absence of dyspnea.

Comorbidities as Risk Factors for Severe Disease in Hospitalized Elderly COVID-19 Patients by Different Age-Groups in Japan.

INTRODUCTION: Old age is an independent risk factor (RF) for severe COVID-19; evidence for clinico-epidemiological characteristics among elderly COVID-19 patients is scarce. We aimed to analyze clinical and epidemiological characteristics and comorbidities associated with COVID-19 inpatients in age-stratified populations of an elderly COVID-19 cohort. METHODS: We conducted a retrospective cohort study, using nationwide registry data of COVID-19 patients hospitalized before October 31, 2020 (major information entered in the registry as of December 28, 2020). Participants were divided by age according to the Japan Geriatrics Society and the Japan Gerontological Society: pre-old (65-74 years), old (75-89 years), and super-old (≥90 years). Multivariable logistic regression (MLR) analyses were conducted to identify stratified risk and relationships with comorbidities associated with worse outcomes in different age-groups of elderly patients. Demographics and supportive care were evaluated by category. RESULTS: Data of 4,701 patients from 444 hospitals were included. Most patients (79.3%) had at least one comorbidity; the proportion of patients with hypertension was high in all categories. The proportion of patients with dementia, cardiovascular disease, and cerebrovascular disease increased with age. The percentage of patients who underwent invasive mechanical ventilation/extracorporeal membrane oxygenation was lower in the super-old group. In total, 11.5% of patients died (5.3%, pre-old; 15.2%, old; and 22.4%, super-old). MLR showed that the risk of critical illness differed among age-groups. Male sex was a significant RF in all ages. Collagen disease, moderate to severe renal disorder, and dialysis were significant RFs in older patients, while hematological malignancies and metastatic tumors were more important RFs for severe disease in relatively younger patients. Most of the RFs for critical illnesses were associated with death. CONCLUSION: Differences in the epidemiological and clinical characteristics among the different age-groups were found.

Smoking and severe illness in hospitalized COVID-19 patients in Japan.

BACKGROUND: The aim of this study was to identify associations between smoking status and the severity of COVID-19, using a large-scale data registry of hospitalized COVID-19 patients in Japan (COVIREGI-JP), and to explore the reasons for the inconsistent results previously reported on this subject. METHODS: The analysis included 17 666 COVID-19 inpatients aged 20-89 years (10 250 men and 7416 women). We graded the severity of COVID-19 (grades 0 to 5) according to the most intensive treatment required during hospitalization. The smoking status of severe grades 3/4/5 (invasive mechanical ventilation/extracorporeal membrane oxygenation/death) and separately of grade 5 (death) were compared with that of grade 0 (no oxygen, reference group) using multiple logistic regression. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and other factors considering the potential intermediate effects of comorbidities. RESULTS: Among men, former smoking significantly increased the risk of grade 3/4/5 and grade 5, using grade 0 as a reference group, with age- and admission-date-adjusted ORs (95% CI) of 1.51 (1.18-1.93) and 1.65 (1.22-2.24), respectively. An additional adjustment for comorbidities weakened the ORs. Similar results were seen for women. Current smoking did not significantly increase the risk of grade 3/4/5 and grade 5 in either sex. CONCLUSIONS: The severity of COVID-19 was not associated with current or former smoking per se but with the comorbidities caused by smoking. Thus, smoking cessation is likely to be a key factor for preventing smoking-related disease and hence for reducing the risk of severe COVID-19.

How we secured a COVID-19 convalescent plasma procurement scheme in Japan.

BACKGROUND: In order to tackle the COVID-19 pandemic, a COVID-19 convalescent plasma (CCP) procurement program was initiated in Japan in April 2020. The program was a collaboration between a government-managed national hospital, an infectious disease research institute, and a blood banking organization. Each party assumed different responsibilities: recruitment, SARS-CoV-2 antibody profiling, and plasmapheresis; conduction of screening tests; and SARS-CoV-2 blood testing, respectively. METHODS: We adopted a two-point screening approach before the collected CCP was labeled as a CCP product for investigational use, for which we mainly tested anti-SARS-CoV-2 antibody eligibility and blood product eligibility. Anti-SARS-CoV-2 spike protein titer was measured using enzyme-linked immunosorbent assay, and the IC50 value was denoted as the neutralizing activity. Blood donor eligibility was extended beyond the normal blood donation guidelines to include a broader range of participants. After both eligibility criteria were confirmed, participants were asked to revisit the hospital for blood donation, which is a unique aspect of the Japanese CCP program, as most donations are taking place in normal blood donation venues in other countries. Some donors were re-scheduled for repeat plasma donations. As public interest in anti-SARS-CoV-2 antibodies increased, test results were given to the participants. RESULTS: As of September 17, 2020, our collection of CCP products was sufficient to treat more than 100 patients. As a result, projects for administration and distribution are also being conducted. CONCLUSIONS: We successfully implemented a CCP procurement scheme with the goal to expand to other parts of the country to improve treatment options for COVID-19.

Risk factors for severity on admission and the disease progression during hospitalisation in a large cohort of patients with COVID-19 in Japan.

OBJECTIVES: To investigate the risk factors contributing to severity on admission. Additionally, risk factors of worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity and fatality. DESIGN: An observational cohort study using data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP. SETTING: As of 28 September 2020, 10480 cases from 802 facilities have been registered. Participating facilities cover a wide range of hospitals where patients with COVID-19 are admitted in Japan. PARTICIPANTS: Participants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests were admitted to participating healthcare facilities. A total of 3829 cases were identified from 16 January to 31 May 2020, of which 3376 cases were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was severe or nonsevere on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2 or respiratory rate. Secondary outcome was the worst severity during hospitalisation, judged by the requirement of oxygen and/orinvasive mechanical ventilation/extracorporeal membrane oxygenation. RESULTS: Risk factors for severity on admission were older age, men, cardiovascular disease, chronic respiratory disease, diabetes, obesity and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumour and hyperlipidaemia did not influence severity on admission; however, it influenced worst severity. Fatality rates for obesity, hypertension and hyperlipidaemia were relatively lower. CONCLUSIONS: This study segregated the comorbidities influencing severity and death. It is possible that risk factors for severity on admission, worst severity and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidaemia and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation. TRIAL REGISTRATION NUMBER: UMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453.

Positive Ratio of Polymerase Chain Reaction (PCR) and Validity of Pre-Screening Criteria at an Outpatient Screening Center during the Early Phase of the COVID-19 Epidemic in Japan.

Despite the increase in COVID-19 cases globally, the number of cases in Japan has been relatively low, and an explosive surge in the prevalence has not occurred. In March 2020, the Ministry of Health, Labour and Welfare (MHLW) in Japan recommended the original criteria for polymerase chain reaction (PCR) testing, although there was a lack of evidence for appropriate targets for COVID-19 testing. This study aimed to evaluate the COVID-19 positive ratio and pre-screening criteria in Tokyo immediately after the insurance-covered SARS-CoV-2 PCR testing became available in Japan. We subjected 277 individuals with mild symptoms in metropolitan Tokyo (positive: 9.0%) from March 9 to 29, 2020, to SARS-CoV-2 PCR testing. The results revealed that 25 (9.0%) of them were PCR-positive. The sensitivity and specificity of the MHLW criteria were 100% and 10.7%, respectively. When the criteria excluded nonspecific symptoms, fatigue, and dyspnea, the sensitivity slightly decreased to 92%, and the specificity increased to 22.2%. The specificity was highest when the fever criterion was ≥37.5°C for ≥4 days, and exposure/travel history, including age and underlying comorbidities, was considered. Our findings suggest that the MHLW criteria, including the symptoms and exposure/travel history, may be useful for COVID-19 pre-screening.

Successful Treatment with Afatinib after Osimertinib-induced Interstitial Lung Disease in a Patient with EGFR-mutant Non-small-cell Lung Cancer.

Osimertinib is the standard treatment for epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer. However, drug-induced interstitial lung disease (ILD) is recognized as a serious adverse event associated with EGFR-tyrosine kinase inhibitors (TKIs). We herein report a 78-year-old woman with stage IV lung adenocarcinoma harboring an EGFR L858R mutation on exon 21 who received rechallenge treatment with afatinib after osimertinib-induced ILD with an organizing pneumonia pattern. This is the first report of successful rechallenge with afatinib after osimertinib-induced ILD. Treatment with other EGFR-TKIs after osimertinib-induced ILD may be an option for subsequent therapy.

Intravenous to oral switch therapy in cancer patients with catheter-related bloodstream infection due to methicillin-sensitive Staphylococcus aureus: A single-center retrospective observational study.

The most common complication in cancer patients is catheter-related bloodstream infection (CRBSI), of which Staphylococcus aureus is a common pathogen. Although S. aureus CRBSI patients are recommended for prolonged intravenous therapy, this is often not feasible. We assessed the effectiveness of switching from intravenous to oral antimicrobial therapy in cancer patients with CRBSI due to methicillin-sensitive S. aureus (MSSA). We conducted a retrospective observational study of 60 patients at one tertiary-care cancer center between April 2005 and March 2016. Patients who received effective intravenous (IV) antibiotics for at least 10 days (IV group) were compared to the IV group of patients who had switched to effective oral (PO) antibiotics after IV treatment for at least 10 days (IV + PO group). The primary endpoint was all-cause mortality within 90 days. Univariate and propensity score-adjusted multivariate logistic regression analyses using variables likely to influence the outcomes were performed. Of the 60 patients, 32 (53.3%) and 28 (46.7%) were in the IV and IV + PO groups, respectively. The median antibiotic treatment durations in the IV and IV + PO groups were 17 (13-31) and 33 (26-52) days, respectively (p<0.001). The 90-day mortality in the IV and IV + PO groups were 53.1% (17/32) and 10.7% (3/28), respectively (p = 0.001). Univariate logistic regression model showed that the odds ratios of oral switch therapy for 90-day mortality was 0.106 (95% confidence interval [CI]: 0.027-0.423; p = 0.001). The propensity score-adjusted multivariate logistic regression model estimated the odds ratios of oral switched therapy for 90-day mortality as 0.377 (95% CI: 0.037-3.884; p = 0.413). Our results suggest that oral switch therapy was not associated with mortality in cancer patients with CRBSI due to MSSA compared with no oral switch therapy. Oral switch therapy may be a reasonable option for patients with CRBSI due to MSSA.

Association between tooth loss and cognitive impairment in community-dwelling older Japanese adults: a 4-year prospective cohort study from the Ohasama study.

BACKGROUND: Numerous prospective studies have investigated the association between the number of remaining teeth and dementia or cognitive decline. However, no agreement has emerged on the association between tooth loss and cognitive impairment, possibly due to past studies differing in target groups and methodologies. We aimed to investigate the association between tooth loss, as evaluated through clinical oral examinations, and the development of cognitive impairment in community-dwelling older adults while considering baseline cognitive function. METHODS: This 4-year prospective cohort study followed 140 older adults (69.3% female) without cognitive impairment aged ≥65 years (mean age: 70.9 ± 4.3 years) living in the town of Ohasama, Iwate Prefecture, Japan. Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) in baseline and follow-up surveys. Based on a baseline oral examination, the participants were divided into those with 0-9 teeth and those with ≥10 teeth. To investigate the association between tooth loss and cognitive impairment, we applied a multiple logistic regression analysis adjusted for age, sex, hypertension, diabetes, cerebrovascular/cardiovascular disease, hypercholesterolemia, depressive symptoms, body mass index, smoking status, drinking status, duration of education, and baseline MMSE score. RESULTS: In the 4 years after the baseline survey, 27 participants (19.3%) developed cognitive impairment (i.e., MMSE scores of ≤24). Multiple logistic regression analysis indicated that participants with 0-9 teeth were more likely to develop cognitive impairment than those with ≥10 teeth were (odds ratio: 3.31; 95% confidence interval: 1.07-10.2). Age, male gender, and baseline MMSE scores were also significantly associated with cognitive impairment. CONCLUSIONS: Tooth loss was independently associated with the development of cognitive impairment within 4 years among community-dwelling older adults. This finding corroborates the hypothesis that tooth loss may be a predictor or risk factor for cognitive decline.

Helicobacter fennelliae Bacteremia: Three Case Reports and Literature Review.

Helicobacter fennelliae is a gram-negative, spiral bacillus that appears as thin-spread colonies on sheep blood agar and is similar to Helicobacter cinaedi. H fennelliae is diagnosed by genetic testing, which is not readily available in all laboratories. Therefore, H fennelliae bacteremia has only been reported sporadically, and little is known about its clinical characteristics.We describe 3 cases of H fennelliae bacteremia with gastrointestinal symptoms, including nausea, vomiting, and diarrhea. Isolates could be differentiated from H cinaedi by biochemical reaction testing, including nitrate reduction and alkaline phosphatase hydrolysis.We retrospectively reviewed 24 cases of H fennelliae bacteremia reported in the literature. Most of the patients had immunosuppressive backgrounds, including solid tumors, hematological malignancies, and autoimmune diseases. Although gastrointestinal symptoms were common, cellulitis was not often observed in patients with H fennelliae bacteremia.Clinicians should bear in mind that H fennelliae may be a differential diagnosis in patients with gastrointestinal manifestations and gram-negative, spiral bacilli. In addition, biochemical reactions, such as nitrate reduction and alkaline phosphatase hydrolysis, are useful in differentiating H fennelliae from H cinaedi.