Frequent premature ventricular contractions induced by fluconazole: A case report.

Introduction: Fluconazole is commonly used to treat and prevent fungal infections caused by Candida and Cryptococcus species. Although there have been reports of fatal arrhythmias induced by fluconazole, such as torsades de pointes, there have been minimal reports of mild, non-fatal arrhythmias associated with it, which may have been overlooked in clinical practice. We encountered a case of frequent premature ventricular contractions induced by fluconazole during the treatment of HIV-related pulmonary cryptococcosis. Herein, we report a case of frequent premature ventricular contractions (PVCs) induced by fluconazole, along with a literature review. Case presentation: A 47-year-old man diagnosed with human immunodeficiency virus-related pulmonary cryptococcosis experienced an irregular heartbeat during antifungal therapy with fluconazole at 400 mg once daily. A 12-lead electrocardiogram was conducted, which displayed frequent unifocal PVCs originating in the right ventricular outflow tract without QT prolongation. After reducing the dose of fluconazole to 200 mg once daily, the patient's symptoms slightly improved, and PVC frequency decreased on a 12-lead ECG; however, PVCs did not disappear. After discontinuing fluconazole, the symptoms improved, and a follow-up 12-lead electrocardiogram showed no PVCs. Conclusions: We encountered the case of frequent PVCs induced by fluconazole during the treatment of human immunodeficiency virus-related pulmonary cryptococcosis. Furthermore, it was suggested that the PVC frequency was dose-dependent for fluconazole. Careful follow-up for new-onset arrhythmias and ECG evaluations are essential before and after fluconazole administration.

Association between a low response to rubella vaccination and reduced anti-severe acute respiratory syndrome coronavirus 2 immune response after vaccination with BNT162b2: a cross-sectional study.

OBJECTIVES: Some vaccinated individuals fail to acquire an adequate immune response against infection. We aimed to determine whether mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination could induce a sufficient immune response against SARS-CoV-2 in low responders to other vaccinations. METHODS: Using data from health-care workers who received two doses of the BNT162b2 vaccine (BioNTech/Pfizer), we conducted a single-centre, cross-sectional study to determine whether low responders to measles, rubella, and hepatitis B virus (HBV) vaccinations could acquire sufficient antibodies after SARS-CoV-2 vaccination. From May 2021 to June 2021, participants were tested for anti-SARS-CoV-2 spike (anti-S) IgG antibodies at least 2 weeks after the second dose of BNT162b2. The association between a low response to measles, rubella, and HBV vaccinations and the post-vaccination anti-S IgG titre was evaluated using the multivariable linear regression analysis. RESULTS: All 714 participants were positive for the anti-S IgG titre (≥50.0 AU/mL) after two doses of BNT162b2 (median, 7126.8 AU/mL; interquartile range, 4496.2-11 296.8). There were 323 (45.2%), 131 (18.3%), and 43 (6.0%) low responders to measles, rubella, and HBV vaccinations, respectively. In the multivariable linear regression analysis, low responders to rubella vaccination had significantly low acquisition of the anti-S IgG titre after two doses of the BNT162b2 vaccine (standardized coefficient ß, -0.110; 95% CI, -0.175 to -0.044). CONCLUSIONS: A low response to rubella vaccination is a potential predictor of a reduced response to SARS-CoV-2 vaccination. Further studies are needed to determine whether a low response to rubella vaccination is associated with the durability of SARS-CoV-2 vaccination-induced immune response.

Risk factors associated with hospitalization in patients with asymptomatic or mild COVID-19 in public accommodation facilities in Tokyo.

INTRODUCTION: In Japan, patients with coronavirus disease 2019 (COVID-19) who do not require medical intervention are provided care in recovery accommodation facilities (RAFs). However, some patients may require hospitalization if their symptoms become more severe during their stay. We conducted an observational study using epidemiological data of patients with COVID-19 admitted to RAFs in Tokyo. METHODS: This was an observational cohort study using data from COVID-19 patients admitted to one of the RAFs in Tokyo from December 2020 to November 2021. Admissions to the facilities were limited to patients with asymptomatic or mild COVID-19 with no underlying disease or at least stable underlying disease at the time of admission. Patients were hospitalized when they required oxygen administration or when they had, or persistent fever, or severe respiratory symptoms. We evaluated the association between hospitalization and the risk factors for hospitalization using a Cox regression model. RESULTS: The number of patients with COVID-19 admitted to the RAF was 6176. The number of hospitalized patients was 393 (6.4%), and the median length of stay was 5.50 days (IQR: 4.50, 6.50). In the Cox regression analysis, the hazard ratio increased with age and was significantly higher among patients aged >60 years (HR = 10.23, 95% CI: 6.72-15.57) than those in other age groups. This trend is similar to that observed in the sensitivity analysis. CONCLUSION: Patients with diabetes, the elderly, obesity, and medications for gout and psychiatric diseases may be at a high risk of hospitalization. In particular, an age over 60 years was strongly associated with hospitalization.

Early prediction of COVID-19 severity using extracellular vesicle COPB2.

The clinical manifestations of COVID-19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID-19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID-19 symptoms at the time of their admission for discovery cohort. After symptomatic treatment without corticosteroids, 9 of the 31 patients developed severe/critical COVID-19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID-19 severity. Strikingly, we identified three distinct groups of markers (antiviral response-related EV proteins, coagulation-related markers, and liver damage-related exRNAs) with the potential to serve as early predictive biomarkers for COVID-19 severity. As the best predictive marker, EV COPB2 protein, a subunit of the Golgi coatomer complex, exhibited significantly higher abundance in patients remained mild than developed severe/critical COVID-19 and healthy controls in discovery cohort (AUC 1.00 (95% CI: 1.00-1.00)). The validation set included 40 COVID-19 patients and 39 healthy controls, and showed exactly the same trend between the three groups with excellent predictive value (AUC 0.85 (95% CI: 0.73-0.97)). These findings highlight the potential of EV COPB2 expression for patient stratification and for making early clinical decisions about strategies for COVID-19 therapy.

Seroprevalence and associated factors of Toxoplasma gondii among HIV-infected patients in Tokyo: A cross sectional study.

HIV infection, in particular in patients with developing AIDS, carries a risk of causing toxoplasmosis with encephalitis, which is mostly caused by a form (bradyzoite) of the protozoan parasite Toxoplasma gondii. HIV/AIDS in Japan has been recognized as a serious health issue in recent years. In this study, to elucidate T. gondii seroprevalence in HIV-positive patients in Japan and associated characteristics with Toxoplasma parasite infection, the titer of T. gondii IgG (Tg-IgG) was measured in 399 HIV-positive patients who visited a hospital in Tokyo, Japan, between 2015 and 2017. A questionnaire survey was also conducted to investigate associations between lifestyle and customs. As a result, the overall prevalence of Tg-IgG-positive serum was 8.27% (33 cases of 399). All the cases positive for Tg-IgG were confirmed using the Sabin-Feldman dye test; the titers between each examination correlated robustly (p < 0.001, r = 0.6). A correlation between Toxoplasma infection rate and age was determined (p < 0.001), whereas there was no significant correlation with lifestyle customs such as consuming undercooked meat or owning a cat. An association between Toxoplasma infection and experience of dwelling in the Hokkaido area, the northern part of Japan, was observed (p = 0.001). These results suggested that the proportion of those who were previously exposed to Toxoplasma parasites in the HIV-positive population has been maintained at a similar level as that of the HIV-negative population in Japan, providing clear information about the potential risk of toxoplasmic encephalitis.

Early prophylactic antibiotics for severe acute pancreatitis: A population-based cohort study using a nationwide database in Japan.

OBJECTIVES: Previous studies evaluating the clinical benefits of prophylactic antibiotics for severe acute pancreatitis (SAP) have generated inconsistent results due to heterogeneities among the study settings. We determined if early prophylactic antibiotics improved the outcomes of SAP patients using a study designed to overcome these previous methodological weaknesses. METHODS: We conducted a retrospective cohort study of SAP patients discharged between July 2010 and March 2016, using a Japanese nationwide inpatient database. We divided patients into those with early prophylactic carbapenem use (prophylaxis group) and those without prophylaxis (control group). The primary outcome was in-hospital mortality and the secondary outcomes included oral vancomycin use and others. RESULTS: We identified a total of 3354 eligible patients, including 2493 in the prophylaxis group and 861 in the control group. The overall in-hospital mortality was 12.8%. Prophylactic antibiotics were not significantly associated reduced in-hospital mortality according to Cox regression analysis (hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.62-1.23) or instrumental variable analysis (risk difference, -1.2%; 95% CI, -9.8%-7.4%). However, prophylactic antibiotic use was significantly associated with oral vancomycin use during hospitalization in a competing-risk model (subdistribution HR, 1.91; 95% CI, 1.02-3.56). CONCLUSIONS: The present study suggests that routine early prophylactic antibiotic use have no significant clinical benefit in SAP patients but may increase the risk of hospital-acquired infections.

Severe Thrombocytopenia During Dolutegravir-containing Antiretroviral Therapy.

A 56-year-old Japanese man diagnosed with acquired immunodeficiency syndrome, Pneumocystis jirovecii pneumonia and cytomegalovirus infection presented with thrombocytopenia after starting antiretroviral therapy, which included dolutegravir (DTG). Although good control of the human immunodeficiency virus and cytomegalovirus infections was achieved, the patient's thrombocytopenia persisted. The patient's platelet count decreased to ≤50,000/µL even after the cessation of valganciclovir, which can cause bone marrow suppression. At five months after starting antiretroviral therapy, DTG was replaced by ritonavir-boosted darunavir. Soon after, his platelet count improved and was maintained at a level of >100,000/µL. This is the first reported case of severe thrombocytopenia during DTG-containing antiretroviral therapy.

Drug-induced liver injury associated with high-dose ceftriaxone: a retrospective cohort study adjusted for the propensity score.

PURPOSE: Ceftriaxone has been recognized as a well-tolerated drug; however, in some instances, liver dysfunction occurs after using high-dose ceftriaxone. We aimed to assess the incidence of liver injury due to high-dose ceftriaxone and to determine whether there is a dose-dependent risk of liver injury with this drug. METHODS: We conducted a retrospective cohort study of hospitalized adult patients treated with ceftriaxone at a tertiary care hospital from January 2012 to October 2013. We collected demographic and clinical data by reviewing their medical records. The incidence of liver injury based on biochemical criteria, defined as a primary outcome, was compared between patients treated with high-dose ceftriaxone (4 g/day) and those treated with a normal dose of ceftriaxone (2 g/day) for ≥5 consecutive days. A propensity score for the use of high-dose ceftriaxone was calculated from five factors. RESULTS: We identified 37 patients treated with high-dose ceftriaxone and 434 patients treated with a normal dose of ceftriaxone. Among these 471 patients, 15 patients (3.2 %) experienced liver injury, of whom six patients (6/37, 16.2 %) had received high-dose ceftriaxone and nine patients (9/434, 2.1 %) had received normal doses of ceftriaxone. In the multivariate analysis adjusted for the propensity score, high-dose ceftriaxone was independently associated with liver injury (odds ratio, 7.23; 95 % confidence interval, 2.01-26.0). CONCLUSIONS: The present study revealed that high-dose ceftriaxone was associated with a significantly higher incidence of liver injury compared with the normal-dose regimen. Therefore, clinicians should carefully observe for signs of liver injury after high-dose ceftriaxone use.

Associations of HIV testing and late diagnosis at a Japanese university hospital.

OBJECTIVES: This study was conducted to clarify the rate of late diagnosis of HIV infection and to identify relationships between the reasons for HIV testing and a late diagnosis. METHODS: This retrospective cohort study was conducted among HIV-positive patients at the Jikei University Hospital between 2001 and 2014. Patient characteristics from medical records, including age, sex, sexuality, the reason for HIV testing and the number of CD4-positive lymphocytes at HIV diagnosis, were assessed. RESULTS: A total of 459 patients (men, n=437; 95.2%) were included in this study and the median age at HIV diagnosis was 36 years (range, 18-71 years). Late (CD4 cell count <350/mm3) and very late (CD4 cell count <200/mm3) diagnoses were observed in 61.4% (282/459) and 36.6% (168/459) of patients, respectively. The most common reason for HIV diagnosis was voluntary testing (38.6%, 177/459 patients), followed by AIDS-defining illness (18.3%, 84/459 patients). Multivariate analysis revealed a significant association of voluntary HIV testing with non-late and non-very-late diagnoses and there was a high proportion of AIDS-defining illness in the late and very late diagnosis groups compared with other groups. Men who have sex with men was a relative factor for non-late diagnosis, whereas nonspecific abnormal blood test results, such as hypergammaglobulinemia and thrombocytopenia, were risk factors for very late diagnosis. CONCLUSIONS: Voluntary HIV testing should be encouraged and physicians should screen all patients who have symptoms or signs and particularly hypergammaglobulinemia and thrombocytopenia, that may nonspecifically indicate HIV infection.

Associations of HIV testing and late diagnosis at a Japanese university hospital

OBJECTIVES: This study was conducted to clarify the rate of late diagnosis of HIV infection and to identify relationships between the reasons for HIV testing and a late diagnosis. METHODS: This retrospective cohort study was conducted among HIV-positive patients at the Jikei University Hospital between 2001 and 2014. Patient characteristics from medical records, including age, sex, sexuality, the reason for HIV testing and the number of CD4-positive lymphocytes at HIV diagnosis, were assessed. RESULTS: A total of 459 patients (men, n=437; 95.2%) were included in this study and the median age at HIV diagnosis was 36 years (range, 18-71 years). Late (CD4 cell count <350/mm3) and very late (CD4 cell count <200/mm3) diagnoses were observed in 61.4% (282/459) and 36.6% (168/459) of patients, respectively. The most common reason for HIV diagnosis was voluntary testing (38.6%, 177/459 patients), followed by AIDS-defining illness (18.3%, 84/459 patients). Multivariate analysis revealed a significant association of voluntary HIV testing with non-late and non-very-late diagnoses and there was a high proportion of AIDS-defining illness in the late and very late diagnosis groups compared with other groups. Men who have sex with men was a relative factor for non-late diagnosis, whereas nonspecific abnormal blood test results, such as hypergammaglobulinemia and thrombocytopenia, were risk factors for very late diagnosis. CONCLUSIONS: Voluntary HIV testing should be encouraged and physicians should screen all patients who have symptoms or signs and particularly hypergammaglobulinemia and thrombocytopenia, that may nonspecifically indicate HIV infection.

Four Cases of Autochthonous Dengue Infection in Japan and 46 Imported Cases: Characteristics of Japanese Dengue.

OBJECTIVE: A dengue outbreak occurred in Japan 2014. We investigated the characteristics of dengue infection among Japanese. METHODS: We investigated the medical charts retrospectively. Patients The study participants are patients who came to our clinic between 2008 and 2014. RESULTS: We investigated 4 domestic cases and 46 imported cases of Japanese with laboratory confirmation of dengue. Major symptoms were fever (100%), rash (86%), fatigue (84%), headache (81%), joint pain (66%), muscle pain (49%), and bleeding (6%). A late rash that appeared near the time of fever resolution was observed in 37 cases (74%). A total of 38/43 (88%) cases had low WBC count (<3,500 /µL) during the febrile period, 42/48 (88%) cases had a low platelet (PLT) count (<130×10(3)/µL), and 44/50 (88%) cases had a C-reactive protein (CRP) <2.0 mg/dL. CONCLUSION: Patients with a high fever, late rash, fever-associated leukopenia, low PLT count, low CRP, and elevated aminotransferases are generally suspected of having a dengue infection.

Predictive factors for metastatic infection in patients with bacteremia caused by methicillin-sensitive Staphylococcus aureus.

BACKGROUND: Metastatic infections such as infective endocarditis and psoas abscess are serious complications of Staphylococcus aureus bacteremia because failure to identify these infections may result in bacteremia relapse or poor prognosis. In the present study, we determined the predictive factors for metastatic infection due to methicillin-sensitive S. aureus bacteremia. METHODS: A retrospective cohort study was conducted among patients with methicillin-sensitive S. aureus bacteremia at the Jikei University Hospital between January 2008 and December 2012. Factors analyzed included the underlying disease, initial antimicrobial treatment and primary site of infection. RESULTS: During the 5-year study period, 73 patients met the inclusion criteria and were assessed. The most common primary site of bacteremia was catheter-related bloodstream infection (25/73 [34.2%]). Metastatic infection occurred in 14 of 73 patients (19.2%) (infective endocarditis [3], septic pulmonary abscess [3], spondylitis [4], psoas abscess [4], epidural abscess [3] and septic arthritis [1]). Six patients had multiple metastatic infections. Multivariate analysis revealed that the predictive factors associated with the development of metastatic infection were a delay in appropriate antimicrobial treatment of >48 hours, persistent fever for >72 hours after starting antibiotic treatment and lowest C-reactive protein levels of >3 mg/dL during 2 weeks after the onset of bacteremia. CONCLUSIONS: This study demonstrated that additional diagnostic tests should be conducted to identify metastatic infection, particularly in patients with delayed antimicrobial treatment, persistent fever and persistently high C-reactive protein levels.

Epidemiology of extended-spectrum ß-lactamase producing Escherichia coli in the stools of returning Japanese travelers, and the risk factors for colonization.

OBJECTIVE: Travel overseas has recently been considered a risk factor for colonization with drug-resistant bacteria. The purpose of this study was to establish the epidemiology and risk factors associated with the acquisition of drug-resistant bacteria by Japanese travelers. METHODS: Between October 2011 and September 2012, we screened the stools of 68 Japanese returning travelers for extended-spectrum ß-lactamase (ESBL) producing Escherichia coli. All specimens were sampled for clinical reasons. Based on the results, the participants were divided into an ESBL-producing E. coli positive group (18 cases; 26%) and an ESBL-producing E. coli negative group (50 cases; 74%), and a case-control study was performed. Microbiological analyses of ESBL-producing strains, including susceptibility tests, screening tests for metallo-ß-lactamase, polymerase chain reaction amplification and sequencing of blaCTX-M genes, multilocus sequence typing, and whole genome sequencing, were also conducted. RESULTS: In a univariate comparison, travel to India was a risk factor (Odds Ratio 13.6, 95% Confidence Interval 3.0-75.0, p<0.0001). There were no statistical differences in the characteristics of the travel, such as backpacking, purpose of travel, interval between travel return and sampling stool, and duration of travel. Although 10 of 13 analyzed strains (77%) produced CTX-M-15, no ST131 clone was detected. CONCLUSION: We must be aware of the possibilities of acquiring ESBL-producing E. coli during travel in order to prevent the spread of these bacteria not only in Japan but globally.