Mpox Neutralizing Antibody Response to LC16m8 Vaccine in Healthy Adults.

BACKGROUND: Vaccination against mpox (formerly known as monkeypox), an infectious disease caused by the monkeypox virus (MPXV), is needed to prevent outbreaks and consequent public health concerns. The LC16m8 vaccine, a dried cell-cultured proliferative live attenuated vaccinia virus­based vaccine, was approved in Japan against smallpox and mpox. However, its immunogenicity and efficacy against MPXV have not been fully assessed. We assessed the safety and immunogenicity of LC16m8 against MPXV in healthy adults. METHODS: We conducted a single-arm study that included 50 participants who were followed up for 168 days postvaccination. The primary end point was the neutralizing antibody seroconversion rate against MPXVs, including the Zr599 and Liberia strains, on day 28. The secondary end points included the vaccine "take" (major cutaneous reaction) rate, neutralizing titer kinetics against MPXV and vaccinia virus (LC16m8) strains, and safety outcomes. RESULTS: Seroconversion rates on day 28 were 72% (36 of 50), 70% (35 of 50), and 88% (44 of 50) against the Zr599 strain, the Liberia strain, and LC16m8, respectively. On day 168, seroconversion rates decreased to 30% (15 of 50) against the Zr599 and Liberia strains and to 76% (38 of 50) against LC16m8. The vaccine "take" (broad definition) rate on day 14 was 94% (46 of 49). Adverse events (AEs), including common solicited cutaneous reactions, occurred in 98% (45 of 48) of participants; grade 3 severity AEs occurred in 16% (8 of 50). No deaths, serious AEs, or mpox onset incidences were observed up to day 168. CONCLUSIONS: The LC16m8 vaccine generated neutralizing antibody responses against MPXV in healthy adults. No serious safety concerns occurred with LC16m8 use. (Funded by the Ministry of Health, Labour and Welfare of Japan; Japan Registry of Clinical Trials number, jRCTs031220171.)

Unfractionated Heparin Safety in COVID-19: Incidence and Risks of Bleeding Complications in Japan.

AIM: Several studies have shown the efficacy and safety of low-molecular-weight heparin use in coronavirus disease 2019 (COVID-19), but that of unfractionated heparin (UFH) has not been investigated. We investigated the prevalence of bleeding complications during UFH administration, its impact on mortality, and the risk factors of bleeding outcomes associated with UFH. METHODS: This retrospective cohort study was conducted at a single-center tertiary care hospital, including hospitalized patients with COVID-19. The primary outcomes were measured as the prevalence of bleeding complications during hospitalization, and the secondary outcomes were thromboembolic events and 60-day mortality rates. Logistic regression analysis and propensity score matching were used to assess risk factors for bleeding complications and their impact on mortality. RESULTS: Among 1035 included patients, 516 patients were treated with UFH. Twelve (2.3%) patients in the UFH group experienced major bleeding. The prevalence of major bleeding in patients treated with therapeutic-dose UFH was 9.2%. Logistic regression analysis showed that age ≥ 60 years (adjusted odds ratio [aOR], 3.89; 95% confidence interval [CI], 1.01-15.0; P＜.05) and COVID-19 severity (aOR, 35.9; 95% CI, 4.57-282; P ＜.05) were associated with major bleeding complications. After propensity score matching, 11 major and 11 non-major bleeding cases (including minor bleeding) were matched. The 60-day cumulative mortality rate between the two groups did not differ significantly (P=.13, log-rank test). CONCLUSIONS: The incidence of major bleeding in COVID-19 patients using therapeutic-dose UFH was relatively high. Critical COVID-19 and older age were risk factors for bleeding complications.

Relapse of toxocariasis after completion of four-week treatment with albendazole.

Food-borne toxocariasis caused by the consumption of raw meat or liver has occasionally been reported from East Asia. We treated a 38-year-old Japanese man who was infected with Toxocara in China and underwent a four-week treatment with albendazole. The liver and lung lesions disappeared after the treatment, suggesting that the treatment was successful. One month after the end of the treatment, the patient relapsed, and albendazole was administered again for eight weeks. The patient has remained relapse-free for one year. Although toxocariasis can heal spontaneously, in some cases, such as the present case, the disease relapses even after long-term treatment. In conclusion, different durations of treatment are recommended by various guidelines, and the duration of treatment needs to be modified with each case, considering the response to the treatment.

Autopsy of tetanus with foot gangrene as portal of entry.

Non-traumatic chronic skin lesions are the second most common cause of tetanus. Herein, we describe an 85-year-old woman who presented with a chronically infected skin lesion. She developed tetanus while in hospital and died of respiratory failure, after refusing mechanical ventilation. Routine immunization against tetanus began in Japan during 1968; hence many people born before 1968 are unvaccinated. Mortality due to tetanus is high and the proportion with protective antibodies is low in older adults. Therefore, we recommend tetanus vaccination for older persons in Japan who have chronic skin lesions and have never been vaccinated.

Characterization of a SARS-CoV-2 EG.5.1 clinical isolate in vitro and in vivo.

EG.5.1 is a subvariant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB variant that is rapidly increasing in prevalence worldwide. However, the pathogenicity, transmissibility, and immune evasion properties of isolates of EG.5.1 are largely unknown. Here, we show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5 in hamsters. We also demonstrate that, like XBB.1.5, EG.5.1 is transmitted more efficiently between hamsters compared to its predecessor, BA.2. In contrast, unlike XBB.1.5, we detect EG.5.1 in the lungs of four of six exposed hamsters, suggesting that the virus properties of EG.5.1 are different from those of XBB.1.5. Finally, we find that the neutralizing activity of plasma from convalescent individuals against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. Our data suggest that the different virus properties after transmission and the altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in humans.

Characteristics of preventive intervention acceptance for international travel among clients aged 60 years and older from a Japanese multicenter pretravel consultation registry.

OBJECTIVES: Pretravel consultation (PTC) is important for older adults owing to health problems associated with overseas travel. Although older adults in Japan, their PTC characteristics are less known. This study aimed to investigate the epidemiology of clients aged ≥ 60 years based on data from the Japan Pre-travel Consultation Registry (J-PRECOR). METHODS: Clients aged ≥ 60 years who visited J-PRECOR cooperative hospitals from February 1, 2018, to May 31, 2022, were included. The primary endpoint was a comparison of prescriptions for vaccines for hepatitis A, tetanus toxoid, and malaria prophylaxis in travelers to high-risk malaria countries in yellow fever vaccination (YFV)-available facilities with and without YFV. RESULTS: In total, 1000 clients (median age: 67 years) were included. Although 523 clients were immunized with YFV, only 38.6% of the 961 unimmunized clients were vaccinated with the tetanus toxoid-containing vaccine. Malaria chemoprophylaxis was prescribed to 25.7% of clients traveling for ≤55 days. At YFV-capable institutes, 557 clients traveling to yellow fever risk countries took PTC, 474 of whom received YFV and 83 were unvaccinated. Lower age (odds rate 0.85 per 1 year; 95% CI 0.80-0.90) and lower hepatitis A vaccination rate (0.29; 95% CI 0.14-0.63) were significantly associated with YFV. CONCLUSIONS: Preventive interventions other than YFV should be offered to older adults.

An open-label, non-randomized study investigating the safety and efficacy of smallpox vaccine, LC16, as post-exposure prophylaxis for mpox.

Mpox is an acute exanthematous disease caused by the monkeypox virus. Since May 2022, it has spread as a community-acquired infection, mainly in Europe and the United States, and urgent measures to prevent this infection were also required in Japan. In this study, we investigated the post-exposure prophylaxis of mpox and safety after inoculating the smallpox vaccine. Participants in close contact with patients with mpox were inoculated with "Freeze-dried cell culture Smallpox Vaccine LC16," within 14 days after close contact. Six cases were registered, and all the participants were inoculated. No mpox symptoms or related complications were observed in the participants for 21 days after the close contact. Adverse events due to inoculation, such as rash, fever, lymphadenopathy, and local reaction at the inoculation site (comprising erythema, swelling, induration, and pain) were observed in the participants; however, all inoculation-related events were non-severe and non-serious, and the participants recovered during the 28-day observation period. The findings of this study suggest that inoculation with LC16 is an effective post-exposure prophylaxis in individuals who had close contact with patients with mpox. Further large-scale studies are warranted to validate these findings.

Efficacy and Safety of the Smallpox Vaccine for Postexposure Prophylaxis in Monkeypox: Protocol for an Open-Labeled, Single-Armed Study.

BACKGROUND: In May 2022, a case of monkeypox (currently known as "mpox") with no history of overseas travel was reported in the United Kingdom, followed by reports of infections reported in Europe, the United States, and other countries worldwide. Due to the significant overlap in immune responses among viruses of the genus Orthopoxvirus (including smallpox virus, mpox virus, and vaccinia virus), it is believed that cross-immunity can be achieved by administering the smallpox virus vaccine. In Japan, a smallpox vaccine (LC16m8 strain vaccine) has been approved; however, there was no regulatory approval for the mpox vaccine during the design of this study. Although it is believed that individuals exposed to the mpox virus may receive smallpox vaccination as mpox prophylaxis, the existing evidence is not clear. OBJECTIVE: The primary objective was to evaluate the efficacy of the LC16m8 strain vaccine, approved for smallpox in Japan, for postexposure prophylaxis against mpox when administered to close contacts of individuals with mpox. The secondary objective was to investigate the safety of the vaccine for postexposure prophylaxis against mpox. METHODS: The study aimed to enroll 100 vaccinated participants who had been identified as close contacts of individuals with mpox. Consent was obtained, and the participants are inoculated with the vaccine. Daily recordings of symptoms (body temperature, headache, rash, and side effects) were made until day 21 and then again on day 28. Furthermore, additional evaluations of adverse events were performed by the investigators on days 7, 14, 21, and 28. Considering that the maximum incubation period for mpox is 21 days, the primary end point is the presence or absence of the disease 21 days after close contact. The primary analysis focused on cases within 4 days of intense contact as it has been reported that vaccination within this timeframe can reduce the incidence of the disease. RESULTS: The first trial participant was enrolled on July 28, 2022, and the research period concluded in March 2023. The study results will be published in a peer-reviewed scientific journal. CONCLUSIONS: This study allowed us to investigate the efficacy and safety of the LC16m8 strain vaccine in postexposure prophylaxis against mpox. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031220137; https://jrct.niph.go.jp/en-latest-detail/jRCTs031220137. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46955.

Clinical Characteristics and Outcomes Among Travelers With Severe Dengue : A GeoSentinel Analysis.

BACKGROUND: Dengue virus is a flavivirus transmitted by Aedes mosquitoes and is an important cause of illness worldwide. Data on the severity of travel-associated dengue illness are limited. OBJECTIVE: To describe the epidemiology, clinical characteristics, and outcomes among international travelers with severe dengue or dengue with warning signs as defined by the 2009 World Health Organization classification (that is, complicated dengue). DESIGN: Retrospective chart review and analysis of travelers with complicated dengue reported to GeoSentinel from January 2007 through July 2022. SETTING: 20 of 71 international GeoSentinel sites. PATIENTS: Returning travelers with complicated dengue. MEASUREMENTS: Routinely collected surveillance data plus chart review with abstraction of clinical information using predefined grading criteria to characterize the manifestations of complicated dengue. RESULTS: Of 5958 patients with dengue, 95 (2%) had complicated dengue. Eighty-six (91%) patients had a supplemental questionnaire completed. Eighty-five of 86 (99%) patients had warning signs, and 27 (31%) were classified as severe. Median age was 34 years (range, 8 to 91 years); 48 (56%) were female. Patients acquired dengue most frequently in the Caribbean (n = 27 [31%]) and Southeast Asia (n = 21 [24%]). Frequent reasons for travel were tourism (46%) and visiting friends and relatives (32%). Twenty-one of 84 (25%) patients had comorbidities. Seventy-eight (91%) patients were hospitalized. One patient died of nondengue-related illnesses. Common laboratory findings and signs were thrombocytopenia (78%), elevated aminotransferase (62%), bleeding (52%), and plasma leakage (20%). Among severe cases, ophthalmologic pathology (n = 3), severe liver disease (n = 3), myocarditis (n = 2), and neurologic symptoms (n = 2) were reported. Of 44 patients with serologic data, 32 confirmed cases were classified as primary dengue (IgM+/IgG-) and 12 as secondary (IgM-/IgG+) dengue. LIMITATIONS: Data for some variables could not be retrieved by chart review for some patients. The generalizability of our observations may be limited. CONCLUSION: Complicated dengue is relatively rare in travelers. Clinicians should monitor patients with dengue closely for warning signs that may indicate progression to severe disease. Risk factors for developing complications of dengue in travelers need further prospective study. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention, International Society of Travel Medicine, Public Health Agency of Canada, and GeoSentinel Foundation.

Effectiveness of oral cephalexin in antibiotic-course completion for methicillin-susceptible Staphylococcus aureus-induced bacteremic vertebral osteomyelitis.

BACKGROUND: Methicillin-susceptible Staphylococcus aureus (MSSA) is the most common causative microorganism of pyogenic vertebral osteomyelitis (PVO). Although oral antimicrobial therapy with first-generation cephalosporins can treat MSSA infection, data on PVO are scarce. This study evaluated the treatment efficacy of cephalexin as oral antibiotic therapy for MSSA-induced PVO. METHODS: This retrospective study included adult patients treated with oral cephalexin as the completing treatment for PVO with MSSA bacteremia from 2012 to 2020. Treatment effectiveness of cephalexin was evaluated by comparing improvement (5-point scale; score ≥ 4/5 indicates treatment success) in symptoms and laboratory and imaging results between intravenous antimicrobial and oral cephalexin treatment. RESULTS: Among 15 participants (8 [53%] women; median [interquartile range, IQR], age 75 [67.5-80.5] years; Charlson Comorbidity Index 2 [0-4]), 10 (67%) had lumbar spine lesions, 12 (80%) had spinal abscesses, and 4 (27%) had remote abscesses; no patients had concomitant endocarditis. In 11 patients with normal renal function, cephalexin 1,500-2,000 mg/day was administered. Five patients (33%) underwent surgery. Median (IQR; range) duration (days) of intravenous antibiotics, cephalexin, and total treatment was 36 (32-61; 21-86), 29 (19-82; 8-251), and 86 (59-125; 37-337), respectively. Cephalexin had an 87% treatment success rate without recurrence during a median follow-up of 119 (IQR, 48.5-350) days. CONCLUSIONS: In patients with MSSA bacteremia and PVO, antibiotic treatment completion with cephalexin is a reasonable option, even in cases with spinal abscess, if at least 3 weeks of effective intravenous antimicrobial therapy is provided.

Evaluating the Immunogenicity and Safety of a Smallpox Vaccine to Monkeypox in Healthy Japanese Adults: A Single-Arm Study.

Monkeypox (mpox) is an acute exanthematous disease caused by the monkeypox virus (MPXV). Since May 2022, patients with mpox have been reported worldwide, mainly in Europe and the Americas. In Japan, LC16"KMB," which is a smallpox vaccine derived from a dried cell culture, against mpox, has been approved. Although inoculation with a smallpox vaccine has been recommended to prevent MPXV infection, the immunogenicity of the smallpox vaccine against the MPXV is unclear, and information regarding postvaccination safety is scarce. We present the protocol for a single-arm open-label study to investigate the immunogenicity and safety of LC16"KMB" against the MPXV in healthy Japanese adults. The primary endpoint is the seroconversion rate of neutralizing antibodies against the MPXV on postvaccination day 28. The secondary endpoints are the seroconversion rates against the MPXV on postvaccination days 14 and 168; the seroconversion rates against the vaccinia virus on postvaccination days 14, 28, and 168; the incidence of mpox until day 168; and adverse and serious adverse events until postvaccination days 28 and 168. These results will pave the way for larger comparative studies using other smallpox vaccines to evaluate the test vaccine's safety and efficacy in preventing mpox.

Treatment with tecovirimat of the first two cases of monkeypox in Japan.

Outbreaks of monkeypox in Europe and North America have been reported since May 2022. At the end of July, we encountered the first two cases of monkeypox diagnosed in Japan. Case 1 was a white man who traveled to Spain where he had sexual intercourse with men. He presented to our hospital with fever, rash, and tiredness, and was diagnosed with monkeypox based on positive PCR test results from the skin lesions. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 15. Case 2 involved a Japanese man who visited us because of fatigue, muscle pain, headache, and oral ulcers. He was living in New York and traveled to Japan one day before presentation. He had experienced sexual intercourse with men four times during the previous month. The patient was diagnosed with monkeypox based on positive PCR results from the blood. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 14. These were the first two cases of monkeypox diagnosed in Japan. Based on their history and epidemiology, the viruses seem to have been imported from Europe and North America, respectively. After initiation of tecovirimat, both patients showed mild symptoms and immediate disappearance of viral DNA. The second case was notable for being diagnosed without skin rash. Our report suggests that tecovirimat could decrease the viral load rapidly, and that our prompt diagnosis contributed to the prevention of a monkeypox outbreak in Japan.

Successful Treatment with Low-dose Crizotinib in a Patient with ROS1-rearranged Lung Cancer Who Developed Crizotinib-induced Heart Failure.

Crizotinib shows antitumor activity against C-ros oncogene 1-rearranged non-small-cell lung cancer (NSCLC). While corrected QT interval (QTc) prolongation and bradycardia are known as cardiac adverse effects, little is known about crizotinib-related heart failure. Our patient with C-ros oncogene 1-rearranged NSCLC on a reduced dose of crizotinib (200 mg twice daily) after initially experiencing bradycardia and QTc prolongation developed crizotinib-induced heart failure. With further dose reduction (250 mg once daily), there was no recurrence of any cardiac adverse effects, and the patient achieved a long-term response. Although crizotinib can cause heart failure, continuation of crizotinib at a low dose may be an effective treatment option.

Antibody titers and neutralizing activity in cases of COVID-19 after a single dose of vaccination.

Vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy in preventing the onset of disease. However, the immune response to infection immediately after the first vaccination remains unknown. We examined the anti-SARS-CoV-2-binding-antibody titers and neutralizing activity in patients who developed coronavirus disease 2019 after the first vaccination. The amount of anti-SARS-CoV-2-binding antibodies and neutralizing activity drastically increased from the first to the second collection. Our results may provide important data on the course of immune response following vaccination.

A novel anticoagulation treatment protocol using unfractionated heparin for coronavirus disease 2019 patients in Japan, 2022.

Hypercoagulability, which can be induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in the pathogenesis of coronavirus disease 2019 (COVID-19). Although anticoagulation therapy is expected to decrease the incidence of thrombosis and mortality in COVID-19 patients, the optimal use of anticoagulation therapy has not been established, especially using unfractionated heparin (UFH). Herein, we suggest a new anticoagulation treatment protocol for the use of UFH in Japanese COVID-19 patients. This protocol considers the safety regarding UFH usage, to lower major bleeding events, and reflects the latest evidence and the current situation regarding anticoagulation therapy in Japan.

Neutralising activity and antibody titre in 10 patients with breakthrough infections of the SARS-CoV-2 Omicron variant in Japan.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 has multiple amino acid mutations in its spike proteins, which may allow it to evade immunity elicited by vaccination. We examined the neutralising activity and S1-IgG titres in patients with breakthrough infections caused by the Omicron variant after two doses of vaccination. We found that neutralising activity was significantly lower for the Omicron variant than for the Wuhan strain. Two doses of vaccination might not induce sufficient neutralising activity for the Omicron variant.

Varicella pneumonia in an immunocompetent, unvaccinated man: A case report.

Varicella is a common vaccine-preventable disease that typically affects children aged 2-8 years and usually has a benign outcome. However, varicella infection in adults may cause serious complications, including varicella pneumonia. We report a case of varicella pneumonia in an immunocompetent, unvaccinated man in Japan. A 50-year-old Egyptian man who had been living in Japan for 20 years was brought to the hospital with a 3-day history of fever and a 2-day history of rash and dyspnea. Chest computed tomography revealed an 8-mm-long nodule with a halo in the right S3 segment and mild ground-glass opacities in both lungs. A final diagnosis was made based on identification of varicella-zoster virus via positive immunochromatographic test and polymerase chain reaction from a blister fluid. The patient's pneumonia had improved with acyclovir for 10 days. In Japan routine varicella vaccination in childhood (at ages 12 and 18 months) was introduced in 2014. However, in Egypt, where the patient spent his childhood, varicella vaccine is still not designated as a routine vaccination. The introduction of universal varicella vaccination in more countries and an increase in vaccination coverage are essential to reduce the number of cases of varicella infection, including varicella pneumonia.