Myeloid cell dynamics correlating with clinical outcomes of severe COVID-19 in Japan.

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.

High titer of antibody against the SARS-CoV-2 spike protein among patients receiving neutralizing antibody cocktail therapy with REGN-COV.

PURPOSE: Casirivimab/imdevimab (REGN-COV), a cocktail of neutralizing antibodies against the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, was shown to be an effective treatment and post-exposure prophylaxis measure for coronavirus disease 2019 (COVID-19). We assessed the antibody titers among patients who received REGN-COV with the purpose of evaluating this therapeutic and prophylactic option from the serological point of view. METHODS: We collected serological data of patients with COVID-19 who were treated with REGN-COV 1200 mg (casirivimab 600 mg/imdevimab 600 mg). Antibody titers were assessed within 24 h before and within 48 h after the administration of REGN-COV using ARCHITECT SARS-CoV-2 immunoglobulin (Ig)G (IgGNC), which is against nucleocapsid protein, and ARCHITECT SARS-CoV-2 IgG II Quant (IgGSP), which is against spike protein. RESULTS: A total of nine patients were evaluated. IgGSP was elevated after REGN-COV administration with a median of 208,370 Arbitrary Units/mL while simultaneous IgGNC remained low. With the simple linear regression model, the IgGSP after the REGN-COV administration was correlated with the reciprocal of ideal body weight. CONCLUSION: The high titer of IgGSP supports the clinical benefit of therapeutic and prophylactic use of REGN-COV from the serological point of view.

Recovery from severe persistent COVID-19 without evidence of an anti-SARS-CoV-2 antibody response in a man with mantle cell lymphoma treated with rituximab.

Lymphoma has been reported to worsen the prognosis of COVID-19 partly because it disturbs the normal production of antibodies. We treated a man with mantle cell lymphoma treated with rituximab, who developed severe COVID-19 with viral shedding that lasted for 78 days. He stayed in the intensive care unit for 28 days and did not respond to any treatment against COVID-19. His increased oxygen demand at rest eventually resolved despite the absence of anti-SARS-CoV-2-IgG. This case illustrates that recovery from COVID-19 can occur without antibody production, and that even patients with an inability to produce antibodies can recover from severe COVID-19. It also illustrates that lymphoma patients who develop severe COVID-19 while on rituximab therapy can recover from a prolonged viral shedding state if the acute lung injury can be overcome.

Antibody response after COVID-19 vaccine BNT162b2 on health care workers in Japan.

BACKGROUND: Vaccination is one of the most important tools to control the COVID-19 pandemic. However, there is little information on the antibody response in humans after the COVID-19 vaccination. METHODS: This single-center, prospective study was conducted in Yokohama, Japan. We included health care workers who had received two doses of COVID-19 vaccination (BNT162b2) 21 days apart. We measured serum immunoglobulin G (IgG) to nucleoprotein and spike protein of SARS-CoV-2 with commercially available kits before and 7, 14, and 35 days after the first dose of vaccination. RESULTS: A total of 104 workers participated in this study. Of these, 7 participants were seropositive with antibodies to spike protein at baseline and 4 of the 7 seropositive participants had COVID-19 history. The mean level of IgG to spike protein (QT) was 45.2, 1219, 2845, and 23489 AU/mL at baseline, on days 7, 14, and 35, respectively, although the values for nucleoprotein (NG) were 0.2, 0.21, 0.22, and 0.19 S/C, respectively. On day 7, QT in seropositive participants at baseline was elevated, whereas it was not elevated in seronegative participants at baseline until day 14. CONCLUSIONS: QT was elevated over the cutoff in all the participants at day 35, but NG did not change between baseline and day 35.

Early combination treatment with baloxavir and peramivir for hospitalized adults with influenza A in Yokohama, Japan.

Baloxavir marboxil is a new anti-influenza drug, but data on the clinical efficacy of a combination treatment of baloxavir and peramivir is scarce. We conducted a single-center retrospective analysis comparing the mortality of a combination of baloxavir and peramivir (B & P, n = 10) and peramivir without baloxavir (P-mono, n = 132) in hospitalized adults with influenza A between 2011 and 2019 in Yokohama City, Japan. Sequencing analysis was conducted in the B & P group to check the I38 mutation in polymerase acidic protein which is associated with baloxavir resistance. The 30-day mortality rates were 0 (0%) in the B & P group and 6 (4.5%) in the P-mono group, respectively, which was not statistically significant. The I38 mutation was not detected before and after the combination treatment. A combination treatment of baloxavir and peramivir might be more effective than peramivir without baloxavir and prevent the emergence of baloxavir resistance in hospitalized adults with influenza A.

A Japanese case of COVID-19: An autopsy report.

A 93-year-old woman was admitted with a 10-day history of cough and prostration. Thoracic computed tomography revealed extensive ground-glass opacities in both the lungs. The polymerase chain reaction test of sputum for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was positive. She was treated with antiviral agents and steroid pulse therapy. However, her oxygen saturation gradually declined, and she died 10 days after hospitalization. The most important autopsy finding was fuzzily segmented diffuse alveolar damage (DAD) that expanded from the subpleural to the medial area. No remarkable changes were observed in organs other than the lungs. Therefore, pneumocytes were suggested as the primary target for SARS-CoV-2, which might explain why coronavirus infectious disease-19 is a serious condition. Thus, early treatment is essential to prevent viral replication from reaching a level that triggers DAD.

Clinical characteristics of the coronavirus disease 2019 (COVID-19) outbreak on a cruise ship.

BACKGROUND: A large COVID-19 outbreak occurred on the cruise ship Diamond Princess in February 2020. Little information has been reported about the clinical characteristics of the patients. METHODS: This single-center, retrospective, observational study was conducted in Yokohama, Japan. We included symptomatic patients who were infected on the ship and admitted to our hospital between 5 and 19 February 2020. All the cases were confirmed with SARS-CoV-2 infection by polymerase chain reaction (PCR). RESULTS: We confirmed 17 cases. The average age was 69 years; 10 patients were Asian and 7 were Caucasian. Eleven patients had one or more chronic diseases. The major symptoms were cough and fever. Chest computed tomography (CT) scans found bilateral ground-glass opacities predominantly in the peripheral area, which were similar to reports from cases in China. C-reactive protein (CRP) levels were higher in severe and critical cases than in mild to moderate cases. The moderate to severe cases reached symptomatic resolution; one of the three critical cases resulted in death due to multiple organ failure. SARS-CoV-2 was detected by PCR at an average of 7 days after symptomatic resolution. CONCLUSIONS: Cough and fever, increased blood CRP levels, and CT findings of bilateral ground-glass opacities predominantly in the peripheral lung were characteristic of the COVID-19 cases in this study. These findings were compatible with those of previous reports.

Desensitization to trimethoprim-sulfamethoxazole in a toxoplasmic encephalitis patient who was intolerant to conventional treatments.

Toxoplasma gondii is an obligate intracellular protozoan that causes toxoplasmic encephalitis (TE) in immunocompromised patients. We describe a case of a 29-year-old Japanese man presenting with headache and vomiting. He had previously been diagnosed with human immunodeficiency virus infection. Magnetic resonance imaging identified some nodules in his brain. We suspected TE and began treatment successively with parenteral trimethoprim-sulfamethoxazole (TMP/SMX) plus clindamycin. After that, we switched to pyrimethamine plus sulfadiazine (PMT/SDZ) because these drugs are the first-line treatment for TE. Because the patient experienced nausea and vomiting, PMT/SDZ was replaced with TMP/SMX, atovaquone, and clindamycin. However, the patient could not tolerate them owing to their adverse reactions. Thus, we attempted oral desensitization to TMP/SMX to treat his TE. We began desensitization with 0.4/2 mg of TMP/SMX. The patient experienced morbilliform rash and elevated aminotransferase levels. Therefore, we administered a glycyrrhizin and an antihistamine and continued the last tolerable dose until these symptoms improved. After 37 days, we achieved desensitization to 160/800 mg of TMP/SMX, and the patient's symptoms improved. After using nested-polymerase chain reaction to identify T. gondii DNA in his frozen cerebrospinal fluid, which was collected at admission, his diagnosis was confirmed as TE. This might be the first case to attempt desensitization to TMP/SMX to treat TE.

Hepatitis A Outbreak Among Men Who Have Sex With Men, Yokohama, Japan, January to May 2018.

Between January and May in 2018, 17 male cases of hepatitis A were reported in Yokohama, Japan. Of these, 14 identified as men who have sex with men. The viral sequence in this outbreak was same as that of the recent European and Taiwanese outbreaks strain.

Diseases affecting patients returning from abroad: Experience of a travel clinic in Japan from 2004 to 2014.

The number of patients returning from or staying abroad is likely to increase in the future. We performed a retrospective study of patients returning from abroad in our travel clinic in Japan. All patients presenting within 6 months of traveling abroad between 2004 and 2014 were included in the present study. A total of 2374 (mean age, 35 years) patients were seen by doctors specializing in treating infectious diseases. Of these, 918 were females and 87 of them lived abroad. Diagnoses and exposure regions were recorded for all patients. The most frequent region visited before attending our clinic was Southeast Asia (n = 1050, 44%), with a median duration for staying abroad of 8 days. The major purposes for overseas travel were tourism (n = 1302, 55%) and business (n = 684, 29%). Of the 2399 individual diagnoses made, the most frequent were diseases of the gastrointestinal system (n = 1083, 45%), skin and soft tissue (n = 440, 18%), systemic febrile disease without specific systems (419, 18%), and the respiratory system (353, 15%). The relative incidences of specific diseases changed drastically due to significant disease outbreaks, such as pandemic influenza in 2009. Exposure regions remained relatively constant throughout the study period, except for Japan. Vaccine-preventable diseases accounted for 5.3% of all the diseases, and 402 (26%) patients received pre-travel consultation and prophylaxis with vaccines and/or anti-malarial drug. We should make an effort to make more people notice the risk of travel and properly perform prophylaxis.

Characterization of proinflammatory cytokines profile during acute SARS-CoV-2 infection in people with human immunodeficiency virus.

Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were assessed in people with HIV (PWH) with effective cART. There were no significant differences in any of the tested cytokines between COVID-19 severity in PWH, while most of them were significantly higher in individuals with severe disease in HIV-uninfected individuals, suggesting that excess cytokines release by hyper-inflammatory responses does not occur in severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, especially between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that PWH are in an enhanced inflammatory state. Loss of the several inter-cytokine correlations were observed in in vitro LPS stimuli-driven cytokines production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially due to the underlying inflammatory state and/or impairment of innate immune cells.

Pioneering cord blood transplantation in relapsed/refractory HIV-related lymphoma: a case study with concurrent intramuscular antiretroviral therapy.

A 44-year-old HIV-positive man diagnosed with diffuse large B-cell lymphoma in 2021 achieved complete remission with six cycles of R-CHOP therapy but had a relapse in November 2022. ESHAP therapy failed to induce remission, leading to complete remission with four cycles of Pola-BR therapy. Post-failure of autologous stem cell harvest, cord blood transplantation (CBT) was performed in June 2023. Notably, this case used recently approved intramuscular antiretroviral therapy (ART) with cabotegravir and rilpivirine, addressing gastrointestinal complications during CBT. This innovative use of intramuscular ART in the treatment of malignancy represents a first in the field, offering a pioneering approach to HIV-related lymphoma.

A predictive model for HIV-related lymphoma: a case series and literature review in Japan.

OBJECTIVES: To address the paucity of human immunodeficiency virus (HIV)-related lymphoma (HRL)-specific prognostic scores for the Japanese population by analyzing domestic cases of HRL and constructing a predictive model. DESIGN: A single-center retrospective study coupled with a review of case reports of HRL. METHODS: We reviewed all patients with HRL treated at our hospital between 2007 and 2023 and conducted a comprehensive search for case reports of HRL from Japan using public databases. A multivariate analysis for overall survival (OS) was performed using clinical parameters, leading to the formulation of the HIV-Japanese Prognostic Index (HIV-JPI). RESULTS: A total of 19 patients with HRL were identified in our institution, while the literature review yielded 44 cases. In the HIV-JPI, a weighted score of 1 was assigned to the following factors: age ≥45 years, HIV-RNA ≥8.0×10 4  copies/mL, Epstein-Barr virus-encoded small RNA positivity, and Ann Arbor classification stage IV. The overall score ranged from 0 to 4. We defined the low-risk group as scores ranging from 0 to 2 and the high-risk group as scores ranging from 3 to 4. The 3-year OS probability of the high-risk group (30.8%; 95% confidence interval [CI]: 9.5-55.4%) was significantly poorer than that of the low-risk group (76.8%; 95% CI: 52.8-89.7%; P  < 0.01). CONCLUSION: This retrospective analysis established pivotal prognostic factors for HRL in Japanese patients. The HIV-JPI, derived exclusively from Japanese patients, highlights the potential for stratified treatments and emphasizes the need for broader studies to further refine this clinical prediction model.

Multimodal single-cell analyses of peripheral blood mononuclear cells of COVID-19 patients in Japan.

SARS-CoV-2 continues to spread worldwide. Patients with COVID-19 show distinct clinical symptoms. Although many studies have reported various causes for the diversity of symptoms, the underlying mechanisms are not fully understood. Peripheral blood mononuclear cells from COVID-19 patients were collected longitudinally, and single-cell transcriptome and T cell receptor repertoire analysis was performed. Comparison of molecular features and patients' clinical information revealed that the proportions of cells present, and gene expression profiles differed significantly between mild and severe cases; although even among severe cases, substantial differences were observed among the patients. In one severely-infected elderly patient, an effective antibody response seemed to have failed, which may have caused prolonged viral clearance. Naïve T cell depletion, low T cell receptor repertoire diversity, and aberrant hyperactivation of most immune cell subsets were observed during the acute phase in this patient. Through this study, we provided a better understanding of the diversity of immune landscapes and responses. The information obtained from this study can help medical professionals develop personalized optimal clinical treatment strategies for COVID-19.

Evaluation of potential rabies exposure among Japanese international travelers: A retrospective descriptive study.

BACKGROUND: Although Japan has been a rabies-free country for >50 years, a few cases have been reported among people traveling abroad. This study aimed to investigate animal exposure among Japanese travelers using the Japanese Registry for Infectious Diseases from Abroad (J-RIDA). METHOD: In this retrospective analysis, we examined Japanese overseas travelers with animal exposure, as included the J-RIDA database, reported from October 1, 2017, to October 31, 2019, with a focus on pre-exposure prophylaxis (PrEP) administration and the animals to which the patients were exposed. RESULTS: Among the 322 cases included in the analysis, 19 (5.9%) patients received PrEP and 303 did not. The most common purpose of travel was a non-package tour (n = 175, 54.3%). Most trips (n = 213, 66.1%) were to a single country for <2 weeks. Most patients (n = 286, 87.9%) traveled to countries with a rabies risk. The majority of patients with and without PrEP were injured in rabies-risk countries [n = 270 (89.1%) for non-PrEP and n = 16 (84.2%) for PrEP]. Animals associated with injuries included dogs (55.0%), cats (25.5%), and monkeys (15.5%). Most patients were classified as World Health Organization Category II/III for contact with suspected rabid animals (39.5% and 44.1% for categories II and III, respectively) and had exposure within 5 days of travel. Southeast Asia (n = 180, 55.9%) was the most common region in which travelers were exposed to animals. CONCLUSIONS: Japanese overseas travelers had contact with animals that could possibly transmit the rabies virus, even on short trips. Promoting pre-travel consultation and increasing awareness of the potential for rabies exposure are important for prevention of rabies among Japanese international travelers.

Earliest histopathological changes in COVID-19 pneumonia with comprehensive gene expression analyses: A case series study.

AIMS: In COVID-19 pneumonia, early detection and appropriate treatment are essential to prevent severe exacerbation. Therefore, it is important to understand the initiating events of COVID-19 pneumonia. However, at present, the literature about early stage disease has been very limited. Here, we investigated the earliest histopathological changes and gene expression profiles associated with COVID-19 pneumonia. METHODS AND RESULTS: We carefully examined 25 autopsied cases with different clinical courses. Dilation of capillaries and edematous thickening of the alveolar septa were found even in areas that macroscopically looked almost normal. Pneumocytes, histocytes/macrophages, and vascular endothelial cells were immunohistochemically positive for tissue factor, which is an important early responder to tissue injuries. Comprehensive gene expression analyses revealed that those lesions presented differential profiles compared to those of control lungs and were associated with a significant upregulation of the lysosomal pathway. CONCLUSIONS: Alveolar capillary dilation and edematous thickening may be the earliest histopathological change detected in COVID-19 pneumonia. Intensive investigations of such lesions may lead to an understanding of the initiating event of not only COVID-19 pneumonia but also of general diffuse alveolar damage.

Comparison of survival times of advanced cancer patients with palliative care at home and in hospital.

OBJECTIVES: One primary concern about receiving care at home is that survival might be shortened because the quality and quantity of treatment provided at home will be inferior to that given in the hospital. Although our previous study demonstrated a longer survival of those with home-based palliative care (PC), it lacked adjustment for some potential confounders including symptoms and treatments during the stay. We aimed to compare the survival times among advanced cancer patients receiving home-based and hospital-based PC with adjusting for symptoms and treatments. METHOD: We compared survival time of participants who enrolled two multicenter, prospective cohort studies of advanced cancer patients at 45-home-based PC services between July 2017 and December 2017, and at 23-hospital-based PC services between January 2017 and December 2017. We analyzed with stratification by the estimated survival of Days, Weeks, and Months, which were defined by modified Prognosis in Palliative care Study predictor models-A. We conducted a Cox regression analysis with adjusting for potential confounders including symptoms and treatments during the stay. RESULTS: A total of 2,998 patients were enrolled in both studies and 2,878 patients were analyzed; 988 patients receiving home-based PC and 1,890 receiving hospital-based PC. The survival time of patients receiving home-based PC was significantly longer than that of patients receiving hospital-based PC for the Days Prognosis (estimated median survival time: 10 days [95% CI 8.1-11.8] vs. 9 days [95% CI 8.3-10.4], p = 0.157), the Weeks prognosis (32 days [95% CI 28.9-35.4] vs. 22 days [95% CI 20.3-22.9], p < 0.001), and the Months Prognosis, (65 days [95% CI 58.2-73.2] vs. 32 days [95% CI 28.9-35.4], p < 0.001). CONCLUSION: In this cohort of advanced cancer patients with a Weeks or Months prognosis, those receiving home-based PC survived longer than those receiving hospital-based PC after adjusting for symptoms and treatments.

Unresolved Palliative Care Needs of Elderly Non-Cancer Patients at Home: A Multicenter Prospective Study.

INTRODUCTION/OBJECTIVES: There is growing consensus on the benefits of initiating palliative care early in the disease trajectory; however, palliative care needs for non-cancer patients remain to be elucidated. We investigated the trajectory of unresolved palliative care needs of non-cancer patients at home and explored associated factors. METHODS: We conducted a multicenter prospective cohort study of elderly non-cancer patients at home in Japan between Jan 2020 and Dec 2020. Physicians assessed their palliative care needs using the Integrated Palliative Care Outcome Scale (IPOS). Unresolved palliative care needs were defined as IPOS symptoms above 2 (moderate). RESULTS: In total, 785 patients were enrolled. The most frequent unresolved palliative care needs at enrollment were poor mobility (n = 438, 55.8%), followed by weakness/lack of energy (n = 181, 23.1%) and poor appetite (n = 160, 20.4%). Multivariate logistic regression analysis revealed that female and musculoskeletal disease were significantly positively associated with pain at starting home visits (OR = 1.89, P = .015; OR = 2.69, P = .005). In addition, neurological diseases were significantly positively associated with constipation and poor mobility 3 months after starting home visits (OR = 3.75, P = .047; OR = 3.04, P = .009). CONCLUSIONS: The order of the prevalence of unresolved palliative care needs may remain relatively stable over time, even for those receiving home-based palliative care services. We identified several specific diseases and conditions that were significantly associated with unresolved palliative care needs.

Intradermal Hepatitis B Vaccination in Non-responder People Living with Human Immunodeficiency Virus in Japan.

We performed a pilot study to assess the immunogenicity and safety of intradermal hepatitis B (HB) virus vaccines in people living with HIV (PLWH). This single-center prospective study was conducted in Yokohama, Japan. Adult PLWH with serum antibodies against HB surface antigen (anti-HBs) <10 mIU/mL at all time points after standard HB vaccination were included. We administered HB surface antigen (total dose of 10 µg) at 5 separate sites intradermally at baseline, one month, and 6-9 months and measured anti-HBs 1-3 months after administration. Eleven PLWH were included in this study. The mean age was 36 years, and all patients were men. At baseline, all patients were on antiretroviral therapy, and the mean CD4+ lymphocyte count was 588 /µL and plasma HIV-RNA was <20 copies/mL, except for one patient. Anti-HB levels were elevated to >10 mIU/mL in one patient after one dose, 6 patients after 2 doses, and 4 patients after 3 doses of the intradermal vaccines. Eight patients experienced grade 1 local adverse events. Additional vaccination via the intradermal route induced an anti-HBs level >10 mIU/mL in all patients, without serious adverse events.

Comparison of the levels of neopterin, CRP, and IL-6 in patients infected with and without SARS-CoV-2.

Background: Neopterin (NP) is a biomarker for activated cellular immunity and is elevated in diseases including viral and bacterial infections, autoimmune diseases, and cancer. However, the clinical assessment of neopterin has not been used for these disorders because the physiological significance of measuring NP is obscure. It would be important to compare the NP profiles with those of other inflammation markers especially in relatively early phase of patients to reveal the significance of NP measurements in pathological states. Methods: Plasma NP, biopterin, CRP, and IL-6 levels were measured in 46 patients with Coronavirus Disease 2019 (COVID-19) and 23 patients with non-COVID-19 disorders. The correlations between these markers were analyzed in the COVID-19 and non-COVID-19 patients independently. Results: The NP levels were significantly higher in the COVID-19 patients than in the non-COVID-19 patients, while biopterin, CRP and IL-6 were not changed significantly. The NP levels were found to show a weak negative correlation against the days after onset in the COVID-19 patients (rs = -0.348, p = 0.0192), suggesting that the elevation of NP would be an early event of viral infection. Correlations between NP and CRP, or between NP and IL-6 in COVID-19 patients were weaker than that between CRP and IL-6. Conclusions: The elevation of NP levels was supposed to be distinct from those of CRP and IL-6 in relatively early and mild COVID-19 patients. Our data suggest that NP is produced at the early phase of infection by different signaling pathways and/or cells from those of CRP and IL-6. Further study on the signaling pathway to induce NP is expected.