Waning cellular immune responses and predictive factors in maintaining cellular immunity against SARS-CoV-2 six months after BNT162b2 mRNA vaccination.

Several clinical trials have shown that the humoral response produced by anti-spike antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines gradually declines. The kinetics, durability and influence of epidemiological and clinical factors on cellular immunity have not been fully elucidated. We analyzed cellular immune responses elicited by BNT162b2 mRNA vaccines in 321 health care workers using whole blood interferon-gamma (IFN-γ) release assays. IFN-γ, induced by CD4 + and CD8 + T cells stimulated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike epitopes (Ag2), levels were highest at 3 weeks after the second vaccination (6 W) and decreased by 37.4% at 3 months (4 M) and 60.0% at 6 months (7 M), the decline of which seemed slower than that of anti-spike antibody levels. Multiple regression analysis revealed that the levels of IFN-γ induced by Ag2 at 7 M were significantly correlated with age, dyslipidemia, focal adverse reactions to full vaccination, lymphocyte and monocyte counts in whole blood, Ag2 levels before the second vaccination, and Ag2 levels at 6 W. We clarified the dynamics and predictive factors for the long-lasting effects of cellular immune responses. The results emphasize the need for a booster vaccine from the perspective of SARS-CoV-2 vaccine-elicited cellular immunity.

Multicenter, single-blind, randomized controlled study of the efficacy and safety of favipiravir and nafamostat mesilate in patients with COVID-19 pneumonia.

OBJECTIVES: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19. METHODS: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO2). RESULTS: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO2 were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group. CONCLUSION: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO2 were observed in the combination group.

Neisseria meningitidis serogroup W135 in a traveler visiting Japan from Argentina, 2019.

Invasive meningococcal disease (IMD) can occur in travelers returning from mass-gathering events or endemic regions. We present a 60-year-old Argentine traveler to Tokyo who developed IMD by Neisseria meningitidis Serogroup W135 during her stay in Japan. N. meningitidis serogroup W135 infection has become common in Argentina, whereas IMD less commonly occurs in Japan. Considering the prevalence, the patient most likely acquired the infection in Argentina, and it developed in Japan. Air travel enables passengers to reach the four corners of the world within a few days. IMD should be considered in travelers due to its potential to induce rapid clinical deterioration and transmission.

Aureobasidium melanigenum catheter-related bloodstream infection: a case report.

BACKGROUND: Aureobasidium melanigenum is a ubiquitous dematiaceous fungus that rarely causes invasive human infections. Here, we present a case of Aureobasidium melanigenum bloodstream infection in a 20-year-old man with long-term catheter use. CASE PRESENTATION: A 20-year-old man receiving home care with severe disabilities due to cerebral palsy and short bowel syndrome, resulting in long-term central venous catheter use, was referred to our hospital with a fever. After the detection of yeast-like cells in blood cultures on day 3, antifungal therapy was initiated. Two identification tests performed at a clinical microbiological laboratory showed different identification results: Aureobasidium pullulans from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and Cryptococcus albidus from a VITEK2 system. Therefore, we changed the antifungal drug to liposomal amphotericin B. The fungus was identified as A. melanigenum by DNA sequence-based analysis. The patient recovered with antifungal therapy and long-term catheter removal. CONCLUSION: It is difficult to correctly identify A. melanigenum by routine microbiological testing. Clinicians must pay attention to the process of identification of yeast-like cells and retain A. melanigenum in cases of refractory fungal infection.

The association between adverse reactions and immune response against SARS-CoV-2 spike protein after vaccination with BNT162b2 among healthcare workers in a single healthcare system: a prospective observational cohort study.

Adverse reactions after vaccination with COVID-19 mRNA vaccines are common; however, the association between adverse reactions and humoral responses is uncertain. To determine whether humoral immune responses after BNT162b2 vaccine administration were associated with local and systemic adverse reactions, we conducted a prospective observational cohort study in a single tertiary referral center. Healthcare workers who received the first dose of BNT162b2 vaccine were recruited. SARS-CoV-2 anti-spike IgG antibody titers were measured three weeks after the second dose and information about adverse reactions after vaccination was collected. Among the 887 participants, 641 (72.3%) were women. The median age was 38 (range, 22-74) years. All but one showed anti-spike IgG levels well above the cutoff, with a median level of 13,600 arbitrary units/mL. Overall, 800 (92.2%) participants reported some reactions after the first dose and 822 (96.3%) after the second dose. Significantly more participants reported systemic reactions after the second dose than after the first dose (P < .01), and 625 (73.6%) reported that reactions were stronger after the second dose. Factors positively associated with elevation of anti-spike IgG levels were history of asthma (24% higher if present, P = .01) and stronger reactions after the second dose (19% higher if experienced, P = .02). The majority of participants showed good humoral responses and reported some adverse reactions after vaccination. Anti-spike IgG levels were significantly higher if adverse reactions after the second dose were stronger than those after the first dose. These findings may help inform current and future vaccine recipients.

Human abdominal abscess caused by Necropsobacter rosorum and tips for its identification: A case report.

Necropsobacter rosorum is a gram-negative facultative anaerobe, which was reclassified from the family Pasteurellaceae in 2011. It has been detected in the gastrointestinal and respiratory tracts of mammals; however, reports of infection in humans are scarce. We report a case of an abdominal abscess in which N. rosorum was detected; it was successfully treated with drainage and antimicrobial therapy. Routine laboratory testing such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and an identification system using biochemical phenotypes could not identify N. rosorum. Instead, it was misidentified as other Pasteurellaceae species, including Aggregatibacter spp. or Pasteurella spp. Sequencing of 16S rRNA was required to identify N. rosorum. We suggest the application of simple methods, such as indole production, oxidase, and catalase tests, to differentiate N. rosorum from genetically similar species.

Protothecosis in the mucosa of the pharynx mimicking pharyngeal cancer in an immunocompetent individual: a case report.

BACKGROUND: Protothecosis is a rare infection in humans and animals caused by the achlorophyllic algae Prototheca species. More than half of the protothecosis cases are cutaneous infections, and most cases are observed in immunocompromised individuals. CASE PRESENTATION: We report a case of Prototheca wickerhamii infection in the mucosa of the pharynx in a 53-year-old immunocompetent woman with an incidentally found mass lesion at the left tongue base. Histopathological findings of the mass lesion suggested cryptococcosis, but P. wickerhamii was identified from the oropharynx scrape culture based on DNA sequencing. After surgical resection, fosfluconazole treatment was initiated, and subsequently, treatment was switched to topical amphotericin B. The residual mass lesion did not deteriorate during the 4-month antifungal treatment and 1-year observational period. CONCLUSIONS: Prototheca species can be easily misdiagnosed as yeasts because of their morphological and pathological similarities. Prototheca, in addition to Cryptococcus should be considered if slow-growing, large Gram-positive organisms are encountered. Lactophenol cotton blue staining of the colony helps distinguish these organisms. Further study is needed to determine the appropriate treatment according to the infection focus.

Incidence and Risk Factors for Inappropriate Use of Non-Culture-Based Fungal Assays: Implication for Diagnostic Stewardship.

BACKGROUND: Non-culture-based fungal assays (NCBFAs) have been used increasingly to help diagnose invasive fungal diseases. However, little is known about inappropriate use of NCBFAs. We aimed to investigate inappropriate use of NCBFAs in a tertiary academic hospital. METHODS: This retrospective cohort study included patients who underwent testing with beta-D glucan (BDG) between January and March 2018 or with galactomannan antigen (GMA) or cryptococcal antigen (CRAG) between January and June 2018. Testing was deemed appropriate if the clinical presentation was compatible with a fungal infection and there was a predisposing host factor at the time of ordering. We compared patients with appropriate and inappropriate use of NCBFAs using multivariate logistic regression analysis. RESULTS: Four hundred seventy patients (BDG, 394; GMA, 138; CRAG, 164) met inclusion criteria and were evaluated. About 80% of NCBFAs were deemed inappropriate. Ordering by transplant medicine physicians, repetitions of the test, the absence of predisposing factors for fungal infections, and the absence of recommendations from infectious diseases consultants were associated with an increased risk of inappropriate NCBFA use. CONCLUSIONS: We found that a large proportion of NCBFAs were deemed inappropriate. There is an opportunity for diagnostic stewardship to reduce avoidable fungal testing among patients at low risk for fungal infection.

Plesiomonas shigelloides Septic Shock Following Ingestion of Dojo Nabe (Loach Hotpot).

Plesiomonas shigelloides is a gram-negative bacillus that commonly causes self-limited diarrhea in humans. We present the case of P shigelloides bacteremia in a 49-year-old man with alcoholic cirrhosis who developed septic shock a day after eating Dojo nabe (loach hotpot), a Japanese traditional dish.

Dynamic changes in fibrinogen and D-dimer levels in COVID-19 patients on nafamostat mesylate.

Critical illnesses associated with coronavirus disease 2019 (COVID-19) are attributable to a hypercoagulable status. There is limited knowledge regarding the dynamic changes in coagulation factors among COVID-19 patients on nafamostat mesylate, a potential therapeutic anticoagulant for COVID-19. First, we retrospectively conducted a cluster analysis based on clinical characteristics on admission to identify latent subgroups among fifteen patients with COVID-19 on nafamostat mesylate at the University of Tokyo Hospital, Japan, between April 6 and May 31, 2020. Next, we delineated the characteristics of all patients as well as COVID-19-patient subgroups and compared dynamic changes in coagulation factors among each subgroup. The subsequent dynamic changes in fibrinogen and D-dimer levels were presented graphically. All COVID-19 patients　were classified into three subgroups: clusters A, B, and C, representing low, intermediate, and high risk of poor outcomes, respectively. All patients were alive 30 days from symptom onset. No patient in cluster A required mechanical ventilation; however, all patients in cluster C required mechanical ventilation, and half of them were treated with venovenous extracorporeal membrane oxygenation. All patients in cluster A maintained low D-dimer levels, but some critical patients in clusters B and C showed dynamic changes in fibrinogen and D-dimer levels. Although the potential of nafamostat mesylate needs to be evaluated in randomized clinical trials, admission characteristics of patients with COVID-19 could predict subsequent coagulopathy.

Establishment of supermicrosurgical lymphaticovenular anastomosis model in rat.

BACKGROUND: Lymphaticovenular anastomosis (LVA) is becoming a choice of treatment for compression-refractory lymphedema. However, LVA requires highly sophisticated microsurgical technique called supermicrosurgery, and no training model for LVA has been developed. This study aimed to develop and evaluate feasibility of a new LVA model using rat thigh lymphatic vessels. METHODS: Ten Sprague-Dawley rats were used for the study. After preoperative indocyanine green (ICG) lymphography, lymphatic vessels in posteromedial aspect of the thigh were dissected. In right limbs, the largest lymphatic vessel was anastomosed to the short saphenous vein or its branch, and the remaining lymphatic vessels were ligated (LVA group). In left limbs, all lymphatic vessels were ligated (control group). Anastomosis patency was evaluated intraoperatively and at postoperative 7 days. RESULTS: Courses of lymphatic vessels in the thigh were constant; lymphatic vessels run along the short saphenous vein. The mean diameter of lymphatic vessel used for LVA was 0.240 ± 0.057 mm, and the mean diameter of vein was 0.370 ± 0.146 mm. All lymphatic vessels were translucent and very thin like human intact lymphatic vessels. In LVA group, intra- and post-operative anastomosis patency rates were 100% (10/10) based on ICG lymphography. In control group, intra- and post-operative patency rates were 0% (0/10). CONCLUSIONS: Rat lymphatic vessels are thin, translucent, and fragile similar to intact human lymphatic vessels. The LVA model uses easily accessible lymphatic vessels in the thigh, and is useful for training of supermicrosurgical LVA. © 2014 Wiley Periodicals, Inc. Microsurgery 37:57-60, 2017.

Efferent Lymphatic Vessel Anastomosis: Supermicrosurgical Efferent Lymphatic Vessel-to-Venous Anastomosis for the Prophylactic Treatment of Subclinical Lymphedema.

BACKGROUND: In lower extremity lymphedema secondary to pelvic cancer treatments, lymphedema develops despite that the inguinal lymph nodes (LNs) are preserved. Obstruction of the efferent lymphatic vessels of the inguinal LNs causes lower extremity lymphedema, and it is considered a radical treatment to bypass the efferent lymphatic vessel. METHODS: Efferent lymphatic vessel anastomosis, supermicrosurgical efferent lymphatic vessel-to-venous anastomosis, was performed on 14 legs with subclinical lymphedema [leg dermal backflow (LDB) stage I]. Efferent lymphatic vessel anastomosis was performed under local anesthesia at the groin region, and an efferent lymphatic vessel of the inguinal LN is anastomosed to a recipient vein. Feasibility and postoperative results were evaluated. RESULTS: All 14 efferent lymphatic vessel anastomoses were successfully performed without perioperative complication. All legs could be free from lymphedematous symptoms without perioperative compression at postoperative 1 year. Postoperative LDB stage included LDB stage 0 (n = 8) and LDB stage I (n = 6), which was significantly downstaged compared with preoperative LDB stage (P < 0.001). CONCLUSIONS: Efferent lymphatic vessel anastomosis allowed lymph flow bypass after filtration by the superficial inguinal LN through a skin incision along the inguinal crease, and was effective to prevent development of symptomatic lymphedema in subclinical lymphedema cases.

Relationship Between Lymphedema and Arteriosclerosis: Higher Cardio-Ankle Vascular Index (CAVI) in Lymphedematous Limbs.

BACKGROUND: Arteriosclerosis is one of the most important public health issues because it is very common in developed countries and its sequelae are lethal. Lymphatic vessel insufficiency has been reported to be associated with atherogenesis. Lymphedema seems to affect progression of arteriosclerosis, but no clinical study has been reported. METHODS: Forty-eight limbs of 24 female patients with pelvic cancer-related lower extremity lymphedema (LEL) were evaluated. Cardio-ankle vascular index (CAVI), an indirect estimate of the arterial stiffness, was measured in each limb. Cardio-ankle vascular index was compared according to known arteriosclerosis risk factors including age (younger than 65 years vs 65 years), body mass index (BMI; <25 vs 25 kg/m), hypertension (HT), diabetes mellitus, hyperlipidemia (HL), and smoking, as well as according to LEL-related factors including duration of LEL (<5 years vs 5 years), pelvic irradiation, leg cellulitis, LEL index (<250 vs 250), and leg dermal backflow (LDB) stage (LDB stage 0/I vs LDB stage II/III/IV/V) using univariable analyses and multivariable analysis. RESULTS: Univariable analyses revealed statistically significant differences in CAVI between lower BMI and higher BMI [7.19 (0.75) vs 8.36 (1.24), P < 0.01], HT (-) and HT (+) [7.25 (0.81) vs 8.17 (1.29), P < 0.01], HL (-) and HL (+) [7.19 (0.74) vs 8.06 (1.27), P < 0.01], and lower LDB stage and higher LDB stage [6.87 (0.65) vs 7.76 (1.05), P < 0.01]. Multivariable analysis revealed statistically significant differences in CAVI between lower BMI and higher BMI (P < 0.01), shorter duration of LEL and longer duration of LEL [7.21 (1.04) vs 7.71 (0.97), P = 0.04], and lower LDB stage and higher LDB stage (P = 0.04) CONCLUSIONS: Higher BMI, longer duration of LEL, and higher LDB stage were independent factors associated with higher CAVI in pelvic cancer-related LEL.