COVID-19 vaccination benefits in preventing severe disease in mild-to-moderate cases: An analysis in the first specialized hospital for COVID-19 in Japan.

BACKGROUND: In Japan, the fourth round of coronavirus disease (COVID-19) vaccination is ongoing and is targeted at medical staff and nursing home workers, individuals aged ≥60 years, and those with comorbidities or other high-risk factors, including body mass index (BMI) ≥30 kg/m2. The incidence of severe COVID-19 decreased markedly after widespread COVID-19 vaccination drives, and our hospital experienced a similar trend. We, therefore, examined the characteristics of our patients to clarify who benefited the most from vaccination. METHODS: We retrospectively investigated all patients hospitalized for COVID-19 in Osaka City Juso Hospital between March 1, 2021, and June 30, 2022. Using multivariable logistic analysis, we calculated the adjusted odds ratios (aORs) for severe disease after vaccination in the whole dataset and in subsets stratified by age, sex, BMI, smoking history, pre-hospitalization location, and comorbidities. RESULTS: The analysis included 1041 patients. Multivariable logistic analysis showed that vaccination was associated with a low risk of severe disease, with an aOR of 0.21 (95% confidence interval: 0.12-0.36, p < 0.001). On stratifying the analysis according to background characteristics, lower aORs for severe COVID-19 were found for patients aged ≥60 years and for those with diabetes or hypertension. Notably, patients with BMI >30 kg/m2 and those with BMI ≥18 kg/m2 and ≤30 kg/m2 benefited from vaccination. CONCLUSIONS: Individuals with diabetes or hypertension and those of age ≥60 years benefited more from vaccination than did their counterparts. We recommend extending the fourth round of vaccinations to individuals with a BMI of 18-30 kg/m2.

Antibody Avidity Maturation Following Recovery From Infection or the Booster Vaccination Grants Breadth of SARS-CoV-2 Neutralizing Capacity.

BACKGROUND: Cross-neutralizing capacity of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is important in mitigating (re-)exposures. Role of antibody maturation, the process whereby selection of higher affinity antibodies augments host immunity, to determine SARS-CoV-2 neutralizing capacity was investigated. METHODS: Sera from SARS-CoV-2 convalescents at 2, 6, or 10 months postrecovery, and BNT162b2 vaccine recipients at 3 or 25 weeks postvaccination, were analyzed. Anti-spike IgG avidity was measured in urea-treated ELISAs. Neutralizing capacity was assessed by surrogate neutralization assays. Fold change between variant and wild-type neutralization inferred the breadth of neutralizing capacity. RESULTS: Compared with early-convalescent, avidity indices of late-convalescent sera were significantly higher (median, 37.7 [interquartile range 28.4-45.1] vs 64.9 [57.5-71.5], P < .0001). Urea-resistant, high-avidity IgG best predicted neutralizing capacity (Spearman r = 0.49 vs 0.67 [wild-type]; 0.18-0.52 vs 0.48-0.83 [variants]). Higher-avidity convalescent sera better cross-neutralized SARS-CoV-2 variants (P < .001 [Alpha]; P < .01 [Delta and Omicron]). Vaccinees only experienced meaningful avidity maturation following the booster dose, exhibiting rather limited cross-neutralizing capacity at week 25. CONCLUSIONS: Avidity maturation was progressive beyond acute recovery from infection, or became apparent after the booster vaccine dose, granting broader anti-SARS-CoV-2 neutralizing capacity. Understanding the maturation kinetics of the 2 building blocks of anti-SARS-CoV-2 humoral immunity is crucial.

Glycated hemoglobin level on admission associated with progression to severe disease in hospitalized patients with non-severe coronavirus disease 2019.

AIMS/INTRODUCTION: Poor glycemic control is known to be associated with severe infection development. This retrospective observational study examined whether glycemic control before coronavirus disease 2019 (COVID-19) onset contributes to progression from non-severe to severe COVID-19. MATERIALS AND METHODS: Glycated hemoglobin (HbA1c) was measured on hospital admission in 415 patients with non-severe COVID-19. The outcome was determined from time of hospital admission to severe progression, based on clinical practice guidelines for COVID-19 in Japan. RESULTS: The median value for HbA1c on admission was 6.1%, with diabetes present in 138 patients (33.3%). Among the total cohort, 93 (22.4%) progressed to severe COVID-19 with a median (interquartile range) time of 4 days (3-7 days), whereas 322 (77.6%) were discharged after 13 days (10-17 days). A multivariable Cox proportional hazards regression model showed that HbA1c level on admission was independently associated with progression to severe COVID-19 (hazard ratio for 1% increase 1.237, 95% confidence interval 1.037-1.475; P = 0.018), with findings consistent among several sensitivity analyses. In subgroup analyses, such an association was significant in patients with diabetes, as well as older age, current smoking habit, lower estimated glomerular filtration rate, higher C-reactive protein level, moderate II COVID-19, dyslipidemia and chronic respiratory disease, with no remarkable inconsistency among the subgroups. Finally, higher HbA1c level (≥7%) was more strongly associated with severe COVID-19 progression than diabetes. CONCLUSIONS: The results suggest that poor glycemic control before COVID-19 onset contributes to progression from non-severe to severe COVID-19, even in patients with severe COVID-19 risk factors regardless of the presence of diabetes.

Treatment and outcome of COVID-19 patients in a specialized hospital during the third wave: advance of age and increased mortality compared with the first/second waves.

PURPOSE: To elucidate the clinical course of patients with coronavirus disease 2019 (COVID-19) treated at a specialized hospital mainly for those with mild and moderate severity during the third wave, and to compare that with the first and second (1st/2nd) waves. METHODS: We retrospectively reviewed the severity on admission, treatment, and outcome of a total of 581 patients from September, 2020, to March, 2021, and examined the risk factors for deterioration of respiratory condition, defined as requiring oxygen ≥ 7 L/min for 12 h. RESULTS: The median age was 78 (interquartile range 62-83) years, older than in the 1st/2nd waves (53 years), and 50% of the patients was male. The number of patients classified as mild (peripheral oxygen saturation (SpO2) ≥ 96%), moderate I, II, and severe (requiring admission to the ICU or mechanical ventilation) was 121, 324, 132, and 4, respectively. Favipiravir, ciclesonide, dexamethasone, and/or heparin were administered for treatment. Respiratory condition recovered in 496 (85%) patients. It worsened in 81 patients (14%); 51 (9%) of whom were transferred to tertiary hospitals and 30 (5%) died. Mortality rate increased by fivefold compared during the 1st/2nd waves. Age, male sex, increased body mass index, and C-reactive protein (CRP) on admission were responsible for worsening of the respiratory condition. CONCLUSION: Patients were older in the third wave compared with the 1st/2nd waves. Respiratory condition recovered in 85%; whereas 5% of the patients died. Old age, male sex, increased body mass index, and CRP would be responsible for worsening of the respiratory condition.

Isoniazid-induced Immune Thrombocytopenia.

Drug-induced thrombocytopenia occurs through immune-mediated platelet destruction, and its management is challenging during tuberculosis treatment. Although rifampicin is the most common drug causing thrombocytopenia, isoniazid can also cause thrombocytopenia. We herein report a 75-year-old man who developed thrombocytopenia during tuberculosis treatment. Platelet-associated immunoglobulin G and a drug-induced lymphocyte stimulation test for isoniazid were positive; no other causes of thrombocytopenia were identified. The patient was diagnosed with isoniazid-induced immune thrombocytopenia, and the platelet count normalized after isoniazid discontinuation. We describe the immunological mechanism of thrombocytosis due to isoniazid, an uncommon cause of thrombocytopenia that physicians should be aware exists.

Clinical profiles and outcome of patients with COVID-19 in a specialized hospital in Japan.

PURPOSE: To characterize the clinical features and outcome of patients treated at a specialized hospital for coronavirus disease 2019 (COVID-19). METHODS: We retrospectively reviewed the symptoms on admission, treatment, and outcome of a total of 300 patients with mild (peripheral oxygen saturation (SpO2) ≥ 96%), moderate I (93% < SpO2 < 96%), moderate II (SpO2 ≤ 93%) and severe (requiring admission to the ICU or mechanical ventilation) COVID-19. RESULTS: Median age was 53 (interquartile range [IQR] 33-72) years and 57% was male. The number of patients with mild, moderate I, II and severe condition was 85, 138, 61 and 16, respectively. Common presenting symptoms were cough (n = 71), loss of taste (42), loss of smell (39), fever ≥ 37.5 °C (36). Dyspnea was observed only 21 cases; 57 reported no symptoms on admission. Favipiravir, ciclesonide, dexamethasone, and heparin were administered in 106, 168, 65, and 38 patients, respectively, but not remdesivir. The median duration of hospitalization was 10 (7-15) days. All patients with mild and moderate I severity were discharged. Among the 77 patients classified as moderate II or severe, 3 were transferred to tertiary hospitals for further treatment on the day of admission. The respiratory condition worsened in 21 patients; 18 required transfer to tertiary hospitals 3 (median) days after admission and 3 died. CONCLUSION: Respiratory condition recovered in 92%; whereas it worsened in 7% and the mortality rate was 1%. The ratios of male patients, of patients with diabetes mellitus in those with the decreased respiratory condition, were significantly higher than recovered.

SARS-CoV-2-induced humoral immunity through B cell epitope analysis in COVID-19 infected individuals.

The aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained serum from forty-three COVID-19 patients from patients in the intensive care unit of Osaka University Hospital (n = 12) and in Osaka City Juso Hospital (n = 31). Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay. The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. We observed the correlation between neutralizing antibody titer and IgG, but not IgM, antibody titer of COVID-19 patients. In the analysis of the predicted the linear B cell epitopes, hot spots in the N-terminal domain of the S protein were observed in the serum from patients in the intensive care unit of Osaka University Hospital. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.

[Primary nasopharyngeal tuberculosis].

A 59-year-old female was complaining of sore throat, right otorrhea, and hearing impairment. There were no abnormal findings suggestive of pulmonary tuberculosis on her chest XP and CT. Nasopharyngoscopic examination detected a lesion coated with white mass on her nasopharynx, and a biopsy-specimen from this lesion revealed histopathological findings compatible with tuberculosis and the presence of acid-fast bacilli. PCR was positive for Mycobacterium tuberculosis complex. Therefore, we diagnosed the case as primary nasopharyngeal tuberculosis and treated her by 4-drug combination regimen with daily isoniazid, rifampicin, ethambutol and pyrazinamide. Later, low degree of resistance was noticed, isoniazid was replaced by levofloxacin. After the anti-tuberculosis chemotherapy, her symptoms almost completely diminished and the mass in her nasopharynx disappeared. As far as we can search, 23 Japanese cases of primary nasopharyngeal tuberculosis, including this case, have been reported in the literatures. We summarized the clinical features of these cases in Table. Nasopharyngeal tuberculosis is a rather rare disease. But, recently, due to the advances in diagnostic technology, the number of the case-reports has been increasing. Difficulties in detecting tubercle bacilli in nasopharyngeal lesion sometimes delayed definite diagnosis and treatment. If a patient complains the symptoms compatible with this disease, such as sore throat, pharyngeal pain and otorrhea, which are refractory to the general antibiotic therapy, we should be aware of the existence of this disease and repeat bacteriological and/or molecular examinations to prove tubercle bacilli to be able to start timely anti-tuberculosis chemotherapy.

A phase I/II study comparing regimen schedules of gemcitabine and docetaxel in Japanese patients with stage IIIB/IV non-small cell lung cancer.

OBJECTIVE: Gemcitabine and docetaxel are non-platinum agents with activity in non-small cell lung cancer (NSCLC). This study was conducted to determine and evaluate the recommended regimen of gemcitabine-docetaxel and evaluated its efficacy and safety in chemonaive Japanese NSCLC patients. METHODS: In phase I, patients with stage IIIB/IV NSCLC were randomized and received either gemcitabine on days 1 and 8 plus docetaxel on day 1 or gemcitabine on days 1 and 8 plus docetaxel on day 8. The recommended regimen was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Efficacy and toxicity were evaluated in all patients. RESULTS: Twenty-five patients were enrolled in phase I and six patients were given the recommended regimen; gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8. An additional 34 patients were enrolled into phase II and administered with the recommended regimen. The response rate was 32.2% [95% confidence interval (CI) 20.6-45.6%] overall and 30.0% (95% CI 16.6-46.5%) in patients with the recommended regimen (40 patients). Although grade 3 interstitial pneumonia was observed in two patients (5.0%) who received the recommended regimen, both recovered shortly after steroid treatment. No unexpected events were observed throughout this study. CONCLUSIONS: Gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8 has comparable efficacy and more tolerable toxicities than previously reported platinum-based regimens. These results should be verified by a phase III study.

Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects.

BACKGROUND: Angiogenesis has recently attracted considerable attention as a component of airway remodeling in bronchial asthma. Vascular endothelial growth factor (VEGF) is highly expressed in asthmatic airways, and its contribution to airway remodeling has been reported. Although angiogenesis is regulated by a balance of angiogenic and antiangiogenic factors, the relative levels of antiangiogenic factors in asthmatic airways have not been evaluated. OBJECTIVE: We sought to determine whether an imbalance between angiogenic and antiangiogenic factors exists in asthmatic airways. METHODS: We simultaneously measured VEGF and endostatin levels and evaluated their correlation and balance in induced sputum from 18 steroid-naive asthmatic subjects and 11 healthy control subjects. After initial sputum induction, asthmatic subjects underwent 8 weeks of inhaled beclomethasone dipropionate (BDP; 800 microg/d) therapy, and sputum induction was then repeated. RESULTS: VEGF and endostatin levels in induced sputum were significantly higher in asthmatic subjects than in control subjects (P <.001). There was a significant correlation between VEGF and endostatin levels in both control subjects (r = 0.995, P <.001) and asthmatic subjects (r = 0.923, P <.001). Moreover, the VEGF/endostatin level ratio in asthmatic subjects was significantly higher than that in control subjects (P <.0001). After 8 weeks of inhaled BDP therapy, the VEGF level in induced sputum in asthmatic subjects was significantly decreased (P <.001), whereas the endostatin level was not. A correlation between VEGF and endostatin levels existed even after BDP therapy (r = 0.861, P <.001). Moreover, the VEGF/endostatin level ratio was significantly decreased to the same level as in the control subjects after BDP therapy (P <.0001). CONCLUSION: There was an imbalance between VEGF and endostatin levels in induced sputum from asthmatic subjects. This imbalance might play an important role in the pathogenesis of bronchial asthma through its effects on angiogenesis.

[A case of interstitial pneumonia in the upper lung field histologically diagnosed as nonspecific interstitial pneumonia complicated by bilateral pneumothorax].

A 55-year-old man was admitted to our hospital because of progressive dyspnea. Chest radiography showed interstitial shadows in the upper lobe. The pathological diagnosis of lung biopsy specimens obtained from upper and middle lobes by video-assisted thoracoscopy was non-specific interstitial pneumonia, group 2. Administration of glucocorticoids improved the symptoms, the chest radiography findings, and the serum KL-6 level. This patient may belong to the new category of idiopathic interstitial pneumonia, though he exhibited several features of idiopathic pulmonary upper lobe fibrosis originally described by Amitani et al.

Bilateral tubal pregnancies after the termination of intrauterine pregnancy following gamete intrafallopian transfer.

It is well known that the prevalence of heterotopic pregnancies following assisted reproductive technology (ART) is much higher than among spontaneous pregnancies. Here, we illustrate a very rare case of bilateral simultaneous tubal pregnancies combined with intrauterine pregnancy (incomplete abortion) following gamete intrafallopian transfer (GIFT). In this case, unsuspected bilateral tubal pregnancies were diagnosed when laparotomy was performed 10 days after the termination of an intrauterine pregnancy. We conclude that a careful monitoring after the termination of an intrauterine pregnancy should be performed when the patient has prolonged genital bleeding, which might be a warning signal of heterotopic pregnancy existence even in patients without any risk factors of ectopic pregnancy. (Reprod Med Biol 2002; 1: 65-67).

Ultrastructure of receptaculum seminis in Haemaphysalis longicornis (Acari: Ixodidae) in relation to inserted endospermatophore.

The receptaculum seminis, opening into the female genital tract, is found only in the metastriate ixodid ticks. An endospermatophore that has been inserted into the female genital aperture at copulation is first stored in the receptaculum seminis, where spermiogenesis is completed before the sperm ascend the oviducts. The receptaculum seminis consists of a simple cuticularized epithelium. Epithelial cells in sexually matured females develop during feeding and become active in secretion. Secretions discharged from epithelial cells are released into the lumen of this organ through the cuticle and may act on the wall of the inserted endospermatophore. The fact that resumption of spermiogenesis (spermateleosis) has already occurred before destruction of the endospermatophore just after copulation suggests that secretions from epithelial cells of the receptaculum seminis are not the trigger of spermateleosis, but a destructive agent of the endospermatophore wall. J Morphol 231:143-147, 1997. © 1997 Wiley-Liss, Inc.

Ultrastructure of the tubular accessory gland in Haemaphysalis longicornis (Acari: Ixodidae).

The paired tubular accessory glands in Haemaphysalis longicornis open at the junction of the cervical and the vestibular parts of vagina via short and narrow ducts. The pseudostratified columnar glandular epithelium covered by the muscle layer consists of both secretory and supporting cells. As feeding proceeds, the secretory cells increase in volume. In ovipositing females, well-developed rough endoplasmic reticulum, the Golgi complex, and membranebound granules that are undergoing exocytosis suggest that the secretory cells are involved in protein synthesis. However, in virgin females that fed 10 days, only small dense granules and no secretion activity were observed. The secretions from the tubular accessory gland may be released into the genital tract during the egg passage through the vagina. However, the supporting cells located between the secretory cells become slender during feeding, cohere to each other at the luminal side, and have a very narrow attachment at the basement membrane. Supporting cells probably help maintain secretory cell shape especially during granular discharge into the lumen. © 1994 Wiley-Liss, Inc.