Effectiveness of Messenger RNA Coronavirus Disease 2019 Vaccines Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Delta Variant Epidemic in Japan: Vaccine Effectiveness Real-time Surveillance for SARS-CoV-2 (VERSUS).

BACKGROUND: Although high vaccine effectiveness of messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines has been reported in studies in several countries, data are limited from Asian countries, especially against the Delta (B.1.617.2) variant. METHODS: We conducted a multicenter test-negative case-control study in patients aged ≥16 years visiting hospitals or clinics with signs or symptoms consistent with COVID-19 from 1 July to 30 September 2021, when the Delta variant was dominant (≥90% of SARS-CoV-2 infections) nationwide in Japan. Vaccine effectiveness of BNT162b2 or mRNA-1273 against symptomatic SARS-CoV-2 infections was evaluated. Waning immunity among patients aged 16-64 years was also assessed. RESULTS: We enrolled 1936 patients, including 396 test-positive cases and 1540 test-negative controls for SARS-CoV-2. The median age was 49 years, 53.4% were male, and 34.0% had underlying medical conditions. Full vaccination (receiving 2 doses ≥14 days before symptom onset) was received by 6.6% of cases and 38.8% of controls. Vaccine effectiveness of full vaccination against symptomatic SARS-CoV-2 infections was 88.7% (95% confidence interval [CI], 78.8%-93.9%) among patients aged 16-64 years and 90.3% (95% CI, 73.6%-96.4%) among patients aged ≥65 years. Among patients aged 16-64 years, vaccine effectiveness was 91.8% (95% CI, 80.3%-96.6%) within 1-3 months after full vaccination, and 86.4% (95% CI, 56.9%-95.7%) within 4-6 months. CONCLUSIONS: mRNA COVID-19 vaccines had high effectiveness against symptomatic SARS-CoV-2 infections in Japan during July-September 2021, when the Delta variant was dominant nationwide.

Respiratory virus detection in the upper respiratory tract of asymptomatic, community-dwelling older people.

BACKGROUND: The prevalence of virus positivity in the upper respiratory tract of asymptomatic community-dwelling older people remains elusive. Our objective was to investigate the prevalence of respiratory virus PCR positivity in asymptomatic community-dwelling older people using saliva samples and nasopharyngeal and oropharyngeal swabs. METHODS: We analyzed 504 community-dwelling adults aged ≥ 65 years who were ambulatory and enrolled in a cross-sectional study conducted from February to December 2018 in Nagasaki city, Japan. Fourteen respiratory viruses were identified in saliva, nasopharyngeal and oropharyngeal samples using multiplex PCR assays. RESULTS: The prevalences of PCR positivity for rhinovirus, influenza A, enterovirus and any respiratory virus were 12.9% (95% CI: 10.1-16.1%), 7.1% (95% CI: 5.1-9.8%), 6.9% (95% CI: 4.9-9.5%) and 25.2% (95% CI: 21.5-29.2%), respectively. Rhinovirus was detected in 21.5% of subjects, influenza A in 38.9% of subjects, enterovirus in 51.4% of subjects and any virus in 32.3% of subjects using only saliva sampling. CONCLUSIONS: The prevalences of several respiratory viruses were higher than the percentages reported previously in pharyngeal samples from younger adults. Saliva sampling is a potentially useful method for respiratory virus detection in asymptomatic populations.

Effectiveness of primary series, first, and second booster vaccination of monovalent mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections and severe diseases during the SARS-CoV-2 omicron BA.5 epidemic in Japan: vaccine effectiveness real-time surveillance for SARS-CoV-2 (VERSUS).

BACKGROUND: This study aimed to evaluate VE of primary, first, and second booster ancestral-strain monovalent mRNA COVID-19 vaccination against symptomatic infections and severe diseases in Japan. METHODS: We conducted a test-negative case-control study. We included medically attended episodes and hospitalizations involving individuals aged ≥16 with signs and symptoms from July to November 2022, when Omicron BA.5 was dominant nationwide. To evaluate VE, we calculated adjusted ORs of vaccination among test-positive versus test-negative individuals using a mixed-effects logistic regression. RESULTS: For VE against symptomatic infections among individuals aged 16 to 59, VE of primary vaccination at > 180 days was 26.1% (95% CI: 10.6-38.8%); VE of the first booster was 58.5% (48.4-66.7%) at ≤90 days, decreasing to 41.1% (29.5-50.8%) at 91 to 180 days. For individuals aged ≥60, VE of the first booster was 42.8% (1.7-66.7%) at ≤90 days, dropping to 15.4% (-25.9-43.2%) at 91 to 180 days, and then increasing to 44.0% (16.4-62.5%) after the second booster. For VE against severe diseases, VE of the first and second booster was 77.3% (61.2-86.7%) at ≤90 days and 55.9% (23.4-74.6%) afterward. CONCLUSION: mRNA booster vaccination provided moderate protection against symptomatic infections and high-level protection against severe diseases during the BA.5 epidemic in Japan.

Antigen-specific cytokine profiles for pulmonary Mycobacterium avium complex disease stage diagnosis.

Introduction: Controlling pulmonary Mycobacterium avium complex (MAC) disease is difficult because there is no way to know the clinical stage accurately. There have been few attempts to use cell-mediated immunity for diagnosing the stage. The objective of this study was to characterize cytokine profiles of CD4+T and CD19+B cells that recognize various Mycobacterium avium-associated antigens in different clinical stages of MAC. Methods: A total of 47 MAC patients at different stages based on clinical information (14 before-treatment, 16 on-treatment, and 17 after-treatment) and 17 healthy controls were recruited. Peripheral blood mononuclear cells were cultured with specific antigens (MAV0968, 1160, 1276, and 4925), and the cytokine profiles (IFN-γ, TNF-α, IL-2, IL-10, IL-13, and IL-17) of CD4+/CD3+ and CD19+ cells were analyzed by flow cytometry. Results: The response of Th1 cytokines such as IFN-γ and TNF-α against various antigens was significantly higher in both the on-treatment and after-treatment groups than in the before-treatment group and control (P < 0.01-0.0001 and P < 0.05-0.0001). An analysis of polyfunctional T cells suggested that the presence of IL-2 is closely related to the stage after the start of treatment (P = 0.0309-P < 0.0001) and is involved in memory function. Non-Th1 cytokines, such as IL-10 and IL-17, showed significantly higher responses in the before-treatment group (P < 0.0001 and P < 0.01-0.0001). These responses were not observed with purified protein derivative (PPD). CD19+B cells showed a response similar to that of CD4+T cells. Conclusion: There is a characteristic cytokine profile at each clinical stage of MAC.

Corrigendum: Antigen-specific cytokine profiles for pulmonary Mycobacterium avium complex disease stage diagnosis.

[This corrects the article DOI: 10.3389/fimmu.2023.1222428.].

Effectiveness of mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infections during the SARS-CoV-2 Omicron BA.1 and BA.2 epidemic in Japan: vaccine effectiveness real-time surveillance for SARS-CoV-2 (VERSUS).

BACKGROUND: Evaluating COVID-19 vaccine effectiveness (VE) domestically is crucial for assessing and determining national vaccination policy. This study aimed to evaluate VE of mRNA COVID-19 vaccines in Japan. METHODS: We conducted a multicenter test-negative case-control study. The study comprised individuals aged ≥16 visiting medical facilities with COVID-19-related signs or symptoms from 1 January to 26 June 2022, when Omicron BA.1 and BA.2 were dominant nationwide. We evaluated VE of primary and booster vaccination against symptomatic SARS-CoV-2 infections and relative VE of booster compared with primary. RESULTS: We enrolled 7,931 episodes, including 3,055 test positive. The median age was 39, 48.0% were male, and 20.5% had underlying medical conditions. In individuals aged 16 to 64, VE of primary vaccination within 90 days was 35.6% (95% CI, 19.0-48.8%). After booster, VE increased to 68.7% (60.6-75.1%). In individuals aged ≥65, VE of primary and booster was 31.2% (-44.0-67.1%) and 76.5% (46.7-89.7%), respectively. Relative VE of booster compared with primary vaccination was 52.9% (41.0-62.5%) in individuals aged 16 to 64 and 65.9% (35.7-81.9%) in individuals aged ≥65. CONCLUSIONS: During BA.1 and BA.2 epidemic in Japan, mRNA COVID-19 primary vaccination provided modest protection. Booster vaccination was necessary to protect against symptomatic infections.

Monocyte chemoattractant protein-1/CC chemokine ligand 2 enhances apoptotic cell removal by macrophages through Rac1 activation.

Apoptotic cell removal (efferocytosis) is an essential process in the regulation of inflammation and tissue repair. We have shown that monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2) enhances efferocytosis by alveolar macrophages in murine bacterial pneumonia. However, the mechanism by which MCP-1 exerts this effect remains to be determined. Here we explored that hypothesis that MCP-1 enhances efferocytosis through a Rac1/phosphatidylinositol 3-kinase (PI3-kinase)-dependent mechanism. We assessed phagocytosis of apoptotic cells by MCP-1 treated murine macrophages in vitro and in vivo. Rac activity in macrophages was measured using a Rac pull down assay and an ELISA based assay (GLISA). The downstream Rac1 activation pathway was studied using a specific Rac1 inhibitor and PI3-kinase inhibitor in in vitro assays. MCP-1 enhanced efferocytosis of apoptotic cells by murine alveolar macrophages (AMs), peritoneal macrophages (PMs), the J774 macrophage cell line (J774s) in vitro, and murine AMs in vivo. Rac1 activation was demonstrated in these cell lines. The effect of MCP-1 on efferocytosis was completely negated by the Rac1 inhibitor and PI3-kinase inhibitor. We demonstrated that MCP-1 enhances efferocytosis in a Rac1-PI3 kinase-dependent manner. Therefore, MCP-1-Rac1-PI3K interaction plays a critical role in resolution of acute lung inflammation.

The low carriage prevalence of pneumococcus among community-dwelling older people: A cross-sectional study in Japan.

BACKGROUND: The carriage prevalence of pneumococcus among community-dwelling older adults is not fully understood, especially in superaged societies. Our purpose was to elucidate the carriage prevalence of pneumococcus in the upper respiratory tract among Japanese community-dwelling adults aged ≥65 years. METHODS: We conducted a cross-sectional study of generally healthy community-dwelling adults aged ≥65 years in Nagasaki city, Japan. Demographic and clinical data and nasopharyngeal, oropharyngeal and saliva samples were collected from February 21st, 2018, to December 17th, 2018. The specimens were tested by culture and molecular methods. RESULTS: Among a total of 504 enrolled participants, none were positive for pneumococcus by culture, and 22 were positive by PCR. The overall carriage prevalence was 4.4% (95% CI: 2.8-6.5%). The prevalence was highest in saliva samples, followed by oropharyngeal and nasopharyngeal samples. No demographic characteristics were associated with carriage prevalence, including age (4.7% among participants aged 65-74 years and 4.1% among those 75 years and older). Among the pneumococcal-positive participants, 18.2% were PCV13-covered serotypes. CONCLUSIONS: Our data suggest a low carriage prevalence of S. pneumoniae among community-dwelling older people in Japan.

[Three adult cases with Corynebacterium propinquum respiratory infections in a community hospital].

Corynebacterium propinquum, which is included in Corynebacterium group ANF-3, exists as a commensal in the oral flora. This organism has not yet been fully recognized as a respiratory pathogen. We previously reported that the first case with respiratory infection caused by C. propinquum. On the other hand, Corynebacterium pseudodiphtheriticum is recognized as a causative organism in respiratory infections. Recently we experienced two cases with C. propinquum respiratory infections in our hospital. Three types of the onset such as a community-acquired infection, a hospital-acquired infection, and a nursing home acquired infections were observed. Our analysis indicated that gram staining of the purulent sputum is an essential tool to evaluate whether C. propinquum is a respiratory pathogen or not, because this organism is a commensal bacteria.

[A retrospective analysis of community-acquired pneumonia between 2000 and 2002 in a community hospital].

We previously reported a hospital-based retrospective study on community-acquired pneumonia (CAP) at Tagami Hospital, which was a community hospital, between 1994 and 1997. This study was designed to clarify the etiology of CAP diagnosed between 2000 and 2002. We analyzed a total of 124 cases of CAP in our hospital during the study period, and compared the results with the previous data. Identification of the causative organisms of CAP was based on gram staining, the morphology of the colonies, quantitative culture of the sputum, and the serological tests. During the study period, we determined the causative organisms in 42 cases (33.8%). Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were the major causative organisms. The severity of the cases was classified into three groups according to the guideline for CAP, which was edited by the Japanese Respiratory Society. The survival rates in the moderate and severe groups were significantly (p < 0.001) higher than that of the mild group, as analyzed by the Kaplan-Meier method, as follows: 70% (moderate) vs 100% (mild); and 40% (severe) vs 100% (mild). In a total of 7 patients who died, we found the following risk factors: elderly male patients, bedridden status with cerebral infarction, and micro-aspiration, including recurrent pneumonia at short intervals of less than 17 days. Our study indicated that the JRS-edited guideline for CAP is a very useful tool for analyzing cases with CAP in Japan.

Defective efferocytosis by alveolar macrophages in IPF patients.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia. The pathogenicity of IPF has been widely investigated but still remains to be clarified. Efferocytosis, the specialized recognition and ingestion of apoptotic cells by phagocytes, is essential for the resolution of inflammation in the lungs and repair of injured tissues. Impaired efferocytosis contributes to the pathogenesis of chronic lung diseases such as emphysema and cystic fibrosis. We hypothesized that efferocytosis would also be reduced in alveolar macrophages isolated from subjects with IPF. METHODS: Efferocytosis, was evaluated using Wright-Giemsa stained cell preparations isolated from the bronchoalveolar lavage (BAL) fluid of patients with IPF (n = 5), nonspecific interstitial pneumonitis (n = 6), cryptogenic organizing pneumonia (n = 4) and eosinophilic pneumonia (EP) (n = 5). RESULTS: Uningested apoptotic cells were significantly higher in BAL fluid from patients with IPF compared to other forms of interstitial lung disease. Macrophages isolated from patients with eosinophilic pneumonia had significantly fewer phagocytic ingestions than macrophages from the other three groups. CONCLUSION: Efferocytosis by alveolar macrophages was significantly lower in subjects with IPF compared to subjects with other interstitial pneumonia. Dysregulated efferocytosis may contribute to the pathogenesis of IPF.

Molecular epidemiological study of Moraxella catarrhalis isolated from nosocomial respiratory infection patients in a community hospital in Japan.

BACKGROUND: Moraxella catarrhalis, occasionally, plays the essential role in nosocomial respiratory infection (NRI). Few studies have reported the route by which this organism spreads in a nosocomial infection outbreak. We identified characteristics of the strains isolated from NRI and attempted to reveal the potential nosocomial transmission routes. METHODS: A follow-up study has been performed in a Japanese community hospital between July 2002 and January 2003. M. catarrhalis clinical isolates were identified and beta-lactamase production test as well as the minimal inhibitory concentrations (MICs) have been examined. Pulsed-field gel electrophoresis (PFGE) and the multi locus sequence typing method (MLST) have been introduced as the effective "fingerprinting" methods. RESULTS: A total of 29 strains were isolated from 17 participants; 7 independent DNA fragment patterns were detected by PFGE. Pattern B (defined in this study) was dominant, and was detected both in strains from a health care worker (HCW) and inpatients. In the 9 selected strains analyzed by MLST, 7 unique MLST types were identified, which showed the congruence with the results of PFGE results. CONCLUSION: Epidemiological analysis proved the transmission route from patient to patient, and suggested that more studies should be focused on identifying the possible transmission route between HCWs and inpatients.

Usefulness of the Japanese Respiratory Society guidelines for community pneumonia: a retrospective analysis of community-acquired pneumonia between 2000 and 2002 in a general hospital.

OBJECTIVE: The aim of this study was to investigate the causative organisms of community-acquired pneumonia (CAP) diagnosed between 2000 and 2002 and to evaluate the Japanese Respiratory Society (JRS) guidelines. METHODOLOGY: A total of 124 cases of CAP diagnosed during the study period were analyzed, and the results were compared with those of a previous study by the authors' research group. Determination of the causative organisms of CAP was based on Gram stain, morphology of colonies, quantitative culture of sputum, identification of bacterial isolates, and serological tests. RESULTS: During the study period, the causative organisms were identified in 42 cases (33.8%). Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were the major causative organisms. Patients were classified into three groups based on the severity of CAP according to the JRS guidelines. The survival rates of patients with moderate and severe CAP were significantly lower than those of the mild group as evaluated by the Kaplan-Meier method (moderate vs mild, 70% vs 100%; severe vs mild, 40% vs 100%; P < 0.001 for both). Seven patients died during the study, and the risk factors were old age, bedridden status with cerebral infarction, and microaspiration, which was associated with recurrent pneumonia within 17 days. CONCLUSION: This study indicates that the JRS guidelines for CAP are useful for treating patients with CAP in Japan.