C oronavirus disease (COVID-19) typically causes febrile illness with respiratory symptoms (1,2), and many countries worldwide have been affected. Before characterizing COVID-19 as a pandemic in March 2020 (3), the World Health Organization advised countries to take measures to reduce spread of the virus, including identifying cases and clusters, isolating patients, tracing contacts, and preventing community transmission (4). Several countries have reported on the characteristics of a small number of clusters of COVID-19 cases (5,6). However, few comprehensive reports provide an overview of clusters of COVID-19 cases in communities and the significance of such clusters. We analyzed 61 COVID-19 clusters among various communities in Japan and identified 22 probable primary cases that might have contributed to the disease incidence in clusters. The Study We analyzed COVID-19 cases in Japan reported during January 15-April 4, 2020. All COVID-19 cases confirmed by reverse transcription-PCR in Japan must be reported to the Ministry of Health, Labour and Welfare. Through case interviews, local health authorities collected demographic and epidemiologic information, such as possible source of infection and contact and travel history. During the study period, a total of 3,184 laboratory-confirmed COVID-19 cases, including 309 imported cases, were reported. Among cases of local transmission, 61% (1,760/2,875) had epidemiologic links to known cases (Figure 1, panel A). We excluded 712 cases detected on a cruise that was anchored at Yokohama Port, Japan, from February 3 through March 1 (7). We defined a cluster as >5 cases with primary exposure reported at a common event or venue, excluding within-household transmissions. Our definition also excluded cases with epidemiologic links to secondary transmission. For example, in the following scenario we would exclude cases A and B: boy A is a friend of boy B whose grandmother C contracted nosocomial COVID-19 in a nursing home from which ≥5 cases were reported; although all 3 have symptoms develop and are diagnosed with COVID-19, we would consider only grandmother C part of a cluster from the nursing home. By investigating the epidemiologic links among cases, we identified 61 COVID-19 clusters in various communities. We observed clusters of COVID-19 cases from 18 (30%) healthcare facilities; 10 (16%) care facilities of other types, such as nursing homes and day care centers; 10 (16%) restaurants or bars; 8 (13%) workplaces; 7 (11%) music-related events, such as live music concerts, chorus group rehearsals, and karaoke parties; 5 (8%) gymnasiums; 2 (3%) ceremonial

Association between nasopharyngeal load of Streptococcus pneumoniae, viral co-infection and radiologically confirmed pneumonia in Vietnamese children.

Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.

Rationale: Efficient removal of apoptotic cells is essential for the resolution of acute pulmonary inflammation. Alveolar macrophages ingest apoptotic cells less avidly than other professional phagocytes at rest but overcome this defect during acute inflammation. Surfactant protein (SP)-A and SP-D are potent modulators of macrophage function and may suppress clearance of apoptotic cells through activation of the transmembrane receptor signal inhibitory regulatory protein a (SIRPa). Objectives: To investigate whether binding of SP-A and SP-D to SIRPa on alveolar macrophages suppresses apoptotic cell clearance. Methods: Phagocytosis of apoptotic cells was assessed using macrophages pretreated with SP-A, SP-D, or the collectin-like molecule C1q. Binding of SP-A and SP-D to SIRPa was confirmed in vitro using blocking antibodies and fibroblasts transfected with active and mutant SIRPa. The effects of downstream molecules SHP-1 and RhoA on phagocytosis were studied using SHP-1-deficient mice, sodium stibogluconate, and a Rho kinase inhibitor. Lipopolysaccharide was given to chimeric mice to study the effects of SP-A and SP-D binding on inflammatory macrophages.

Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa O 2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO 2 ] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 mg Days 1-8, none Days 9-14; 3 six cycles; 12 wk); low-dose therapy (125 mg Days 1-4, none Days 5-14; 3 six cycles; 12 wk), and follow-up (52 wk). Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high-and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO 2 of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n 5 35, P , 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO 2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.

The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor–related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal–regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7.

Clearance of apoptotic cells is necessary for tissue development, homeostasis and resolution of inflammation. The uptake of apoptotic cells is initiated by an 'eat-me' signal, such as phosphatidylserine, on the cell surface and phagocytes recognize the signal by using specific receptors. In this study, we show that the soluble form of the receptor for advanced glycation end products (RAGE) binds to phosphatidylserine as well as to the apoptotic thymocytes. RAGE-deficient (Rage À/À ) alveolar macrophages showed impaired phagocytosis of apoptotic thymocytes and defective clearance of apoptotic neutrophils in Rage À/À mice. Our results indicate that RAGE functions as a phosphatidylserine receptor and assists in the clearance of apoptotic cells.

BackgroundThe increasing burden of pneumonia in adults is an emerging health issue in the era of global population aging. This study was conducted to elucidate the burden of community-onset pneumonia (COP) and its etiologic fractions in Japan, the world’s most aged society.MethodsA multicenter prospective surveillance for COP was conducted from September 2011 to January 2013 in Japan. All pneumonia patients aged ≥15 years, including those with community-acquired pneumonia (CAP) and health care-associated pneumonia (HCAP), were enrolled at four community hospitals on four major islands. The COP burden was estimated based on the surveillance data and national statistics.ResultsA total of 1,772 COP episodes out of 932,080 hospital visits were enrolled during the surveillance. The estimated overall incidence rates of adult COP, hospitalization, and in-hospital death were 16.9 (95% confidence interval, 13.6 to 20.9), 5.3 (4.5 to 6.2), and 0.7 (0.6 to 0.8) per 1,000 person-years (PY), respectively. The incidence rates sharply increased with age; the incidence in people aged ≥85 years was 10-fold higher than that in people aged 15-64 years. The estimated annual number of adult COP cases in the entire Japanese population was 1,880,000, and 69.4% were aged ≥65 years. Aspiration-associated pneumonia (630,000) was the leading etiologic category, followed by Streptococcus pneumoniae-associated pneumonia (530,000), Haemophilus influenzae-associated pneumonia (420,000), and respiratory virus-associated pneumonia (420,000), including influenza-associated pneumonia (30,000).ConclusionsA substantial portion of the COP burden occurs among elderly members of the Japanese adult population. In addition to the introduction of effective vaccines for S. pneumoniae and influenza, multidimensional approaches are needed to reduce the pneumonia burden in an aging society.