Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection.

BACKGROUND: Patients who present to an emergency department with respiratory symptoms are often conservatively triaged in favour of hospitalization. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalization in order to improve the precision of clinical decision-making in the emergency department. PATIENTS AND METHODS: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from emergency departments in an international multicentre study: Canada (n=310), Italy (n=131), and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed COVID-19 patients (n=245). An inflammatory profile was determined using a rapid, 50-minute, biomarker panel: Rapid Acute Lung Injury Diagnostic (RALI-Dx), which measures IL-6, IL-8, IL-10, sTNFR1, and sTREM1. RESULTS: RALI-Dx biomarkers were significantly elevated in patients who required hospitalization across all three sites. A machine learning algorithm that was applied to predict hospitalization using RALI-Dx biomarkers had an area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy), and 86±3% (Brazil). Model performance in COVID-19 patients was 82±3% and 87±7% for patients with a confirmed pneumonia diagnosis. CONCLUSIONS: The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions and represents an important diagnostic adjunct to advance emergency department decision-making protocols.

Genomic and epidemiologic surveillance of SARS-CoV-2 in Southern Brazil and identification of a new Omicron-L452R sublineage.

Recently, SARS-CoV-2 Omicron variant (B.1.1.529) was first identified in Botswana in November 2021. In a short period of time, this highly mutated variant replaced the previous dominant Delta variant, causing an exponential increase in the number of COVID-19 cases, resulting in a new wave of pandemic. This current research article aims to analyze and summarize information about the genetic characteristics, amino acid mutations and epidemiological data providing scientific findings to enrich the SARS-CoV-2 knowledge. More importantly, we describe here, for the first time, the identification of a new Omicron variant of concern: Omicron-L452R in Brazil.

Seroprevalence of anti-SARS-CoV-2 antibodies in a cohort of New York City metro blood donors using multiple SARS-CoV-2 serological assays: Implications for controlling the epidemic and "Reopening".

Projections of the stage of the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic and local, regional and national public health policies to limit coronavirus spread as well as "reopen" cities and states, are best informed by serum neutralizing antibody titers measured by reproducible, high throughput, and statically credible antibody (Ab) assays. To date, a myriad of Ab tests, both available and FDA authorized for emergency, has led to confusion rather than insight per se. The present study reports the results of a rapid, point-in-time 1,000-person cohort study using serial blood donors in the New York City metropolitan area (NYC) using multiple serological tests, including enzyme-linked immunosorbent assays (ELISAs) and high throughput serological assays (HTSAs). These were then tested and associated with assays for neutralizing Ab (NAb). Of the 1,000 NYC blood donor samples in late June and early July 2020, 12.1% and 10.9% were seropositive using the Ortho Total Ig and the Abbott IgG HTSA assays, respectively. These serological assays correlated with neutralization activity specific to SARS-CoV-2. The data reported herein suggest that seroconversion in this population occurred in approximately 1 in 8 blood donors from the beginning of the pandemic in NYC (considered March 1, 2020). These findings deviate with an earlier seroprevalence study in NYC showing 13.7% positivity. Collectively however, these data demonstrate that a low number of individuals have serologic evidence of infection during this "first wave" and suggest that the notion of "herd immunity" at rates of ~60% or higher are not near. Furthermore, the data presented herein show that the nature of the Ab-based immunity is not invariably associated with the development of NAb. While the blood donor population may not mimic precisely the NYC population as a whole, rapid assessment of seroprevalence in this cohort and serial reassessment could aid public health decision making.

Impact of COVID-19 mitigation strategies on asthma hospitalizations in Brazil.

Background: In 2020, a unique social experience was provided by the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2. Interventions to tackle the pandemic may affect the burden of other respiratory diseases. Objective: This study aims to assess the impact of the COVID-19 mitigation strategies on hospitalizations for asthma in children aged between 1 and 14 years, adults aged between 20 and 59 years, and elderly older than 60 years. Methods: Data from hospital admissions for asthma were obtained from the Department of Informatics of Brazilian Public Health System database in the period between January 2016 and December 2020 and analyzed by age groups. To evaluate the effect of containment measures on the incidence of asthma and respiratory system diseases (total), the absolute reduction and relative reduction were calculated by analyzing the subsets from 2016 to 2019 versus 2020. Results: There was a significant reduction in the average incidence of hospitalizations in 2020, with numbers ranging from -59% (incidence rate ratio, 0.41 [0.37-0.45]) for age 1 to 14 years (prepandemic 1,393.2/100,000 vs pandemic 574.9/100.000), -37% (incidence rate ratio, 0.63 [0.49-0.80]) for age 20 to 59 years (prepandemic 160.2/100,000 vs pandemic 101.1/100,000), and -60% (incidence rate ratio, 0.40 [0.33-0.47]) for older than 60 years (prepandemic 460.6/100,000 vs pandemic 185.3/100,000). Conclusions: Ashtma hospitalizations decreased in 2020, especially in the pediatric group and the older group during the COVID-19 pandemic, which may be associated with the reduction in the incidence of many respiratory viral infections.

Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2-2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10-8) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10-13), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1, MHC, DPP9 and IFNAR2). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone.

Short-chain fatty acid acetate triggers antiviral response mediated by RIG-I in cells from infants with respiratory syncytial virus bronchiolitis.

BACKGROUND: Gut microbiota-derived short-chain fatty-acid (SFCA) acetate protects mice against RSV A2 strain infection by increasing interferon-ß production and expression of interferon-stimulated genes (ISGs). However, the role of SFCA in RSV infection using strains isolated from patients is unknown. METHODS: We first used RSV clinical strains isolated from infants hospitalized with RSV bronchiolitis to investigate the effects of in vitro SCFA-acetate treatment of human pulmonary epithelial cells. We next examined whether SCFA-acetate treatment is beneficial in a mouse model of RSV infection using clinical isolates. We sought to investigate the relationship of gut microbiota and fecal acetate with disease severity among infants hospitalized with RSV bronchiolitis, and whether treating their respiratory epithelial cells with SCFA-acetate ex-vivo impacts viral load and ISG expression. We further treated epithelial cells from SARS-CoV-2 infected patients with SCFA-acetate. FINDINGS: In vitro pre-treatment of A549 cells with SCFA-acetate reduced RSV infection with clinical isolates and increased the expression of RIG-I and ISG15. Animals treated with SCFA-acetate intranasally recovered significantly faster, with reduction in the RSV clinical isolates viral load, and increased lung expression of IFNB1 and the RIG-I. Experiments in RIG-I knockout A549 cells demonstrated that the protection relies on RIG-I presence. Gut microbial profile was associated with bronchiolitis severity and with acetate in stool. Increased SCFA-acetate levels were associated with increasing oxygen saturation at admission, and shorter duration of fever. Ex-vivo treatment of patients' respiratory cells with SCFA-acetate reduced RSV load and increased expression of ISGs OAS1 and ISG15, and virus recognition receptors MAVS and RIG-I, but not IFNB1. These SCFA-acetate effects were not found on cells from SARS-CoV-2 infected patients. INTERPRETATION: SCFA-acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression. FUNDING: FAPERGS (FAPERGS/MS/CNPq/SESRS no. 03/2017 - PPSUS 17/2551-0001380-8 and COVID-19 20/2551-0000258-6); CNPq 312504/2017-9; CAPES) - Finance Code 001.

Impact of nonpharmacological COVID-19 interventions in hospitalizations for childhood pneumonia in Brazil.

BACKGROUND AND OBJECTIVE: The knowledge about the impact of the nonpharmacological measures to control the COVID-19 pandemic can give insight into ways in which they can also be applied for other respiratory diseases. To assess the impact of containment measures of the COVID-19 pandemic on pneumonia hospitalizations in children from 0 to 14 years of age in Brazil. METHODS: Data from hospital admissions for pneumonia were obtained from the Department of Informatics of Brazilian Public Health System database in the period of 2015-2020 and analyzed by macroregions and age groups. To evaluate the effect of containment measures, on the incidence of pneumonia, the absolute reduction and relative reduction were calculated by analyzing the subsets 2015-2019 vs. 2020. RESULTS: Comparing the subsets of April-August 2015-2019 vs. April-August 2020 for Brazil (total), there was an significant reduction in the average incidence of hospitalizations, with numbers ranging from -82% [IRR 0.17 (0.14-0.21)] for <4 years (prepandemic 741.8/100,000 vs. pandemic 132.7/100.000), -83% [IRR 0.17 (0.10-0.27)] for 5-9 years (prepandemic 113.6/100,000 vs. pandemic 19.6/100.000), -77% [IRR 0.23 (0.11-0.46)] for 10-14 (prepandemic 42.0/100,000 vs. pandemic 9.8/100.000) and -82% [IRR 0.18 (0.15-0.21)] for all children ≤14 years (prepandemic 897.4/100,000 vs. pandemic 162.1/100.000). CONCLUSION: We found a significant decrease in cases of all cause pneumonia in children under 14 years and especially in the age group <9 years during the COVID-19 pandemic, which may be associated with the nonpharmacological measures applied to control the SARS-CoV-2.

Early Impact of Social Distancing in Response to Coronavirus Disease 2019 on Hospitalizations for Acute Bronchiolitis in Infants in Brazil.

BACKGROUND: Interventions to tackle the coronavirus disease 2019 (COVID-19) pandemic may affect the burden of other respiratory diseases. Considering the repercussions of these unique social experiences to infant health, this study aims to assess the early impact of social distancing due to the COVID-19 pandemic in hospital admissions for acute bronchiolitis. METHODS: Data from hospitalizations of acute bronchiolitis in infants <1 year of age were obtained from the Department of Informatics of the Brazilian Public Health database for the period between 2016 and 2020. These data were also analyzed by macroregions of Brazil (North, Northeast, Southeast, South, and Midwest). To evaluate the effect of social distancing strategy on the incidence of acute bronchiolitis, the absolute and relative reductions were calculated by analyzing the yearly subsets of 2016 vs 2020, 2017 vs 2020, 2018 vs 2020, and 2019 vs 2020. RESULTS: There was a significant reduction in all comparisons, ranging from -78% (incidence rate ratio [IRR], 0.22 [95% confidence interval {CI}, .20-.24]) in 2016 vs 2020 to -85% (IRR, 0.15 [95% CI, .13-.16]) in 2019 vs 2020, for the data from Brazil. For analyses by macroregions, the reduction varied from -58% (IRR, 0.41 [95% CI, .37-.45]) in the Midwest in 2016 vs 2020 to -93% (IRR, 0.07 [95% CI, .06-.08]) in the South in 2019 vs 2020. CONCLUSIONS: There was a significant reduction in hospitalization for acute bronchiolitis in children <1 year old in Brazil, on the order of >70% for most analysis. Our data suggest an important impact of social distancing on reducing the transmission of viruses related to acute bronchiolitis. Such knowledge may guide strategies for prevention of viral spread.