The SARS-CoV-2 B.1.1.529 Omicron virus causes attenuated infection and disease in mice and hamsters

Despite the development and deployment of antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. The recent emergence of B.1.1.529, the Omicron variant1,2, which has more than 30 mutations in the spike protein, has raised concerns for escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in pre-clinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of multiple B.1.1.529 Omicron isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2) expressing mice and hamsters. Despite modeling and binding data suggesting that B.1.1.529 spike can bind more avidly to murine ACE2, we observed attenuation of infection in 129, C57BL/6, and BALB/c mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. Although K18-hACE2 transgenic mice sustained infection in the lungs, these animals did not lose weight. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from multiple independent laboratories of the SAVE/NIAID network with several different B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

FEATURES OF RESIDUAL PHENOMENA AND CONSEQUENCES OF COVID-19 (REVIEW)

Проведен литературный обзор об особенностях остаточных явлений и последствий COVID-19 на основе данных, опубликованных до настоящего времени. К началу января 2021 года COVID-19, сопровождающийся тяжелым острым респираторным синдромом, вызванным коронавирусом (SARS-CoV-2), привел к более чем 83 миллионам подтвержденных случаев и более чем 1,8 миллионам смертей. Клинический спектр инфекции SARS-CoV-2 широк, включая бессимптомную инфекцию, лихорадку, усталость, миалгии, легкое заболевание верхних дыхательных путей, тяжелую и опасную для жизни вирусную пневмонию, требующую госпитализации и летальный исход. COVID-19 - это новое заболевание, и остается неопределенность в отношении возможных долгосрочных последствий для здоровья. На сегодняшний день известно, что у большинства инфицированных, особенно в молодом возрасте, заболевание имеет легкое течение, по сравнению с лицами старшего возраста. У некоторых пациентов заболевание быстро прогрессирует и развиваются различные осложнения, в т.ч. полиорганная недостаточность. Поэтому раннее выявление и своевременное лечение критических случаев имеет решающее значение. A literature review on the features of residual phenomena and consequences of COVID-19 is analyzed on the basis of data published so far. By the beginning of January 2021, COVID-19, accompanied by severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2), led to more than 83 million confirmed cases and more than 1.8 million deaths. The clinical spectrum of SARS-CoV-2 infection is wide, including asymptomatic infection, fever, fatigue, myalgia, mild upper respiratory tract disease, severe and life-threatening viral pneumonia requiring hospitalization, and death. COVID-19 is a new disease, and uncertainty remains about possible long-term health consequences. To date, it is known that the majority of infected people, especially at a young age, have a mild course of the disease, compared with older people. In some patients, the disease progresses rapidly and various complications develop, including multiple organ failure. Therefore, early detection and timely treatment of critical cases is crucial.

Immunopathology of RSV: An Updated Review

RSV is a leading cause of respiratory tract disease in infants and the elderly. RSV has limited therapeutic interventions and no FDA-approved vaccine. Gaps in our understanding of virus–host interactions and immunity contribute to the lack of biological countermeasures. This review updates the current understanding of RSV immunity and immunopathology with a focus on interferon responses, animal modeling, and correlates of protection.

Weight Status and Risk of Inpatient Admission for Children With Lower Respiratory Tract Disease

OBJECTIVES To identify associations between weight category and hospital admission for lower respiratory tract disease (LRTD), defined as asthma, community-acquired pneumonia, viral pneumonia, or bronchiolitis, among children evaluated in pediatric emergency departments (PEDs). METHODS We performed a retrospective cohort study of children 2 to <18 years of age evaluated in the PED at 6 children’s hospitals within the PEDSnet clinical research network from 2009 to 2019. BMI percentile of children was classified as underweight, healthy weight, overweight, and class 1, 2, or 3 obesity. Children with complex chronic conditions were excluded. Mixed-effects multivariable logistic regression was used to assess associations between BMI categories and hospitalization or 7- and 30-day PED revisits, adjusted for covariates (age, sex, race and ethnicity, and payer). RESULTS Among 107 446 children with 218 180 PED evaluations for LRTD, 4.5% had underweight, 56.4% had healthy normal weight, 16.1% had overweight, 14.6% had class 1 obesity, 5.5% had class 2 obesity, and 3.0% had class 3 obesity. Underweight was associated with increased risk of hospital admission compared with normal weight (odds ratio [OR] 1.76; 95% confidence interval [CI] 1.69–1.84). Overweight (OR 0.87; 95% CI 0.85–0.90), class 1 obesity (OR 0.88; 95% CI 0.85–0.91), and class 2 obesity (OR 0.91; 95% CI 0.87–0.96) had negative associations with hospital admission. Class 1 and class 2, but not class 3, obesity had small positive associations with 7- and 30-day PED revisits. CONCLUSIONS We found an inverse relationship between patient weight category and risk for hospital admission in children evaluated in the PED for LRTD.

Phase 2b Study of an Ad26.RSV.preF Vaccine for Prevention of RSV-mediated Respiratory Tract Disease in Older Adults

Respiratory syncytial virus (RSV) may cause serious lower respiratory tract disease (LRTD) in older adults, and there is currently no licensed vaccine. CYPRESS (NCT03982199) is a randomized, double-blind, placebo-controlled Phase 2b proof-of-concept trial of an Ad26.RSV.preF-based vaccine for the prevention of RSV-mediated LRTD in older adults. Adults aged ≥65 years were randomized 1:1 before the RSV season to receive Ad26.RSV.preF-based vaccine or placebo. Acute respiratory infection symptoms were collected through a patient eDiary and/or clinician assessment until the end of the RSV season. The primary endpoint was the first occurrence of RTPCR-confirmed RSV-mediated LRTD according to any of 3 case definitions: (1) ≥3 symptoms of lower respiratory tract infection (LRTI), (2) ≥2 symptoms of LRTI, or (3) ≥2 symptoms of LRTI or ≥1 symptom of LRTI with ≥1 systemic symptom. Immunogenicity was assessed in a subset of approximately 200 participants. A total of 2891 participants in each study arm received study treatment. Vaccine efficacy was 80% (94.2% CI, 52.2-92.9%), 75% (50.1-88.5%), and 69.8% (43.7-84.7%) for case definition 1, 2, and 3, respectively (all P <0.001). In the vaccine arm, geometric mean fold increase in antibody titers 14 days after vaccination was 13.5 for RSV neutralizing antibodies and 8.6 for RSV prefusion F-specific binding antibodies, and median frequency of RSV-F-specific INFγ T-cells increased from 34 to 444 SFC/10^6 PBMC; no relevant changes were observed in the placebo arm. The Ad26.RSV.preF-based vaccine was highly effective against RSV-mediated LRTD through the first RSV season and elicited robust immune responses in older adults.

Diagnostic Errors Are Common in Acute Pediatric Respiratory Disease: A Prospective, Single-Blinded Multicenter Diagnostic Accuracy Study in Australian Emergency Departments

Background: Diagnostic errors are a global health priority and a common cause of preventable harm. There is limited data available for the prevalence of misdiagnosis in pediatric acute-care settings. Respiratory illnesses, which are particularly challenging to diagnose, are the most frequent reason for presentation to pediatric emergency departments.Objective: To evaluate the diagnostic accuracy of emergency department clinicians in diagnosing acute childhood respiratory diseases, as compared with expert panel consensus (reference standard).Methods: Prospective, multicenter, single-blinded, diagnostic accuracy study in two well-resourced pediatric emergency departments in a large Australian city. Between September 2016 and August 2018, a convenience sample of children aged 29 days to 12 years who presented with respiratory symptoms was enrolled. The emergency department discharge diagnoses were reported by clinicians based upon standard clinical diagnostic definitions. These diagnoses were compared against consensus diagnoses given by an expert panel of pediatric specialists using standardized disease definitions after they reviewed all medical records.Results: For 620 participants, the sensitivity and specificity (%, [95% CI]) of the emergency department compared with the expert panel diagnoses were generally poor: isolated upper respiratory tract disease (64.9 [54.6, 74.4], 91.0 [88.2, 93.3]), croup (76.8 [66.2, 85.4], 97.9 [96.2, 98.9]), lower respiratory tract disease (86.6 [83.1, 89.6], 92.9 [87.6, 96.4]), bronchiolitis (66.9 [58.6, 74.5], 94.3 [80.8, 99.3]), asthma/reactive airway disease (91.0 [85.8, 94.8], 93.0 [90.1, 95.3]), clinical pneumonia (63·9 [50.6, 75·8], 95·0 [92·8, 96·7]), focal (consolidative) pneumonia (54·8 [38·7, 70·2], 86.2 [79.3, 91.5]). Only 59% of chest x-rays with consolidation were correctly identified. Between 6.9 and 14.5% of children were inappropriately prescribed based on their eventual diagnosis.Conclusion: In well-resourced emergency departments, we have identified a previously unrecognized high diagnostic error rate for acute childhood respiratory disorders, particularly in pneumonia and bronchiolitis. These errors lead to the potential of avoidable harm and the administration of inappropriate treatment.

LB14. Efficacy and Immunogenicity of an Ad26.RSV.preF-based Vaccine in the Prevention of RT-PCR-confirmed RSV-mediated Lower Respiratory Tract Disease in Adults Aged ≥65 Years: A Randomized, Placebo-controlled, Phase 2b Study

Background Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease (LRTD) in older adults. Despite a high burden of disease, there is currently no licensed vaccine for RSV. Here, we report the primary efficacy and immunogenicity results from a Phase 2b proof-of-concept trial of an Ad26.RSV.preF-based vaccine for the prevention of RSV-mediated LRTD in adults aged ≥65 years. Methods CYPRESS (NCT03982199) is a randomized, double-blind, placebo-controlled Phase 2b trial. Adults ≥65 years of age were randomized 1:1 prior to the RSV season to receive an Ad26.RSV.preF-based vaccine or placebo. Symptoms of acute respiratory infection (ARI) were collected through an RSV-specific patient-reported Respiratory Infection Intensity and Impact Questionnaire (RiiQ) and/or by a clinician assessment until the end of the RSV season. The primary endpoint was the first occurrence of RT-PCR-confirmed RSV-mediated LRTD according to any of 3 case definitions: (1) ≥3 symptoms of lower respiratory tract infection (LRTI), (2) ≥2 symptoms of LRTI, or (3) ≥2 symptoms of LRTI or ≥1 symptom of LRTI with ≥1 systemic symptom. The secondary endpoint was the first occurrence of any RT-PCR-confirmed RSV-mediated ARI. Immunogenicity assessments were performed in a subset of approximately 200 participants. Results A total of 5782 participants (2891 in each study arm) received study treatment (92.5% white, 57.7% female, median age 71 years). Vaccine efficacy was 80% (94.2% CI, 52.2–92.9%), 75% (50.1–88.5%), and 69.8% (43.7–84.7%) for case definition 1, 2, and 3, respectively (all P values < 0.001). Efficacy for any RSV-mediated ARI was 69.8% (95% CI, 42.7–85.1%). In the vaccine arm of the immunogenicity subset, geometric mean fold increase in antibody titers 14 days after vaccination was 13.5 for RSV neutralizing antibodies and 8.6 for RSV prefusion F-specific binding antibodies. Median frequency of RSV-F-specific INFγ T-cells increased from 34 to 444 SFC/106 PBMC 14 days after vaccination in the vaccine arm; no relevant changes were observed in the placebo arm. Conclusion In CYPRESS, the Ad26.RSV.preF-based vaccine was highly effective against RSV-mediated LRTD through the first RSV season and elicited robust humoral and cellular immune responses in adults aged ≥65 years. Disclosures Ann R. Falsey, MD, AstraZeneca (Individual(s) Involved: Self): Grant/Research Support; BioFire Diagnostics (Individual(s) Involved: Self): Grant/Research Support; Janssen (Individual(s) Involved: Self): Grant/Research Support; Merck, Sharpe and Dohme (Individual(s) Involved: Self): Grant/Research Support; Novavax (Individual(s) Involved: Self): Other Financial or Material Support, Paid DSMB member; Pfizer (Individual(s) Involved: Self): Grant/Research Support Kristi Williams, PhD, Janssen R&D US (Employee) Efi Gymnopoulou, MSc, Janssen Infectious Diseases BV (Employee) Arangassery Rosemary Bastian, PhD, Janssen Vaccines & Prevention BV (Employee) Joris Menten, n/a, Janssen Infectious Diseases BV (Employee) Els De Paepe, MSc, Janssen Infectious Diseases BV (Employee) Hilde de Boer, MSc, Janssen-Cilag (Employee) Sjoukje Vandenberghe, n/a, Janssen Infectious Diseases BV (Employee) Eric Chan, PhD, Janssen Global Services, LLC (Employee) Jerald Sadoff, MD, Johnson & Johnson (Employee, Shareholder) Macaya Douoguih, MD, MPH, Janssen (Employee) Benoit Callendret, PhD, Janssen Vaccines & Prevention BV (Employee) Christy Comeaux, MD, Janssen Vaccines & Prevention BV (Employee) Esther Heijnen, MD, Janssen Vaccines & Prevention BV (Employee)

Influenza A Virus (H1N1) Infection Induces Microglial Activation and Temporal Dysbalance in Glutamatergic Synaptic Transmission

Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms, such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression.

Association of sinusitis and upper respiratory tract diseases with incident rheumatoid arthritis: A case-control study

Objective We aimed to determine whether specific respiratory tract diseases are associated with increased rheumatoid arthritis (RA) risk. Methods This case-control study within the Mass General Brigham Biobank matched newly diagnosed RA cases to three controls on age, sex, and electronic health record history. We identified RA using a validated algorithm and confirmed by medical record review. Respiratory tract disease exposure required one inpatient or two outpatient codes at least two years before index date of RA clinical diagnosis or matched date. Logistic regression models calculated odds ratios (OR) for RA with 95% confidence intervals (CI), adjusting for confounders. We then stratified by serostatus ("seropositive" was positive rheumatoid factor and/or anti-citrullinated protein antibodies) and smoking. Results We identified 741 RA cases and 2,223 controls (both median age 55, 76% female). Acute sinusitis (OR 1.61, 95% CI:1.05,2.45), chronic sinusitis (OR 2.16, 95% CI:1.39,3.35), and asthma (OR 1.39, 95% CI:1.03,1.87) were associated with increased risk of RA. Acute respiratory tract disease burden during the pre-index exposure period was also associated with increased RA risk (OR 1.30 per 10 codes, 95% CI:1.08,1.55). Acute pharyngitis was associated with seronegative (OR 1.68, 95% CI:1.02,2.74) but not seropositive RA; chronic rhinitis/pharyngitis was associated with seropositive (OR 2.46, 95% CI:1.01,5.99) but not seronegative RA. Respiratory tract diseases tended towards higher associations in smokers, especially >10 packyears (OR 1.52, 95% CI:1.02,2.27; p=0.10 for interaction). Conclusion Acute/chronic sinusitis and pharyngitis and acute respiratory burden increased RA risk. The mucosal paradigm of RA pathogenesis may involve the upper respiratory tract.

Early Detection of ARI Disease and First Aid in Children with Fever Seizures at Posyandu Cadres at Kantil Depok, Sleman

Background: Acute Respiratory Infection (ARI) is one of the problems of death in children in developing countries. ARI is an upper or lower respiratory tract disease, usually contagious, which can cause a wide spectrum of disease that ranges from asymptomatic disease or mild infection to severe and deadly disease.Objective: Yandu cadres can improve knowledge, attitudes and skills in handling ARI and febrile seizures in children, so as to optimize growth and development in children optimally.Methods: socialization and simulation of the handling of ARI and febrile seizures in children through cadres. Cadres were given material about ARI and febrile seizures, followed by interactive activities about the steps taken to overcome/handle ARI and febrile seizures in children. The cadres were divided into three groups and accompanied by one trainer.Results: the cadres stated that they understood, and seemed capable of handling febrile seizures in children.Suggestion: The existence of counseling and training to parents/mothers about ARI and handling febrile seizures in children, providing first aid kits and simple medicines for handling febrile seizures at Posyandu, also in families who have children and often experience febrile seizures under the supervision of a doctor, it is necessary the existence of socialization in physical form contains the importance of handling febrile seizures in children.