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The recent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key issues are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and postinfection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study results also suggest that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation. The high susceptibility of humans to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019 (COVID-19), reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and peripheral blood mononuclear cells (PBMCs) from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBC levels. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG, and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 were higher in convalescent subjects than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane. IMPORTANCE The recent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key issues are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and postinfection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study results also suggest that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.

Unnecessary antibiotic use is a major driver of antimicrobial resistance, an urgent public health threat. Acute respiratory infection (ARI) is a leading cause of inappropriate antibiotic use, creating an unmet need for improved diagnostics to identify bacterial etiology in ARI. In this work we show a 4-gene signature defining the absence of bacterial ARI which may be useful for managing antibiotics in ARI. Hospitalized adults with ARI underwent comprehensive microbiologic testing and those with definitive viral (n = 280), bacterial (n = 129), or mixed viral-bacterial infection (n = 95) had whole blood RNA sequencing. A hard-thresholded, mostly relaxed, LASSO-constrained logistic regression model is used to select a parsimonious gene set ( ITGB4, ITGA7, IFI27, FAM20A ) highly capable of discriminating any bacterial from nonbacterial infection (cross-validated AUC = 0.90). The 4-gene signature is validated in five independent adult RNAseq cohorts (AUC = 0.89−0.98), two adult microarray cohorts (AUC = 0.73–0.90), and one pediatric pneumonia RNAseq cohort (AUC 0.74). Thresholding the 4-gene risk score to yield 90% sensitivity to detect bacterial infection results in 71% specificity and 91% negative predictive value. Acute respiratory infections (ARI) account for substantial morbidity and mortality in adults, and can be a common cause for antibiotic overuse, due to unknown microbial etiology. In this work, authors present their 4-gene signature, capable of discriminating bacterial and non-bacterial illness in adults hospitalized with ARI.

Background COVID‐19‐associated hospitalization rates by age and comorbid conditions can more precisely assess risk for severe illness and target prevention and treatment strategies. Methods We performed a retrospective study to estimate population‐based COVID‐19‐associated hospitalization among patients by age and selected comorbid conditions in three hospital systems in Rochester and New York City (NYC), NY. Incidence rate ratios (IRR) comparing incidence rates for patients with and without these comorbidities were determined. Results From March 2020 to December 2021, 7779 patients were hospitalized with COVID‐19 of whom 43.8% had ≥3 comorbid conditions. Overall annual incidence ranged from 325.3 to 965.8 per 100,000 persons. Age group‐specific incidence was lowest in children 10–14 years (range 4.4–58.9) and highest in adults ≥85 years (range 2790.5–5889.6). Incidence rates for comorbid conditions generally increased with increasing age while IRR decreased with increasing age. Children in NYC 5–17 years with asthma or obesity had 3.4 and 53.3 times higher hospitalization rates, respectively, than children without these conditions. Adults in all age groups with obesity, diabetes, coronary artery disease, or congestive heart failure CHF had 1.6–4.7 times, 1.7–7.2 times, 2.0–10.1 times, or 1.7–20.2 times higher hospitalization rates, respectively, than those without these conditions. Adults ≥50 years with asthma had 1.5 to 1.8 times higher hospitalization rates than those without asthma. Conclusions The burden of hospitalization with COVID‐19 was high, particularly among adults ≥85 years and adults with obesity, diabetes, CAD, or CHF. However, the impact of comorbidities was less in older adults. Population‐based incidence rates by age and comorbidities provide more precise estimates of the benefits of vaccines and antiviral medications.

Respiratory syncytial virus is increasingly recognised as a global cause of lower respiratory tract disease in older adults, resulting in prolonged and often severe illnesses and significant morbidity from exacerbations of underlying cardiopulmonary conditions, and decline in function, cognition, and quality of life. 1 In 2019, respiratory syncytial virus was estimated to cause 5·2 million cases of acute respiratory infections, 470 000 hospitalisations, and 33 000 in-hospital deaths among adults aged at least 60 years in high-income countries. 2 In the USA, estimates in adults aged at least 65 years range from 600 000 to 1 million medically attended visits, 140 000–177 000 hospitalisations, and approximately 11 000–14 000 deaths annually. 3–5 Further highlighting the effect of respiratory syncytial virus-associated lower respiratory tract disease, older adults hospitalised with the virus are 2–3 times more likely to require supplemental oxygen and 1·5 times more likely to be admitted to an intensive care unit (ICU) than those hospitalised with either COVID-19 or influenza, with a 2 times higher odds of mechanical ventilation or death than those with influenza. 6 In June, 2023, the US Advisory Committee on Immunization Practices voted to recommend respiratory syncytial virus vaccination for adults aged at least 60 years using shared clinical decision making. What is remarkable is how closely vaccine effectiveness against hospitalisation or emergency department encounters matches the clinical trial efficacy estimates against lower respiratory tract disease. [...]these data also provide answers to several crucial questions including: effectiveness in the oldest adults with no difference in vaccine effectiveness for adults aged 60–74 years and those aged at least 75 years; effectiveness in immunocompromised individuals, excluded from the trials, but for whom the point estimates were only slightly lower at 73% (48–85); and within-season waning of vaccine-induced protection, which was refuted by similar point estimates at 14–59 days versus at least 60 days after vaccination, with overlapping confidence intervals.

Pneumococcus is a commensal of the upper respiratory tract and colonization is common in young children. Carriage studies have provided insights on vaccine effects in children and may also be useful for assessing vaccines in adults. However, culture based prevalence studies in older adults describe low colonization rates. Therefore, we assessed cumulative incidence of pneumococcal colonization in older adults using polymerase chain reaction (PCR) targeting the lytA gene and risk factors for carriage. 100 community-dwelling adults ≥65 years were enrolled the winter of 2015 and followed biweekly for 12 months. Medical, vaccination and illness history as well as nasopharyngeal (NP) and oropharyngeal (OP) samples were collected. Combined OP and NP were incubated in enrichment broth and screened using real-time lytA PCR. Samples from new colonization events (lytA PCR+) were cultured on gentamicin blood agar plates. Isolates identified by colony morphology as S. pneumoniae were serotyped using a multiplex combined immunoassay-PCR platform which classifies 96 serotypes. Cumulative incidence of pneumococcal carriage was calculated and risk factors for carriage assessed. The cumulative incidence of colonization was 41% by PCR and 14% by culture. Monthly prevalence ranged from 0 to 17% by PCR and 1 to 4% by culture with peaks in the spring and fall. Demographics were similar between colonized and never colonized subjects although colonized were younger (72.4 vs. 75.0 years, P = 0.06). Vaccination with any pneumococcal vaccine before or during study period was associated with decreased risk of becoming colonized (p < 0.001) as was vaccination with either the 13-valent conjugated pneumococcal vaccine (PCV13) or 23-valent polysaccharide vaccine (PPSV23) (p < 0.001). Pneumococcal colonization in older adults as detected by lytA PCR is frequent and pneumococcal vaccination appears to be associated with decreased risk of carriage. Further study is needed to understand the biological significance of molecular detection of pneumococcus in adults.

Lower respiratory tract illness (LRTI) frequently causes adult hospitalization and antibiotic overuse. Procalcitonin (PCT) treatment algorithms have been used successfully in Europe to safely reduce antibiotic use for LRTI but have not been adopted in the United States. We recently performed a feasibility study for a randomized clinical trial (RCT) of PCT and viral testing to guide therapy for non-pneumonic LRTI. The primary objective of the current study was to understand factors influencing PCT algorithm adherence during the RCT and evaluate factors influencing provider antibiotic prescribing practices for LRTI. From October 2013-April 2014, 300 patients hospitalized at a community teaching hospital with non-pneumonic LRTI were randomized to standard or PCT-guided care with viral PCR testing. Algorithm adherence data was collected and multivariate stepwise logistic regression of clinical variables used to model algorithm compliance. 134 providers were surveyed anonymously before and after the trial to assess knowledge of biomarkers and viral testing and antibiotic prescribing practices. Diagnosis of pneumonia on admission was the only variable significantly associated with non-adherence [7% (adherence) vs. 26% (nonadherence), p = 0.01]. Surveys confirmed possible infiltrate on chest radiograph as important for provider decisions, as were severity of illness, positive sputum culture, abnormal CBC and fever. However, age, patient expectations and medical-legal concerns were also at least somewhat important to prescribing practices. Physician agreement with the importance of viral and PCT testing increased from 42% to 64% (p = 0.007) and 49% to 74% (p = 0.001), respectively, after the study. Optimal algorithm adherence will be important for definitive PCT intervention trials in the US to determine if PCT guided algorithms result in better outcomes than reliance on traditional clinical variables. Factors influencing treatment decisions such as patient age, presence of fever, patient expectations and medical legal concerns may be amenable to education to improve PCT algorithm compliance for LRTI.

Human respiratory syncytial virus (RSV) is an enveloped, single-stranded, negative-sense RNA virus and member of the Paramyxoviridae family of the genus Pneumovirus that was first reported as a major pathogen in pediatric populations. However, since its discovery, RSV has not infrequently been detected in adults. Reinfection occurs throughout life, with more severe disease occurring in older adults, immunocompromised patients, and those with underlying cardiopulmonary disease. Initially described as the cause of nursing home outbreaks of respiratory disease, there is a now significant body of literature describing the clinical importance of RSV in older adults in a multitude of settings including long-term care, adult daycares, and in community-dwelling adults. Moreover, recent reports from China and other countries emphasize that RSV is a global pathogen that will become increasingly important in developed nations with aging populations. Annual attack rates in the USA range from 2 to 10 % in community-dwelling older adults and 5–10 % in older adults living in congregate settings. Population-based calculations of the proportion of acute respiratory illnesses attributable to RSV estimate that 11,000 elderly persons die annually in the USA of illnesses related to RSV infection. Clinical manifestations of RSV infections are similar to that of other viral respiratory pathogens and include cough, nasal congestion, rhinorrhea, sore throat, and dyspnea. Lower respiratory tract disease is common and may result in respiratory failure (8–13 %) or death (2–5 %). Recent advances in molecular diagnostics have made it possible to rapidly identify RSV infection using nucleic acid amplification tests, although clinicians will need to suspect the diagnosis when viral activity is high. At the present time, treatment is supportive. Effective antiviral agents for the treatment and vaccines for prevention of RSV remain a significant unmet medical need in the older adult population.

Background Respiratory syncytial virus (RSV) causes severe respiratory illnesses in infants and older adults. Older adults are frequently hospitalized with RSV illness and may experience loss of function. This study evaluated longitudinal changes in function associated with RSV hospitalization in older adults. Methods Adults ≥60 years hospitalized with laboratory‐confirmed RSV were enrolled (N = 302). Demographics and comorbidities were collected. Functional status was assessed 2 weeks pre‐hospitalization by recall, at enrollment, hospital discharge and 2, 4, and 6 months post‐discharge using the Lawton–Brody Instrumental Activities of Daily Living (IADL) (scale 0–8) and Barthel ADL Index (scale 0–100). Results RSV‐associated hospitalization resulted in acute functional loss. Median IADL (5 vs. 3, p < 0.0001) and ADL (90 vs. 70, p < 0.0001) scores decreased significantly from pre‐hospitalization to admission and remained decreased at discharge. There were no statistically significant differences between pre‐hospitalization and 2‐, 4‐, or 6‐month scores. However, 33% and 32% of subjects experienced decreased 6‐month IADL and ADL scores, respectively. Additionally, 14% required a higher level of care at discharge. When stratified by pre‐hospitalization living situation, 6‐month IADL scores declined significantly for those admitted from a skilled nursing facility (3 vs. 1, p = 0.001). In multivariate analysis, male sex and diabetes were associated with a 6‐month decline in ADL score of ≥10. Conclusions Older adults hospitalized with RSV demonstrate acute functional decline that may become prolonged. Pre‐hospitalization living situation may predict patient outcomes. Further study is needed with hospitalized age‐matched controls and refined measurement tools to better define the specific impact of RSV on function.

Background. Viral lower respiratory tract illness (LRTI) frequently causes adult hospitalization and is linked to antibiotic overuse. European studies suggest that the serum procalcitonin (PCT) level may be used to guide antibiotic therapy. We conducted a trial assessing the feasibility of using PCT algorithms with viral testing to guide antibiotic use in a US hospital. Methods. Three hundred patients hospitalized with nonpneumonic LRTI during October 2013-April 2014 were randomly assigned at a ratio of 1:1 to receive standard care or PCT-guided care and viral PCR testing. The primary outcome was antibiotic exposure, and safety was assessed at 1 and 3 months. Results. Among the 151 patients in the intervention group, viruses were identified in 42% (63), and 83% (126) had PCT values of <0.25 μg/mL. There were no significant differences in antibiotic use or adverse events between intervention patients and those in the nonintervention group. Subgroup analyses revealed fewer subjects with positive results of viral testing and low PCT values who were discharged receiving antibiotics (20% vs 45%; P = .002) and shorter antibiotic durations among algorithm-adherent intervention patients versus nonintervention patients (2.0 vs 4.0 days; P = .004). Compared with historical controls (from 2008-2011), antibiotic duration in nonintervention patients decreased by 2 days (6.0 vs 4.0 days; P< .001), suggesting a study effect. Conclusions. Although antibiotic use was similar in the 2 arms, subgroup analyses of intervention patients suggest that physicians responded to viral and biomarker data. These data can inform the design of future US studies. Clinical Trials Registration. NCT01907659