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Vaccine protection against COVID-19 wanes over time and has been impacted by the emergence of new variants with increasing escape of neutralization. The COVID-19 Variant Immunologic Landscape (COVAIL) randomized clinical trial (clinicaltrials.gov NCT 05289037) compares the breadth, magnitude and durability of antibody responses induced by a second COVID-19 vaccine boost with mRNA (Moderna mRNA-1273 and Pfizer-BioNTech BNT162b2), or adjuvanted recombinant protein (Sanofi CoV2 preS DTM-AS03) monovalent or bivalent vaccine candidates targeting ancestral and variant SARS-CoV-2 spike antigens (Beta, Delta and Omicron BA.1). We found that boosting with a variant strain is not associated with loss in neutralization against the ancestral strain. However, while variant vaccines compared to the prototype/wildtype vaccines demonstrated higher neutralizing activity against Omicron BA.1 and BA.4/5 subvariants for up to 3 months after vaccination, neutralizing activity was lower for more recent Omicron subvariants. Our study, incorporating both antigenic distances and serologic landscapes, can provide a framework for objectively guiding decisions for future vaccine updates.

Background Older patients have a less pronounced immune response to infection, which may also influence infection biomarkers. There is currently insufficient data regarding clinical effects of procalcitonin (PCT) to guide antibiotic treatment in older patients. Objective and design We performed an individual patient data meta-analysis to investigate the association of age on effects of PCT-guided antibiotic stewardship regarding antibiotic use and outcome. Subjects and methods We had access to 9,421 individual infection patients from 28 randomized controlled trials comparing PCT-guided antibiotic therapy (intervention group) or standard care. We stratified patients according to age in four groups (85 years [n = 505]). The primary endpoint was the duration of antibiotic treatment and the secondary endpoints were 30-day mortality and length of stay. Results Compared to control patients, mean duration of antibiotic therapy in PCT-guided patients was significantly reduced by 24, 22, 26 and 24% in the four age groups corresponding to adjusted differences in antibiotic days of −1.99 (95% confidence interval [CI] −2.36 to −1.62), −1.98 (95% CI −2.94 to −1.02), −2.20 (95% CI −3.15 to −1.25) and − 2.10 (95% CI −3.29 to −0.91) with no differences among age groups. There was no increase in the risk for mortality in any of the age groups. Effects were similar in subgroups by infection type, blood culture result and clinical setting (P interaction >0.05). Conclusions This large individual patient data meta-analysis confirms that, similar to younger patients, PCT-guided antibiotic treatment in older patients is associated with significantly reduced antibiotic exposures and no increase in mortality.

BACKGROUND: Respiratory syncytial virus (RSV)-associated acute respiratory infection (ARI) is an underrecognized cause of illness in older adults. We conducted a systematic literature review and meta-analysis to estimate the RSV disease burden in adults ≥60 years in high-income countries.METHODS: Data on RSV-ARI and hospitalization attack rates and in-hospital case fatality rates (hCFR) in adults ≥60 years from the United States, Canada, European countries, Japan, and South Korea were collected based on a systematic literature search (January 1, 2000-November 3, 2021) or via other methods (citation search, unpublished studies cited by a previous meta-analysis, gray literature, and an RSV-specific abstract booklet). A random effects meta-analysis was performed on estimates from the included studies.RESULTS: Twenty-one studies were included in the meta-analysis. The pooled estimates were 1.62% (95% confidence interval [CI]: 0.84-3.08) for RSV-ARI attack rate, 0.15% (95% CI: 0.09-0.22) for hospitalization attack rate, and 7.13% (95% CI: 5.40-9.36) for hCFR. In 2019, this would translate into approximately 5.2 million cases, 470,000 hospitalizations, and 33,000 in-hospital deaths in ≥60-year-old adults in high-income countries.CONCLUSIONS: RSV disease burden in adults aged ≥60 years in high-income countries is higher than previously estimated, highlighting the need for RSV prophylaxis in this age group.

Although traditional egg-based inactivated influenza vaccines can protect against infection, there have been significant efforts to develop improved formats to overcome disadvantages of this platform. Here, we have assessed human CD4 T cell responses to a traditional egg-based influenza vaccine with recently available cell-derived vaccines and recombinant baculovirus-derived vaccines. Adults were administered either egg-derived Fluzone®, mammalian cell-derived Flucelvax® or recombinant HA (Flublok®). CD4 T cell responses to each HA protein were assessed by cytokine EliSpot and intracellular staining assays. The specificity and magnitude of antibody responses were quantified by ELISA and HAI assays. By all criteria, Flublok vaccine exhibited superior performance in eliciting both CD4 T cell responses and HA-specific antibody responses, whether measured by mean response magnitude or percent of responders. Although the mechanism(s) underlying this advantage is not yet clear, it is likely that both qualitative and quantitative features of the vaccines impact the response.

The most effective measure to induce protection from influenza is vaccination. Thus, yearly vaccination is recommended, which, together with infections, establishes diverse repertoires of B cells, antibodies, and T cells. We examined the impact of this accumulated immunity on human responses in adults to split, subunit, and recombinant protein-based influenza vaccines. Enzyme-linked immunosorbent assay (ELISA) assays, to quantify serum antibodies, and peptide-stimulated CD4 T-cell cytokine ELISpots revealed that preexisting levels of hemagglutinin (HA)-specific antibodies were negatively associated with gains in antibody postvaccination, while preexisting levels of CD4 T cells were negatively correlated with vaccine-induced expansion of CD4 T cells. These patterns were seen independently of the vaccine formulation administered and the subjects’ influenza vaccine history. Thus, although memory CD4 T cells and serum antibodies consist of components that can enhance vaccine responses, on balance, the accumulated immunity specific for influenza A H1 and H3 proteins is associated with diminished future responses.

Background Respiratory syncytial virus (RSV) infections are common in adults, but data describing the cost of RSV‐associated hospitalization are lacking due to inconsistency in diagnostic coding and incomplete case ascertainment. We evaluated costs of RSV‐associated hospitalization in adult patients with laboratory‐confirmed, community‐onset RSV. Methods We included adults ≥ 18 years of age admitted to three hospital systems in New York during two RSV seasons who were RSV‐positive by polymerase chain reaction (PCR) and had more than or equal to two acute respiratory infection symptoms or exacerbation of underlying cardiopulmonary disease. We abstracted costs from hospital finance systems or converted hospital charges to cost using cost‐charge ratios. We converted cost into 2020 US dollars and extrapolated to the United States. We used a generalized linear model to determine predictors of hospitalization cost, stratified by admission to intensive care units (ICU). Results Cost data were available for 79% (601/756) of eligible patients. The mean total cost of hospitalization was $8403 (CI95 $7240–$9741). The highest costs were those attributed to ICU services $7885 (CI95 $5877–$10,240), whereas the lowest were radiology $324 (CI95 $275–$376). Other than longer length of stay, predictors of higher cost included having chronic liver disease (odds ratio [OR] 1.38 [CI95 1.05–1.80]) for patients without ICU admission and antibiotic use (OR 1.49 [CI95 1.10–2.03]) for patients with ICU admission. The annual US cost was estimated to be $1.2 (CI95 0.9–1.4) billion. Conclusion The economic burden of RSV hospitalization of adults ≥ 18 years of age in the United States is substantial. RSV vaccine programs may be useful in reducing this economic burden.

Background Adding procalcitonin (PCT) to antibiotic stewardship algorithms may improve antibiotic use. However, PCT protocols need to be adapted to clinical settings and patient populations. Objectives To review PCT use in different medical settings and patient populations. Sources Most recent trials and meta-analyses investigating PCT for antibiotic stewardship were reviewed. Content Several trials found PCT-guided antibiotic stewardship to reduce antibiotic exposure and associated side-effects among patients with respiratory infection and sepsis. Decisions regarding antibiotic use in an individual patient are complex and should be based on the pre-test probability for bacterial infection, the severity of presentation and the results of PCT. In the context of a low pre-test probability for bacterial infections and a low-risk patient, a low PCT level helps to rule out bacterial infection and empiric antibiotic therapy can be avoided. In the context of a high pre-test probability for bacterial infections and/or a high-risk patient with sepsis, monitoring of PCT over time helps to track the resolution of infection and decisions regarding early stop of antibiotic treatment. Although these concepts have been successful in several respiratory infection and sepsis trials, some studies failed to show an added benefit of PCT due to factors such as low protocol adherence and relying on single rather than repeat PCT measurements. Implication As an adjunct to other clinical and laboratory parameters, PCT provides information about risk for bacterial infection and resolution of infection, and improves antibiotic stewardship decisions, thereby offering more individualized treatment courses with overall reduced antibiotic exposure.

Lower respiratory tract infections are a leading cause of hospitalization and viruses are important causal pathogens, especially in the elderly, immunocompromised patients and those with respiratory or cardiovascular comorbidities. Respiratory syncytial virus (RSV) is recognized as comprising a substantial burden of morbidity and mortality in older and at-risk adults, and the emergence of rapid point-of-care molecular testing has made it possible to confirm an RSV diagnosis accurately, in a clinically actionable timeframe. RSV patients have significantly higher healthcare resource use (including hospital stays and emergency room/urgent care visits) than non-RSV matched controls, especially if aged ≥65 years, a longer length of hospitalization than those with influenza, and associated costs nearly three times higher. We found no direct clinical outcome data specific to rapid molecular testing for RSV in adults and very little in children. There is very limited evidence that prompt diagnosis may reduce hospital length of stay but this and other outcome parameters need confirmation in larger, prospective clinical trials. Regarding reducing inappropriate antibiotic prescribing, the picture is mixed and testing alone is unlikely to change entrenched habits. There is little incentive for clinicians to order routine RSV tests in adults given the absence of a specific antiviral therapy. However, with numerous vaccine and antiviral candidates in clinical development, we believe it is good practice to plan and start establishing standardized testing protocols – perhaps as part of outcome studies. For especially vulnerable patients, e.g., immunocompromised and transplant patients, prompt accurate RSV diagnosis may prevent disease spread and save lives.

There is convincing evidence linking antibiotic-stewardship efforts which include the infection marker procalcitonin (PCT) to more rational use of antibiotics with improvements in side-effects and clinical outcomes. This is particularly true in the setting of respiratory infection and sepsis. Yet, some recent trials have shown no benefit of PCT-guided care. Our aim was to discuss the benefits and limitations of using PCT for early infection recognition, severity assessment and therapeutic decisions in individual patients based on most the recent study data.Current evidence from randomized trials, and meta-analyses of these trials, indicates that PCT-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side-effects, which translates into improved survival of patients with respiratory infections and sepsis. Notably, initial PCT levels have been found to be helpful in defining the risk for bacterial infection in the context of a low pretest probability for bacterial infections (i.e., patients with bronchitis or chronic bastructive pulmonary disease exacerbation). Monitoring of repeated PCT measurements over time has also been found helpful for estimating recovery from bacterial infection and prognosis in higher risk situations (i.e., pneumonia or sepsis) and results in early and safe discontinuation of antibiotic therapy. Some trials, however, did not find a strong effect of PCT guidance which may be explained by low protocol adherence, assessment using only a single rather than repeat PCT levels and lower antibiotic exposure in control group patients. Using PCT in the right patient population, with high-sensitivity assays and with adequate training of physicians is important to increase protocol adherence and reduce antibiotic exposure.Inclusion of PCT into antibiotic stewardship algorithms has the potential to improve the diagnostic and therapeutic management of patients presenting with respiratory illnesses and sepsis, and holds great promise to mitigate the global bacterial resistance crisis and move from a default position of standardized care to more personalized treatment decisions.

Background Respiratory syncytial virus (RSV) causes acute respiratory illness (ARI) and triggers exacerbations of cardiopulmonary disease. Estimates of incidence in hospitalized adults range widely, with few data on incidence in adults with comorbidities that increase the risk of severity. We conducted a prospective, population-based, surveillance study to estimate incidence of RSV hospitalization among adults overall and those with specific comorbidities. Methods Hospitalized adults aged ≥18 years residing in the surveillance area with ≥2 ARI symptoms or exacerbation of underlying cardiopulmonary disease were screened during the 2017–2018, 2018–2019, and 2019–2020 RSV seasons in 3 hospitals in Rochester, New York and New York City. Respiratory specimens were tested for RSV using polymerase chain reaction assays. RSV incidence per 100 000 was adjusted by market share. Results Active and passive surveillance identified 1099 adults hospitalized with RSV. Annual incidence during 3 seasons ranged from 44.2 to 58.9/100 000. Age-group–specific incidence ranged from 7.7 to 11.9/100 000, 33.5 to 57.5/100 000, and 136.9 to 255.6/100 000 in patients ages 18–49, 50–64, and ≥65 years, respectively. Incidence rates in patients with chronic obstructive pulmonary disease, coronary artery disease, and congestive heart failure were 3–13, 4–7, and 4–33 times, respectively, the incidence in patients without these conditions. Conclusions We found a high burden of RSV hospitalization in this large prospective study. Notable was the high incidence among older patients and those with cardiac conditions. These data confirm the need for effective vaccines to prevent RSV infection in older and vulnerable adults.

Influenza virus exposures in childhood can establish long-lived memory B cell responses that can be recalled later in life. Here, we complete a large serological survey to elucidate the specificity of antibodies against contemporary H3N2 viruses in differently aged individuals who were likely primed with different H3N2 strains in childhood. We find that most humans who were first infected in childhood with H3N2 viral strains from the 1960s and 1970s possess non-neutralizing antibodies against contemporary 3c2.A H3N2 viruses. We find that 3c2.A H3N2 virus infections boost non-neutralizing H3N2 antibodies in middle-aged individuals, potentially leaving many of them in a perpetual state of 3c2.A H3N2 viral susceptibility., Influenza exposure in early childhood can affect the immune response to distinct viral strains later in life. Here, Gouma et al. show that contemporary 3c2.A H3N2 virus infections boost non-neutralizing H3N2 antibodies in middle-aged individuals, potentially leaving them vulnerable to recurrent infections.

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.

Background Whether procalcitonin (PCT)–guided antibiotic management in patients with positive blood cultures is safe remains understudied. We performed a patient-level meta-analysis to investigate effects of PCT-guided antibiotic management in patients with bacteremia. Methods We extracted and analyzed individual data of 523 patients with positive blood cultures included in 13 trials, in which patients were randomly assigned to receive antibiotics based on PCT levels (PCT group) or a control group. The main efficacy endpoint was duration of antibiotic treatment. The main safety endpoint was mortality within 30 days. Results Mean duration of antibiotic therapy was significantly shorter for 253 patients who received PCT-guided treatment than for 270 control patients (–2.86 days [95% confidence interval [CI], –4.88 to –.84]; P = .006). Mortality was similar in both arms (16.6% vs 20.0%; P = .263). In subgroup analyses by type of pathogen, we noted a trend of shorter mean antibiotic durations in the PCT arm for patients infected with gram-positive organisms or Escherichia coli and significantly shorter treatment for subjects with pneumococcal bacteremia. In analysis by site of infection, antibiotic exposure was shortened in PCT subjects with Streptococcus pneumoniae respiratory infection and those with E. coli urogenital infections. Conclusions This meta-analysis of patients with bacteremia receiving PCT-guided antibiotic management demonstrates lower antibiotic exposure without an apparent increase in mortality. Few differences were demonstrated in subgroup analysis stratified by type or site of infection but notable for decreased exposure in patients with pneumococcal pneumonia and E. coli urogenital infections. Fundo Se o manejo antibiótico guiado por procalcitonina (PCT) em pacientes com hemoculturas positivas é seguro permanece pouco estudado. Realizamos uma meta-análise em nível de paciente para investigar os efeitos do manejo antibiótico guiado por PCT em pacientes com bacteremia. Métodos Extraímos e analisamos dados individuais de 523 pacientes com hemoculturas positivas incluídos em 13 ensaios, nos quais os pacientes foram aleatoriamente designados para receber antibióticos com base nos níveis de PCT (grupo PCT) ou um grupo controle. O principal parâmetro de eficácia foi a duração do tratamento com antibióticos. O principal parâmetro de segurança foi a mortalidade em 30 dias. Resultados A duração média da antibioticoterapia foi significativamente menor para 253 pacientes que receberam tratamento guiado por PCT do que para 270 pacientes controle (–2,86 dias [intervalo de confiança de 95% [IC], –4,88 a –,84]; P = 0,006). A mortalidade foi semelhante em ambos os braços (16,6% vs 20,0%; P = 0,263). Em análises de subgrupo por tipo de patógeno, observamos uma tendência de duração média de antibióticos mais curta no braço de PCT para pacientes infectados com organismos gram-positivos ou Escherichia coli e tratamento significativamente mais curto para indivíduos com bacteremia pneumocócica. Na análise por local de infecção, a exposição a antibióticos foi reduzida em indivíduos PCT com infecção respiratória por Streptococcus pneumoniae e naqueles com infecções urogenitais por E. coli. Conclusões Esta meta-análise de pacientes com bacteremia recebendo tratamento antibiótico guiado por PCT demonstra menor exposição a antibióticos sem um aumento aparente na mortalidade. Poucas diferenças foram demonstradas na análise de subgrupos estratificados por tipo ou local de infecção, mas notáveis ​​pela diminuição da exposição em pacientes com pneumonia pneumocócica e infecções urogenitais por E. coli.

Due to overlap of clinical findings and low sensitivity of bacterial diagnostic tests, differentiation between bacterial and viral respiratory tract infections remains challenging, ultimately leading to antibiotic overuse in this population of patients. Addition of procalcitonin, a blood biomarker expressed by epithelial cells in response to bacterial infections, to the clinical assessment leads to a reduction in inappropriate antibiotic initiation. Procalcitonin also provides prognostic information about the resolution of illness, and significant decreases over time are a strong signal for the discontinuation of antibiotics. Current evidence from randomized trials indicates that procalcitonin-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side effects, which importantly translates into improved survival of patients with respiratory infections. Inclusion of procalcitonin into antibiotic stewardship algorithms thus improves the diagnostic and therapeutic management of patients presenting with respiratory illnesses and holds great promise to mitigate the global bacterial resistance crisis.

Background The H3N2 component of egg-based 2017–2018 influenza vaccines possessed an adaptive substitution that alters antigenicity. Several influenza vaccines include antigens that are produced through alternative systems, but a systematic comparison of different vaccines used during the 2017–2018 season has not been completed. Methods We compared antibody responses in humans vaccinated with Fluzone (egg-based, n = 23), Fluzone High-Dose (egg-based, n = 16), Flublok (recombinant protein–based, n = 23), or Flucelvax (cell-based, n = 23) during the 2017–2018 season. We completed neutralization assays using an egg-adapted H3N2 virus, a cell-based H3N2 virus, wild-type 3c2.A and 3c2.A2 H3N2 viruses, and the H1N1 vaccine strain. We also performed enzyme-linked immunosorbent assays using a recombinant wild-type 3c2.A hemagglutinin. Antibody responses were compared in adjusted analysis. Results Postvaccination neutralizing antibody titers to 3c2.A and 3c2.A2 were higher in Flublok recipients compared with Flucelvax or Fluzone recipients (P < .01). Postvaccination titers to 3c2.A and 3c2.A2 were similar in Flublok and Fluzone High-Dose recipients, though seroconversion rates trended higher in Flublok recipients. Postvaccination titers in Flucelvax recipients were low to all H3N2 viruses tested, including the cell-based H3N2 strain. Postvaccination neutralizing antibody titers to H1N1 were similar among the different vaccine groups. Conclusions These data suggest that influenza vaccine antigen match and dose are both important for eliciting optimal H3N2 antibody responses in humans. Future studies should be designed to determine if our findings directly impact vaccine effectiveness. Clinical Trials Registration NCT03068949.

Human parainfluenza viruses (HPIVs) are single-stranded, enveloped RNA viruses of the Paramyoviridaie family. There are four serotypes which cause respiratory illnesses in children and adults. HPIVs bind and replicate in the ciliated epithelial cells of the upper and lower respiratory tract and the extent of the infection correlates with the location involved. Seasonal HPIV epidemics result in a significant burden of disease in children and account for 40% of pediatric hospitalizations for lower respiratory tract illnesses (LRTIs) and 75% of croup cases. Parainfluenza viruses are associated with a wide spectrum of illnesses which include otitis media, pharyngitis, conjunctivitis, croup, tracheobronchitis, and pneumonia. Uncommon respiratory manifestations include apnea, bradycardia, parotitis, and respiratory distress syndrome and rarely disseminated infection. Immunity resulting from disease in childhood is incomplete and reinfection with HPIV accounts for 15% of respiratory illnesses in adults. Severe disease and fatal pneumonia may occur in elderly and immunocompromised adults. HPIV pneumonia in recipients of hematopoietic stem cell transplant (HSCT) is associated with 50% acute mortality and 75% mortality at 6 months. Though sensitive molecular diagnostics are available to rapidly diagnose HPIV infection, effective antiviral therapies are not available. Currently, treatment for HPIV infection is supportive with the exception of croup where the use of corticosteroids has been found to be beneficial. Several novel drugs including DAS181 appear promising in efforts to treat severe disease in immunocompromised patients, and vaccines to decrease the burden of disease in young children are in development.

Introduction: Although evidence indicates that use of procalcitonin to guide antibiotic decisions for the treatment of acute respiratory infections (ARI) decreases antibiotic consumption and improves clinical outcomes, algorithms used within studies had differences in PCT cut-off points and frequency of testing. We therefore analyzed studies evaluating procalcitonin-guided antibiotic therapy and propose consensus algorithms for different respiratory infection types. Areas covered: We systematically searched randomized-controlled trials (search strategy updated on February 2018) on procalcitonin-guided antibiotic therapy of ARI in adults using a pre-specified Cochrane protocol and analyzed algorithms from 32 trials that included 10,285 patients treated in primary care settings, emergency departments (ED), and intensive care units (ICU). We derived consensus algorithms for use of procalcitonin by the type of ARI including community-acquired pneumonia, bronchitis, chronic obstructive pulmonary disease or asthma exacerbation, sepsis, and post-operative sepsis due to respiratory infection. Consensus algorithm recommendations differ with regard to timing of treatment (i.e. timing of initiation in low-risk patients or discontinuation in high-risk patients) and procalcitonin cut-off points for the recommendation/strong recommendation to discontinue antibiotics (≤ 0.25/≤ 0.1 µg/L in ED and inpatients, ≤ 0.5/≤ 0.25 µg/L in ICU patients, and reduction by ≥ 80% from peak levels in sepsis patients). Expert commentary: Our proposed algorithms may facilitate safe and efficient implementation of procalcitonin-guided antibiotic protocols in diverse healthcare settings. Still, the decision about initiation and cessation of antibiotic treatment remains a clinical decision based on the patient assessment and the severity of illness and use of procalcitonin should not delay empirical treatment in high risk situations.

Background Respiratory syncytial virus (RSV) infection has been increasingly recognized as an important cause of acute respiratory illness (ARI) and a trigger for exacerbation of underlying cardiopulmonary disease in adults. Incidence of hospitalized RSV infection remains uncertain as adults have not been systematically screened. Previous incidence estimates, derived primarily from modeling studies, have ranged from 84 to 190/100K population in adults >65 years of age. Accurate burden data are critical to inform RSV vaccine development for adults. We used active surveillance among hospitalized adults to determine population-based incidence rates of RSV infection. Methods Hospitalized adults ≥ 18 years old residing in the surveillance area with >2 ARI symptoms or exacerbation of underlying cardiopulmonary disease were screened for eligibility during October 2017–April 2018 and October 2018 to April 2019 in 3 hospitals in Rochester, NY and New York City. Respiratory specimens were tested for RSV using PCR assays. RSV incidence per 100,000 persons (per 2010 US Census data) was adjusted by percent market share for study hospitals in their catchment area. Results In total, 8,217 hospitalized adults residing in the surveillance area that met the surveillance case definition were tested for RSV; 768 (9.4%) were positive. Adults were aged 18–49 (12%), 50–64 (30%), and ≥65 years old (58%); 55% were female. RSV infection incidence varied from year 1 to year 2 and was highest in patients aged ≥65 years old (table). Conclusion This is the largest prospective RSV incidence study to date. Preliminary results indicate that the incidence of RSV infection may be higher than previously reported, especially in urban-dwelling adults >65 years of age. Results confirm the need for vaccines to prevent RSV infections in older adults. Disclosures All Authors: No reported Disclosures.

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

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.

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.

Respiratory tract infections are frequent causes of hospitalization and initiation of empirical antimicrobial therapy. Testing for a broad panel of respiratory viruses has been advocated as a useful tool for antibiotic stewardship. We conducted a prospective observational study to assess the impact of rapid viral test results on antimicrobial prescriptions and clinical outcomes among hospitalized adults.Eight hundred patients admitted with respiratory symptoms were tested by a 12-virus respiratory panel (RVP) during 3 consecutive winters in Montreal, Canada. The primary outcome measure was change in antimicrobial prescriptions (ie, de-escalation of empirical antimicrobial therapy or commencement of new antimicrobial therapy) after RVP results were available. Clinical outcomes were also assessed.Influenza virus was identified in 53% of individuals in the study population, and other viruses were identified in 10%. Influenza virus positivity was associated with shorter duration of hospitalization and appropriate antiviral management. Antibiotic management was most significantly correlated with radiographic suspicion of pneumonia and less so with results of the RVP. Positivity for viruses other than influenza virus was not correlated with significantly different outcomes.Physicians respond to results of testing for influenza virus when managing hospitalized adult patients but respond less to test results for other viruses. These data can inform the design of stewardship interventions and the selection of viral testing panels for hospitalized patients.

Background Respiratory syncytial virus (RSV) infection is a common cause of acute respiratory infection (ARI) in adults. Prospective surveillance enables collection of representative data on demographic and clinical characteristics. Few data of this kind are available for adults hospitalized with RSV infection. We used active population-based surveillance to identify patients with laboratory-confirmed RSV infection and evaluated demographic characteristics and clinical outcomes. Methods Hospitalized adults ≥ 18 years old residing in a predefined catchment area with ≥ 2 ARI symptoms or exacerbation of underlying cardiopulmonary disease were screened for eligibility during October 2017–April 2018 and October 2018–April 2019 in 3 hospitals in Rochester, NY and New York City. Respiratory specimens were tested for RSV using PCR assays. Clinical and demographic data were abstracted from the medical record. Multivariate analysis was used to evaluate the relationship of patient characteristics with clinical outcomes. Results 8,217 hospitalized adults were screened and 9.4% positive for RSV infection. Preliminary clinical and demographic data were available for 348 patients including 14% 18–49 years, 28% 50–64 years and 58% > 65 years. Mean age was 68 years and 60% were female (Figure 1). Patients had a mean of 3 co-morbidities, with diabetes (40%), chronic obstructive pulmonary disease (30%), chronic kidney disease (28%), congestive heart failure (28%), coronary artery disease (25%) and asthma (24%) the most common co-morbidities (Figure 2). Median hospital length of stay was 6 days (IQR 4–10), 13% of patients were admitted to the ICU, 5% were mechanically ventilated and 5% died during admission and 12% within 6 months. In multivariate analysis having > 3 comorbidities, cardiac disease or a lower baseline functional status measured by activities of daily living scores was significantly associated with 6-month mortality. Conclusion The majority of hospitalized patients with RSV infection were older adults with ≥ 3 chronic comorbid conditions. Baseline functional status may be predictive of worse clinical outcomes in patients with RSV infection. These insights into patient characteristics and clinical outcomes will provide information for prevention programs. Disclosures All authors: No reported disclosures.

Background Influenza is associated with increased mortality and morbidity for older adults. High-dose egg grown trivalent inactivated influenza vaccine (Fluzone HD) is safe and provides superior immune responses in older adults compared with standard dose (SD). Recently, two new vaccines have been licensed in the United States: cell cultured inactivated vaccine FluCelVax and baculovirus-expressed pure hemagglutinin (HA) vaccine FluBlok. Data from one study demonstrated higher efficacy with FluBlok than SD Fluzone in older adults. There is no data however comparing HD Fluzone to FluBlok and FluCelVax has not been studied at all. The purpose of this study was to assess hemagglutinin inhibition (HAI) antibody responses to vaccination with three vaccines in adults ≥ 60 years. Methods Adults ≥ 60 years were randomly assigned to receive one of the three vaccines: Fluzone HD, FluBlok and FluCelVax (Figure 1). Active influenza-like illness (ILI) surveillance was conducted with bi-weekly telephone calls. Serum samples were collected prior to vaccination and at day 7, 14, 28 and 180 and antibody responses assessed by HAI titer to A/Singapore/INFIMH-16–0019(H3N2), A/Michigan/45/2015(H1N1) and B/Colorado/6/2017 (Victoria) viruses as well as a circulating H3N2 strain. The primary endpoint was a 4-fold rise in antibody titer at day 28. Results 48 subjects were vaccinated in October 2018. Mean age was 69 and 65% were female. Two subjects reported ILI symptoms and one was positive for infection (H1N1). A majority of subjects demonstrated pre-existing antibody to all three viruses (Figure 2, Blue). Geometric mean titers (GMT) for antibody responses to the influenza A viruses were similar for FluBlok (FB) and HD Fluzone (FZ) but lower for FluCelVax(FCB) subjects (Figure 2, Orange). A higher percent of FlubBlok subjects demonstrated 4-fold rise in antibody responses to the Victoria influenza B virus (FB GMT 140 vs. FZ GMT 116, P = 0.26). Conclusion In this small study, antibody responses were similar or higher in older adults after vaccination with FluBlok compared with Fluzone HD with lower responses demonstrated with FluCelvax. Emerging concerns about HA egg adaptation during vaccine development compels further study to determine the appropriate vaccination strategy for this vulnerable population. Disclosures All authors: No reported disclosures.

Background: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. Objectives: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. Selection criteria: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. Data collection and analysis: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. Main results: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects. Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. Authors' conclusions: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

Rationale 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. Objective 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. Study Design 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. Results 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. Conclusions 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.

Background Respiratory Syncytial Virus (RSV) causes severe respiratory illnesses in infants and older adults. Mortality disproportionately affects the elderly, can exacerbate chronic cardiopulmonary conditions and may result in loss of function. The purpose of this study was to determine the incidence of RSV infection in hospitalized adults and evaluate functional changes associated with RSV hospitalization in older adults ≥60 years. Methods Adults ≥18 years of age admitted with an acute respiratory infection (ARI) or exacerbation of chronic cardiopulmonary disease (e.g. CHF, COPD, asthma) preceded by an ARI within 14 days were screened. Subjects were included if hospitalized for ≥24 hours with laboratory confirmed RSV and residing in two catchment areas (Rochester, NY and New York, NY). Illness history, comorbidities and demographic characteristics were collected at enrollment. Enrolled subjects ≥60 years underwent functional status evaluation retrospectively 2 weeks prior to hospitalization, at enrollment, discharge and 2 months using the Lawton–Brody Instrumental Activity of Daily Living (IADL) Scale (0–8), Barthel (ADL) Index (0–100), MRC Breathlessness score (1–5) and Mini-Cog instrument. Results From October 2017 to March 2018, 2,883 adults hospitalized with ARI were tested and 322 (11%) positive for RSV. Seventy-two adults ≥60 years underwent functional assessment. Mean age was 75 years, 53% were female and 58% demonstrated impaired cognition on admission. Five subjects died during hospitalization and one prior to 2-month follow-up. Interim analysis of 2-month functional assessment was available for 39 subjects. RSV illness resulted in acute functional loss in almost all patients. Although there were no statistically significant differences between mean pre-hospitalization and 2-month functional scores, IADL (6.7 vs. 6.0, P = 0.27), ADL (90.4 vs. 88.5, P = 0.67) and MRC (2.96 vs. 2.7, P = 0.57), 23% of subjects required a higher level of care at discharge. Additionally, RSV hospitalization resulted in decreased ADL scores in 36% of subjects and worsening respiratory function in 18% assessed at 2 months (figure). Conclusion Older adults hospitalized with RSV infection demonstrate acute functional decline which may result in prolonged loss of function in some patients. Disclosures A. Branche, Merck: Investigator, Grant recipient and Research grant. E. Granieri, Merck: Investigator, Research grant. E. Walsh, Merck: Investigator, Research grant. L. Finelli, Merck: Employee, Salary. A. R. Falsey, sanofi pasteur: Consultant and Grant Investigator, Consulting fee and Research grant. Gilead: Consultant, Consulting fee. Merck Sharpe and Dome: Investigator, Grant recipient. Janssen Pharmacueticals: Investigator, Grant recipient. Pfizer: Consultant, Research grant. Novavax: Consultant, none. A. Barrett, Merck: Investigator, Research support. L. Saiman, Merck: Investigator, Research grant.

Respiratory tract infections (RTI) frequently cause hospital admissions among adults. Diagnostic viral reverse transcriptase PCR (RT-PCR) of nose and throat swabs (NTS) is useful for patient care by informing antiviral use and appropriate isolation. However, automated RT-PCR systems are not amenable to utilizing sputum due to its viscosity. We evaluated a simple method of processing sputum samples in a fully automated respiratory viral panel RT-PCR assay (FilmArray). Archived sputum and NTS samples collected in 2008-2012 from hospitalized adults with RTI were evaluated. A subset of sputum samples positive for 10 common viruses by a uniplex RT-PCR was selected. A sterile cotton-tip swab was dunked in sputum, swirled in 700 μL of sterile water (dunk and swirl method) and tested by the FilmArray assay. Quantitative RT-PCR was performed on “dunked” sputum and NTS samples for influenza A (Flu A), respiratory syncytial virus (RSV), coronavirus OC43 (OC43), and human metapneumovirus (HMPV). Viruses were identified in 31% of 965 illnesses using a uniplex RT-PCR. The sputum sample was the only sample positive for 105 subjects, including 35% (22/64) of influenza cases and significantly increased the diagnostic yield of NTS alone (302/965 [31%] versus 197/965 [20%]; P = 0.0001). Of 108 sputum samples evaluated by the FilmArray assay using the dunk and swirl method, 99 (92%) were positive. Quantitative RT-PCR revealed higher mean viral loads in dunked sputum samples compared to NTS samples for Flu A, RSV, and HMPV ( P = 0.0001, P = 0.006, and P = 0.011, respectively). The dunk and swirl method is a simple and practical method for reliably processing sputum samples in a fully automated PCR system. The higher viral loads in sputa may increase detection over NTS testing alone.

The goal of this study was to assess the overtreatment of asymptomatic bacteriuria (ASB) in hospitalized patients, calculate the total costs of inappropriate treatment, and determine if a multi-faceted educational intervention was effective in reducing the overtreatment of ASB in a resource-limited community hospital. The study encompassed three phases: a retrospective pre-intervention assessment of the baseline cost and treatment of ASB, the implementation of a multi-faceted educational intervention, and a prospective post-intervention assessment of the efficacy of the intervention. A positive urine culture was defined by bacterial counts ≤ 10 5 cfu/mL. In the pre-intervention group, 64 (83%) of 109 patients were asymptomatic: 30 (47%) were treated. In the post-intervention group, 13 (17%) of 55 patients were asymptomatic: 2 (15%) were treated, (p = 0.04). Fewer urine cultures were collected during the post-intervention period than the pre-intervention period (3,127 and 3,419, respectively) (p < 0.001). The total cost of inappropriately treating ASB in the pre-intervention group was $1200 compared to $600 in the post-intervention group. The results demonstrated a significant decrease in the inappropriate treatment of ASB and the associated costs. Keywords: practice guidelines as topic; guideline adherence; trends; urinary tract infections; economics; prevention and control; disease management (Published: 16 July 2012) Citation: Journal of Community Hospital Internal Medicine Perspectives 2012, 2 : 17814 - http://dx.doi.org/10.3402/jchimp.v2i2.17814