Influenza During the 2010-2020 Decade in the United States: Seasonal Outbreaks and Vaccine Interventions.

The 10 years between the last influenza pandemic and start of the severe acute respiratory syndrome coronavirus 2 pandemic have been marked by great advances in our ability to follow influenza occurrence and determine vaccine effectiveness (VE), largely based on widespread use of the polymerase chain reaction assay. We examine the results, focusing mainly on data from the United States and inactivated vaccines. Surveillance has expanded, resulting in increased ability to characterize circulating viruses and their impact. The surveillance has often confirmed previous observations on timing of outbreaks and age groups affected, which can now be examined in greater detail. Selection of strains for vaccines is now based on enhanced viral characterization using immunologic, virologic, and computational techniques not previously available. Vaccine coverage has been largely stable, but VE has remained modest and, in some years, very low. We discuss ways to improve VE based on existing technology while we work toward supraseasonal vaccines.

There are no equal opportunity infectors: Epidemiological modelers must rethink our approach to inequality in infection risk.

Mathematical models have come to play a key role in global pandemic preparedness and outbreak response: helping to plan for disease burden, hospital capacity, and inform nonpharmaceutical interventions. Such models have played a pivotal role in the COVID-19 pandemic, with transmission models-and, by consequence, modelers-guiding global, national, and local responses to SARS-CoV-2. However, these models have largely not accounted for the social and structural factors, which lead to socioeconomic, racial, and geographic health disparities. In this piece, we raise and attempt to clarify several questions relating to this important gap in the research and practice of infectious disease modeling: Why do epidemiologic models of emerging infections typically ignore known structural drivers of disparate health outcomes? What have been the consequences of a framework focused primarily on aggregate outcomes on infection equity? What should be done to develop a more holistic approach to modeling-based decision-making during pandemics? In this review, we evaluate potential historical and political explanations for the exclusion of drivers of disparity in infectious disease models for emerging infections, which have often been characterized as "equal opportunity infectors" despite ample evidence to the contrary. We look to examples from other disease systems (HIV, STIs) and successes in including social inequity in models of acute infection transmission as a blueprint for how social connections, environmental, and structural factors can be integrated into a coherent, rigorous, and interpretable modeling framework. We conclude by outlining principles to guide modeling of emerging infections in ways that represent the causes of inequity in infection as central rather than peripheral mechanisms.

Racial Disparities in Coronavirus Disease 2019 (COVID-19) Mortality Are Driven by Unequal Infection Risks.

BACKGROUND: As of 1 November 2020, there have been >230 000 deaths and 9 million confirmed and probable cases attributable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States. However, this overwhelming toll has not been distributed equally, with geographic, race/ethnic, age, and socioeconomic disparities in exposure and mortality defining features of the US coronavirus disease 2019 (COVID-19) epidemic. METHODS: We used individual-level COVID-19 incidence and mortality data from the state of Michigan to estimate age-specific incidence and mortality rates by race/ethnic group. Data were analyzed using hierarchical Bayesian regression models, and model results were validated using posterior predictive checks. RESULTS: In crude and age-standardized analyses we found rates of incidence and mortality more than twice as high than for Whites for all groups except Native Americans. Blacks experienced the greatest burden of confirmed and probable COVID-19 (age-standardized incidence, 1626/100 000 population) and mortality (age-standardized mortality rate, 244/100 000). These rates reflect large disparities, as Blacks experienced age-standardized incidence and mortality rates 5.5 (95% posterior credible interval [CrI], 5.4-5.6) and 6.7 (95% CrI, 6.4-7.1) times higher than Whites, respectively. We found that the bulk of the disparity in mortality between Blacks and Whites is driven by dramatically higher rates of COVID-19 infection across all age groups, particularly among older adults, rather than age-specific variation in case-fatality rates. CONCLUSIONS: This work suggests that well-documented racial disparities in COVID-19 mortality in hard-hit settings, such as Michigan, are driven primarily by variation in household, community, and workplace exposure rather than case-fatality rates.

Effectiveness of Influenza Vaccines in the HIVE Household Cohort Over 8 Years: Is There Evidence of Indirect Protection?

BACKGROUND: The evidence that influenza vaccination programs regularly provide protection to unvaccinated individuals (ie, indirect effects) of a community is lacking. We sought to determine the direct, indirect, and total effects of influenza vaccine in the Household Influenza Vaccine Evaluation (HIVE) cohort. METHODS: Using longitudinal data from the HIVE cohort from 2010-11 through 2017-18, we estimated direct, indirect, and total influenza vaccine effectiveness (VE) and the incidence rate ratio of influenza virus infection using adjusted mixed-effect Poisson regression models. Total effectiveness was determined through comparison of vaccinated members of full or partially vaccinated households to unvaccinated individuals in completely unvaccinated households. RESULTS: The pooled, direct VE against any influenza was 30.2% (14.0-43.4). Direct VE was higher for influenza A/H1N1 43.9% (3.9 to 63.5) and B 46.7% (17.2 to 57.5) than A/H3N2 31.7% (10.5 to 47.8) and was higher for young children 42.4% (10.1 to 63.0) than adults 18.6% (-6.3 to 37.7). Influenza incidence was highest in completely unvaccinated households (10.6 per 100 person-seasons) and lower at all other levels of household vaccination coverage. We found little evidence of indirect VE after adjusting for potential confounders. Total VE was 56.4% (30.1-72.9) in low coverage, 43.2% (19.5-59.9) in moderate coverage, and 33.0% (12.1 to 49.0) in fully vaccinated households. CONCLUSIONS: Influenza vaccines may have a benefit above and beyond the direct effect but that effect in this study was small. Although there may be exceptions, the goal of global vaccine recommendations should remain focused on provision of documented, direct protection to those vaccinated.

Coronavirus Occurrence and Transmission Over 8 Years in the HIVE Cohort of Households in Michigan.

BACKGROUND: As part of the Household Influenza Vaccine Evaluation (HIVE) study, acute respiratory infections (ARI) have been identified in children and adults from 2010 to 2018. METHODS: Annually, 890 to 1441 individuals were followed and contacted weekly to report ARIs. Specimens collected during illness were tested for human coronaviruses (HCoV) types OC43, 229E, HKU1, and NL63. RESULTS: In total, 993 HCoV infections were identified during the 8 years, with OC43 most commonly seen and 229E the least. HCoVs were detected in a limited time period, between December and April/May and peaked in January/February. Highest infection frequency was in children <5 years (18 per 100 person-years), with little variation in older age groups (range, 7 to 11 per 100 person-years). Overall, 9% of adult cases and 20% of cases in children were associated with medical consultation. Of the 993 infections, 260 were acquired from an infected household contact. The serial interval between index and household-acquired cases ranged from 3.2 to 3.6 days and the secondary infection risk ranged from 7.2% to 12.6% by type. CONCLUSIONS: Coronaviruses are sharply seasonal. They appear, based on serial interval and secondary infection risk, to have similar transmission potential to influenza A(H3N2) in the same population.

Influenza Vaccine Effectiveness in the Inpatient Setting: Evaluation of Potential Bias in the Test-Negative Design by Use of Alternate Control Groups.

The test-negative design is validated in outpatient, but not inpatient, studies of influenza vaccine effectiveness. The prevalence of chronic pulmonary disease among inpatients can lead to nonrepresentative controls. Test-negative design estimates are biased if vaccine administration is associated with incidence of noninfluenza viruses. We evaluated whether control group selection and effects of vaccination on noninfluenza viruses biased vaccine effectiveness in our study. Subjects were enrolled at the University of Michigan and Henry Ford hospitals during the 2014-2015 and 2015-2016 influenza seasons. Patients presenting with acute respiratory infection were enrolled and tested for respiratory viruses. Vaccine effectiveness was estimated using 3 control groups: negative for influenza, positive for other respiratory virus, and pan-negative individuals; it was also estimated for other common respiratory viruses. In 2014-2015, vaccine effectiveness was 41.1% (95% CI: 1.7, 64.7) using influenza-negative controls, 24.5% (95% CI: -42.6, 60.1) using controls positive for other virus, and 45.8% (95% CI: 5.7, 68.9) using pan-negative controls. In 2015-2016, vaccine effectiveness was 68.7% (95% CI: 44.6, 82.5) using influenza-negative controls, 63.1% (95% CI: 25.0, 82.2) using controls positive for other virus, and 71.1% (95% CI: 46.2, 84.8) using pan-negative controls. Vaccination did not alter odds of other respiratory viruses. Results support use of the test-negative design among inpatients.

Influenza Vaccine Effectiveness Against Hospitalization in Fully and Partially Vaccinated Children in Israel: 2015-2016, 2016-2017, and 2017-2018.

BACKGROUND: Influenza vaccine effectiveness (VE) varies by season, circulating influenza strain, age, and geographic location. There have been few studies of influenza VE among hospitalized children, particularly in Europe and the Middle East. METHODS: We estimated VE against influenza hospitalization among children aged 6 months to 8 years at Clalit Health Services hospitals in Israel in the 2015-2016, 2016-2017, and 2017-2018 influenza seasons, using the test-negative design. Estimates were computed for full and partial vaccination. RESULTS: We included 326 influenza-positive case patients and 2821 influenza-negative controls (140 case patients and 971 controls from 2015-2016, 36 case patients and 1069 controls from 2016-2017, and 150 case patients and 781 controls from 2017-2018). Over all seasons, VE was 53.9% for full vaccination (95% confidence interval [CI], 38.6%-68.3%), and 25.6% for partial vaccination (-3% to 47%). In 2015-2016, most viruses were influenza A(H1N1) and vaccine lineage-mismatched influenza B/Victoria; the VE for fully vaccinated children was statistically significant for influenza A (80.7%; 95% CI, 40.3%-96.1%) but not B (23.0%; -38.5% to 59.4%). During 2016-2017, influenza A(H3N2) predominated, and VE was (70.8%; 95% CI, 17.4%-92.4%). In 2017-2018, influenza A(H3N2), H1N1 and lineage-mismatched influenza B/Yamagata cocirculated; VE was statistically significant for influenza B (63.0%; 95% CI, 24.2%-83.7%) but not influenza A (46.3%; -7.2% to 75.3%). CONCLUSIONS: Influenza vaccine was effective in preventing hospitalizations among fully vaccinated Israeli children over 3 influenza seasons, but not among partially vaccinated children. There was cross-lineage protection in a season where the vaccine contained B/Victoria and the circulating strain was B/Yamagata, but not in a season with the opposite vaccine-circulating strain distribution.

Social patterning of acute respiratory illnesses in the Household Influenza Vaccine Evaluation (HIVE) Study 2014-2015.

Social patterning of infectious diseases is increasingly recognised. Previous studies of social determinants of acute respiratory illness (ARI) have found that highly educated and lower income families experience more illnesses. Subjective social status (SSS) has also been linked to symptomatic ARI, but the association may be confounded by household composition. We examined SSS and ARI in the Household Influenza Vaccine Evaluation (HIVE) Study in 2014-2015. We used SSS as a marker of social disadvantage and created a workplace disadvantage score for working adults. We examined the association between these measures and ARI incidence using mixed-effects Poisson regression models with random intercepts to account for household clustering. In univariate analyses, mean ARI was higher among children <5 years old (P < 0.001), and females (P = 0.004) at the individual level. At the household level, mean ARI was higher for households with at least one child <5 years than for those without (P = 0.002). In adjusted models, individuals in the lowest tertile of SSS had borderline significantly higher rates of ARI than those in the highest tertile (incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 0.98-1.92). Households in the lowest tertile of SSS had significantly higher ARI incidence in household-level models (IRR 1.46, 95% CI 1.05-2.03). We observed no association between workplace disadvantage and ARI. We detected an increase in the incidence of ARI for households with low SSS compared with those with high SSS, suggesting that socio-economic position has a meaningful impact on ARI incidence.

Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials.

Background: Oseltamivir has been used to treat children with influenza for nearly 2 decades, with treatment currently approved for infants aged ≥2 weeks. However, efficacy and safety remain controversial. Newer randomized, placebo-controlled trials (RCTs), not included in previous meta-analyses, can add to the evidence base. Methods: We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a 2-stage, random-effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RMST) by treatment group. We also examined complications and safety. Results: We identified 5 trials that included 2561 patients in the intention-to-treat (ITT) and 1598 in the intention-to-treat infected (ITTI) populations. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference, -17.6 hours; 95% confidence interval [CI], -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours; 95% CI, -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group. Conclusions: Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.

Maximum likelihood estimation of influenza vaccine effectiveness against transmission from the household and from the community.

Influenza vaccination is recommended as the best way to protect against influenza infection and illness. Due to seasonal changes in influenza virus types and subtypes, a new vaccine must be produced, and vaccine effectiveness (VE) must be estimated, annually. Since 2010, influenza vaccination has been recommended universally in the United States, making randomized clinical trials unethical. Recent studies have used a monitored household cohort study design to determine separate VE estimates against influenza transmission from the household and community. We developed a probability model and accompanying maximum likelihood procedure to estimate vaccine-related protection against transmission of influenza from the household and the community. Using agent-based stochastic simulations, we validated that we can obtain maximum likelihood estimates of transmission parameters and VE close to their true values. Sensitivity analyses to examine the effect of deviations from our assumptions were conducted. We used our method to estimate transmission parameters and VE from data from a monitored household study in Michigan during the 2012-2013 influenza season and were able to detect a significant protective effect of influenza vaccination against community-acquired transmission.

Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol.

BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work. METHODS: Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum. DISCUSSION: SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients. TRIAL REGISTRATION: NCT03331991 . Registered on November 6, 2017.

The Doctrine of Original Antigenic Sin: Separating Good From Evil.

The term "original antigenic sin" was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed "negative antigenic interaction," given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies.

The Household Influenza Vaccine Effectiveness Study: Lack of Antibody Response and Protection Following Receipt of 2014-2015 Influenza Vaccine.

BACKGROUND: Antigenically drifted A(H3N2) viruses circulated extensively during the 2014-2015 influenza season. Vaccine effectiveness (VE) was low and not significant among outpatients but in a hospitalized population was 43%. At least one study paradoxically observed increased A(H3N2) infection among those vaccinated 3 consecutive years. METHODS: We followed a cohort of 1341 individuals from 340 households. VE against laboratory-confirmed influenza was estimated. Hemagglutination-inhibition and neuraminidase-inhibition antibody titers were determined in subjects ≥13 years. RESULTS: Influenza A(H3N2) was identified in 166 (12%) individuals and B(Yamagata) in 34 (2%). VE against A(H3N2) was -3% (95% confidence interval [CI]: -55%, 32%) and similarly ineffective between age groups; increased risk of infection was not observed among those vaccinated in 2 or 3 previous years. VE against influenza B(Yamagata) was 57% (95% CI: -3%, 82%) but only significantly protective in children <9 years (87% [95% CI: 43%, 97%]). Less than 20% of older children and adults had ≥4-fold antibody titer rise against influenza A(H3N2) and B antigens following vaccination; responses were surprisingly similar for antigens included in the vaccine and those similar to circulating viruses. Antibody against A/Hong Kong/4801/14, similar to circulating 2014-2015 A(H3N2) viruses and included in the 2016-2017 vaccine, did not significantly predict protection. CONCLUSIONS: Absence of VE against A(H3N2) was consistent with circulation of antigenically drifted viruses; however, generally limited antibody response following vaccination is concerning even in the context of antigenic mismatch. Although 2014-2015 vaccines were not effective in preventing A(H3N2) infection, no increased susceptibility was detected among the repeatedly vaccinated.

Application of an Individual-Based Transmission Hazard Model for Estimation of Influenza Vaccine Effectiveness in a Household Cohort.

Household cohort studies are an important design for the study of respiratory virus transmission. Inferences from these studies can be improved through the use of mechanistic models to account for household structure and risk as an alternative to traditional regression models. We adapted a previously described individual-based transmission hazard (TH) model and assessed its utility for analyzing data from a household cohort maintained in part for study of influenza vaccine effectiveness (VE). Households with ≥4 individuals, including ≥2 children <18 years of age, were enrolled and followed during the 2010-2011 influenza season. VE was estimated in both TH and Cox proportional hazards (PH) models. For each individual, TH models estimated hazards of infection from the community and each infected household contact. Influenza A(H3N2) infection was laboratory-confirmed in 58 (4%) subjects. VE estimates from both models were similarly low overall (Cox PH: 20%, 95% confidence interval: -57, 59; TH: 27%, 95% credible interval: -23, 58) and highest for children <9 years of age (Cox PH: 40%, 95% confidence interval: -49, 76; TH: 52%, 95% credible interval: 7, 75). VE estimates were robust to model choice, although the ability of the TH model to accurately describe transmission of influenza presents continued opportunity for analyses.

Antibodies Against the Current Influenza A(H1N1) Vaccine Strain Do Not Protect Some Individuals From Infection With Contemporary Circulating Influenza A(H1N1) Virus Strains.

During the 2013-2014 influenza season, nearly all circulating 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) strains possessed an antigenically important mutation in hemagglutinin (K166Q). Here, we performed hemagglutination-inhibition (HAI) assays, using sera collected from 382 individuals prior to the 2013-2014 season, and we determined whether HAI titers were associated with protection from A(H1N1)pdm09 infection. Protection was associated with HAI titers against an A(H1N1)pdm09 strain possessing the K166Q mutation but not with HAI titers against the current A(H1N1)pdm09 vaccine strain, which lacks this mutation. These data indicate that contemporary A(H1N1)pdm09 strains are antigenically distinct from the current A(H1N1)pdm09 vaccine strain.

Substantial Influenza Vaccine Effectiveness in Households With Children During the 2013-2014 Influenza Season, When 2009 Pandemic Influenza A(H1N1) Virus Predominated.

BACKGROUND: We examined the influenza vaccine effectiveness (VE) during the 2013-2014 influenza season, in which 2009 pandemic influenza A(H1N1) virus (influenza A[H1N1]pdm09) predominated. In 2 previous years when influenza A(H3N2) virus predominated, the VE was low and negatively affected by prior year vaccination. METHODS: We enrolled and followed 232 households with 1049 members, including 618 children; specimens were collected from subjects with acute respiratory illnesses. The VE in preventing laboratory-confirmed influenza A(H1N1)pdm09 infection was estimated in adjusted models. Preseason hemagglutination-inhibition and neuraminidase-inhibition antibody titers were determined to assess susceptibility. RESULTS: Influenza A(H1N1)pdm09 was identified in 25 households (10.8%) and 47 individuals (4.5%). Adjusted VE against infection with influenza A(H1N1)pdm09 was 66% (95% confidence interval [CI], 23%-85%), with similar point estimates in children and adults, and against both community-acquired and household-acquired infections. VE did not appear to be different for live-attenuated and inactivated vaccines among children aged 2-8 years, although numbers were small. VE was similar for subjects vaccinated in both current and prior seasons and for those vaccinated in the current season only; susceptibility titers were consistent with this observation. CONCLUSIONS: Findings, including substantial significant VE and a lack of a negative effect of repeated vaccination on VE, were in contrast to those seen in prior seasons in which influenza A(H3N2) virus predominated.

Influenza Vaccine Effectiveness Against Antigenically Drifted Influenza Higher Than Expected in Hospitalized Adults: 2014-2015.

BACKGROUND: The 2014-2015 influenza season was severe, with circulating influenza A (H3N2) viruses that were antigenically drifted from the vaccine virus. Reported vaccine effectiveness (VE) estimates from ambulatory care settings were markedly decreased. METHODS: Adults, hospitalized at 2 hospitals in southeast Michigan for acute respiratory illnesses, defined by admission diagnoses, of ≤10 days duration were prospectively enrolled. Throat and nasal swab specimens were collected, combined, and tested for influenza by real-time reverse transcription polymerase chain reaction. VE was estimated by comparing the vaccination status of those testing positive for influenza with those testing negative in logistic regression models adjusted for age, sex, hospital, calendar time, time from illness onset to specimen collection, frailty score, and Charlson comorbidity index (CCI). RESULTS: Among 624 patients included in the analysis, 421 (68%) were vaccinated, 337 (54%) were female, 220 (35%) were age ≥65 years, and 92% had CCI > 0, indicating ≥1 comorbid conditions. Ninety-eight (16%) patients tested positive for influenza A (H3N2); among 60 (61%) A (H3N2) viruses tested by pyrosequencing, 53 (88%) belonged to the drifted 3C.2a genetic group. Adjusted VE was 43% (95% confidence interval [CI], 4-67) against influenza A (H3N2); 40% (95% CI, -13 to 68) for those <65 years, and 48% (95% CI, -33 to 80) for those ≥65 years. Sensitivity analyses largely supported these estimates. CONCLUSIONS: VE estimates appeared higher than reports from similar studies in ambulatory care settings, suggesting that the 2014-2015 vaccine may have been more effective in preventing severe illness requiring hospitalization.

Illness Severity and Work Productivity Loss Among Working Adults With Medically Attended Acute Respiratory Illnesses: US Influenza Vaccine Effectiveness Network 2012-2013.

BACKGROUND: Influenza causes significant morbidity and mortality, with considerable economic costs, including lost work productivity. Influenza vaccines may reduce the economic burden through primary prevention of influenza and reduction in illness severity. METHODS: We examined illness severity and work productivity loss among working adults with medically attended acute respiratory illnesses and compared outcomes for subjects with and without laboratory-confirmed influenza and by influenza vaccination status among subjects with influenza during the 2012-2013 influenza season. RESULTS: Illnesses laboratory-confirmed as influenza (ie, cases) were subjectively assessed as more severe than illnesses not caused by influenza (ie, noncases) based on multiple measures, including current health status at study enrollment (≤7 days from illness onset) and current activity and sleep quality status relative to usual. Influenza cases reported missing 45% more work hours (20.5 vs 15.0; P < .001) than noncases and subjectively assessed their work productivity as impeded to a greater degree (6.0 vs 5.4; P < .001). Current health status and current activity relative to usual were subjectively assessed as modestly but significantly better for vaccinated cases compared with unvaccinated cases; however, no significant modifications of sleep quality, missed work hours, or work productivity loss were noted for vaccinated subjects. CONCLUSIONS: Influenza illnesses were more severe and resulted in more missed work hours and productivity loss than illnesses not confirmed as influenza. Modest reductions in illness severity for vaccinated cases were observed. These findings highlight the burden of influenza illnesses and illustrate the importance of laboratory confirmation of influenza outcomes in evaluations of vaccine effectiveness.

Classification and Regression Tree (CART) analysis to predict influenza in primary care patients.

BACKGROUND: The use of neuraminidase-inhibiting anti-viral medication to treat influenza is relatively infrequent. Rapid, cost-effective methods for diagnosing influenza are needed to enable appropriate prescribing. Multi-viral respiratory panels using reverse transcription polymerase chain reaction (PCR) assays to diagnose influenza are accurate but expensive and more time-consuming than low sensitivity rapid influenza tests. Influenza clinical decision algorithms are both rapid and inexpensive, but most are based on regression analyses that do not account for higher order interactions. This study used classification and regression trees (CART) modeling to estimate probabilities of influenza. METHODS: Eligible enrollees ≥ 5 years old (n = 4,173) who presented at ambulatory centers for treatment of acute respiratory illness (≤7 days) with cough or fever in 2011-2012, provided nasal and pharyngeal swabs for PCR testing for influenza, information on demographics, symptoms, personal characteristics and self-reported influenza vaccination status. RESULTS: Antiviral medication was prescribed for just 15 % of those with PCR-confirmed influenza. An algorithm that included fever, cough, and fatigue had sensitivity of 84 %, specificity of 48 %, positive predictive value (PPV) of 23 % and negative predictive value (NPV) of 94 % for the development sample. CONCLUSIONS: The CART algorithm has good sensitivity and high NPV, but low PPV for identifying influenza among outpatients ≥5 years. Thus, it is good at identifying a group who do not need testing or antivirals and had fair to good predictive performance for influenza. Further testing of the algorithm in other influenza seasons would help to optimize decisions for lab testing or treatment.

Influenza vaccine effectiveness in households with children during the 2012-2013 season: assessments of prior vaccination and serologic susceptibility.

BACKGROUND: There are recognized needs to identify determinants of influenza vaccine effectiveness (VE), including the effect of repeated annual vaccination. METHODS: We recruited 321 households with 1426 members, including 833 children, and followed them during the 2012-2013 influenza season; specimens were collected from subjects with reported acute respiratory illnesses. We estimated the effectiveness of documented influenza vaccination in preventing laboratory-confirmed influenza, using adjusted Cox proportional hazards models. Antibody titers in a subset of subjects were determined by a hemagglutination inhibition assay to determine the subjects' preseason susceptibility to influenza. RESULTS: Influenza was identified in 76 (24%) households and 111 (8%) individuals. VE point estimates indicated significant protection in adults (48%; 95% confidence interval [CI], 1%-72%), similar protection in children aged 9-17 years (49%; 95% CI, -16% to 78%), but no evidence of effectiveness in children aged <9 years (-4%; 95% CI, -110% to 49%). Lower VE was observed in those vaccinated in both the current and prior seasons, compared with those vaccinated in the current season only; susceptibility titers against type A but not type B were consistent with this observation. Residual protection from vaccination in the prior season was indicated by both VE and serologic results. CONCLUSIONS: Prior vaccination appears to modify VE by both residual protection and reduced vaccine response.