Respiratory virus circulation during the first year of the COVID-19 pandemic in the Household Influenza Vaccine Evaluation (HIVE) cohort.

Background: The annual reappearance of respiratory viruses has been recognized for decades. COVID-19 mitigation measures taken during the pandemic were targeted at respiratory transmission and broadly impacted the burden of acute respiratory illnesses (ARIs). Methods: We used the longitudinal Household Influenza Vaccine Evaluation (HIVE) cohort in southeast Michigan to characterize the circulation of respiratory viruses from March 1, 2020, to June 30, 2021, using RT-PCR of respiratory specimens collected at illness onset. Participants were surveyed twice during the study period, and SARS-CoV-2 antibodies were measured in serum by electrochemiluminescence immunoassay. Incidence rates of ARI reports and virus detections were compared between the study period and a preceding pre-pandemic period of similar duration. Results: Overall, 437 participants reported a total of 772 ARIs; 42.6% had respiratory viruses detected. Rhinoviruses were the most frequent virus, but seasonal coronaviruses, excluding SARS-CoV-2, were also common. Illness reports and percent positivity were lowest from May to August 2020, when mitigation measures were most stringent. Seropositivity for SARS-CoV-2 was 5.3% in summer 2020 and increased to 11.3% in spring 2021. The incidence rate of total reported ARIs for the study period was 50% lower (95% CI: 0.5, 0.6; p < 0.001) than the incidence rate from a pre-pandemic comparison period (March 1, 2016, to June 30, 2017). Conclusions: The burden of ARI in the HIVE cohort during the COVID-19 pandemic fluctuated, with declines occurring concurrently with the widespread use of public health measures. Rhinovirus and seasonal coronaviruses continued to circulate even when influenza and SARS-CoV-2 circulation was low.

Comparing the Etiology of Viral Acute Respiratory Illnesses Between Children Who Do and Do Not Attend Childcare.

BACKGROUND AND OBJECTIVE: Childcare attendance is a common risk factor for acute respiratory illness (ARI) in young children. Our goal was to better understand the specific respiratory viruses that predominate in childcare, which may support the development of tailored illness prevention and intervention strategies in childcare settings. METHODS: Using data from a prospective household cohort of ARI surveillance, we assessed specimen from 1418 ARIs reported by 359 childcare-aged children over 6 study seasons (2012/2013 through 2017/2018). Respiratory swabs were tested by polymerase chain reaction for 9 respiratory viruses. A mixed-effect logistic regression model was used to compare odds of various viral detection outcomes. The Shannon's Diversity index was used to compare the richness (ie, number of species) and diversity (ie, relative species abundance) associated with respiratory viruses detected in both groups. RESULTS: At least 1 virus was detected in 75.5% of childcare-associated ARIs and in 80.1% of homecare ARIs. Compared with illnesses among homecare children, childcare illnesses were associated with significantly higher odds of detected adenovirus (odds ratio = 1.86, 95% confidence interval = 1.05-3.28) and human metapneumovirus (odds ratio = 1.76, 95% confidence interval = 1.03-3.0). The pool of viruses associated with childcare ARI was found to be significantly richer and more diverse than that of viruses associated with homecare ARI ( P < 0.0001). CONCLUSIONS: Children attending childcare experience a higher risk of adenovirus and human metapneumovirus infection and are regularly exposed to a rich and diverse pool of respiratory viruses in childcare environments. Our results underscore the necessity of thorough and multifaceted viral prevention strategies in childcare settings.

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.

Respiratory Virus Circulation during the First Year of the COVID-19 Pandemic in the Household Influenza Vaccine Evaluation (HIVE) Cohort.

Background: The annual reappearance of respiratory viruses has been recognized for decades. The onset of the COVID-19 pandemic altered typical respiratory virus transmission patterns. COVID-19 mitigation measures taken during the pandemic were targeted at SARS-CoV-2 respiratory transmission and thus broadly impacted the burden of acute respiratory illnesses (ARIs), in general. Methods: We used the longitudinal Household Influenza Vaccine Evaluation (HIVE) cohort of households in southeast Michigan to characterize mitigation strategy adherence, respiratory illness burden, and the circulation of 15 respiratory viruses during the COVID-19 pandemic determined by RT-PCR of respiratory specimens collected at illness onset. Study participants were surveyed twice during the study period (March 1, 2020, to June 30, 2021), and serologic specimens were collected for antibody measurement by electrochemiluminescence immunoassay. Incidence rates of ARI reports and virus detections were calculated and compared using incidence rate ratios for the study period and a pre-pandemic period of similar length. Results: Overall, 437 participants reported a total of 772 ARIs and 329 specimens (42.6%) had respiratory viruses detected. Rhinoviruses were the most frequently detected organism, but seasonal coronaviruses-excluding SARS-CoV-2-were also common. Illness reports and percent positivity were lowest from May to August 2020, when mitigation measures were most stringent. Study participants were more adherent to mitigation measures in the first survey compared with the second survey. Supplemental serology surveillance identified 5.3% seropositivity for SARS-CoV-2 in summer 2020; 3.0% between fall 2020 and winter 2021; and 11.3% in spring 2021. Compared to a pre-pandemic period of similar length, the incidence rate of total reported ARIs for the study period was 50% lower (95% CI: 0.5, 0.6; p<0.001) than the incidence rate from March 1, 2016, to June 30, 2017. Conclusions: The burden of ARI in the HIVE cohort during the COVID-19 pandemic fluctuated, with declines occurring concurrently with the widespread use of public health measures. It is notable, however, that rhinovirus and seasonal coronaviruses continued to circulate even as influenza and SARS-CoV-2 circulation was low.

Distinct influenza surveillance networks and their agreement in recording regional influenza circulation: Experience from Southeast Michigan.

INTRODUCTION: In Southeast Michigan, active surveillance studies monitor influenza activity in hospitals, ambulatory clinics, and community households. Across five respiratory seasons, we assessed the contribution of data from each of the three networks towards improving our overall understanding of regional influenza circulation. METHODS: All three networks used case definitions for acute respiratory illness (ARI) and molecularly tested for influenza from research-collected respiratory specimens. Age- and network-stratified epidemic curves were created for influenza A and B. We compared stratified epidemic curves visually and by centering at seasonal midpoints. RESULTS: Across all seasons (from 2014/2015 through 2018/2019), epidemic curves from each of the three networks were comparable in terms of both timing and magnitude. Small discrepancies in epidemics recorded by each network support previous conclusions about broader characteristics of particular influenza seasons. CONCLUSION: Influenza surveillance systems based in hospital, ambulatory clinic, and community household settings appear to provide largely similar information regarding regional epidemic activity. Together, multiple levels of influenza surveillance provide a detailed view of regional influenza epidemics, but a single surveillance system-regardless of population subgroup monitored-appears to be sufficient in providing vital information regarding community influenza epidemics.

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.

Home collection of nasal swabs for detection of influenza in the Household Influenza Vaccine Evaluation Study.

BACKGROUND: Community-based studies of influenza and other respiratory viruses (eg, SARS-CoV-2) require laboratory confirmation of infection. During the current COVID-19 pandemic, social distancing guidelines require alternative data collection in order to protect both research staff and participants. Home-collected respiratory specimens are less resource-intensive, can be collected earlier after symptom onset, and provide a low-contact means of data collection. A prospective, multi-year, community-based cohort study is an ideal setting to examine the utility of home-collected specimens for identification of influenza. METHODS: We describe the feasibility and reliability of home-collected specimens for the detection of influenza. We collected data and specimens between October 2014 and June 2017 from the Household Influenza Vaccine Evaluation (HIVE) Study. Cohort participants were asked to collect a nasal swab at home upon onset of acute respiratory illness. Research staff also collected nose and throat swab specimens in the study clinic within 7 days of onset. We estimated agreement using Cohen's kappa and calculated sensitivity and specificity of home-collected compared to staff-collected specimens. RESULTS: We tested 336 paired staff- and home-collected respiratory specimens for influenza by RT-PCR; 150 staff-collected specimens were positive for influenza A/H3N2, 23 for influenza A/H1N1, 14 for influenza B/Victoria, and 31 for influenza B/Yamagata. We found moderate agreement between collection methods for influenza A/H3N2 (0.70) and B/Yamagata (0.69) and high agreement for influenza A/H1N1 (0.87) and B/Victoria (0.86). Sensitivity ranged from 78% to 86% for all influenza types and subtypes. Specificity was high for influenza A/H1N1 and both influenza B lineages with a range from 96% to 100%, and slightly lower for A/H3N2 infections (88%). CONCLUSIONS: Collection of nasal swab specimens at home is both feasible and reliable for identification of influenza virus infections.

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.

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.

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.

Evaluation of correlates of protection against influenza A(H3N2) and A(H1N1)pdm09 infection: Applications to the hospitalized patient population.

BACKGROUND: Influenza vaccines are important for prevention of influenza-associated hospitalization. However, the effectiveness of influenza vaccines can vary by year and influenza type and subtype and mechanisms underlying this variation are incompletely understood. Assessments of serologic correlates of protection can support interpretation of influenza vaccine effectiveness in hospitalized populations. METHODS: We enrolled adults hospitalized for treatment of acute respiratory illnesses during the 2014-2015 and 2015-2016 influenza seasons whose symptoms began <10 days prior to enrollment. Influenza infection status was determined by RT-PCR. Influenza vaccination status was defined by self-report and medical record/registry documentation. Serum specimens collected at hospital admission were tested in hemagglutination-inhibition (HAI) and neuraminidase-inhibition (NAI) assays. We evaluated how well antibody measured in these specimens represented pre-infection immune status, and measured associations between antibody and influenza vaccination and infection. RESULTS: Serum specimens were retrieved for 315 participants enrolled during the 2014-2015 season and 339 participants during the 2015-2016 season. Specimens were collected within 3 days of illness onset from 65% of participants. Geometric mean titers (GMTs) did not vary by the number of days from illness onset to specimen collection among influenza positive participants suggesting that measured antibody was representative of pre-infection immune status rather than a de novo response to infection. In both seasons, vaccinated participants had higher HAI and NAI GMTs than unvaccinated. HAI titers against the 2014-2015 A(H3N2) vaccine strain did not correlate with protection from infection with antigenically-drifted A(H3N2) viruses that circulated that season. In contrast, higher HAI titers against the A(H1N1)pdm09 vaccine strain were associated with reduced odds of A(H1N1)pdm09 infection in 2015-2016. CONCLUSIONS: Serum collected shortly after illness onset at hospital admission can be used to assess correlates of protection against influenza infection. Broader implementation of similar studies would provide an opportunity to understand the successes and shortcomings of current influenza vaccines.

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.

Stochastic processes constrain the within and between host evolution of influenza virus.

The evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define influenza virus dynamics in human hosts through sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected from individuals in a prospective community-based cohort, they are broadly representative of natural infections with seasonal viruses. Consistent with a neutral model of evolution, sequence data from 49 serially sampled individuals illustrated the dynamic turnover of synonymous and nonsynonymous single nucleotide variants and provided little evidence for positive selection of antigenic variants. We also identified 43 genetically-validated transmission pairs in this cohort. Maximum likelihood optimization of multiple transmission models estimated an effective transmission bottleneck of 1-2 genomes. Our data suggest that positive selection is inefficient at the level of the individual host and that stochastic processes dominate the host-level evolution of influenza viruses.

Contemporary Social Disparities in TB Infection and Disease in the USA: a Review.

PURPOSE OF REVIEW: Socioeconomic status (SES) has long been understood to be a key determinant of the distribution of tuberculosis (TB), and the role of social factors has long been a truism of TB epidemiology. We review studies that have examined the social determinants of TB in the USA in the past 20 years. We pay particular attention to how the findings of these studies fit within the framework of fundamental cause theory and argue that a more explicit linkage with fundamental cause theory is critical for understanding the current state of TB health disparities in the USA and for charting a way towards TB elimination in the USA. RECENT FINDINGS AND SUMMARY: Our review finds that while in the past 20 years there have been studies that have documented the ongoing association between social factors and TB disease in the USA, few studies explore the precise mechanisms through which social factors continue to influence TB patterns. We advocate for a move towards a system-based approach both in theory development and analyses, allowing for the incorporation of more complex social dynamics to address long-standing disparities in TB disease.

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.

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.

The risk of lower respiratory tract infection following influenza virus infection: A systematic and narrative review.

BACKGROUND: Lower respiratory tract infections (LRTI) are a major cause of morbidity and mortality worldwide, particularly in young children and older adults. Influenza is known to cause severe disease but the risk of developing LRTI following influenza virus infection in various populations has not been systematically reviewed. Such data are important for estimating the impact specific influenza vaccine programs would have on LRTI outcomes in a community. We sought to review the published literature to determine the risk of developing LRTI following an influenza virus infection in individuals of any age. METHODS AND FINDINGS: We conducted a systematic review to identify prospective studies that estimated the incidence of LRTI following laboratory-confirmed influenza virus infection. We searched PubMed, Medline, and Embase databases for relevant literature. We supplemented this search with a narrative review of influenza and LRTI. The systematic review identified two prospective studies that both followed children less than 5 years. We also identified one additional pediatric study from our narrative review meeting the study inclusion criteria. Finally, we summarized recent case-control studies on the etiology of pneumonia in both adults and children. CONCLUSIONS: There is a dearth of prospective studies evaluating the risk of developing LRTI following influenza virus infection. Determining the burden of severe LRTI that is attributable to influenza is necessary to estimate the benefits of influenza vaccine on this important public health outcome. Vaccine probe studies are an efficient way to evaluate these questions and should be encouraged going forward.

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.