A Pharmacokinetics-Time to Alleviation of Symptoms Model to Support Extrapolation of Baloxavir Marboxil Clinical Efficacy in Different Ethnic Groups with Influenza A or B.

Baloxavir marboxil, the prodrug of baloxavir acid, is an anti-influenza antiviral. Here, a pharmacokinetics-time to alleviation of symptoms (PK-TTAS) model was developed and used to (I) characterize the PK-TTAS relationship, (II) quantify the impact of covariates, and (III) predict TTAS in different ethnic groups. Data from 1781 otherwise-healthy (OwH) or high-risk (HR) patients included in phase II (JapicCTI-153090) and III studies (NCT02954354 and NCT02949011) were used; patients received either placebo or oral baloxavir marboxil. The natural distribution of TTAS in placebo-treated patients was modeled, then TTAS data from the baloxavir marboxil arms were added to model the impact of baloxavir acid concentration on TTAS. PK parameters estimated by a population PK model and informed by phase I data (NCT03959332 and KCT0003535) were included to simulate TTAS in Chinese and South Korean patients. Composite symptom score at baseline (TSS0), ethnicity, sex, and patient type (OwH or HR) significantly impacted the natural TTAS distribution. TTAS reduced with increasing baloxavir acid concentrations. Compared with placebo, high and low baloxavir acid exposures (AUC0-inf 5.13-16.65 and 0.72-5.13 µg.hr/mL, respectively) significantly reduced TTAS; no covariates affected the drug effect on TTAS. Simulated TTAS was similar between OwH or HR Chinese, South Korean, and other Asian patients, with median reductions from placebo between 18.3-18.8 hours and 21.2-22.0 hours in OwH and HR patients, respectively, assuming TSS0 > 10. Ethnicity (Asian vs. non-Asian) did not significantly impact the drug effect on TTAS; predicted TTAS was similar across different Asian populations. This suggests Chinese and South Korean patients may benefit from similar efficacy as other Asian patients.

Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans.

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+ -specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.

Factors associated with seasonal influenza and HPV vaccination uptake among different ethnic groups in Arab and Jewish society in Israel.

BACKGROUND: Parents in the Arab population of Israel are known to be "pro-vaccination" and vaccinate their children at higher rates than the Jewish population, specifically against human papilloma virus (HPV) and seasonal influenza. OBJECTIVES: This study seeks to identify and compare variables associated with mothers' uptake of two vaccinations, influenza and HPV, among different subgroups in Arab and Jewish society in Israel. METHODS: A cross-sectional study of the entire spectrum of the Israeli population was conducted using a stratified sample of Jewish mothers (n = 159) and Arab mothers (n = 534) from different subgroups: Muslim, Christian, Druse and Northern Bedouins. From March 30, 2019 through October 20, 2019, questionnaires were distributed manually to eighth grade pupils (13-14 years old) who had younger siblings in second (7-8 years old) or third (8-9 years old) grades. RESULTS: Arab mothers exhibited a higher rate of uptake for both vaccinations (p < .0001, HPV - 90%; influenza - 62%) than Jewish mothers (p = 0.0014, HPV - 46%; influenza - 34%). Furthermore, results showed that HPV vaccination uptake is significantly higher than seasonal influenza vaccination uptake in both populations. Examination of the different ethnic subgroups revealed differences in vaccination uptake. For both vaccinations, the Northern Bedouins exhibited the highest uptake rate of all the Arab subgroups (74%), followed by the Druse (74%) and Muslim groups (60%). The Christian Arab group exhibited the lowest uptake rate (46%). Moreover, the uptake rate among secular Jewish mothers was lower than in any of the Arab groups (38%), though higher than among religious/traditional Jewish mothers, who exhibited the lowest uptake rate (26%). A comparison of the variables associated with mothers' vaccination uptake revealed differences between the ethnic subgroups. Moreover, the findings of the multiple logistic regression revealed the following to be the most significant factors in Arab mothers' intake of both vaccinations: school-located vaccination and mothers' perceived risk and perceived trust in the system and in the family physician. These variables are manifested differently in the different ethnic groups. CONCLUSIONS: This research shows that all Arabs cannot be lumped together as one monolithic group in that they exhibit major differences according to religion, education and access to information. Ranking of variables associated with uptake of the two vaccines can provide decision-makers an empirical basis for tailoring appropriate and specific interventions to each subgroup to achieve the highest vaccine uptake rate possible. Media campaigns targeting the Arab population should be segmented to appeal to the various sub-groups according to their viewpoints, needs and health literacy.

Rates of Influenza-Associated Hospitalization, Intensive Care Unit Admission, and In-Hospital Death by Race and Ethnicity in the United States From 2009 to 2019.

Importance: Racial and ethnic minority groups, such as Black, Hispanic, American Indian or Alaska Native, and Asian or Pacific Islander persons, often experience higher rates of severe influenza disease. Objective: To describe rates of influenza-associated hospitalization, intensive care unit (ICU) admission, and in-hospital death by race and ethnicity over 10 influenza seasons. Design, Setting, and Participants: This cross-sectional study used data from the Influenza-Associated Hospitalization Surveillance Network (FluSurv-NET), which conducts population-based surveillance for laboratory-confirmed influenza-associated hospitalizations in selected counties, representing approximately 9% of the US population. Influenza hospitalizations from the 2009 to 2010 season to the 2018 to 2019 season were analyzed. Data were analyzed from October 2020 to July 2021. Main Outcomes and Measures: The main outcomes were age-adjusted and age-stratified rates of influenza-associated hospitalization, ICU admission, and in-hospital death by race and ethnicity overall and by influenza season. Results: Among 113 352 persons with an influenza-associated hospitalization (34 436 persons [32.0%] aged ≥75 years; 61 009 [53.8%] women), 70 225 persons (62.3%) were non-Hispanic White (White), 24 850 persons (21.6%) were non-Hispanic Black (Black), 11 903 persons (10.3%) were Hispanic, 5517 persons (5.1%) were non-Hispanic Asian or Pacific Islander, and 857 persons (0.7%) were non-Hispanic American Indian or Alaska Native. Among persons aged younger than 75 years and compared with White persons of the same ages, Black persons were more likely to be hospitalized (eg, age 50-64 years: rate ratio [RR], 2.50 95% CI, 2.43-2.57) and to be admitted to an ICU (eg, age 50-64 years: RR, 2.09; 95% CI, 1.96-2.23). Among persons aged younger than 50 years and compared with White persons of the same ages, American Indian or Alaska Native persons were more likely to be hospitalized (eg, age 18-49 years: RR, 1.72; 95% CI, 1.51-1.96) and to be admitted to an ICU (eg, age 18-49 years: RR, 1.84; 95% CI, 1.40-2.42). Among children aged 4 years or younger and compared with White children, hospitalization rates were higher in Black children (RR, 2.21; 95% CI, 2.10-2.33), Hispanic children (RR, 1.87; 95% CI, 1.77-1.97), American Indian or Alaska Native children (RR, 3.00; 95% CI, 2.55-3.53), and Asian or Pacific Islander children (RR, 1.26; 95% CI, 1.16-1.38), as were rates of ICU admission (Black children: RR, 2.74; 95% CI, 2.43-3.09; Hispanic children: RR, 1.96; 95% CI, 1.73-2.23; American Indian and Alaska Native children: RR, 3.51; 95% CI, 2.45-5.05). In this age group and compared with White children, in-hospital death rates were higher among Hispanic children (RR, 2.98; 95% CI, 1.23-7.19), Black children (RR, 3.39; 95% CI, 1.40-8.18), and Asian or Pacific Islander children (RR, 4.35; 95% CI, 1.55-12.22). Few differences were observed in rates of severe influenza-associated outcomes by race and ethnicity among adults aged 75 years or older. For example, in this age group, compared with White adults, hospitalization rates were slightly higher only among Black adults (RR, 1.05; 95% CI 1.02-1.09). Overall, Black persons had the highest age-adjusted hospitalization rate (68.8 [95% CI, 68.0-69.7] hospitalizations per 100 000 population) and ICU admission rate (11.6 [95% CI, 11.2-11.9] admissions per 100 000 population). Conclusions and Relevance: This cross-sectional study found racial and ethnic disparities in rates of severe influenza-associated disease. These data identified subgroups for whom improvements in influenza prevention efforts could be targeted.

The "saddest repudiation" redux: Structural racism and the unlearned lesson of 1918.

The COVID-19 pandemic reveals how the systems and structures of racism devastate the health and well-being of people of color. The debate is an old one and the lesson we have yet to learn was tragically apparent a century ago during the 1918-1919 influenza pandemic. Any history of structural racism in America must begin with the chronicles of African Americans, Native Alaskans, and Indigenous North Americans as they were the originally enslaved and displaced people, subjected to overt and covert policies of oppression ever since. The experiences of Native Alaskans of Bristol Bay Alaska in 1918-1919 present a parallel, illuminating a wrenching example of structural racism that cost lives and impoverished society, then as now. Proven policy solutions exist to remove the structures that produce inequitable health outcomes, but implementing them will require public health officials and policymakers to take multidisciplinary policy actions, to find policy opportunities for change to be made, and, likely, a change in the political environment. The first exists now, the second is afforded because of the current pandemic and the urgent need for policy solutions, and the third is likely coming soon.

Geographic Variation in Racial Disparities in Mortality From Influenza and Pneumonia in the United States in the Pre-Coronavirus Disease 2019 Era.

BACKGROUND: In 2018, influenza and pneumonia was the eighth leading cause of death in the United States. Since 1950, non-Hispanic blacks (NHBs) have experienced higher rates of mortality than non-Hispanic whites (NHWs). Previous studies have revealed geographic variation in mortality rates by race. The identification of areas with the greatest disparity in influenza and pneumonia mortality may assist policymakers in the allocation of resources, including for the coronavirus disease 2019 pandemic. RESEARCH QUESTION: Does geographic variation in racial disparity in influenza and pneumonia mortality exist? STUDY DESIGN AND METHODS: The Centers for Disease Control and Prevention database for Multiple Cause of Death between 1999 and 2018 for NHB and NHW decedents ≥ 25 years of age with a Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems code for influenza (J09-J11) and pneumonia (J12-J18) was used. Age-adjusted mortality rates (AAMRs) with 95% CIs were computed by race for Health & Human Services (HHS) regions and urbanization in NHBs and NHWs. RESULTS: In 1999 through 2018, there were 540,476 deaths among NHBs and NHWs 25 to 84 years of age. AAMRs were higher in NHBs than NHWs in each age group and in seven of 10 HHS regions. The greatest disparity was in HHS regions 2 (New York and New Jersey) and 9 (Arizona, California, Hawaii, and Nevada). In HHS region 2, NHBs (24.6; 95% CI, 24.1-25.1) were more likely to die than NHWs (15.7; 95% CI, 15.6-15.9). Similarly, in region 9, NHBs (23.2; 95% CI, 22.7-23.8) had higher mortality than NHWs (16.1; 95% CI, 15.9-16.2). Within these regions, disparities were greatest in the core of major metropolitan areas. A very high AAMR in NHBs was noted in large, central metropolitan areas of region 2: 28.2 (95% CI, 27.6-28.9). INTERPRETATION: In 1999 through 2018, the NHB-NHW disparity in AAMRs from influenza and pneumonia was greatest in central metropolitan areas of HHS regions 2 and 9.

Polymorphisms in Processing and Antigen Presentation-Related Genes and Their Association with Host Susceptibility to Influenza A/H1N1 2009 Pandemic in a Mexican Mestizo Population.

(1) Background: The influenza A/H1N1 pdm09 virus rapidly spread throughout the world. Despite the inflammatory and virus-degradation pathways described in the pathogenesis of influenza A virus (IAV) infection, little is known about the role of the single nucleotide polymorphisms (SNPs) in the genes involved in the processing and antigenic presentation-related mechanisms. (2) Methods: In this case-control study, we evaluated 17 SNPs in five genes (TAP1, TAP2, TAPBP, PSMB8, and PSMB9). One hundred and twenty-eight patients with influenza A/H1N1 infection (INF-P) and 111 healthy contacts (HC) were included; all of them are Mexican mestizo. (3) Results: In allele and genotype comparison, the rs241433/C allele (TAP2), as well as AG haplotype (rs3763365 and rs4148882), are associated with reduced risk for influenza A/H1N1 infection (p < 0.05). On the other hand, the rs2071888G allele (TAPBP) and GG haplotype (rs3763365 and rs9276810) are associated with a higher risk for influenza A/H1N1 infection. In addition, after adjustment for covariates, the association to a reduced risk for influenza A/H1N1 infection remains with rs241433/C allele (p < 0.0001, OR = 0.24, 95% CI = 0.13-0.43), and the association with TAPBP is also maintained with the G allele (p = 0.0095, OR = 1.89, 95% CI = 1.17-3.06) and GG genotype models (p < 0.05, OR = 2.18, 95% CI = 1.27-3.74). (4) Conclusion: The rs241433/C allele and AC genotype (TAP2) and the AG haplotype are associated with a reduced risk for influenza A/H1N1 infection. In addition, the rs2071888/G allele and GG genotype (TAPBP) and the GG haplotype are associated with a higher risk for developing influenza A/H1N1 infection in a Mexican mestizo population.

Historical Insights on Coronavirus Disease 2019 (COVID-19), the 1918 Influenza Pandemic, and Racial Disparities: Illuminating a Path Forward.

The coronavirus disease 2019 (COVID-19) pandemic is exacting a disproportionate toll on ethnic minority communities and magnifying existing disparities in health care access and treatment. To understand this crisis, physicians and public health researchers have searched history for insights, especially from a great outbreak approximately a century ago: the 1918 influenza pandemic. However, of the accounts examining the 1918 influenza pandemic and COVID-19, only a notable few discuss race. Yet, a rich, broader scholarship on race and epidemic disease as a "sampling device for social analysis" exists. This commentary examines the historical arc of the 1918 influenza pandemic, focusing on black Americans and showing the complex and sometimes surprising ways it operated, triggering particular responses both within a minority community and in wider racial, sociopolitical, and public health structures. This analysis reveals that critical structural inequities and health care gaps have historically contributed to and continue to compound disparate health outcomes among communities of color. Shifting from this context to the present, this article frames a discussion of racial health disparities through a resilience approach rather than a deficit approach and offers a blueprint for approaching the COVID-19 crisis and its afterlives through the lens of health equity.

High-dose influenza vaccination and mortality among predominantly male, white, senior veterans, United States, 2012/13 to 2014/15.

IntroductionIt is unclear whether high-dose influenza vaccine (HD) is more effective at reducing mortality among seniors.AimThis study aimed to evaluate the relative vaccine effectiveness (rVE) of HD. MethodsWe linked electronic medical record databases in the Veterans Health Administration (VHA) and Medicare administrative files to examine the rVE of HD vs standard-dose influenza vaccines (SD) in preventing influenza/pneumonia-associated and cardiorespiratory mortality among VHA-enrolled veterans 65 years or older during the 2012/13, 2013/14 and 2014/15 influenza seasons. A multivariable Cox proportional hazards model was performed on matched recipients of HD vs SD, based on vaccination time, location, age, sex, ethnicity and VHA priority level. ResultsAmong 569,552 person-seasons of observation, 207,574 (36%) were HD recipients and 361,978 (64%) were SD recipients, predominantly male (99%) and white (82%). Pooling findings from all three seasons, the adjusted rVE estimate of HD vs SD during the high influenza periods was 42% (95% confidence interval (CI): 24-59) against influenza/pneumonia-associated mortality and 27% (95% CI: 23-32) against cardiorespiratory mortality. Residual confounding was evident in both early and late influenza periods despite matching and multivariable adjustment. Excluding individuals with high 1-year predicted mortality at baseline reduced the residual confounding and yielded rVE of 36% (95% CI: 10-62) and 25% (95% CI: 12-38) against influenza/pneumonia-associated and cardiorespiratory mortality, respectively. These were confirmed by results from two-stage residual inclusion estimations.DiscussionThe HD was associated with a lower risk of influenza/pneumonia-associated and cardiorespiratory death in men during the high influenza period.

Decreased ratio of influenza-specific IgG versus IgM in response to influenza vaccination in antiretroviral-treated HIV-infected African Americans compared to Caucasians, and its direct correlation with the percentages of peripheral Tfh cells.

BACKGROUND: Racial differences have been observed in the rate of bacterial infection and disease progression in HIV. Here, we evaluate racial differences in seasonal influenza vaccine responses. METHODS: 16 healthy controls (9 Caucasians (CC) and 7 African Americans (AA)) and 26 antiretroviral therapy (ART)-treated aviremic HIV+ subjects (11 CC and 15 AA) were enrolled in the current study. Blood was collected at pre-vaccination (D0) and day 14 (D14) following seasonal influenza vaccination. Serologic responses were characterized in plasma by ELISA. B and T cells were assessed by flow cytometry ex vivo. RESULTS: The absolute counts of CD4+ CD3+ T cells and CD19+ B cells were similar in healthy controls and HIV-infected individuals, and similar in CC and AA in the two study groups. However, the percentage of peripheral T follicular helper (pTfh) cells was decreased in HIV+ AA compared to HIV+ CC. There were no racial differences in IgG antibody responses against vaccination in the two study groups. However, the ratio of anti-influenza-specific IgG versus IgM induction following vaccination was decreased in HIV+ AA compared to HIV+ CC, which was directly correlated with the percentages of pTfh cells. This racial difference and correlation were not demonstrable in healthy controls. CONCLUSION: Here we report that HIV + AA has decreased fold induction of IgG versus IgM after influenza vaccination, which may suggest impaired class-switching from IgM to IgG in AA HIV-infected individuals.

Modifiable and non-modifiable risk factors for COVID-19, and comparison to risk factors for influenza and pneumonia: results from a UK Biobank prospective cohort study.

OBJECTIVES: We aimed to investigate demographic, lifestyle, socioeconomic and clinical risk factors for COVID-19, and compared them to risk factors for pneumonia and influenza in UK Biobank. DESIGN: Cohort study. SETTING: UK Biobank. PARTICIPANTS: 49-83 year olds (in 2020) from a general population study. MAIN OUTCOME MEASURES: Confirmed COVID-19 infection (positive SARS-CoV-2 test). Incident influenza and pneumonia were obtained from primary care data. Poisson regression was used to study the association of exposure variables with outcomes. RESULTS: Among 235 928 participants, 397 had confirmed COVID-19. After multivariable adjustment, modifiable risk factors were higher body mass index and higher glycated haemoglobin (HbA1C) (RR 1.28 and RR 1.14 per SD increase, respectively), smoking (RR 1.39), slow walking pace as a proxy for physical fitness (RR 1.53), and use of blood pressure medications as a proxy for hypertension (RR 1.33). Higher forced expiratory volume in 1 s (FEV1) and high-density lipoprotein (HDL) cholesterol were both associated with lower risk (RR 0.84 and RR 0.83 per SD increase, respectively). Non-modifiable risk factors included male sex (RR 1.72), black ethnicity (RR 2.00), socioeconomic deprivation (RR 1.17 per SD increase in Townsend Index), and high cystatin C (RR 1.13 per SD increase). The risk factors overlapped with pneumonia somewhat, less so for influenza. The associations with modifiable risk factors were generally stronger for COVID-19, than pneumonia or influenza. CONCLUSION: These findings suggest that modification of lifestyle may help to reduce the risk of COVID-19 and could be a useful adjunct to other interventions, such as social distancing and shielding of high risk.

Seasonal Influenza Vaccination Patterns Among Pregnant Women in New Mexico.

INTRODUCTION: Seasonal influenza vaccination is recommended for pregnant women, but half of the pregnant women in the United States remain unvaccinated. Vaccine coverage in U.S.-Mexico border states has not been examined in depth even though risk factors for low vaccine coverage exist in these states, especially in the counties bordering Mexico. METHOD: Using 2012-2014 New Mexico (NM) Pregnancy Risk Assessment and Monitoring System data, this study examined the weighted annual seasonal influenza vaccination rates and the relationship of various factors to vaccination among NM residents with a live birth during those years. RESULTS: Among respondents, 53.8% were Hispanic, 15.7% were Native American, and 30.5% were non-Hispanic White. The vaccination rate in NM increased from 49.0% in 2012 to 64.8% in 2014. The adjusted odds of vaccination were higher among women whose health care provider recommended/offered vaccination during the year prior to delivery compared to women whose provider did not (AOR = 11.92, 95% confidence interval [CI: 9.86, 14.42]) and among those living in the U.S.-Mexico nonborder counties compared to those living in the border counties (AOR = 1.23, 95% CI [1.18, 1.25]). CONCLUSION: Efforts to increase the vaccination rate among pregnant women in border states should concentrate on health care providers and the highest risk women, such as those resident in the border region.

Influenza epidemiology in patients admitted to sentinel Australian hospitals in 2017: the Influenza Complications Alert Network (FluCAN).

The Influenza Complications Alert Network (FluCAN) is a sentinel-hospital-based surveillance program that operates at sites in all jurisdictions in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2017 influenza season. In this observational surveillance system, cases were defined as patients admitted to any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data are also collected on a frequency-matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 3 April to 31 October 2017 (the 2017 influenza season), 4,359 patients were admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 52% were elderly (≥65 years), 14% were children (<16 years), 6.5% were Aboriginal and Torres Strait Islander peoples, 1.6% were pregnant and 78% had chronic comorbidities. A significant proportion were due to influenza B (31%). Estimated vaccine coverage was 72% in the elderly (≥65 years), 50% in non-elderly adults with medical comorbidities and 24% in children (<16 years) with medical comorbidities. The estimated vaccine effectiveness (VE) in the target population was 23% (95% CI: 7%, 36%). There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2017, with case numbers more than twice that reported in 2016.

A Forgotten Danger: Burden of Influenza Mortality Among American Indians and Alaska Natives, 1999-2016.

American Indians and Alaska Natives (AI/ANs) are the only racial group in the United States that is identified as having a higher risk for developing influenza-related complications. As such, influenza-related mortality has consistently been one of the leading causes of death among AI/ANs. In addition, estimating influenza-related mortality is hampered by significant degrees of racial misclassification and underreporting of both morbidity and mortality data in the AI/AN population. Using data available from the Centers for Disease Control and Prevention, we analyzed influenza mortality by geography, race, gender, and age group to improve our understanding of the influenza burden on AI/AN communities. We found that while mortality rates generally declined across the AI/AN population, significant disparities exist between AI/ANs and non-Hispanic whites (NHWs). The greatest disparities occurred at the earliest stages of life, with mortality rates for AI/AN children younger than 5 years being more than 2 times higher than for NHW children. Similarly, the burden of influenza-related mortality among AI/AN adults emerged much earlier in life compared with NHWs. Perhaps most important, though, we found significant disparities in the geographic distribution of influenza-related mortality among AI/ANs. Because these are largely vaccine-preventable deaths, these results identify an area for targeted intervention to reduce the overall deaths attributable to influenza.

Association of Influenza-like Illness Activity With Hospitalizations for Heart Failure: The Atherosclerosis Risk in Communities Study.

Importance: Influenza is associated with an increased risk of cardiovascular events, but to our knowledge, few studies have explored the temporal association between influenza activity and hospitalizations, especially those caused by heart failure (HF). Objective: To explore the temporal association between influenza activity and hospitalizations due to HF and myocardial infarction (MI). We hypothesized that increased influenza activity would be associated with an increase in hospitalizations for HF and MI among adults in the community. Design, Setting, and Participants: As part of the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) study, a population-based study with hospitalizations sampled from 4 US communities, data were collected from 451 588 adults aged 35 to 84 years residing in the ARIC communities from annual cross-sectional stratified random samples of hospitalizations during October 2010 to September 2014. Exposures: Monthly influenza activity, defined as the percentage of patient visits to sentinel clinicians for influenza-like illness by state, as reported by the Centers for Disease Control and Prevention Surveillance Network. Main Outcomes and Measures: The monthly frequency of MI hospitalizations (n = 3541) and HF hospitalizations (n = 4321), collected through community surveillance and adjudicated as part of the ARIC Study. Results: Between October 2010 and September 2014, 2042 (47.3%) and 1599 (45.1%) of the sampled patients who were hospitalized for HF and MI, respectively, were women and 2391 (53.3%) and 2013 (57.4%) were white, respectively. A 5% monthly absolute increase in influenza activity was associated with a 24% increase in HF hospitalization rates, standardized to the total population in each community, within the same month after adjusting for region, season, race/ethnicity, sex, age, and number of MI/HF hospitalizations from the month before (incidence rate ratio, 1.24; 95% CI, 1.11-1.38; P < .001), while overall influenza activity was not significantly associated with MI hospitalizations (incidence rate ratio, 1.02; 95% CI, 0.90-1.17; P = .72). Influenza activity in the months before hospitalization was not associated with either outcome. Our model suggests that in a month with high influenza activity, approximately 19% of HF hospitalizations (95% CI, 10%-28%) could be attributable to influenza. Conclusions and Relevance: Influenza activity was temporally associated with an increase in HF hospitalizations across 4 influenza seasons. These data suggest that influenza may contribute to the risk of HF hospitalization in the general population.

Testing for Urinary Tract Infection in the Influenza/Respiratory Syncytial Virus-Positive Febrile Infant Aged 2 to 12 Months.

OBJECTIVE: Infants 12 months or younger with influenza and respiratory syncytial virus (RSV) commonly present to the emergency department (ED) with fever. Previous publications have recommended that these patients have a urinalysis and urine culture performed. We aimed to assess the prevalence of urinary tract infection (UTI) in febrile RSV/influenza positive infants aged 2 to 12 months presenting to the ED. We also examined whether the 2011 American Academy of Pediatrics (AAP) UTI clinical practice guidelines could be used to identify patients at lower risk of UTI. METHODS: This was a retrospective chart review examining all infants aged 2 to 12 months with a documented fever of higher than 38°C who presented to our ED from 2009 to 2013 and tested positive for influenza and/or RSV. RESULTS: One thousand seven hundred twenty-four patients were found to meet our inclusion criteria. Of these, 98 were excluded because of known urinary tract anomaly or systemic antibiotic use in the 24 hours preceding evaluation. Of those patients remaining, 10 (0.62%) of 1626 had positive urine cultures (95% confidence interval, 0.3%-1.1%), and 8 (0.49%) of 1626 (95% confidence interval, 0.2%-0.97%) had positive urine cultures with positive urinalyses as defined in the 2011 AAP UTI clinical practice guidelines. All subjects with positive urine cultures as defined by the AAP had risk factors for UTI that placed their risk for UTI above 1%. CONCLUSIONS: Our population of 2- to 12-month-old febrile infants with positive influenza/RSV testing, who did not have risk factors to make their risk of UTI higher than 1%, may not have required evaluation with urinalysis or urine culture.

Natality Decline and Spatial Variation in Excess Death Rates During the 1918-1920 Influenza Pandemic in Arizona, United States.

A large body of epidemiologic research has concentrated on the 1918 influenza pandemic, but more work is needed to understand spatial variation in pandemic mortality and its effects on natality. We collected and analyzed 35,151 death records from Arizona for 1915-1921 and 21,334 birth records from Maricopa county for 1915-1925. We estimated the number of excess deaths and births before, during, and after the pandemic period, and we found a significant decline in the number of births occurring 9-11 months after peak pandemic mortality. Moreover, excess mortality rates were highest in northern Arizona counties, where Native Americans were historically concentrated, suggesting a link between ethnic and/or sociodemographic factors and risk of pandemic-related death. The relationship between birth patterns and pandemic mortality risk should be further studied at different spatial scales and in different ethnic groups.

Influenza in New Zealand Before 1918: A Preliminary Report.

In the present article, I aimed to test the hypothesis that possible fatal immunological reactions to the A/H1N1 virus of the 1918 "Spanish" influenza pandemic were the result of previous exposure to the A/H3N8 virus of the 1890-1892 "Russian" influenza pandemic. Using newspapers and official death records to reconstruct mortality peaks from influenza and excess pneumonia deaths in New Zealand before 1918 enabled comparisons with peaks of influenza mortality by age in 1918 from individual death records. For males, mortality peaks in the 1885, 1890-1892, 1894, and 1898 influenza outbreaks appeared to match those from the 1918 pandemic. For females, peaks of deaths in 1918 corresponded to those from the influenza outbreaks of 1887 and 1890-1892. The highest mortality rates for both sexes were among those 28-32 years of age. Although they lend strong support to the hypothesis of fatal immunological reactions derived from early exposure to a different influenza virus, the results from this study also raise more questions: Given that the A/H1N1 virus of 1918 was exceptionally virulent, why did so few children 5-15 years of age die from it? Influenza normally kills only the very young and the very old. In addition, why did twice as many European males as females die in the young-adult age groups, whereas Maori males and females died at almost identical rates?

Association between IFITM3 rs12252 polymorphism and influenza susceptibility and severity: A meta-analysis.

Intrinsic host susceptibility to viral infections plays a major role in determining infection severity in different individuals. In human influenza virus infections, multiple genetic association studies have identified specific human gene variants that might contribute to enhanced susceptibility or resistance to influenza. Recent studies suggested, the rs12252 T > C polymorphism in the interferon-inducible transmembrane protein 3 (IFITM3) gene might be associated with susceptibility to severe influenza. However, the studies reported conflicting and inconclusive results. To resolve the controversy, we conducted a systematic meta-analysis to evaluate the role of the IFITM3 rs12252 polymorphism in influenza susceptibility and severity, including twelve studies published before February 19, 2018 with a total 16,263 subjects (1836 influenza cases and 14,427 controls). Odds ratios (OR) and 95% confidence intervals were used to assess the strength of the association. Our results indicated increased risk of both severe and mild influenza in subjects carrying the IFITM3 rs12252 polymorphism in the allele contrast C vs. T: OR (severe) = 1.69, 95% CI = 1.23-2.33, P = 0.001, and OR (mild) = 1.46, 95% CI = 1.13-1.87, P = 0.004. Similar results were obtained in the homozygote comparison and dominant model. Stratified analyses by ethnicity revealed increased risk of severe influenza in both the White and East Asian populations, but significant association with mild influenza was found only in the White population. Overall, our meta-analysis suggests a significant association between the IFITM3 rs12252 polymorphism and the risk of influenza in both the White and East Asian populations.