Publications by authors named "Joshua G Petrie"

67 Publications

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

Influenza Other Respir Viruses 2021 Nov 25. Epub 2021 Nov 25.

Michigan Influenza Center, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

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.
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http://dx.doi.org/10.1111/irv.12944DOI Listing
November 2021

SARS-CoV-2 Genomic Surveillance Reveals Little Spread From a Large University Campus to the Surrounding Community.

Open Forum Infect Dis 2021 Nov 17;8(11):ofab518. Epub 2021 Nov 17.

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.

Background: Coronavirus disease 2019 (COVID-19) has had high incidence rates at institutions of higher education (IHE) in the United States, but the transmission dynamics in these settings are poorly understood. It remains unclear to what extent IHE-associated outbreaks have contributed to transmission in nearby communities.

Methods: We implemented high-density prospective genomic surveillance to investigate these dynamics at the University of Michigan and the surrounding community during the Fall 2020 semester (August 16-November 24). We sequenced complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from 1659 individuals, including 468 students, representing 20% of cases in students and 25% of total cases in Washtenaw County over the study interval.

Results: Phylogenetic analysis identified >200 introductions into the student population, most of which were not related to other student cases. There were 2 prolonged student transmission clusters, of 115 and 73 individuals, that spanned multiple on-campus residences. Remarkably, <5% of nonstudent genomes were descended from student clusters, and viral descendants of student cases were rare during a subsequent wave of infections in the community.

Conclusions: The largest outbreaks among students at the University of Michigan did not significantly contribute to the rise in community cases in Fall 2020. These results provide valuable insights into SARS-CoV-2 transmission dynamics at the regional level.
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http://dx.doi.org/10.1093/ofid/ofab518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600169PMC
November 2021

Health Care-Acquired Viral Respiratory Diseases.

Infect Dis Clin North Am 2021 12;35(4):1055-1075

Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, 1161 21st Avenue South, A-2200 MCN, Nashville, TN 37232, USA. Electronic address:

Health care-acquired viral respiratory infections are common and cause increased patient morbidity and mortality. Although the threat of viral respiratory infection has been underscored by the coronavirus disease 2019 (COVID-19) pandemic, respiratory viruses have a significant impact in health care settings even under normal circumstances. Studies report decreased nosocomial transmission when aggressive infection control measures are implemented, with more success noted when using a multicomponent approach. Influenza vaccination of health care personnel furthers decrease rates of transmission; thus, mandatory vaccination is becoming more common. This article discusses the epidemiology, transmission, and control of health care-associated respiratory viral infections.
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http://dx.doi.org/10.1016/j.idc.2021.07.007DOI Listing
December 2021

Agreement between state registry, health record, and self-report of influenza vaccination.

Vaccine 2021 09 9;39(38):5341-5345. Epub 2021 Aug 9.

Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, United States.

Background: Documentation of influenza vaccination, including the specific product received, is critical to estimate annual vaccine effectiveness (VE).

Methods: We assessed performance of the Michigan Care Improvement Registry (MCIR) in defining influenza vaccination status relative to documentation by provider records or self-report among subjects enrolled in a study of influenza VE from 2011 through 2019.

Results: The specificity and positive predictive value of MCIR were high; however, >10% of vaccinations were identified only by other sources each season. The proportion of records captured by MCIR increased from a low of 67% in 2013-2014 to a high of 89% in 2018-2019, largely driven by increased capture of vaccination among adults.

Conclusions: State vaccine registries, such as MCIR, are important tools for documenting influenza vaccination, including the specific product received. However, incomplete capture suggests that documentation from other sources and self-report should be used in combination with registries to reduce misclassification.
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http://dx.doi.org/10.1016/j.vaccine.2021.07.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452147PMC
September 2021

Coronavirus disease 2019 (COVID-19) Versus Influenza in Hospitalized Adult Patients in the United States: Differences in Demographic and Severity Indicators.

Clin Infect Dis 2021 12;73(12):2240-2247

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Background: Novel coronavirus disease 2019 (COVID-19) is frequently compared with influenza. The Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) conducts studies on the etiology and characteristics of U.S. hospitalized adults with influenza. It began enrolling patients with COVID-19 hospitalizations in March 2020. Patients with influenza were compared with those with COVID-19 in the first months of the U.S. epidemic.

Methods: Adults aged ≥ 18 years admitted to hospitals in 4 sites with acute respiratory illness were tested by real-time reverse transcription polymerase chain reaction for influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19. Demographic and illness characteristics were collected for influenza illnesses during 3 seasons 2016-2019. Similar data were collected on COVID-19 cases admitted before June 19, 2020.

Results: Age groups hospitalized with COVID-19 (n = 914) were similar to those admitted with influenza (n = 1937); 80% of patients with influenza and 75% of patients with COVID-19 were aged ≥50 years. Deaths from COVID-19 that occurred in younger patients were less often related to underlying conditions. White non-Hispanic persons were overrepresented in influenza (64%) compared with COVID-19 hospitalizations (37%). Greater severity and complications occurred with COVID-19 including more ICU admissions (AOR = 15.3 [95% CI: 11.6, 20.3]), ventilator use (AOR = 15.6 [95% CI: 10.7, 22.8]), 7 additional days of hospital stay in those discharged alive, and death during hospitalization (AOR = 19.8 [95% CI: 12.0, 32.7]).

Conclusions: While COVID-19 can cause a respiratory illness like influenza, it is associated with significantly greater severity of illness, longer hospital stays, and higher in-hospital deaths.
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http://dx.doi.org/10.1093/cid/ciab123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195096PMC
December 2021

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

Clin Infect Dis 2021 10;73(7):1248-1256

University of Michigan School of Public Health, Department of Epidemiology, Ann Arbor, Michigan, USA.

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.
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http://dx.doi.org/10.1093/cid/ciab395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492146PMC
October 2021

Severe Acute Respiratory Syndrome Coronavirus 2 Total and Subgenomic RNA Viral Load in Hospitalized Patients.

J Infect Dis 2021 10;224(8):1287-1293

Division of Infectious Disease, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Background: Previous studies demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA can be detected for weeks after infection. The significance of this finding is unclear and, in most patients, does not represent active infection. Detection of subgenomic RNA has been proposed to represent productive infection and may be a useful marker for monitoring infectivity.

Methods: We used quantitative reverse-transcription polymerase chain reaction (RT-qPCR) to quantify total and subgenomic nucleocapsid (sgN) and envelope (sgE) transcripts in 185 SARS-CoV-2-positive nasopharyngeal swab samples collected on hospital admission and to relate to symptom duration.

Results: We find that all transcripts decline at the same rate; however, sgE becomes undetectable before other transcripts. The median duration of symptoms to a negative test is 14 days for sgE and 25 days for sgN. There is a linear decline in subgenomic compared to total RNA, suggesting that subgenomic transcript copy number is dependent on copy number of total transcripts. The mean difference between total and sgN is 16-fold and the mean difference between total and sgE is 137-fold. This relationship is constant over duration of symptoms, allowing prediction of subgenomic copy number from total copy number.

Conclusions: Subgenomic RNA may be no more useful in determining infectivity than a copy number threshold determined for total RNA.
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http://dx.doi.org/10.1093/infdis/jiab215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083294PMC
October 2021

Temporal dynamics of SARS-CoV-2 mutation accumulation within and across infected hosts.

PLoS Pathog 2021 04 7;17(4):e1009499. Epub 2021 Apr 7.

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.

Analysis of SARS-CoV-2 genetic diversity within infected hosts can provide insight into the generation and spread of new viral variants and may enable high resolution inference of transmission chains. However, little is known about temporal aspects of SARS-CoV-2 intrahost diversity and the extent to which shared diversity reflects convergent evolution as opposed to transmission linkage. Here we use high depth of coverage sequencing to identify within-host genetic variants in 325 specimens from hospitalized COVID-19 patients and infected employees at a single medical center. We validated our variant calling by sequencing defined RNA mixtures and identified viral load as a critical factor in variant identification. By leveraging clinical metadata, we found that intrahost diversity is low and does not vary by time from symptom onset. This suggests that variants will only rarely rise to appreciable frequency prior to transmission. Although there was generally little shared variation across the sequenced cohort, we identified intrahost variants shared across individuals who were unlikely to be related by transmission. These variants did not precede a rise in frequency in global consensus genomes, suggesting that intrahost variants may have limited utility for predicting future lineages. These results provide important context for sequence-based inference in SARS-CoV-2 evolution and epidemiology.
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http://dx.doi.org/10.1371/journal.ppat.1009499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055005PMC
April 2021

Coronavirus Occurrence in the Household Influenza Vaccine Evaluation (HIVE) Cohort of Michigan Households: Reinfection Frequency and Serologic Responses to Seasonal and Severe Acute Respiratory Syndrome Coronaviruses.

J Infect Dis 2021 07;224(1):49-59

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Background: We investigated frequency of reinfection with seasonal human coronaviruses (HCoVs) and serum antibody response following infection over 8 years in the Household Influenza Vaccine Evaluation (HIVE) cohort.

Methods: Households were followed annually for identification of acute respiratory illness with reverse-transcription polymerase chain reaction-confirmed HCoV infection. Serum collected before and at 2 time points postinfection were tested using a multiplex binding assay to quantify antibody to seasonal, severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins and SARS-CoV-2 spike subdomains and N protein.

Results: Of 3418 participants, 40% were followed for ≥3 years. A total of 1004 HCoV infections were documented; 303 (30%) were reinfections of any HCoV type. The number of HCoV infections ranged from 1 to 13 per individual. The mean time to reinfection with the same type was estimated at 983 days for 229E, 578 days for HKU1, 615 days for OC43, and 711 days for NL63. Binding antibody levels to seasonal HCoVs were high, with little increase postinfection, and were maintained over time. Homologous, preinfection antibody levels did not significantly correlate with odds of infection, and there was little cross-response to SARS-CoV-2 proteins.

Conclusions: Reinfection with seasonal HCoVs is frequent. Binding anti-spike protein antibodies do not correlate with protection from seasonal HCoV infection.
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http://dx.doi.org/10.1093/infdis/jiab161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083771PMC
July 2021

Differences between Frequentist and Bayesian inference in routine surveillance for influenza vaccine effectiveness: a test-negative case-control study.

BMC Public Health 2021 03 16;21(1):516. Epub 2021 Mar 16.

Kaiser Permanente Washington Health Research Institute, 1730 Minor Ave, Suite 1600, Seattle, WA, 98101-1448, USA.

Background: Routine influenza vaccine effectiveness (VE) surveillance networks use frequentist methods to estimate VE. With data from more than a decade of VE surveillance from diverse global populations now available, using Bayesian methods to explicitly account for this knowledge may be beneficial. This study explores differences between Bayesian vs. frequentist inference in multiple seasons with varying VE.

Methods: We used data from the United States Influenza Vaccine Effectiveness (US Flu VE) Network. Ambulatory care patients with acute respiratory illness were enrolled during seasons of varying observed VE based on traditional frequentist methods. We estimated VE against A(H1N1)pdm in 2015/16, dominated by A(H1N1)pdm; against A(H3N2) in 2017/18, dominated by A(H3N2); and compared VE for live attenuated influenza vaccine (LAIV) vs. inactivated influenza vaccine (IIV) among children aged 2-17 years in 2013/14, also dominated by A(H1N1)pdm. VE was estimated using both frequentist and Bayesian methods using the test-negative design. For the Bayesian estimates, prior VE distributions were based on data from all published test-negative studies of the same influenza type/subtype available prior to the season of interest.

Results: Across the three seasons, 16,342 subjects were included in the analyses. For 2015/16, frequentist and Bayesian VE estimates were essentially identical (41% each). For 2017/18, frequentist and Bayesian estimates of VE against A(H3N2) viruses were also nearly identical (26% vs. 23%, respectively), even though the presence of apparent antigenic match could potentially have pulled Bayesian estimates upward. Precision of estimates was similar between methods in both seasons. Frequentist and Bayesian estimates diverged for children in 2013/14. Under the frequentist approach, LAIV effectiveness was 62 percentage points lower than IIV, while LAIV was only 27 percentage points lower than IIV under the Bayesian approach.

Conclusion: Bayesian estimates of influenza VE can differ from frequentist estimates to a clinically meaningful degree when VE diverges substantially from previous seasons.
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http://dx.doi.org/10.1186/s12889-021-10543-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968177PMC
March 2021

SARS-CoV-2 Total and Subgenomic RNA Viral Load in Hospitalized Patients.

medRxiv 2021 Mar 1. Epub 2021 Mar 1.

Division of Infectious Disease, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Understanding viral load in patients infected with SARS-CoV-2 is critical to epidemiology and infection control. Previous studies have demonstrated that SARS-CoV-2 RNA can be detected for many weeks after symptom onset. The clinical significance of this finding is unclear and, in most patients, likely does not represent active infection. There are, however, patients who shed infectious virus for weeks. Detection of subgenomic RNA transcripts expressed by SARS-CoV-2 has been proposed to represent productive infection and may be a tractable marker for monitoring infectivity. Here, we use RT-PCR to quantify total and subgenomic nucleocapsid (N) and envelope (E) transcripts in 190 SARS-CoV-2 positive samples collected on hospital admission. We relate these findings to duration of symptoms. We find that all transcripts decline at the same rate; however, subgenomic E becomes undetectable before other transcripts. In Kaplan-Meier analysis the median duration of symptoms to a negative test is 14 days for sgE and 25 days for sgN. There is a linear decline in subgenomic RNA compared to total RNA suggesting subgenomic transcript copy number is highly dependent on copy number of total transcripts. The mean difference between total N and subgenomic N is 16-fold (4.0 cycles) and the mean difference between total E and sub-genomic E is 137-fold (7.1 cycles). This relationship is constant over duration of symptoms allowing prediction of subgenomic copy number from total copy number. Although Subgenomic E is undetectable at a time that may more closely reflect the duration of infectivity, its utility in determining active infection may be no more useful than a copy number threshold determined for total transcripts.
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http://dx.doi.org/10.1101/2021.02.25.21252493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941648PMC
March 2021

Donor to recipient transmission of SARS-CoV-2 by lung transplantation despite negative donor upper respiratory tract testing.

Am J Transplant 2021 08 15;21(8):2885-2889. Epub 2021 Mar 15.

Division of Infectious Disease, Department of Internal Medicine and Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan.

We describe a case of proven transmission of SARS-CoV-2 from lung donor to recipient. The donor had no clinical history or findings suggestive of infection with SARS-CoV-2 and tested negative by reverse transcriptase polymerase chain reaction (RT-PCR) on a nasopharyngeal (NP) swab obtained within 48 h of procurement. Lower respiratory tract testing was not performed. The recipient developed fever, hypotension, and pulmonary infiltrates on posttransplant day (PTD) 3, and RT-PCR testing for SARS-CoV-2 on an NP swab specimen was non-reactive, but positive on bronchoalveolar lavage (BAL) fluid. One thoracic surgeon present during the transplantation procedure developed COVID-19. Sequence analysis of isolates from donor BAL fluid (obtained at procurement), the recipient, and the infected thoracic surgeon proved donor origin of recipient and health-care worker (HCW) infection. No other organs were procured from this donor. Transplant centers and organ procurement organizations should perform SARS-CoV-2 testing of lower respiratory tract specimens from potential lung donors, and consider enhanced personal protective equipment for HCWs involved in lung procurement and transplantation.
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http://dx.doi.org/10.1111/ajt.16532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014875PMC
August 2021

Temporal dynamics of SARS-CoV-2 mutation accumulation within and across infected hosts.

bioRxiv 2021 Jan 20. Epub 2021 Jan 20.

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Analysis of SARS-CoV-2 genetic diversity within infected hosts can provide insight into the generation and spread of new viral variants and may enable high resolution inference of transmission chains. However, little is known about temporal aspects of SARS-CoV-2 intrahost diversity and the extent to which shared diversity reflects convergent evolution as opposed to transmission linkage. Here we use high depth of coverage sequencing to identify within-host genetic variants in 325 specimens from hospitalized COVID-19 patients and infected employees at a single medical center. We validated our variant calling by sequencing defined RNA mixtures and identified a viral load threshold that minimizes false positives. By leveraging clinical metadata, we found that intrahost diversity is low and does not vary by time from symptom onset. This suggests that variants will only rarely rise to appreciable frequency prior to transmission. Although there was generally little shared variation across the sequenced cohort, we identified intrahost variants shared across individuals who were unlikely to be related by transmission. These variants did not precede a rise in frequency in global consensus genomes, suggesting that intrahost variants may have limited utility for predicting future lineages. These results provide important context for sequence-based inference in SARS-CoV-2 evolution and epidemiology.
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http://dx.doi.org/10.1101/2021.01.19.427330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836113PMC
January 2021

Low Influenza Vaccine Effectiveness Against A(H3N2)-Associated Hospitalizations in 2016-2017 and 2017-2018 of the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN).

J Infect Dis 2021 06;223(12):2062-2071

Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: The 2016-2017 and 2017-2018 influenza seasons were notable for the high number of hospitalizations for influenza A(H3N2) despite vaccine and circulating strain match.

Methods: We evaluated vaccine effectiveness (VE) against hospitalization in the test-negative HAIVEN study. Nasal-throat swabs were tested by quantitative reverse transcription polymerase chain reaction (RT-PCR) for influenza and VE was determined based on odds of vaccination by generalized estimating equations. Vaccine-specific antibody was measured in a subset of enrollees.

Results: A total of 6129 adults were enrolled from 10 hospitals. Adjusted VE against A(H3N2) was 22.8% (95% confidence interval [CI], 8.3% to 35.0%), pooled across both years and 49.4% (95% CI, 34.3% to 61.1%) against B/Yamagata. In 2017-2018, the A(H3N2) VE point estimate for the cell-based vaccine was 43.0% (95% CI, -36.3% to 76.1%; 56 vaccine recipients) compared to 24.0% (95% CI, 3.9% to 39.9%) for egg-based vaccines. Among 643 with serology data, hemagglutinin antibodies against the egg-based A(H3N2) vaccine strain were increased in influenza-negative individuals.

Conclusions: Low VE for the A/Hong Kong/4801/2014 vaccine virus in both A(H3N2) seasons emphasizes concerns for continued changes in H3N2 antigenic epitopes, including changes that may impact glycosylation and ultimately reduce VE.
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http://dx.doi.org/10.1093/infdis/jiaa685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205618PMC
June 2021

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

Influenza Other Respir Viruses 2021 03 26;15(2):227-234. Epub 2020 Oct 26.

Department of Epidemiology, University of Michigan School of Public Health, 1415 Washingon Heights, Ann Arbor, MI, 48109, USA.

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.
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http://dx.doi.org/10.1111/irv.12822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902250PMC
March 2021

Hospital Associated Respiratory Virus Infection in Children and Adults: It Does Not Just Occur During Cold and Flu Season.

Open Forum Infect Dis 2020 Jun 26;7(6):ofaa200. Epub 2020 May 26.

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Hospital-associated respiratory virus infections (HARVI) are an underappreciated source of morbidity and mortality. We examined HARVI incidence and clinical respiratory virus testing practices in a cohort of hospitalized patients with acute respiratory illness. HARVI were identified in patients of all ages, both during and outside of the influenza season.
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http://dx.doi.org/10.1093/ofid/ofaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314589PMC
June 2020

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

J Infect Dis 2020 06;222(1):9-16

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

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.
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http://dx.doi.org/10.1093/infdis/jiaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184402PMC
June 2020

Influenza B Viruses Exhibit Lower Within-Host Diversity than Influenza A Viruses in Human Hosts.

J Virol 2020 02 14;94(5). Epub 2020 Feb 14.

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

Influenza B virus (IBV) undergoes seasonal antigenic drift more slowly than influenza A virus, but the reasons for this difference are unclear. While the evolutionary dynamics of influenza viruses play out globally, they are fundamentally driven by mutation, reassortment, drift, and selection at the level of individual hosts. These processes have recently been described for influenza A virus, but little is known about the evolutionary dynamics of IBV during individual infections and transmission events. Here, we define the within-host evolutionary dynamics of IBV by sequencing virus populations from naturally infected individuals enrolled in a prospective, community-based cohort over 8,176 person-seasons of observation. Through analysis of high depth-of-coverage sequencing data from samples from 91 individuals with influenza B, we find that IBV accumulates lower genetic diversity than previously observed for influenza A virus during acute infections. Consistent with studies of influenza A viruses, the within-host evolution of IBVs is characterized by purifying selection and the general absence of widespread positive selection of within-host variants. Analysis of shared genetic diversity across 15 sequence-validated transmission pairs suggests that IBV experiences a tight transmission bottleneck similar to that of influenza A virus. These patterns of local-scale evolution are consistent with the lower global evolutionary rate of IBV. The evolution of influenza virus is a significant public health problem and necessitates the annual evaluation of influenza vaccine formulation to keep pace with viral escape from herd immunity. Influenza B virus is a serious health concern for children, in particular, yet remains understudied compared to influenza A virus. Influenza B virus evolves more slowly than influenza A virus, but the factors underlying this are not completely understood. We studied how the within-host diversity of influenza B virus relates to its global evolution by sequencing viruses from a community-based cohort. We found that influenza B virus populations have lower within-host genetic diversity than influenza A virus and experience a tight genetic bottleneck during transmission. Our work provides insights into the varying dynamics of influenza viruses in human infection.
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http://dx.doi.org/10.1128/JVI.01710-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022338PMC
February 2020

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

Am J Epidemiol 2020 03;189(3):250-260

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan.

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.
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http://dx.doi.org/10.1093/aje/kwz248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567846PMC
March 2020

HAI and NAI titer correlates of inactivated and live attenuated influenza vaccine efficacy.

BMC Infect Dis 2019 May 22;19(1):453. Epub 2019 May 22.

Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, 48109, USA.

Background: High hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk. While repeated influenza vaccination reduces seroresponse, vaccine effectiveness is not always reduced.

Methods: During the 2007-2008 influenza season, a randomized, placebo-controlled trial (FLUVACS) evaluated the efficacies of live-attenuated (LAIV) and inactivated influenza vaccines (IIV) among healthy adults aged 18-49 in Michigan; IIV vaccine efficacy (VE) and LAIV VE against influenza disease were estimated at 68% and 36%. Using the principal stratification/VE moderation framework, we analyzed data from this trial to assess how each VE varied by HAI or NAI responses to vaccination observed for vaccinated individuals and predicted counterfactually for placebo recipients. We also assessed how each VE varied with pre-vaccination/baseline variables including HAI titer, NAI titer, and vaccination history.

Results: IIV VE appeared to increase with Day 30 post-vaccination HAI titer, albeit not significantly (p=0.20 and estimated VE 14.4%, 70.5%, and 85.5% at titer below the assay lower quantification limit, 512, and 4096 (maximum)). Moreover, IIV VE increased significantly with Day 30 post-vaccination NAI titer (p=0.040), with estimated VE zero at titer 10 and 92.2% at highest titer 640. There was no evidence that fold-change in post-vaccination HAI or NAI titer associated with IIV VE (p=0.76, 0.38). For LAIV, there was no evidence that VE associated with post-vaccination or fold-rise HAI or NAI titers (p-values >0.40). For IIV, VE increased with increasing baseline NAI titer in those previously vaccinated, but VE decreased with increasing baseline NAI titer in those previously unvaccinated. In contrast, for LAIV, VE did not depend on previous vaccination or baseline HAI or NAI titer.

Conclusions: Future efficacy trials should measure baseline and post-vaccination antibody titers in both vaccine and control/placebo recipients, enabling analyses to better elucidate correlates of vaccine- and natural-protection.

Trial Registration: ClinicalTrials.gov NCT00538512. October 1, 2007.
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http://dx.doi.org/10.1186/s12879-019-4049-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530189PMC
May 2019

Comparison of a frailty short interview to a validated frailty index in adults hospitalized for acute respiratory illness.

Vaccine 2019 06 18;37(29):3849-3855. Epub 2019 May 18.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN, United States.

Background: Frailty is an important physiologic factor in studies of influenza and influenza vaccines carried out in older adults and hospitalized populations. Unfortunately, comprehensive assessments of frailty requiring physical assessments and extensive medical record review are not often feasible in time- and resource-limited settings common to studies of influenza and influenza vaccines.

Methods: We developed a 5-question frailty short interview, and implemented it in a multicenter, hospital-based study of influenza over two years. Frailty status defined by the frailty short interview was compared to a validated frailty index based on medical record review of 59 parameters. Agreement between the two frailty measures was assessed, and multivariable linear regression models were used to explore differences between the measures. The association between each frailty measure and likelihood of influenza vaccination was also assessed.

Results: During the 2015-2016 and 2016-2017 influenza seasons, 2070 adult patients hospitalized with acute respiratory illness were enrolled and included in analyses. Frailty was frequently identified in the study population; 43% of participants were defined as frail by the frailty short interview and 32% by frailty index. Responses to the frailty short interview were only moderately correlated with the frailty index, and agreement between the two frailty measures was low. Women were more likely to be defined as frail by the frailty short interview than men. White individuals were more likely than other races to be defined as frail by the frailty index. Increasing frailty index was associated with increased likelihood of influenza vaccination, but the frailty short interview was not associated with vaccination.

Conclusions: The frailty short interview provided a feasible and consistent measure of frailty across study hospitals and study years. However, its modest correlation with the frailty index and differential association with likelihood of influenza vaccination highlight differences in the conceptualization of frailty.
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http://dx.doi.org/10.1016/j.vaccine.2019.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564875PMC
June 2019

Improving Influenza Vaccine Effectiveness: Ways to Begin Solving the Problem.

Clin Infect Dis 2019 10;69(10):1824-1826

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor.

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http://dx.doi.org/10.1093/cid/ciz416DOI Listing
October 2019

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

Vaccine 2019 02 7;37(10):1284-1292. Epub 2019 Feb 7.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, United States.

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.
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http://dx.doi.org/10.1016/j.vaccine.2019.01.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595494PMC
February 2019

Effects of Sequential Influenza A(H1N1)pdm09 Vaccination on Antibody Waning.

J Infect Dis 2019 06;220(1):12-19

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor.

Background: Antibody waning following influenza vaccination has been repeatedly evaluated, but waning has rarely been studied in the context of longitudinal vaccination history.

Methods: We developed a Bayesian hierarchical model to assess the effects of sequential influenza A(H1N1)pdm09 vaccination on hemagglutination inhibition antibody boosting and waning in a longitudinal cohort of older children and adults from 2011 to 2016, a period during which the A(H1N1)pdm09 vaccine strain did not change.

Results: Antibody measurements from 2057 serum specimens longitudinally collected from 388 individuals were included. Average postvaccination antibody titers were similar across successive vaccinations, but the rate of antibody waning increased with each vaccination. The antibody half-life was estimated to decrease from 32 months (95% credible interval [CrI], 22-61 months) following first vaccination to 9 months (95% CrI, 7-15 months) following a seventh vaccination.

Conclusions: Although the rate of antibody waning increased with successive vaccination, the estimated antibody half-life was longer than a typical influenza season even among the most highly vaccinated. This supports current recommendations for vaccination at the earliest opportunity. Patterns of boosting and waning might be different with the influenza A(H3N2) subtype, which evolves more rapidly and has been most associated with reduced effectiveness following repeat vaccination.
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http://dx.doi.org/10.1093/infdis/jiz055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548909PMC
June 2019

Antibodies Against Egg- and Cell-Grown Influenza A(H3N2) Viruses in Adults Hospitalized During the 2017-2018 Influenza Season.

J Infect Dis 2019 05;219(12):1904-1912

Department of Epidemiology, University of Michigan School of Public Health.

Background: Influenza vaccine effectiveness was low in 2017-2018, yet circulating influenza A(H3N2) viruses were antigenically similar to cell-grown vaccine strains. Notably, most influenza vaccines are egg propagated.

Methods: Serum specimens were collected shortly after illness onset from 15 influenza A(H3N2) virus-infected cases and 15 uninfected hospitalized adults. Geometric mean titers against egg- and cell-grown influenza A/Hong Kong/4801/2014(H3N2) virus vaccine strains and representative circulating viruses (including A/Washington/16/2017) were determined by a microneutralization (MN) assay. Independent effects of strain-specific titers on susceptibility were estimated by logistic regression.

Results: MN titers against egg-grown influenza A/Hong Kong virus were significantly higher among vaccinated individuals (173 vs 41; P = 0.01). In unadjusted models, a 2-fold increase in titers against egg-grown influenza A/Hong Kong virus was not significantly protective (29% reduction; P = .09), but a similar increase in the cell-grown influenza A/Washington virus antibody titer (3C.2a2) was protective (60% reduction; P = .02). Higher egg-grown influenza A/Hong Kong virus titers were not significantly associated with infection, when adjusted for antibody titers against influenza A/Washington virus (15% reduction; P = .61). A 54% reduction in the odds of infection was observed with a 2-fold increase in titer against influenza A/Washington virus (P = not significant), adjusted for the titer against egg-grown influenza A/Hong Kong virus titer.

Conclusion: Individuals vaccinated in 2017-2018 had high antibody titers against the egg-adapted vaccine strain and lower titers against circulating viruses. Titers against circulating but not egg-adapted strains were correlated with protection.
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http://dx.doi.org/10.1093/infdis/jiz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534188PMC
May 2019

Assessing the Protective Potential of H1N1 Influenza Virus Hemagglutinin Head and Stalk Antibodies in Humans.

J Virol 2019 04 3;93(8). Epub 2019 Apr 3.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Seasonal influenza viruses are a major cause of human disease worldwide. Most neutralizing antibodies (Abs) elicited by influenza viruses target the head domain of the hemagglutinin (HA) protein. Anti-HA head Abs can be highly potent, but they have limited breadth since the HA head is variable. There is great interest in developing new universal immunization strategies that elicit broadly neutralizing Abs against conserved regions of HA, such as the stalk domain. Although HA stalk Abs can provide protection in animal models, it is unknown if they are present at sufficient levels in humans to provide protection against naturally acquired influenza virus infections. Here, we quantified H1N1 HA head- and stalk-specific Abs in 179 adults hospitalized during the 2015-2016 influenza virus season. We found that HA head Abs, as measured by hemagglutinin inhibition (HAI) assays, were associated with protection against naturally acquired H1N1 infection. HA stalk-specific serum total IgG titers were also associated with protection, but this association was attenuated and not statistically significant after adjustment for HA head-specific Ab titers. We found slightly higher titers of HA stalk-specific IgG1 and IgA Abs in sera from uninfected participants than in sera from infected participants; however, we found no difference in serum antibody-dependent cellular cytotoxicity activity. In passive transfer experiments, sera from participants with high HAI activity efficiently protected mice, while sera with low HAI activity protected mice to a lower extent. Our data suggest that HA head Abs are more efficient at protecting against H1N1 infection than HA stalk Abs. Abs targeting the HA head of influenza viruses are often associated with protection from influenza virus infections. These Abs typically have limited breadth, since mutations frequently arise in HA head epitopes. New vaccines targeting the more conserved HA stalk domain are being developed. Abs that target the HA stalk are protective in animal models, but it is unknown if these Abs exist at protective levels in humans. Here, we completed experiments to determine if Abs against the HA head and stalk were associated with protection from naturally acquired human influenza virus infections during the 2015-2016 influenza season.
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http://dx.doi.org/10.1128/JVI.02134-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450120PMC
April 2019

Outpatient Antibiotic Prescribing for Acute Respiratory Infections During Influenza Seasons.

JAMA Netw Open 2018 06 1;1(2):e180243. Epub 2018 Jun 1.

Centers for Disease Control and Prevention, Atlanta, Georgia.

Importance: Acute respiratory infections (ARIs) are the syndrome for which antibiotics are most commonly prescribed; viruses for which antibiotics are ineffective cause most ARIs.

Objectives: To characterize antibiotic prescribing among outpatients with ARI during influenza season and to identify targets for reducing inappropriate antibiotic prescribing for common ARI diagnoses, including among outpatients with laboratory-confirmed influenza.

Design, Setting, And Participants: Cohort study enrolling outpatients aged 6 months or older with ARI evaluated at outpatient clinics associated with 5 US Influenza Vaccine Effectiveness Network sites during the 2013-2014 and 2014-2015 influenza seasons. All patients received influenza testing by real-time reverse transcriptase-polymerase chain reaction for research purposes only. Antibiotic prescriptions, medical history, and International Classification of Diseases, Ninth Revision diagnosis codes were collected from medical and pharmacy records, as were group A streptococcal (GAS) testing results in a patient subset.

Exposure: Visit for ARI, defined by a new cough of 7 days' duration or less.

Main Outcomes And Measures: Antibiotic prescription within 7 days of enrollment. Appropriateness of antibiotic prescribing was based on diagnosis codes, clinical information, and influenza and GAS testing results.

Results: Of 14 987 patients with ARI (mean [SD] age, 32 [24] years; 8638 [58%] women; 11 892 [80%] white), 6136 (41%) were prescribed an antibiotic. Among these 6136 patients, 2522 (41%) had diagnoses for which antibiotics are not indicated; 2106 (84%) of these patients were diagnosed as having a viral upper respiratory tract infection or bronchitis (acute or not otherwise specified). Among the 3306 patients (22%) not diagnosed as having pneumonia and who had laboratory-confirmed influenza, 945 (29%) were prescribed an antibiotic, accounting for 17% of all antibiotic prescriptions among patients with nonpneumonia ARI. Among 1248 patients with pharyngitis, 1137 (91%) had GAS testing; 440 of the 1248 patients (35%) were prescribed antibiotics, among whom 168 (38%) had negative results on GAS testing. Of 1200 patients with sinusitis and no other indication for antibiotic treatment who received an antibiotic, 454 (38%) had symptoms for 3 days or less prior to the outpatient visit, suggesting acute viral sinusitis not requiring antibiotics.

Conclusions And Relevance: Antibiotic overuse remains widespread in the treatment of outpatient ARIs, including among patients with laboratory-confirmed influenza, although study sites may not be representative of other outpatient settings. Identified targets for improved outpatient antibiotic stewardship include eliminating antibiotic treatment of viral upper respiratory tract infections and bronchitis and improving adherence to prescribing guidelines for pharyngitis and sinusitis. Increased access to sensitive and timely virus diagnostic tests, particularly for influenza, may reduce unnecessary antibiotic use for these syndromes.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324415PMC
June 2018

Influenza Vaccine Effectiveness and Statin Use Among Adults in the United States, 2011-2017.

Clin Infect Dis 2019 05;68(10):1616-1622

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Statin medications have immunomodulatory effects. Several recent studies suggest that statins may reduce influenza vaccine response and reduce influenza vaccine effectiveness (VE).

Methods: We compared influenza VE in statin users and nonusers aged ≥45 years enrolled in the US Vaccine Effectiveness Network study over 6 influenza seasons (2011-2012 through 2016-2017). All enrollees presented to outpatients clinics with acute respiratory illness and were tested for influenza. Information on vaccination status, medical history, and statin use at the time of vaccination were collected by medical and pharmacy records. Using a test-negative design, we estimated VE as (1 - OR) × 100, in which OR is the odds ratio for testing positive for influenza virus among vaccinated vs unvaccinated participants.

Results: Among 11692 eligible participants, 3359 (30%) were statin users and 2806 (24%) tested positive for influenza virus infection; 78% of statin users and 60% of nonusers had received influenza vaccine. After adjusting for potential confounders, influenza VE was 36% (95% confidence interval [CI], 22%-47%) among statin users and 39% (95% CI, 32%-45%) among nonusers. We observed no significant modification of VE by statin use. VE against influenza A(H1N1)pdm09, A(H3N2), and B viruses were similar among statin users and nonusers.

Conclusions: In this large observational study, influenza VE against laboratory-confirmed influenza illness was not affected by current statin use among persons aged ≥45 years. Statin use did not modify the effect of vaccination on influenza when analyzed by type and subtype.
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http://dx.doi.org/10.1093/cid/ciy780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495015PMC
May 2019

Sera from Individuals with Narrowly Focused Influenza Virus Antibodies Rapidly Select Viral Escape Mutations .

J Virol 2018 10 12;92(19). Epub 2018 Sep 12.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Influenza viruses use distinct antibody escape mechanisms depending on the overall complexity of the antibody response that is encountered. When grown in the presence of a hemagglutinin (HA) monoclonal antibody, influenza viruses typically acquire a single HA mutation that reduces the binding of that specific monoclonal antibody. In contrast, when confronted with mixtures of HA monoclonal antibodies or polyclonal sera that have antibodies that bind several HA epitopes, influenza viruses acquire mutations that increase HA binding to host cells. Recent data from our laboratory and others suggest that some humans possess antibodies that are narrowly focused on HA epitopes that were present in influenza virus strains that they were likely exposed to in childhood. Here, we completed a series of experiments to determine if humans with narrowly focused HA antibody responses are able to select for influenza virus antigenic escape variants We identified three human donors that possessed HA antibody responses that were heavily focused on a single HA antigenic site. Sera from all three of these donors selected single HA escape mutations during passage experiments, similar to what has been previously reported for single monoclonal antibodies. These single HA mutations directly reduced binding of serum antibodies used for selection. We propose that new antigenic variants of influenza viruses might originate in individuals who produce antibodies that are narrowly focused on HA epitopes that were present in viral strains that they encountered in childhood. Influenza vaccine strains must be updated frequently since circulating viral strains continuously change in antigenically important epitopes. Our previous studies have demonstrated that some individuals possess antibody responses that are narrowly focused on epitopes that were present in viral strains that they encountered during childhood. Here, we show that influenza viruses rapidly escape this type of polyclonal antibody response when grown by acquiring single mutations that directly prevent antibody binding. These studies improve our understanding of how influenza viruses evolve when confronted with narrowly focused polyclonal human antibodies.
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http://dx.doi.org/10.1128/JVI.00859-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146816PMC
October 2018
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