Publications by authors named "Timothy M Uyeki"

240 Publications

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

medRxiv 2021 Feb 26. Epub 2021 Feb 26.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
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http://dx.doi.org/10.1101/2021.02.23.21252221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924286PMC
February 2021

COVID-19 Clinical Phenotypes: Presentation and Temporal Progression of Disease in a Cohort of Hospitalized Adults in Georgia, United States.

Open Forum Infect Dis 2021 Jan 7;8(1):ofaa596. Epub 2020 Dec 7.

CDC COVID-19 Emergency Response, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: The epidemiological features and outcomes of hospitalized adults with coronavirus disease 2019 (COVID-19) have been described; however, the temporal progression and medical complications of disease among hospitalized patients require further study. Detailed descriptions of the natural history of COVID-19 among hospitalized patients are paramount to optimize health care resource utilization, and the detection of different clinical phenotypes may allow tailored clinical management strategies.

Methods: This was a retrospective cohort study of 305 adult patients hospitalized with COVID-19 in 8 academic and community hospitals. Patient characteristics included demographics, comorbidities, medication use, medical complications, intensive care utilization, and longitudinal vital sign and laboratory test values. We examined laboratory and vital sign trends by mortality status and length of stay. To identify clinical phenotypes, we calculated Gower's dissimilarity matrix between each patient's clinical characteristics and clustered similar patients using the partitioning around medoids algorithm.

Results: One phenotype of 6 identified was characterized by high mortality (49%), older age, male sex, elevated inflammatory markers, high prevalence of cardiovascular disease, and shock. Patients with this severe phenotype had significantly elevated peak C-reactive protein creatinine, D-dimer, and white blood cell count and lower minimum lymphocyte count compared with other phenotypes ( < .01, all comparisons).

Conclusions: Among a cohort of hospitalized adults, we identified a severe phenotype of COVID-19 based on the characteristics of its clinical course and poor prognosis. These findings need to be validated in other cohorts, as improved understanding of clinical phenotypes and risk factors for their development could help inform prognosis and tailored clinical management for COVID-19.
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http://dx.doi.org/10.1093/ofid/ofaa596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798484PMC
January 2021

Bioaerosol sampling for SARS-CoV-2 in a referral center with critically ill COVID-19 patients March-May 2020.

Clin Infect Dis 2021 Jan 28. Epub 2021 Jan 28.

Division of Infectious Diseases, Department of Medicine Emory University, Atlanta, GA, USA.

Background: Previous research has shown that rooms of patients with COVID-19 present the potential for healthcare-associated transmission through aerosols containing SARS-CoV-2. However, data on the presence of these aerosols outside of patient rooms are limited. We investigated whether virus-containing aerosols were present in nursing stations and patient room hallways in a referral center with critically ill COVID-19 patients.

Methods: Eight National Institute for Occupational Safety and Health BC 251 two-stage cyclone samplers were set up throughout six units, including nursing stations and visitor corridors in intensive care units and general medical units, for six hours each sampling period. Samplers were placed on tripods which held two samplers positioned 102 cm and 152 cm above the floor. Units were sampled for three days. Extracted samples underwent reverse transcription polymerase chain reaction for selected gene regions of the SARS-CoV-2 virus nucleocapsid and the housekeeping gene human RNase P as an internal control.

Results: The units sampled varied in the number of laboratory-confirmed COVID-19 patients present on the days of sampling. Some of the units included patient rooms under negative pressure, while most were maintained at a neutral pressure. Of 528 aerosol samples collected, none were positive for SARS-CoV-2 RNA by the estimated limit of detection of 8 viral copies/m 3 of air.

Conclusion: Aerosolized SARS-CoV-2 outside of patient rooms was undetectable. While healthcare personnel should avoid unmasked close contact with each other, these findings may provide reassurance for the use of alternatives to tight-fitting respirators in areas outside of patient rooms during the current pandemic.
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http://dx.doi.org/10.1093/cid/ciaa1880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953966PMC
January 2021

Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series.

J Infect Dis 2021 03;223(5):752-764

Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues.

Methods: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing.

Results: SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR-positive case patients.

Conclusions: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes.
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http://dx.doi.org/10.1093/infdis/jiab039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928839PMC
March 2021

Influenza Vaccine for Patients With High-risk Cardiovascular Disease.

JAMA 2021 01;325(1):33-35

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

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http://dx.doi.org/10.1001/jama.2020.23948DOI Listing
January 2021

Serological evidence of human infections with highly pathogenic avian influenza A(H5N1) virus: a systematic review and meta-analysis.

BMC Med 2020 12 2;18(1):377. Epub 2020 Dec 2.

School of Public Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, 200032, China.

Background: Highly pathogenic avian influenza A(H5N1) virus poses a global public health threat given severe and fatal zoonotic infections since 1997 and ongoing A(H5N1) virus circulation among poultry in several countries. A comprehensive assessment of the seroprevalence of A(H5N1) virus antibodies remains a gap and limits understanding of the true risk of A(H5N1) virus infection.

Methods: We conducted a systematic review and meta-analysis of published serosurveys to assess the risk of subclinical and clinically mild A(H5N1) virus infections. We assessed A(H5N1) virus antibody titers and changes in titers among populations with variable exposures to different A(H5N1) viruses.

Results: Across studies using the World Health Organization-recommended seropositive definition, the point estimates of the seroprevalence of A(H5N1) virus-specific antibodies were higher in poultry-exposed populations (range 0-0.6%) and persons exposed to both human A(H5N1) cases and infected birds (range 0.4-1.8%) than in close contacts of A(H5N1) cases or the general population (none to very low frequencies). Seroprevalence was higher in persons exposed to A(H5N1) clade 0 virus (1.9%, range 0.7-3.2%) than in participants exposed to other clades of A(H5N1) virus (range 0-0.5%) (p < 0.05). Seroprevalence was higher in poultry-exposed populations (range 0-1.9%) if such studies utilized antigenically similar A(H5N1) virus antigens in assays to A(H5N1) viruses circulating among poultry.

Conclusions: These low seroprevalences suggest that subclinical and clinically mild human A(H5N1) virus infections are uncommon. Standardized serological survey and laboratory methods are needed to fully understand the extent and risk of human A(H5N1) virus infections.
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http://dx.doi.org/10.1186/s12916-020-01836-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709391PMC
December 2020

Point-of-care molecular testing and antiviral treatment of influenza in residents of homeless shelters in Seattle, WA: study protocol for a stepped-wedge cluster-randomized controlled trial.

Trials 2020 Nov 23;21(1):956. Epub 2020 Nov 23.

Division of Allergy and Infectious Diseases, University of Washington, UW Medicine at South Lake Union, Chu Lab Room E630, 750 Republican St., Seattle, WA, 98109, USA.

Introduction: Influenza is an important public health problem, but data on the impact of influenza among homeless shelter residents are limited. The primary aim of this study is to evaluate whether on-site testing and antiviral treatment of influenza in residents of homeless shelters reduces influenza spread in these settings.

Methods And Analysis: This study is a stepped-wedge cluster-randomized trial of on-site testing and antiviral treatment for influenza in nine homeless shelter sites within the Seattle metropolitan area. Participants with acute respiratory illness (ARI), defined as two or more respiratory symptoms or new or worsening cough with onset in the prior 7 days, are eligible to enroll. Approximately 3200 individuals are estimated to participate from October to May across two influenza seasons. All sites will start enrollment in the control arm at the beginning of each season, with routine surveillance for ARI. Sites will be randomized at different timepoints to enter the intervention arm, with implementation of a test-and-treat strategy for individuals with two or fewer days of symptoms. Eligible individuals will be tested on-site with a point-of-care influenza test. If the influenza test is positive and symptom onset is within 48 h, participants will be administered antiviral treatment with baloxavir or oseltamivir depending upon age and comorbidities. Participants will complete a questionnaire on demographics and symptom duration and severity. The primary endpoint is the incidence of influenza in the intervention period compared to the control period, after adjusting for time trends.

Trial Registration: ClinicalTrials.gov NCT04141917 . Registered 28 October 2019. Trial sponsor: University of Washington.
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http://dx.doi.org/10.1186/s13063-020-04871-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682130PMC
November 2020

Remote Household Observation for Non-influenza Respiratory Viral Illness.

Clin Infect Dis 2020 Nov 17. Epub 2020 Nov 17.

Department of Medicine, University of Washington.

Background: Non-influenza respiratory viruses are responsible for a substantial burden of disease in the United States. Household transmission is thought to contribute significantly to subsequent transmission through the broader community. In the context of the COVID-19 pandemic, contactless surveillance methods are of particular importance.

Methods: From November 2019 to April 2020, 303 households in the Seattle area were remotely monitored in a prospective longitudinal study for symptoms of respiratory viral illness. Enrolled participants reported weekly symptoms and submitted respiratory samples by mail in the event of an acute respiratory illness (ARI). Specimens were tested for fourteen viruses, including SARS-CoV-2, using RT-PCR. Participants completed all study procedures at home without physical contact with research staff.

Results: In total, 1171 unique participants in 303 households were monitored for ARI. Of participating households, 128 (42%) included a child aged <5 years and 202 (67%) included a child aged 5-12 years. Of the 678 swabs collected during the surveillance period, 237 (35%) tested positive for one or more non-influenza respiratory viruses. Rhinovirus, common human coronaviruses, and respiratory syncytial virus were the most common. Four cases of SARS-CoV-2 were detected in three households.

Conclusions: This study highlights the circulation of respiratory viruses within households during the winter months during the emergence of the SARS-CoV-2 pandemic. Contactless methods of recruitment, enrollment and sample collection were utilized throughout this study, and demonstrate the feasibility of home-based, remote monitoring for respiratory infections.
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http://dx.doi.org/10.1093/cid/ciaa1719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717193PMC
November 2020

High-risk Groups for Influenza Complications.

Authors:
Timothy M Uyeki

JAMA 2020 12;324(22):2334

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

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http://dx.doi.org/10.1001/jama.2020.21869DOI Listing
December 2020

Preparing for the 2020-2021 Influenza Season.

JAMA 2020 12;324(22):2318-2319

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

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http://dx.doi.org/10.1001/jama.2020.21849DOI Listing
December 2020

Serological evidence of human infection with avian influenza A(H7N9) virus: a systematic review and meta-analysis.

J Infect Dis 2020 Oct 29. Epub 2020 Oct 29.

School of Public Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, China.

Background: The extent of human infections with avian influenza A(H7N9) virus, including mild and asymptomatic infections, is uncertain.

Methods: We performed a systematic review and meta-analysis of serosurveys for avian influenza A(H7N9) virus infections in humans published during 2013-2020. Three seropositive definitions were assessed to estimate pooled seroprevalence, seroconversion rate and seroincidence by types of exposures. We applied a scoring system to assess the quality of included studies.

Results: Of 31 included studies, pooled seroprevalence of A(H7N9)-virus antibodies from all participants was 0.02%, with poultry workers, close contacts, and general populations having seroprevalence of 0.1%, 0.2% and 0.02% based on the WHO-recommended definition, respectively. Although most infections were asymptomatic, evidence of infection was highest in poultry workers (5% seroconversion, 19.1% seroincidence per 100 person-years). Use of different virus clades did not significantly affect seroprevalence estimates. Most serological studies were of low to moderate quality and did not follow standardized seroepidemiological protocols or WHO-recommended laboratory methods.

Conclusions: Human infections with avian influenza A(H7N9) virus have been uncommon, especially for general populations. Workers with occupational exposures to poultry and close contacts of A(H7N9) human cases had low risks of infection.
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http://dx.doi.org/10.1093/infdis/jiaa679DOI Listing
October 2020

Predictors at admission of mechanical ventilation and death in an observational cohort of adults hospitalized with COVID-19.

Clin Infect Dis 2020 Sep 24. Epub 2020 Sep 24.

CDC COVID-19 Emergency Response.

Background: Coronavirus disease (COVID-19) can cause severe illness and death. Predictors of poor outcome collected on hospital admission may inform clinical and public health decisions.

Methods: We conducted a retrospective observational cohort investigation of 297 adults admitted to eight academic and community hospitals in Georgia, United States, during March 2020. Using standardized medical record abstraction, we collected data on predictors including admission demographics, underlying medical conditions, outpatient antihypertensive medications, recorded symptoms, vital signs, radiographic findings, and laboratory values. We used random forest models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CI) for predictors of invasive mechanical ventilation (IMV) and death.

Results: Compared with age <45 years, ages 65-74 years and ≥75 years were predictors of IMV (aOR 3.12, CI 1.47-6.60; aOR 2.79, CI 1.23-6.33) and the strongest predictors for death (aOR 12.92, CI 3.26-51.25; aOR 18.06, CI 4.43-73.63). Comorbidities associated with death (aORs from 2.4 to 3.8, p <0.05) included end-stage renal disease, coronary artery disease, and neurologic disorders, but not pulmonary disease, immunocompromise, or hypertension. Pre-hospital use vs. non-use of angiotensin receptor blockers (aOR 2.02, CI 1.03-3.96) and dihydropyridine calcium channel blockers (aOR 1.91, CI 1.03-3.55) were associated with death.

Conclusions: After adjustment for patient and clinical characteristics, older age was the strongest predictor of death, exceeding comorbidities, abnormal vital signs, and laboratory test abnormalities. That coronary artery disease, but not chronic lung disease, was associated with death among hospitalized patients warrants further investigation, as do associations between certain antihypertensive medications and death.
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http://dx.doi.org/10.1093/cid/ciaa1459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543323PMC
September 2020

Baloxavir for Postexposure Prophylaxis against Influenza in Households.

Authors:
Timothy M Uyeki

N Engl J Med 2020 07 8;383(4):389-390. Epub 2020 Jul 8.

From the Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta.

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http://dx.doi.org/10.1056/NEJMe2022702DOI Listing
July 2020

Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020.

MMWR Morb Mortal Wkly Rep 2020 May 8;69(18):545-550. Epub 2020 May 8.

SARS-CoV-2, the novel coronavirus that causes coronavirus disease 2019 (COVID-19), was first detected in the United States during January 2020 (1). Since then, >980,000 cases have been reported in the United States, including >55,000 associated deaths as of April 28, 2020 (2). Detailed data on demographic characteristics, underlying medical conditions, and clinical outcomes for persons hospitalized with COVID-19 are needed to inform prevention strategies and community-specific intervention messages. For this report, CDC, the Georgia Department of Public Health, and eight Georgia hospitals (seven in metropolitan Atlanta and one in southern Georgia) summarized medical record-abstracted data for hospitalized adult patients with laboratory-confirmed* COVID-19 who were admitted during March 2020. Among 305 hospitalized patients with COVID-19, 61.6% were aged <65 years, 50.5% were female, and 83.2% with known race/ethnicity were non-Hispanic black (black). Over a quarter of patients (26.2%) did not have conditions thought to put them at higher risk for severe disease, including being aged ≥65 years. The proportion of hospitalized patients who were black was higher than expected based on overall hospital admissions. In an adjusted time-to-event analysis, black patients were not more likely than were nonblack patients to receive invasive mechanical ventilation (IMV) or to die during hospitalization (hazard ratio [HR] = 0.63; 95% confidence interval [CI] = 0.35-1.13). Given the overrepresentation of black patients within this hospitalized cohort, it is important for public health officials to ensure that prevention activities prioritize communities and racial/ethnic groups most affected by COVID-19. Clinicians and public officials should be aware that all adults, regardless of underlying conditions or age, are at risk for serious illness from COVID-19.
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http://dx.doi.org/10.15585/mmwr.mm6918e1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737948PMC
May 2020

Oseltamivir provides up to 3 days earlier time to recovery over usual care.

J Pediatr 2020 05;220:264-267

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

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http://dx.doi.org/10.1016/j.jpeds.2020.02.064DOI Listing
May 2020

First Case of Covid-19 in the United States. Reply.

N Engl J Med 2020 05 22;382(21):e53. Epub 2020 Apr 22.

Providence Regional Medical Center, Everett, WA.

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http://dx.doi.org/10.1056/NEJMc2004794DOI Listing
May 2020

Clinical Characteristics of Patients Hospitalized with Coronavirus Disease, Thailand.

Emerg Infect Dis 2020 Jul 21;26(7):1580-1585. Epub 2020 Jun 21.

Among 11 patients in Thailand infected with severe acute respiratory syndrome coronavirus 2, we detected viral RNA in upper respiratory specimens a median of 14 days after illness onset and 9 days after fever resolution. We identified viral co-infections and an asymptomatic person with detectable virus RNA in serial tests. We describe implications for surveillance.
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http://dx.doi.org/10.3201/eid2607.200598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323520PMC
July 2020

Fifty Years of Influenza A(H3N2) Following the Pandemic of 1968.

Am J Public Health 2020 05;110(5):669-676

Barbara J. Jester (formerly Battelle contractor), Timothy M. Uyeki, and Daniel B. Jernigan are with the Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA.

In 2018, the world commemorated the centennial of the 1918 influenza A(H1N1) pandemic, the deadliest pandemic in recorded history; however, little mention was made of the 50th anniversary of the 1968 A(H3N2) pandemic. Although pandemic morbidity and mortality were much lower in 1968 than in 1918, influenza A(H3N2) virus infections have become the leading cause of seasonal influenza illness and death over the last 50 years, with more than twice the number of hospitalizations from A(H3N2) as from A(H1N1) during the past six seasons. We review the emergence, progression, clinical course, etiology, epidemiology, and treatment of the 1968 pandemic and highlight the short- and long-term impact associated with A(H3N2) viruses. The 1968 H3N2 pandemic and its ongoing sequelae underscore the need for improved seasonal and pandemic influenza prevention, control, preparedness, and response efforts.
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http://dx.doi.org/10.2105/AJPH.2019.305557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144439PMC
May 2020

First Case of 2019 Novel Coronavirus in the United States.

N Engl J Med 2020 03 31;382(10):929-936. Epub 2020 Jan 31.

From the Epidemic Intelligence Service (M.L.H.), the National Center for Immunizations and Respiratory Diseases (A.C., L.F., A.P.), the Division of Viral Diseases (S.I.G., L.K., S.T., X.L., S. Lindstrom, M.A.P., W.C.W., H.M.B.), the Influenza Division (T.M.U.), and the Division of Preparedness and Emerging Infections (S.K.P.), Centers for Disease Control and Prevention, Atlanta; and the Washington State Department of Health, Shoreline (M.L.H., C.D., S. Lindquist, K.H.L., J.W.), Snohomish Health District (H.B., C.S.), Providence Medical Group (K.E.), and Providence Regional Medical Center (S.W., A.T., G.D.), Everett, and Department of Medicine, University of Washington School of Medicine, Seattle (C.S.) - all in Washington.

An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient's initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.
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http://dx.doi.org/10.1056/NEJMoa2001191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092802PMC
March 2020

Specificity, kinetics and longevity of antibody responses to avian influenza A(H7N9) virus infection in humans.

J Infect 2020 03 16;80(3):310-319. Epub 2020 Jan 16.

School of Public Health, Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Building 8, 130 Dong'an Road, Xuhui District, Shanghai 200032, China. Electronic address:

Objectives: The long-term dynamics of antibody responses in patients with influenza A(H7N9) virus infection are not well understood.

Methods: We conducted a longitudinal serological follow-up study in patients who were hospitalized with A(H7N9) virus infection, during 2013-2018. A(H7N9) virus-specific antibody responses were assessed by hemagglutination inhibition (HAI) and neutralization (NT) assays. A random intercept model was used to fit a curve to HAI antibody responses over time. HAI antibody responses were compared by clinical severity.

Results: Of 67 patients with A(H7N9) virus infection, HAI antibody titers reached 40 on average 11 days after illness onset and peaked at a titer of 290 after three months, and average titers of ≥80 and ≥40 were present until 11 months and 22 months respectively. HAI antibody responses were significantly higher in patients who experienced severe disease, including respiratory failure and acute respiratory distress syndrome, compared with patients who experienced less severe illness.

Conclusions: Patients with A(H7N9) virus infection who survived severe disease mounted higher antibody responses that persisted for longer periods compared with those that experienced moderate disease. Studies of convalescent plasma treatment for A(H7N9) patients should consider collection of donor plasma from survivors of severe disease between 1 and 11 months after illness onset.
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http://dx.doi.org/10.1016/j.jinf.2019.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112568PMC
March 2020

Evaluation of potential risk of transmission of avian influenza A viruses at live bird markets in response to unusual crow die-offs in Bangladesh.

Influenza Other Respir Viruses 2020 05 7;14(3):349-352. Epub 2020 Jan 7.

Institute of Epidemiology, Disease Control and Research, Dhaka, Bangladesh.

In response to unusual crow die-offs from avian influenza A(H5N1) virus infection during January-February 2017 in Dhaka, Bangladesh, a One Health team assessed potential infection risks in live bird markets (LBMs). Evidence of aerosolized avian influenza A viruses was detected in LBMs and in the respiratory tracts of market workers, indicating exposure and potential for infection. This study highlighted the importance of surveillance platforms with a coordinated One Health strategy to investigate and mitigate zoonotic risk.
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http://dx.doi.org/10.1111/irv.12716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182606PMC
May 2020

Reply to Verweij et al.

Clin Infect Dis 2020 01;70(2):350-351

Division of Pediatric Infectious Diseases, University of Utah, Salt Lake City.

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http://dx.doi.org/10.1093/cid/ciz568DOI Listing
January 2020

Novel Avian Influenza A Virus Infections of Humans.

Infect Dis Clin North Am 2019 12;33(4):907-932

School of Public Health, The University of Hong Kong, L6-42, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong.

A high index of suspicion and early diagnosis of avian influenza A virus infection is essential reduce transmission risk. Clinical suspicion relies on eliciting a history of recent exposure to poultry or to sick persons. Diagnosis requires collection of appropriate respiratory specimens. Patients with suspected infection should be isolated immediately and patients with lower respiratory tract disease should be placed on airborne precautions if possible. Antiviral treatment should be started as soon as possible based upon clinical suspicion while awaiting specific viral diagnosis. Corticosteroids and salicylates should be avoided. Clinical management focuses on supportive care of complications.
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http://dx.doi.org/10.1016/j.idc.2019.07.003DOI Listing
December 2019

Seasonal Influenza and Avian Influenza A(H5N1) Virus Surveillance among Inpatients and Outpatients, East Jakarta, Indonesia, 2011-2014.

Emerg Infect Dis 2019 11;25(11):2031-2039

During October 2011-September 2014, we screened respiratory specimens for seasonal and avian influenza A(H5N1) virus infections among outpatients with influenza-like illness and inpatients with severe acute respiratory infection (SARI) in East Jakarta, an Indonesia district with high incidence of H5N1 virus infection among poultry. In total, 31% (1,875/6,008) of influenza-like illness case-patients and 15% (571/3,811) of SARI case-patients tested positive for influenza virus. Influenza A(H1N1)pdm09, influenza A(H3N2), and influenza B virus infections were detected in all 3 years, and the epidemic season extended from November through May. Although 28% (2,810/10,135) of case-patients reported exposure to poultry, only 1 SARI case-patient with an H5N1 virus infection was detected. Therefore, targeted screening among case-patients with high-risk poultry exposures (e.g., a recent visit to a live bird market or close proximity to sick or dead poultry) may be a more efficient routine surveillance strategy for H5N1 virus in these types of settings.
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http://dx.doi.org/10.3201/eid2511.181844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810195PMC
November 2019

Response to Apewokin and Onyishi.

Clin Infect Dis 2020 06;70(12):2749-2750

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

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http://dx.doi.org/10.1093/cid/ciz839DOI Listing
June 2020

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection.

J Infect Dis 2020 01;221(3):356-366

Division of Epidemiology and Public Health, University of Nottingham, Nottingham.

Background: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear.

Methods: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded.

Results: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS.

Conclusions: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.
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http://dx.doi.org/10.1093/infdis/jiz152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313925PMC
January 2020

Estimated Incubation Period and Serial Interval for Human-to-Human Influenza A(H7N9) Virus Transmission.

Emerg Infect Dis 2019 10 17;25(10):1982-1983. Epub 2019 Oct 17.

We estimated the incubation period and serial interval for human-to-human-transmitted avian influenza A(H7N9) virus infection using case-patient clusters from epidemics in China during 2013-2017. The median incubation period was 4 days and serial interval 9 days. China's 10-day monitoring period for close contacts of case-patients should detect most secondary infections.
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http://dx.doi.org/10.3201/eid2510.190117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759274PMC
October 2019

Influenza virus-related critical illness: prevention, diagnosis, treatment.

Crit Care 2019 Jun 12;23(1):214. Epub 2019 Jun 12.

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Mailstop H24-7, 1600 Clifton Road, N.E., Atlanta, GA, 30329, USA.

Annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the United States (U.S.) and worldwide. In temperate climate countries, including the U.S., influenza activity peaks during the winter months. Annual influenza vaccination is recommended for all persons in the U.S. aged 6 months and older, and among those at increased risk for influenza-related complications in other parts of the world (e.g. young children, elderly). Observational studies have reported effectiveness of influenza vaccination to reduce the risks of severe disease requiring hospitalization, intensive care unit admission, and death. A diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. Molecular tests are recommended for influenza testing of respiratory specimens in hospitalized patients. Antigen detection assays are not recommended in critically ill patients because of lower sensitivity; negative results of these tests should not be used to make clinical decisions, and respiratory specimens should be tested for influenza by molecular assays. Because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay for detection of influenza viruses.Observational studies have reported that antiviral treatment of critically ill adult influenza patients with a neuraminidase inhibitor is associated with survival benefit. Since earlier initiation of antiviral treatment is associated with the greatest clinical benefit, standard-dose oseltamivir (75 mg twice daily in adults) for enteric administration is recommended as soon as possible as it is well absorbed in critically ill patients. Based upon observational data that suggest harms, adjunctive corticosteroid treatment is currently not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or COPD exacerbation, or septic shock. A number of pharmaceutical agents are in development for treatment of severe influenza.
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http://dx.doi.org/10.1186/s13054-019-2491-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563376PMC
June 2019

Quality of life reported by survivors after hospitalization for Middle East respiratory syndrome (MERS).

Health Qual Life Outcomes 2019 Jun 11;17(1):101. Epub 2019 Jun 11.

Department of Medicine, King Faisal Specialist Hospital and Research Center, University of Jeddah, P.O BOX 40047 Jeddah 21499 MBC J 46, Jeddah, Saudi Arabia.

Introduction: Data are lacking on impact of Middle East Respiratory Syndrome (MERS) on health-related quality of life (HRQoL) among survivors.

Methods: We conducted a cross-sectional survey of MERS survivors who required hospitalization in Saudi Arabia during 2016-2017, approximately 1 year after diagnosis. The Short-Form General Health Survey 36 (SF-36) was administered by telephone interview to assess 8 quality of life domains for MERS survivors and a sample of survivors of severe acute respiratory infection (SARI) without MERS. We compared mean SF-36 scores of MERS and non-MERS SARI survivors using independent t-test, and compared categorical variables using chi-square test. Adjusted analyses were performed using multiple linear regression.

Results: Of 355 MERS survivors, 83 were eligible and 78 agreed to participate. MERS survivors were younger than non-MERS SARI survivors (mean ± SD): (44.9 years ±12.9) vs (50.0 years ±13.6), p = 0.031. Intensive care unit (ICU) admissions were similar for MERS and non-MERS SARI survivors (46.2% vs. 57.1%), p = 0.20. After adjusting for potential confounders, there were no significant differences between MERS and non-MERS SARI survivors in physical component or mental component summary scores. MERS ICU survivors scored lower than MERS survivors not admitted to an ICU for physical function (p = 0.05), general health (p = 0.01), vitality (p = 0.03), emotional role (p = 0.03) and physical component summary (p < 0.02).

Conclusions: Functional scores were similar for MERS and non-MERS SARI survivors. However, MERS survivors of critical illness reported lower quality of life than survivors of less severe illness. Efforts are needed to address the long-term medical and psychological needs of MERS survivors.
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http://dx.doi.org/10.1186/s12955-019-1165-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560892PMC
June 2019

Clinical Development of Therapeutic Agents for Hospitalized Patients With Influenza: Challenges and Innovations.

Open Forum Infect Dis 2019 Apr 14;6(4):ofz137. Epub 2019 Mar 14.

US Department of Health and Human Services, Biomedical Advanced Research and Development Authority, Washington, District of Columbia.

Background: Since 1999, the US Food and Drug Administration approved neuraminidase and endonuclease inhibitors to treat uncomplicated outpatient influenza but not severe hospitalized influenza. After the 2009 pandemic, several influenza hospital-based clinical therapeutic trials were unsuccessful, possibly due to certain study factors. Therefore, in 2014, the US Health and Human Services agencies formed a Working Group (WG) to address related clinical challenges.

Methods: Starting in 2014, the WG obtained retrospective data from failed hospital-based influenza therapeutic trials and nontherapeutic hospital-based influenza studies. These data allowed the WG to identify factors that might improve hospital-based therapeutic trials. These included primary clinical endpoints, increased clinical site enrollment, and appropriate baseline enrollment criteria.

Results: During 2018, the WG received retrospective data from a National Institutes of Health hospital-based influenza therapeutic trial that demonstrated time to resolution of respiratory status, which was not a satisfactory primary endpoint. The WG statisticians examined these data and believed that ordinal outcomes might be a more powerful primary endpoint. Johns Hopkins' researchers provided WG data from an emergency-department (ED) triage study to identify patients with confirmed influenza using molecular testing. During the 2013-2014 influenza season, 4 EDs identified 1074 influenza-patients, which suggested that triage testing should increase enrollment by hospital-based clinical trial sites. In 2017, the WG received data from Northwestern Memorial Hospital researchers regarding 703 influenza inpatients over 5 seasons. The WG applied National Early Warning Score (NEWS) at patient baseline to identify appropriate criteria to enroll patients into hospital-based therapeutic trials.

Conclusions: Data received by the WG indicated that hospital-based influenza therapeutic trials could use ordinal outcome analyses, ED triage to identify influenza patients, and NEWS for enrollment criteria.
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http://dx.doi.org/10.1093/ofid/ofz137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479095PMC
April 2019