Showing papers by "Timothy M. Uyeki published in 2018"

Factors Associated With Prolonged Viral Shedding in Patients With Avian Influenza A(H7N9) Virus Infection

Abstract: Background Data are limited on the impact of neuraminidase inhibitor (NAI) treatment on avian influenza A(H7N9) virus RNA shedding. Methods In this multicenter, retrospective study, data were collected from adults hospitalized with A(H7N9) infection during 2013-2017 in China. We compared clinical features and A(H7N9) shedding among patients with different NAI doses and combination therapies and evaluated factors associated with A(H7N9) shedding, using Cox proportional hazards regression. Results Among 478 patients, the median age was 56 years, 71% were male, and 37% died. The median time from illness onset to NAI treatment initiation was 8 days (interquartile range [IQR], 6-10 days), and the median duration of A(H7N9) RNA detection from onset was 15.5 days (IQR, 12-20 days). A(H7N9) RNA shedding was shorter in survivors than in patients who died (P < .001). Corticosteroid administration (hazard ratio [HR], 0.62 [95% confidence interval {CI}, .50-.77]) and delayed NAI treatment (HR, 0.90 [95% CI, .91-.96]) were independent risk factors for prolonged A(H7N9) shedding. There was no significant difference in A(H7N9) shedding duration between NAI combination treatment and monotherapy (P = .65) or between standard-dose and double-dose oseltamivir treatment (P = .70). Conclusions Corticosteroid therapy and delayed NAI treatment were associated with prolonged A(H7N9) RNA shedding. NAI combination therapy and double-dose oseltamivir treatment were not associated with a reduced A(H7N9) shedding duration as compared to standard-dose oseltamivir.

Readiness for Responding to a Severe Pandemic 100 Years After 1918

Abstract: The 1918 H1N1 pandemic caused an unprecedented number of deaths worldwide. The tools to deal with the global emergency were limited; there were insufficient surveillance systems and a dearth of diagnostic, treatment, and prevention options. With continuing focus on pandemic planning, technologic advances in surveillance, vaccine capabilities, and 21st century medical care and countermeasures, we are more prepared for a severe pandemic than people were 100 years ago; however, notable gaps remain.

Disease characteristics and management of hospitalised adolescents and adults with community-acquired pneumonia in China: a retrospective multicentre survey

Abstract: Objectives To describe the clinical characteristics and management of patients hospitalised with community-acquired pneumonia (CAP) in China. Design This was a multicentre, retrospective, observational study. Setting 13 teaching hospitals in northern, central and southern China from 1 January 2014 to 31 December 2014 Participants Information on hospitalised patients aged ≥14 years with radiographically confirmed pneumonia with illness onset in the community was collected using standard case report forms. Primary and secondary outcome measures Resource use for CAP management. Results Of 14 793 patients screened, 5828 with radiographically confirmed CAP were included in the final analysis. Low mortality risk patients with a CURB-65 score 0–1 and Pneumonia Severity Index risk class I–II accounted for 81.2% (4434/5594) and 56.4% (2034/3609) patients, respectively. 21.7% (1111/5130) patients had already achieved clinical stability on admission. A definite or probable pathogen was identified only in 12.7% (738/5828) patients. 40.9% (1575/3852) patients without pseudomonal infection risk factors received antimicrobial overtreatment regimens. The median duration between clinical stability to discharge was 5.0 days with 30-day mortality of 4.2%. Conclusions These data demonstrated the overuse of health resources in CAP management, indicating that there is potential for improvement and substantial savings to healthcare systems in China. Trial registration number NCT02489578; Results.

Clusters of Human Infection and Human-to-Human Transmission of Avian Influenza A(H7N9) Virus, 2013-2017.

Abstract: To detect changes in human-to-human transmission of influenza A(H7N9) virus, we analyzed characteristics of 40 clusters of case-patients during 5 epidemics in China in 2013-2017. Similarities in number and size of clusters and proportion of clusters with probable human-to-human transmission across all epidemics suggest no change in human-to-human transmission risk.

Characteristics and Outcomes of Influenza-Associated Encephalopathy Cases Among Children and Adults in Japan, 2010-2015.

Abstract: Background Influenza-associated encephalopathy (IAE) can result in severe neurologic disease with high mortality. Most IAE cases are reported among children worldwide. Understanding of IAE among adults is limited. Methods Data were collected on IAE cases reported through the National Epidemiological Surveillance of Infectious Diseases database in Japan from 2010 through 2015. IAE cases were stratified by age category and analyzed using descriptive statistics to assess differences in characteristics and outcomes. Results Among 385 IAE cases, median age at diagnosis was 7 years (range, 0-90), and 283 (74%) were aged <18 years. Mean seasonal incidence of IAE cases among children and adults (aged ≥18 years) was 2.83 and 0.19 cases per 1000000 population, respectively. IAE incidence did not vary by predominant influenza A virus subtype. IAE frequency was highest in school-aged (5-12 years) children (38%), followed by children aged 2-4 years (21%) and adults aged 18-49 years (11%). The proportion of cases with seizures was more common in children. There were more cases with cerebrospinal fluid pleocytosis among adults than in children (P < .01), especially among those aged 18-49 (17%) and 50-64 (19%) years. Case fatality proportion was highest in those aged 40-64 (17%) and ≥65 (20%) years. Conclusions We found differences in the clinical features of IAE between adults and children in Japan. Although IAE incidence was higher in children, mortality was higher in adults. Efforts are needed to prevent and improve survival of patients with IAE, especially in adults.

100 Years of Medical Countermeasures and Pandemic Influenza Preparedness

Abstract: The 1918 influenza pandemic spread rapidly around the globe, leading to high mortality and social disruption. The countermeasures available to mitigate the pandemic were limited and relied on nonpharmaceutical interventions. Over the past 100 years, improvements in medical care, influenza vaccines, antiviral medications, community mitigation efforts, diagnosis, and communications have improved pandemic response. A number of gaps remain, including vaccines that are more rapidly manufactured, antiviral drugs that are more effective and available, and better respiratory protective devices.

Influenza-Associated Acute Necrotizing Encephalopathy in Siblings.

Abstract: Encephalopathy is an important complication associated with influenza, most frequently observed in young children, with a wide range of severity. The most severe category of influenza-associated encephalopathy (IAE) is acute necrotizing encephalopathy (ANE), characterized by high frequency of neurologic sequelae and fatal outcomes. We report two young siblings who developed fever and seizures with altered mental status. Influenza A(H1N1)pdm09 virus infection was identified in upper respiratory tract specimens from both patients, and neuroimaging revealed bilateral inflammatory lesions, consistent with acute necrotizing encephalopathy. Neither child had received influenza vaccination. Both children progressed to critical illness and required invasive mechanical ventilation. In addition to critical care management, both patients received high-dose corticosteroids, mannitol, anticonvulsants, and antiviral treatment of influenza. The older child recovered fully and was discharged 2 weeks after illness onset, but the younger sibling developed severe brainstem edema and cerebellar tonsillar herniation, and died on illness day 11. Both children tested positive for Ran Binding Protein 2 (RANBP2) gene mutations. RANBP2 is a genetic polymorphism associated with recurrent episodes of necrotizing encephalitis with respiratory viral infections. Annual influenza vaccination is especially important for ANE survivors, with or without RANBP2 mutations, their household contacts, and caregivers. During influenza season, close monitoring of any child with a history of neurological complications associated with respiratory illness is indicated, with prompt initiation of antiviral treatment with onset of acute respiratory illness, and influenza testing performed by molecular assay.

Gaps in the clinical management of influenza a century since the 1918 pandemic

Abstract: This year marks the centennial of the devastating 1918 influenza A(H1N1) pandemic, which killed an estimated 50 million people worldwide. Prevention and control activities were limited in 1918 because global surveillance did not exist, influenza viruses were not yet discovered, and no influenza vaccines had been developed. Diagnostic tests for influenza were unavailable prior to isolation of influenza viruses in the 1930s, so spread of the pandemic virus was tracked by news reports of increased respiratory disease and related deaths. Establishment of the World Health Organization’s Global Influenza Surveillance Network in 1952 has contributed substantially to coordinated surveillance, vaccine development, and influenza vaccine strain selection. Pandemic influenza vaccine was not available until the 1957 influenza A(H2N2) pandemic, so prevention and control efforts in 1918 relied on nonpharmaceutical interventions, including isolation and quarantine, social distancing, public gathering bans, school closures, and mask wearing. Treatment options were limited: antivirals were not available until the 1968 influenza A(H3N2) pandemic; antibiotics for secondary bacterial infections had not yet been discovered; and organ supporting care strategies, other than supplemental oxygen, did not exist until the mid-1950s. While advances in influenza surveillance and availability of influenza vaccines have been increasingly effective, major gaps remain in the clinical response to seasonal influenza epidemics and pandemics. During the 2009 influenza A(H1N1) pandemic, rapid antigen tests had suboptimal sensitivity in detecting the pandemic virus, frequently yielding false-negative results. Clinicians caring for hospitalized patients often had to wait at least one day for reverse transcriptase– polymerase chain reaction testing results from a referral laboratory. Recently, molecular-based diagnostic tests (including rapid molecular assays) that can detect influenza viral nucleic acids in upper respiratory tract specimens with high sensitivity and specificity have become available in ambulatory and inpatient settings. However, the molecular assays in use in clinical settings do not distinguish between seasonal and novel influenza A viruses of zoonotic origin and cannot specifically identify the next pandemic virus. Clinicians need to work closely with public health laboratories to monitor surveillance data. Development of tests based on nextgeneration sequencing technology may facilitate more accurate and timely identification of antigenically drifted seasonal influenza viruses, novel influenza A viruses, and viruses with known markers of antiviral resistance. Whether this would ultimately improve health outcomes would need to be determined. Currently, antiviral treatment of influenza is focused on early initiation of monotherapy with one drug class, neuraminidase inhibitors (NAIs). Randomized clinical trials (RCTs) demonstrated shortened duration of fever and illness in outpatients with uncomplicated influenza who start treatment with the NAI oseltamivir within 2 days of symptom onset compared with placebo.1,2 A meta-analysis of RCTs involving adults and an observational study of high-risk children and adults reported reduced risk of hospitalization in outpatients treated with NAIs.1,3 However, enrolling hospitalized patients in RCTs of NAI treatment vs placebo has proved problematic, and challenges remain in identifying optimal end points.4 Evidence for NAI effectiveness in hospitalized patients with influenza includes observational studies of variable quality. One meta-analysis of observational data from 29 234 hospitalized patients (86% with laboratory-confirmed influenza A(H1N1) pdm09 virus infection) reported survival benefit in NAI-treated adults.5 However, not all observational studies of NAI treatment have reported benefit in hospitalized patients with influenza, and disagreement exists on the strength of the evidence base and the overall effectiveness of NAIs.6 Influenzavirusresistancetoantiviraldrugscanemerge sporadically during or after antiviral treatment, particularly in severely immunocompromised patients. Oseltamivirresistant influenza A(H1N1) viruses became prevalent worldwide between 2007 and early 2009. These viruses were replaced by the 2009 influenza A(H1N1) pandemic virus (now referred to as influenza A(H1N1)pdm09) which continues to circulate as a seasonal influenza A virus with sporadic detection of oseltamivir resistance. Given the potential for a widely circulating influenza virus with resistance to all NAIs, new and more effective antivirals, as well as tests to rapidly detect resistant viruses, are needed. Antivirals with different mechanisms of action than NAIs not only would treat NAI-resistant viruses but would also allow combination therapy of susceptible influenza virus infection. However, ensuring access to early antiviral treatment may be challenging: spot shortages of NAIs were reported this past winter in the United States. Because clinical benefit is greatest when NAI treatment is started soonafterillnessonset,sufficientsuppliesofantiviralsmust beavailableforimmediatelarge-scaledistributioninsevere pandemics. To facilitate early treatment and help mitigate patient surge at emergency departments and clinics, distribution may require strategies such as fever clinics, nurse telephone triage consultation; and antiviral provision in pharmacies, schools, or other community settings. Efforts to educate clinicians and the public about the clinical benefit of early antiviral treatment are vital, including those at high risk of influenza complications. Although current understanding of influenza virus pathogenesis has advanced considerably since 1918, VIEWPOINT

A Step Forward in the Treatment of Influenza.

Abstract: For many years, antiviral treatment of influenza has consisted of monotherapy with a neuraminidase inhibitor. The Food and Drug Administration (FDA) approved the neuraminidase inhibitors oseltamivi...

Kinetics of Serological Responses in Critically Ill Patients Hospitalized With 2009 Pandemic Influenza A(H1N1) Virus Infection in Canada, 2009-2011.

Abstract: Background The kinetics of the antibody response during severe influenza are not well documented. Methods Critically ill patients infected with 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09), confirmed by reverse-transcription polymerase chain reaction analysis or seroconversion (defined as a ≥4-fold rise in titers), during 2009-2011 in Canada were prospectively studied. Antibody titers in serially collected sera were determined using hemagglutinin inhibition (HAI) and microneutralization assays. Average antibody curves were estimated using linear mixed-effects models and compared by patient outcome, age, and corticosteroid treatment. Results Of 47 patients with A(H1N1)pdm09 virus infection (median age, 47 years), 59% had baseline HAI titers of <40, and 68% had baseline neutralizing titers of <40. Antibody titers rose quickly after symptom onset, and, by day 14, 83% of patients had HAI titers of ≥40, and 80% had neutralizing titers ≥40. Baseline HAI titers were significantly higher in patients who died compared with patients who survived; however, the antibody kinetics were similar by patient outcome and corticosteroid treatment. Geometric mean titers over time in older patients were lower than those in younger patients. Conclusions Critically ill patients with influenza A(H1N1)pdm09 virus infection had strong HAI and neutralizing antibody responses during their illness. Antibody kinetics differed by age but were not associated with patient outcome.

Influence of molecular testing on influenza diagnosis

Abstract: Influenza viruses infect millions of people each year, leading to several hundred thousand hospitalizations and thousands of deaths annually in the US Early antiviral therapy reduces illness duration, complications, and mortality associated with influenza Yet, antivirals are consistently used at a suboptimal rate Patients with positive influenza diagnostic testing results are more likely to receive antiviral therapy and less likely to be prescribed unnecessary antibiotics Thus, access to reliable influenza testing in both ambulatory and inpatient settings is critical to facilitate both optimal patient outcomes and antimicrobial stewardship Recently, the first point-of-care (POC)7 molecular diagnostic test was cleared by the US Food and Drug Administration (FDA) for the detection of influenza At the same time, concerns about the performance of commonly used rapid antigen tests, particularly the test sensitivity, led to modified regulatory requirements for these devices The landscape of influenza diagnostics is rapidly evolving, and clinical laboratorians are certain to face pressure regarding new testing modalities In this article, 5 experts that span the continuum of influenza diagnosis from the clinical laboratory to industry to public health and regulatory agencies discuss recent advances and ongoing challenges in influenza diagnostics During influenza season, how does rapid influenza diagnostic testing affect clinical management and clinical workflows? Neil Anderson: During influenza season, most infected individuals will present to 1 of 2 places: an outpatient clinic or an emergency department (ED) These initial interactions with the healthcare system are often very brief During this short amount of time, clinicians must make many decisions Should the patient be given antibiotics, antivirals, or neither? Should the patient be admitted? Given the overlap in symptomatology of different respiratory pathogens, these questions can be very difficult to answer on presentation alone In this situation, a rapid influenza diagnostic test is an essential component of patient management …

Invasive Streptococcus pneumoniae infection among hospitalized patients in Jingzhou city, China, 2010-2012.

Abstract: Background Streptococcus pneumoniae (Sp) is a leading cause of bacterial pneumonia, meningitis, and sepsis and a major source of morbidity and mortality worldwide. Invasive pneumococcal disease (IPD) is defined as isolation of Sp from a normally sterile site, including blood or cerebrospinal fluid. The aim of this study is to describe outcomes as well as clinical and epidemiological characteristics of hospitalized IPD case patients in central China. Methods We conducted surveillance for IPD among children and adults from April 5, 2010 to September 30, 2012, in four major hospitals in Jingzhou City, Hubei Province. We collected demographic, clinical, and outcome data for all enrolled hospitalized patients with severe acute respiratory infection (SARI) or meningitis, and collected blood, urine, and cerebrospinal fluid (CSF) for laboratory testing for Sp infections. Collected data were entered into Epidata software and imported into SPSS for analysis. Results We enrolled 22,375 patients, including 22,202 (99%) with SARI and 173 (1%) with meningitis. One hundred and eighteen (118, 3%) with either SARI or meningitis were Sp positive, 32 (0.8%) from blood/CSF culture, and 87 (5%) from urine antigen testing. Of those 118 patients, 57% were aged ≥65 years and nearly 100% received antibiotics during hospitalization. None were previously vaccinated with 7-valent pneumococcal conjugate vaccine (PCV 7), 23-valent pneumococcal polysaccharide vaccine, or seasonal influenza vaccine. The main serotypes identified were 14, 12, 3, 1, 19F, 4, 5, 9V, 15 and 18C, corresponding to serotype coverage rates of 42%, 63%, and 77% for PCV7, PCV10, and PCV13, respectively. Conclusions Further work is needed to expand access to pneumococcal vaccination in China, both among children and potentially among the elderly, and inappropriate use of antibiotics is a widespread and serious problem in China.