Publications by authors named "Peter W Horby"

43 Publications

Ebola virus antibody decay-stimulation in a high proportion of survivors.

Nature 2021 02 27;590(7846):468-472. Epub 2021 Jan 27.

Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, UK.

Neutralizing antibody function provides a foundation for the efficacy of vaccines and therapies. Here, using a robust in vitro Ebola virus (EBOV) pseudo-particle infection assay and a well-defined set of solid-phase assays, we describe a wide spectrum of antibody responses in a cohort of healthy survivors of the Sierra Leone EBOV outbreak of 2013-2016. Pseudo-particle virus-neutralizing antibodies correlated with total anti-EBOV reactivity and neutralizing antibodies against live EBOV. Variant EBOV glycoproteins (1995 and 2014 strains) were similarly neutralized. During longitudinal follow-up, antibody responses fluctuated in a 'decay-stimulation-decay' pattern that suggests de novo restimulation by EBOV antigens after recovery. A pharmacodynamic model of antibody reactivity identified a decay half-life of 77-100 days and a doubling time of 46-86 days in a high proportion of survivors. The highest antibody reactivity was observed around 200 days after an individual had recovered. The model suggests that EBOV antibody reactivity declines over 0.5-2 years after recovery. In a high proportion of healthy survivors, antibody responses undergo rapid restimulation. Vigilant follow-up of survivors and possible elective de novo antigenic stimulation by vaccine immunization should be considered in order to prevent EBOV viral recrudescence in recovering individuals and thereby to mitigate the potential risk of reseeding an outbreak.
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http://dx.doi.org/10.1038/s41586-020-03146-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839293PMC
February 2021

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study.

Lancet Respir Med 2021 04 11;9(4):349-359. Epub 2021 Jan 11.

School of Informatics, University of Edinburgh, Edinburgh, UK.

Background: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.

Methods: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).

Findings: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.

Interpretation: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.

Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.
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http://dx.doi.org/10.1016/S2213-2600(20)30559-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832571PMC
April 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

Hydroxychloroquine for COVID-19: Balancing contrasting claims.

Eur J Intern Med 2020 12 23;82:25-26. Epub 2020 Nov 23.

MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom.

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http://dx.doi.org/10.1016/j.ejim.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682326PMC
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

Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID-19 Therapeutic Development.

Clin Pharmacol Ther 2020 Oct 28. Epub 2020 Oct 28.

Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.

The urgent global public health need presented by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has brought scientists from diverse backgrounds together in an unprecedented international effort to rapidly identify interventions. There is a pressing need to apply clinical pharmacology principles and this has already been recognized by several other groups. However, one area that warrants additional specific consideration relates to plasma and tissue protein binding that broadly influences pharmacokinetics and pharmacodynamics. The principles of free drug theory have been forged and applied across drug development but are not currently being routinely applied for SARS-CoV-2 antiviral drugs. Consideration of protein binding is of critical importance to candidate selection but requires correct interpretation, in a drug-specific manner, to avoid either underinterpretation or overinterpretation of its consequences. This paper represents a consensus from international researchers seeking to apply historical knowledge, which has underpinned highly successful antiviral drug development for other viruses, such as HIV and hepatitis C virus for decades.
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http://dx.doi.org/10.1002/cpt.2099DOI Listing
October 2020

Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study.

BMJ 2020 08 27;370:m3249. Epub 2020 Aug 27.

Respiratory Medicine, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK

Objective: To characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C).

Design: Prospective observational cohort study with rapid data gathering and near real time analysis.

Setting: 260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020).

Participants: 651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2.

Main Outcome Measures: Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.

Results: Median age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 (8.3-14.1) 1.6 (0.2-12.9) years; P<0.001) and more likely to be of non-white ethnicity (64% (29/45) 42% (148/355); P=0.004). Children with MIS-C were five times more likely to be admitted to critical care (73% (38/52) 15% (62/404); P<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% (24/47) 28% (86/302); P=0.004), headache (34% (16/47) 10% (26/263); P<0.001), myalgia (34% (15/44) 8% (21/270); P<0.001), sore throat (30% (14/47) (12% (34/284); P=0.003), and lymphadenopathy (20% (9/46) 3% (10/318); P<0.001) and to have a platelet count of less than 150 × 10/L (32% (16/50) 11% (38/348); P<0.001) than children who did not have MIS-C. No deaths occurred in the MIS-C group.

Conclusions: Children and young people have less severe acute covid-19 than adults. A systemic mucocutaneous-enteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive).

Study Registration: ISRCTN66726260.
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http://dx.doi.org/10.1136/bmj.m3249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488201PMC
August 2020

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.

BMJ 2020 09 9;370:m3339. Epub 2020 Sep 9.

NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.

Objective: To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).

Design: Prospective observational cohort study.

Setting: International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium-ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020 PARTICIPANTS: Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.

Main Outcome Measure: In-hospital mortality.

Results: 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).

Conclusions: An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.

Study Registration: ISRCTN66726260.
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http://dx.doi.org/10.1136/bmj.m3339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116472PMC
September 2020

Compassionate drug (mis)use during pandemics: lessons for COVID-19 from 2009.

BMC Med 2020 08 21;18(1):265. Epub 2020 Aug 21.

Epidemic Diseases Research Group Oxford (ERGO), Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7FZ, UK.

Background: New emerging infections have no known treatment. Assessing potential drugs for safety and efficacy enables clinicians to make evidence-based treatment decisions and contributes to overall outbreak control. However, it is difficult to launch clinical trials in the unpredictable environment of an outbreak. We conducted a bibliometric systematic review for the 2009 influenza pandemic to determine the speed and quality of evidence generation for treatments. This informs approaches to high-quality evidence generation in this and future pandemics.

Methods: We searched PubMed for all clinical data (including clinical trial, observational and case series) describing treatment for patients with influenza A(H1N1)pdm09 and ClinicalTrials.gov for research that aimed to enrol patients with the disease.

Results: Thirty-three thousand eight hundred sixty-nine treatment courses for patients hospitalised with A(H1N1)pdm09 were detailed in 160 publications. Most were retrospective observational studies or case series. Five hundred ninety-two patients received treatment (or placebo) as participants in a registered interventional clinical trial with results publicly available. None of these registered trial results was available during the timeframe of the pandemic, and the median date of publication was 213 days after the Public Health Emergency of International Concern ended.

Conclusion: Patients were frequently treated for pandemic influenza with drugs not registered for this indication, but rarely under circumstances of high-quality data capture. The result was a reliance on use under compassionate circumstances, resulting in continued uncertainty regarding the potential benefits and harms of anti-viral treatment. Rapid scaling of clinical trials is critical for generating a quality evidence base during pandemics.
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http://dx.doi.org/10.1186/s12916-020-01732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441224PMC
August 2020

Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis.

Front Med 2020 Oct 3;14(5):601-612. Epub 2020 Jul 3.

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, 100029, China.

The possible effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on COVID-19 disease severity have generated considerable debate. We performed a single-center, retrospective analysis of hospitalized adult COVID-19 patients in Wuhan, China, who had definite clinical outcome (dead or discharged) by February 15, 2020. Patients on anti-hypertensive treatment with or without ACEI/ARB were compared on their clinical characteristics and outcomes. The medical records from 702 patients were screened. Among the 101 patients with a history of hypertension and taking at least one anti-hypertensive medication, 40 patients were receiving ACEI/ARB as part of their regimen, and 61 patients were on antihypertensive medication other than ACEI/ARB. We observed no statistically significant differences in percentages of in-hospital mortality (28% vs. 34%, P = 0.46), ICU admission (20% vs. 28%, P = 0.37) or invasive mechanical ventilation (18% vs. 26%, P = 0.31) between patients with or without ACEI/ARB treatment. Further multivariable adjustment of age and gender did not provide evidence for a significant association between ACEI/ARB treatment and severe COVID-19 outcomes. Our findings confirm the lack of an association between chronic receipt of renin-angiotensin system antagonists and severe outcomes of COVID-19. Patients should continue previous anti-hypertensive therapy until further evidence is available.
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http://dx.doi.org/10.1007/s11684-020-0800-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333369PMC
October 2020

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial.

Trials 2020 May 24;21(1):422. Epub 2020 May 24.

Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.

Background: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30 January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19.

Methods: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed.

Discussion: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6 February 2020.

Trial Registration: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.
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http://dx.doi.org/10.1186/s13063-020-04352-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245636PMC
May 2020

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.

BMJ 2020 May 22;369:m1985. Epub 2020 May 22.

NIHR Health Protection Research Unit in Emerging and Zoonotic Infections and Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK

Objective: To characterise the clinical features of patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United Kingdom during the growth phase of the first wave of this outbreak who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study, and to explore risk factors associated with mortality in hospital.

Design: Prospective observational cohort study with rapid data gathering and near real time analysis.

Setting: 208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020. A case report form developed by ISARIC and WHO was used to collect clinical data. A minimal follow-up time of two weeks (to 3 May 2020) allowed most patients to complete their hospital admission.

Participants: 20 133 hospital inpatients with covid-19.

Main Outcome Measures: Admission to critical care (high dependency unit or intensive care unit) and mortality in hospital.

Results: The median age of patients admitted to hospital with covid-19, or with a diagnosis of covid-19 made in hospital, was 73 years (interquartile range 58-82, range 0-104). More men were admitted than women (men 60%, n=12 068; women 40%, n=8065). The median duration of symptoms before admission was 4 days (interquartile range 1-8). The commonest comorbidities were chronic cardiac disease (31%, 5469/17 702), uncomplicated diabetes (21%, 3650/17 599), non-asthmatic chronic pulmonary disease (18%, 3128/17 634), and chronic kidney disease (16%, 2830/17 506); 23% (4161/18 525) had no reported major comorbidity. Overall, 41% (8199/20 133) of patients were discharged alive, 26% (5165/20 133) died, and 34% (6769/20 133) continued to receive care at the reporting date. 17% (3001/18 183) required admission to high dependency or intensive care units; of these, 28% (826/3001) were discharged alive, 32% (958/3001) died, and 41% (1217/3001) continued to receive care at the reporting date. Of those receiving mechanical ventilation, 17% (276/1658) were discharged alive, 37% (618/1658) died, and 46% (764/1658) remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital.

Conclusions: ISARIC WHO CCP-UK is a large prospective cohort study of patients in hospital with covid-19. The study continues to enrol at the time of this report. In study participants, mortality was high, independent risk factors were increasing age, male sex, and chronic comorbidity, including obesity. This study has shown the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks.

Study Registration: ISRCTN66726260.
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http://dx.doi.org/10.1136/bmj.m1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243036PMC
May 2020

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.

Lancet 2020 05 29;395(10236):1569-1578. Epub 2020 Apr 29.

Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.

Background: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models.

Methods: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656.

Findings: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early.

Interpretation: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.

Funding: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.
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http://dx.doi.org/10.1016/S0140-6736(20)31022-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190303PMC
May 2020

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

N Engl J Med 2020 05 18;382(19):1787-1799. Epub 2020 Mar 18.

From the Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases (B.C., Yeming Wang, G.F., F.Z., X.G., Z.L., Y.Z., Hui Li, L.S., C.W.), and the Institute of Clinical Medical Sciences (G.F., X.G.), China-Japan Friendship Hospital, the Institute of Respiratory Medicine, Chinese Academy of Medical Sciences (B.C., Yeming Wang, F.Z., Z.L., Y.Z., Hui Li, C.W.), the Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University (Xingwang Li), Peking University Clinical Research Institute, Peking University First Hospital (C.D.), Tsinghua University School of Medicine (Jiuyang Xu), Beijing University of Chinese Medicine (L.S.), NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences (L.G.), and Peking Union Medical College (L.G., C.W.), Beijing, and Jin Yin-tan Hospital, Wuhan (D.W., W.L., Jingli Wang, L.R., B.S., Y.C., M.W., Jiaan Xia, N.C., Jie Xiang, T.Y., T.B., X.X., L.Z., C.L., Y.Y., H.C., Huadong Li, H.H., S.T., F.G., Y.L., Yuan Wei, K.W., K.L., X.Z., X.D., Z.Q., Sixia Lu, X.H., S.R., Shanshan Luo, Jing Wu, Lu Peng, F.C., Lihong Pan, J.Z., C.J., Juan Wang, Xia Liu, S.W., X.W., Q.G., J.H., H.Z., F.Q., C.H., D.Z.) - all in China; Lancaster University, Lancaster (T.J.), and the University of Oxford, Oxford (P.W.H.) - both in the United Kingdom; and the University of Virginia School of Medicine, Charlottesville (F.G.H.).

Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.

Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao) to the fraction of inspired oxygen (Fio) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
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http://dx.doi.org/10.1056/NEJMoa2001282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121492PMC
May 2020

A novel coronavirus outbreak of global health concern.

Lancet 2020 02 24;395(10223):470-473. Epub 2020 Jan 24.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.

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http://dx.doi.org/10.1016/S0140-6736(20)30185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135038PMC
February 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

A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups.

Sci Transl Med 2019 11;11(520)

Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013-2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.
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http://dx.doi.org/10.1126/scitranslmed.aaw1049DOI Listing
November 2019

Core Minimal Datasets to Advance Clinical Research for Priority Epidemic Diseases.

Clin Infect Dis 2020 02;70(4):696-697

Epidemic Diseases Research Group, University of Oxford, United Kingdom.

The Ebola virus disease outbreak in west Africa has prompted significant progress in responding to the clinical needs of patients affected by emerging infectious disease outbreaks. Among the noteworthy successes of vaccine trials, and the commendable efforts to implement clinical treatment trials during Ebola outbreaks, we should also focus on strengthening the collection and curation of epidemiological and observational data that can improve the conception and design of clinical research.
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http://dx.doi.org/10.1093/cid/ciz760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108131PMC
February 2020

Sero-Prevalence Surveillance to Predict Vaccine-Preventable Disease Outbreaks; A Lesson from the 2014 Measles Epidemic in Northern Vietnam.

Open Forum Infect Dis 2019 Mar 24;6(3):ofz030. Epub 2019 Jan 24.

Oxford University Clinical Research Unit, Wellcome Trust Asia Programme, Hanoi, Vietnam.

Background: During the first half of 2014, a severe outbreak of measles occurred in northern Vietnam, causing 15 033 confirmed cases and 146 deaths.

Methods: To evaluate the population-level seroprevalence of protection against measles in the period before the outbreak, we made use of an existing age-stratified serum bank, collected over the year before the outbreak, between November 2012 and December 2013, from 4 sites across the country (Hanoi, Hue, Dak Lak, and Ho Chi Minh City). Data from the UNICEF's Multiple Indicator Clustered Surveys (MICS), carried out in Vietnam during the first quarter of 2014, were used to assess the vaccine coverage in 6 ecological regions of Vietnam.

Results: Results revealed a large discrepancy between levels of protection, as estimated from the serology and vaccine coverage estimated by UNICEF's MICS. Variation in seroprevalence across locations and age groups corresponded with reported numbers of measles cases, most of which were among the 0-2-year-old age group and in the northern part of the country.

Conclusions: Our study presents a strong case in favor of a serosurveillance sentinel network that could be used to proactively tune vaccination policies and other public health interventions.
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http://dx.doi.org/10.1093/ofid/ofz030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405937PMC
March 2019

Assessment of Human-to-Human Transmissibility of Avian Influenza A(H7N9) Virus Across 5 Waves by Analyzing Clusters of Case Patients in Mainland China, 2013-2017.

Clin Infect Dis 2019 02;68(4):623-631

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

Background: The 2016-17 epidemic of human infections with avian influenza A(H7N9) virus was alarming, due to the surge in reported cases across a wide geographic area and the emergence of highly-pathogenic A(H7N9) viruses. Our study aimed to assess whether the human-to-human transmission risk of A(H7N9) virus has changed across the 5 waves since 2013.

Methods: Data on human cases and clusters of A(H7N9) virus infection were collected from the World Health Organization, open access national and provincial reports, informal online sources, and published literature. We compared the epidemiological characteristics of sporadic and cluster cases, estimated the relative risk (RR) of infection in blood relatives and non-blood relatives, and estimated the bounds on the effective reproductive number (Re) across waves from 2013 through September 2017.

Results: We identified 40 human clusters of A(H7N9) virus infection, with a median cluster size of 2 (range 2-3). The overall RR of infection in blood relatives versus non-blood relatives was 1.65 (95% confidence interval [CI]: 0.88, 3.09), and was not significantly different across waves (χ2 = 2.66, P = .617). The upper limit of Re for A(H7N9) virus was 0.12 (95% CI: 0.10, 0.14) and was not significantly different across waves (χ2 = 1.52, P = .822).

Conclusions: The small cluster size and low Re suggest that human-to-human transmissibility of A(H7N9) virus has not changed over time and remains limited to date. Continuous assessment of A(H7N9) virus infections and human case clusters is of crucial importance for public health.
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http://dx.doi.org/10.1093/cid/ciy541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355824PMC
February 2019

Prolonged Evolution of Virus-Specific Memory T Cell Immunity after Severe Avian Influenza A (H7N9) Virus Infection.

J Virol 2018 09 16;92(17). Epub 2018 Aug 16.

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

Since 2013, influenza A H7N9 virus has emerged as the most common avian influenza virus subtype causing human infection, and it is associated with a high fatality risk. However, the characteristics of immune memory in patients who have recovered from H7N9 infection are not well understood. We assembled a cohort of 45 H7N9 survivors followed for up to 15 months after infection. Humoral and cellular immune responses were analyzed in sequential samples obtained at 1.5 to 4 months, 6 to 8 months, and 12 to 15 months postinfection. H7N9-specific antibody concentrations declined over time, and protective antibodies persisted longer in severely ill patients admitted to the intensive care unit (ICU) and patients presenting with acute respiratory distress syndrome (ARDS) than in patients with mild disease. Frequencies of virus-specific gamma interferon (IFN-γ)-secreting T cells were lower in critically ill patients requiring ventilation than in patients without ventilation within 4 months after infection. The percentages of H7N9-specific IFN-γ-secreting T cells tended to increase over time in patients ≥60 years or in critically ill patients requiring ventilation. Elevated levels of antigen-specific CD8 T cells expressing the lung-homing marker CD49a were observed at 6 to 8 months after H7N9 infection compared to those in samples obtained at 1.5 to 4 months. Our findings indicate the prolonged reconstruction and evolution of virus-specific T cell immunity in older or critically ill patients and have implications for T cell-directed immunization strategies. Avian influenza A H7N9 virus remains a major threat to public health. However, no previous studies have determined the characteristics and dynamics of virus-specific T cell immune memory in patients who have recovered from H7N9 infection. Our findings showed that establishment of H7N9-specific T cell memory after H7N9 infection was prolonged in older and severely affected patients. Severely ill patients mounted lower T cell responses in the first 4 months after infection, while T cell responses tended to increase over time in older and severely ill patients. Higher levels of antigen-specific CD8 T cells expressing the lung-homing marker CD49a were detected at 6 to 8 months after infection. Our results indicated a long-term impact of H7N9 infection on virus-specific memory T cells. These findings advance our understanding of the dynamics of virus-specific memory T cell immunity after H7N9 infection, which is relevant to the development of T cell-based universal influenza vaccines.
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http://dx.doi.org/10.1128/JVI.01024-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096810PMC
September 2018

Spectrum of Enterovirus Serotypes Causing Uncomplicated Hand, Foot, and Mouth Disease and Enteroviral Diagnostic Yield of Different Clinical Samples.

Clin Infect Dis 2018 11;67(11):1729-1735

Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Centre for Disease Control and Prevention, Beijing, China.

Background: Hand, foot, and mouth disease (HFMD) represents a substantial disease burden in the Western Pacific region. We investigated the spectrum of causative enteroviruses of HFMD, and evaluated different clinical samples' diagnostic yield for enteroviruses.

Methods: We enrolled pediatric patients hospitalized for HFMD among 6 hospitals in Anhua County, Hunan Province, China between October 2013 and September 2016. Throat swabs and stool samples (or rectal swabs) were collected to detect the enterovirus serotypes by real-time reverse-transcription polymerase chain reaction (PCR) or nested PCR.

Results: Among the 2836 patients, only 1 developed severe illness. Seventeen serotypes were identified in 2401 patients (85%), with the most frequently detected being CV-A16 (29% [814]), CV-A6 (28% [784]), EV-A71 (17% [491]), CV-A10 (4% [114]), and CV-A4 (2% [53]). Children were younger in CV-A6, CV-A10, and CV-A4 infections (median, 12 months; interquartile range [IQR], 12-24 months) than EV-A71 and CV-A16 infections (median, 24 months; IQR, 12-36 months; P < .05). The predominant enterovirus serotype shifted between CV-A16 and CV-A6 during the 3 years. Stool had a higher diagnostic yield (89%) than rectal (77%) and throat swabs (74%). Detection rates reached 93% when testing stools followed by throat swabs if stools were negative, and 89% when testing rectal swabs followed by throat swabs if rectal swabs were negative.

Conclusions: Our results provide a virological benchmark for future surveillance and diagnostics. Continuous comprehensive virological surveillance is essential, especially after implementation of the EV-A71 vaccine in China, to monitor serotype replacement and the vaccine's impact.
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http://dx.doi.org/10.1093/cid/ciy341DOI Listing
November 2018

Clinical assessment is a neglected component of outbreak preparedness: evidence from refugee camps in Greece.

BMC Med 2018 03 19;16(1):43. Epub 2018 Mar 19.

Epidemic Diseases Research Group, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK.

Background: Refugees may have an increased vulnerability to infectious diseases, and the consequences of an outbreak are more severe in a refugee camp. When an outbreak is suspected, access to clinical information is critical for investigators to verify that an outbreak is occurring, to determine the cause and to select interventions to control it. Experience from previous outbreaks suggests that the accuracy and completeness of this information is poor. This study is the first to assess the adequacy of clinical characterisation of acute medical illnesses in refugee camps. The objective is to direct improvements in outbreak identification and management in this vulnerable setting.

Methods: We collected prospective data in 13 refugee camps in Greece. We passively observed consultations where patients presented with syndromes that might warrant inclusion into an existing syndromic surveillance system and then undertook a structured assessment of routine clinical data collection to examine the extent to which key clinical parameters required for an outbreak response were ascertained and then documented.

Results: A total of 528 patient consultations were included. The most common presenting condition was an acute respiratory illness. Clinicians often made a comprehensive clinical assessment, especially for common syndromes of respiratory and gastrointestinal conditions, but documented their findings less frequently. For fewer than 5% of patients were a full set of vital signs ascertained and so the severity of patient illnesses was largely unknown. In only 11% of consultations was it verified that a patient who met the case criteria for syndromic surveillance reporting based on an independent assessment was reported into the system.

Discussion: Opportunities exist to strengthen clinical data capture and recording in refugee camps, which will produce a better calibrated and directed public health response.

Conclusion: Information of significant utility for outbreak response is collected at the clinical interface and we recommend improving how this information is recorded and linked into surveillance systems.
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http://dx.doi.org/10.1186/s12916-018-1015-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858141PMC
March 2018

Regulatory and Operational Complexities of Conducting a Clinical Treatment Trial During an Ebola Virus Disease Epidemic.

Clin Infect Dis 2018 04;66(9):1454-1457

Epidemic Diseases Research Group Oxford (ERGO), Centre for Tropical Medicine and Global Health, University of Oxford, United Kingdom.

The first phase II and III clinical trials for Ebola virus disease treatments were conducted during the West Africa outbreak. We report the operational practicalities of conducting a phase II clinical trial of TKM-130803 to international standards during this outbreak.
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http://dx.doi.org/10.1093/cid/cix1061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905621PMC
April 2018

The Breadth of Viruses in Human Semen.

Emerg Infect Dis 2017 11;23(11):1922-1924

Zika virus RNA is frequently detected in the semen of men after Zika virus infection. To learn more about persistence of viruses in genital fluids, we searched PubMed for relevant articles. We found evidence that 27 viruses, across a broad range of virus families, can be found in human semen.
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http://dx.doi.org/10.3201/eid2311.171049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652425PMC
November 2017

Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory-confirmed case series.

Lancet Infect Dis 2017 08 2;17(8):822-832. Epub 2017 Jun 2.

WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Centre of Influenza Research and State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory of Emerging Infectious Diseases (The University of Hong Kong-Shenzhen Branch), Shenzhen Third People's Hospital, Shenzhen, China; Shantou University-The University of Hong Kong Joint Institute of Virology, Shantou University, Shantou, China.

Background: The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016-17 prompted concerns that the epidemiology of the virus might have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016-17 epidemic compared with previous epidemics.

Methods: In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques.

Findings: Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory-confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013-14, 219 in 2014-15, 114 in 2015-16, and 447 in 2016-17. The 2016-17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016-17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015-16 and 2016-17 epidemics (63% [72 of 114] and 61% [274 of 447], respectively) were higher than those in the first three epidemics (39% [52 of 134], 55% [169 of 306], and 56% [122 of 219], respectively). The clinical severity of individuals admitted to hospital in the 2016-17 epidemic was similar to that in the previous epidemics.

Interpretation: Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus.

Funding: The National Science Fund for Distinguished Young Scholars.
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http://dx.doi.org/10.1016/S1473-3099(17)30323-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988584PMC
August 2017

Offering patients more: how the West Africa Ebola outbreak can shape innovation in therapeutic research for emerging and epidemic infections.

Philos Trans R Soc Lond B Biol Sci 2017 May;372(1721)

Epidemic Diseases Research Group Oxford (ERGO), Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK.

Although, after an epidemic of over 28 000 cases, there are still no licensed treatments for Ebola virus disease (EVD), significant progress was made during the West Africa outbreak. The pace of pre-clinical development was exceptional and a number of therapeutic clinical trials were conducted in the face of considerable challenges. Given the on-going risk of emerging infectious disease outbreaks in an era of unprecedented population density, international travel and human impact on the environment it is pertinent to focus on improving the research and development landscape for treatments of emerging and epidemic-prone infections. This is especially the case since there are no licensed therapeutics for some of the diseases considered by the World Health Organization as most likely to cause severe outbreaks-including Middle East respiratory syndrome coronavirus, Marburg virus, Crimean Congo haemorrhagic fever and Nipah virus. EVD, therefore, provides a timely exemplar to discuss the barriers, enablers and incentives needed to find effective treatments in advance of health emergencies caused by emerging infectious diseases.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.
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http://dx.doi.org/10.1098/rstb.2016.0294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394634PMC
May 2017

Clinical Trials of Therapeutics for the Prevention of Congenital Zika Virus Disease: Challenges and Potential Solutions.

Ann Intern Med 2017 May 21;166(10):725-732. Epub 2017 Mar 21.

From University of Oxford, Oxford, United Kingdom.

Zika virus (ZIKV) infection in pregnancy is associated with adverse fetal outcomes, such as microcephaly and other congenital malformations. No therapeutic options are available to pregnant women with ZIKV infection to prevent these effects. Drug trials in pregnancy raise several scientific, ethical, and logistic challenges, which are compounded further in ZIKV because of limited knowledge of the disease pathophysiology and a product development pipeline in its infancy. We evaluate the major challenges in choosing therapeutics to prevent congenital ZIKV disease and conducting clinical trials of these treatments, with a focus on preventing congenital central nervous system malformations. These challenges must be characterized and planned for now so that clinical trials can progress expediently and effectively in the future.
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http://dx.doi.org/10.7326/M16-2530DOI Listing
May 2017

Modernising epidemic science: enabling patient-centred research during epidemics.

BMC Med 2016 Dec 19;14(1):212. Epub 2016 Dec 19.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7FZ, UK.

Background: Emerging and epidemic infectious disease outbreaks are a significant public health problem and global health security threat. As an outbreak begins, epidemiological investigations and traditional public health responses are generally mounted very quickly. However, patient-centred research is usually not prioritised when planning and enacting the response. Instead, the clinical research response occurs subsequent to and separate from the public health response, and is inadequate for evidence-based decision-making at the bedside or in the offices of public health policymakers.

Discussion: The deficiencies of the clinical research response to severe acute respiratory syndrome, pandemic influenza, Middle East respiratory syndrome coronavirus and Ebola virus demonstrate that current research models do not adequately inform and improve the quality of clinical care or public health response. Three suggestions for improvements are made. First, integrate the data and sample collection needs for clinical and public health decision-making within a unified framework, combined with a risk-based, rather than a discipline-based, approach to ethical review and consent. Second, develop clinical study methods and tools that are specifically designed to meet the epidemiological and contextual challenges of emerging and epidemic infectious diseases. Third, invest in investigator-led clinical research networks that are primed and incentivised to respond to outbreak infections, and which can call on the support and resources of a central centre of excellence.

Conclusions: It is crucial that the field of epidemic science matures to place patients at the heart of the response. This can only be achieved when patient-centred research is integrated in the outbreak response from day one and practical steps are taken to reduce the barriers to the generation of reliable and useful evidence.
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http://dx.doi.org/10.1186/s12916-016-0760-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165716PMC
December 2016