Imperial College London

Peter Openshaw - Professor of Experimental Medicine

Faculty of MedicineNational Heart & Lung Institute

Senior Consul, Professor of Experimental Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 3854p.openshaw Website CV

 
 
//

Assistant

 

Ms Gale Lewis +44 (0)20 7594 0944

 
//

Location

 

353Norfolk PlaceSt Mary's Campus

//

Summary

 

Publications

Publication Type
Year
to

326 results found

Openshaw P, 2020, Global disease burden estimates of respiratory syncytial virus associated with acute respiratory infections in older adults in 015: a systemic review and meta-analysis, Journal of Infectious Diseases, Vol: 222, Pages: S577-S583, ISSN: 0022-1899

Respiratory syncytial virus associated acute respiratory infection (RSV-ARI)constitutes a substantial disease burden in older adults≥65 years. We aimed to identify all studies worldwide investigating the disease burden ofRSV-ARIin this population. We estimated thecommunityincidence, hospitalisationrate and in-hospital case fatality ratio (hCFR) of RSV-ARI in older adults stratified by industrialized anddeveloping regions, with data from a systematic review ofstudies published between January 1996 and April 2018, and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015, to calculate the global and regional burdenin older adults with RSV-ARIin community and in hospital duringthat year. We estimated thenumber ofin-hospital RSV-ARIdeaths by combining hCFR with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5million(95% CI 0.3-6.9) episodes of RSV-ARIin older adults in41industrialised countries (data missing in developing countries), and of these 214,000 (~14.5%; 95% CI 100,000-459,000) were admitted to hospitals. The global number of hospital admissionsforRSV-ARI in older adults was estimated at 336,000 (UR 186,000-614,000).We further estimated about 14,000 (UR 5,000-50,000) in-hospital deaths related to RSV-ARIglobally.The hospital admission rate and hCFR were higher for those ≥65 years than those aged 50-64 years. The disease burden of RSV-ARIamong older adults is substantialwith limited data from developing countries; appropriate prevention and management strategiesare needed to reduce this burden.

Journal article

Shi T, Arnott A, Semogas I, Falsey AR, Openshaw P, Wedzicha JA, Campbell H, Nair H, RESCEU Investigatorset al., 2020, The etiological role of common respiratory viruses in acute respiratory infections in older adults: a systematic review and meta-analysis, Journal of Infectious Diseases, Vol: 222, Pages: S563-S569, ISSN: 0022-1899

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9-18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4-15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3-41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7-13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0-4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report.

Journal article

Shi T, Denouel A, Tietjen AK, Lee JW, Falsey AR, Demont C, Nyawanda BO, Cai B, Fuentes R, Stoszek SK, Openshaw P, Campbell H, Nair H, RESCEU Investigatorset al., 2020, Global and regional burden of hospital admissions for pneumonia in older adults: A systematic review and meta-analysis, Journal of Infectious Diseases, Vol: 222, Pages: S570-S576, ISSN: 0022-1899

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8-8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9-1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

Journal article

Wiseman DJ, Thwaites RS, Drysdale SB, Janet S, Donaldson GC, Wedzicha JA, Openshaw PJ, RESCEU Investigatorset al., 2020, Immunological and inflammatory biomarkers of susceptibility and severity in adult respiratory syncytial virus infections, Journal of Infectious Diseases, Vol: 222, Pages: S584-S591, ISSN: 0022-1899

BACKGROUND: . Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults. METHODS: A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources. RESULTS: From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection. CONCLUSIONS: Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

Journal article

Habibi M, Thwaites R, Chang M, Jozwik A, Paras A, Kirsebom F, Varese A, Owen A, Cuthbertson L, James P, Tunstall T, Nickle D, Hansel T, Moffatt M, Johansson C, Chiu C, Openshaw Pet al., 2020, Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection, Science, Vol: 370, Pages: 1-15, ISSN: 0036-8075

INTRODUCTIONEven with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood.RATIONALEWe reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection.RESULTSAfter nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient

Journal article

Lin G-L, Golubchik T, Drysdale S, O'Connor D, Jefferies K, Brown A, de Cesare M, Bonsall D, Ansari MA, Aerssens J, Bont L, Openshaw P, Martinón-Torres F, Bowden R, Pollard AJ, RESCEU Investigatorset al., 2020, Simultaneous Viral Whole-Genome Sequencing and Differential Expression Profiling in Respiratory Syncytial Virus Infection of Infants., J Infect Dis, Vol: 222, Pages: S666-S671

Targeted metagenomics using strand-specific libraries with target enrichment is a sensitive, generalized approach to pathogen sequencing and transcriptome profiling. Using this method, we recovered 13 (76%) complete human respiratory syncytial virus (RSV) genomes from 17 clinical respiratory samples, reconstructed the phylogeny of the infecting viruses, and detected differential gene expression between 2 RSV subgroups, specifically, a lower expression of the P gene and a higher expression of the M2 gene in RSV-A than in RSV-B. This methodology can help to relate viral genetics to clinical phenotype and facilitate ongoing population-level RSV surveillance and vaccine development. Clinical Trials Registration. NCT03627572 and NCT03756766.

Journal article

Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, Babu S, Barber CM, Barratt S, Bendstrup E, Bianchi S, Castillo Villegas D, Chaudhuri N, Chua F, Coker R, Chang W, Crawshaw A, Crowley LE, Dosanjh D, Fiddler CA, Forrest IA, George PM, Gibbons MA, Groom K, Haney S, Hart SP, Heiden E, Henry M, Ho L-P, Hoyles RK, Hutchinson J, Hurley K, Jones MG, Jones S, Kokosi M, Kreuter M, Mackay LS, Mahendran S, Margaritopoulos G, Molina-Molina M, Molyneaux PL, O'Brien A, O'Reilly K, Packham A, Parfrey H, Poletti V, Porter JC, Renzoni E, Rivera-Ortega P, Russell A-M, Saini G, Spencer LG, Stella GM, Stone H, Sturney S, Thickett D, Thillai M, Wallis T, Ward K, Wells AU, West A, Wickremasinghe M, Woodhead F, Hearson G, Howard L, Baillie JK, Openshaw PJM, Semple MG, Stewart I, Jenkins RG, ISARIC4C Investigatorset al., 2020, Outcome of hospitalization for COVID-19 in patients with interstitial lung disease: an international multicenter study., American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

RATIONALE: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. OBJECTIVES: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. METHODS: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. MEASUREMENTS AND MAIN RESULTS: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39-3.71). CONCLUSIONS: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal article

Auffray C, Balling R, Blomberg N, Bonaldo MC, Boutron B, Brahmachari S, Bréchot C, Cesario A, Chen S-J, Clément K, Danilenko D, Di Meglio A, Gelemanović A, Goble C, Gojobori T, Goldman JD, Goldman M, Guo Y-K, Heath J, Hood L, Hunter P, Jin L, Kitano H, Knoppers B, Lancet D, Larue C, Lathrop M, Laville M, Lindner AB, Magnan A, Metspalu A, Morin E, Ng LFP, Nicod L, Noble D, Nottale L, Nowotny H, Ochoa T, Okeke IN, Oni T, Openshaw P, Oztürk M, Palkonen S, Paweska JT, Pison C, Polymeropoulos MH, Pristipino C, Protzer U, Roca J, Rozman D, Santolini M, Sanz F, Scambia G, Segal E, Serageldin I, Soares MB, Sterk P, Sugano S, Superti-Furga G, Supple D, Tegner J, Uhlen M, Urbani A, Valencia A, Valentini V, van der Werf S, Vinciguerra M, Wolkenhauer O, Wouters Eet al., 2020, COVID-19 and beyond: a call for action and audacious solidarity to all the citizens and nations, it is humanity’s fight, F1000Research, Vol: 9, Pages: 1130-1130

<ns4:p><ns4:bold>Background</ns4:bold>: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to a subgroup of coronaviruses rampant in bats for centuries. It caused the coronavirus disease 2019 (COVID-19) pandemic. Most patients recover, but a minority of severe cases experience acute respiratory distress or an inflammatory storm devastating many organs that can lead to patient death. The spread of SARS-CoV-2 was facilitated by the increasing intensity of air travel, urban congestion and human contact during the past decades. Until therapies and vaccines are available, tests for virus exposure, confinement and distancing measures have helped curb the pandemic.</ns4:p><ns4:p> <ns4:bold>Vision</ns4:bold>: The COVID-19 pandemic calls for safeguards and remediation measures through a systemic response. Self-organizing initiatives by scientists and citizens are developing an advanced collective intelligence response to the coronavirus crisis. Their integration forms Olympiads of Solidarity and Health. Their ability to optimize our response to COVID-19 could serve as a model to trigger a global metamorphosis of our societies with far-reaching consequences for attacking fundamental challenges facing humanity in the 21<ns4:sup>st</ns4:sup> century.</ns4:p><ns4:p> <ns4:bold>Mission</ns4:bold>: For COVID-19 and these other challenges, there is no alternative but action. Meeting in Paris in 2003, we set out to "rethink research to understand life and improve health." We have formed an international coalition of academia and industry ecosystems taking a systems medicine approach to understanding COVID-19 by thoroughly characterizing viruses, patients and populations during the pandemic, using openly shared tools. All results will be publicly available with no initial claims for intellectual property rights. This World Alliance

Journal article

Knight SR, Ho A, Pius R, Buchan I, Carson G, Drake TM, Dunning J, Fairfield CJ, Gamble C, Green CA, Gupta R, Halpin S, Hardwick HE, Holden KA, Horby PW, Jackson C, Mclean KA, Merson L, Nguyen-Van-Tam JS, Norman L, Noursadeghi M, Olliaro PL, Pritchard MG, Russell CD, Shaw CA, Sheikh A, Solomon T, Sudlow C, Swann OV, Turtle LCW, Openshaw PJM, Baillie JK, Semple MG, Docherty AB, Harrison EMet al., 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, Vol: 370, ISSN: 1759-2151

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 sco

Journal article

Peng Y, Mentzer AJ, Liu G, Yao X, Yin Z, Dong D, Dejnirattisai W, Rostron T, Supasa P, Liu C, López-Camacho C, Slon-Campos J, Zhao Y, Stuart DI, Paesen GC, Grimes JM, Antson AA, Bayfield OW, Hawkins DEDP, Ker D, Wang B, Turtle L, Subramaniam K, Thomson P, Zhang P, Dold C, Ratcliff J, Simmonds P, de Silva T, Sopp P, Wellington D, Rajapaksa U, Chen Y, Salio M, Napolitani G, Paes W, Borrow P, Kessler BM, Fry JW, Schwabe NF, Semple MG, Baillie JK, Moore SC, Openshaw PJM, Ansari MA, Dunachie S, Barnes E, Frater J, Kerr G, Goulder P, Lockett T, Levin R, Zhang Y, Jing R, Ho L, Barnes E, Dong D, Dong T, Dunachie S, Frater J, Goulder P, Kerr G, Klenerman P, Liu G, McMichael A, Napolitani G, Ogg G, Peng Y, Salio M, Yao X, Yin Z, Kenneth Baillie J, Klenerman P, Mentzer AJ, Moore SC, Openshaw PJM, Semple MG, Stuart DI, Turtle L, Cornall RJ, Conlon CP, Klenerman P, Screaton GR, Mongkolsapaya J, McMichael A, Knight JC, Ogg G, Dong T, Oxford Immunology Network Covid-19 Response T cell Consortium, ISARIC4C Investigatorset al., 2020, Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19, Nature Immunology, ISSN: 1529-2916

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.

Journal article

Wiseman DJ, Thwaites RS, Openshaw PJM, 2020, A new role for CXCL4 in RSV disease., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 1-2, ISSN: 1073-449X

Journal article

Siegers JY, Novakovic B, Hulme KD, Marshall R, Bloxham CJ, Thomas WG, Reichelt ME, Leijten L, van Run P, Knox K, Sokolowski KA, Tse BWC, Chew KY, Christ AN, Howe G, Bruxner TJC, Karolyi M, Pawelka E, Koch RM, Bellmann-Weiler R, Burkert F, Weiss G, Samanta RJ, Openshaw PJM, Bielefeldt-Ohmann H, van Riel D, Short KRet al., 2020, A high fat diet increases influenza A virus-associated cardiovascular damage, Journal of Infectious Diseases, Vol: 222, Pages: 820-831, ISSN: 0022-1899

BACKGROUND: Influenza A virus (IAV) causes a wide range of extra-respiratory complications. However, the role of host factors in these complications of influenza virus infection remains to be defined. METHODS: Here, we sought to use transcriptional profiling, virology, histology and echocardiograms to investigate the role of a high fat diet in IAV associated cardiac damage. RESULTS: Transcriptional profiling showed that, compared to their low fat (LF) counterparts, mice fed a high fat (HF) diet had impairments in inflammatory signalling in the lung and heart after IAV infection. This was associated with increased viral titres in the heart, increased left ventricular mass and thickening of the left ventricular wall in IAV-infected HF mice compared to both IAV-infected LF mice and uninfected HF mice. Retrospective analysis of clinical trials revealed that cardiac complications were more common in patients with excess weight, an association which was significant in 2 out of 4 studies. CONCLUSIONS: Together, these data provide the first evidence that a high fat diet may be a risk factor for the development of IAV-associated cardiovascular damageand emphasises the need for further clinical research in this area.

Journal article

Jefferies K, Drysdale SB, Robinson H, Clutterbuck EA, Blackwell L, McGinley J, Lin G-L, Galal U, Nair H, Aerssens J, Öner D, Langedijk A, Bont L, Wildenbeest JG, Martinon-Torres F, Rodríguez-Tenreiro Sánchez C, Nadel S, Openshaw P, Thwaites R, Widjojoatmodjo M, Zhang L, Nguyen TL-A, Giaquinto C, Giordano G, Baraldi E, Pollard AJ, Respiratory Syncytial Virus Consortium in Europe RESCEU Investigatorset al., 2020, Presumed risk factors and biomarkers for severe respiratory syncytial virus disease and related sequelae: protocol for an observational multicenter, case-control study from the respiratory syncytial virus consortium in Europe (RESCEU)., Journal of Infectious Diseases, ISSN: 0022-1899

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity. CLINICAL TRIALS REGISTRATION: NCT03756766.

Journal article

Jacob J, Alexander D, Baillie JK, Berka R, Bertolli O, Blackwood J, Buchan I, Bloomfield C, Cushnan D, Docherty A, Edey A, Favaro A, Gleeson F, Halling-Brown M, Hare S, Jefferson E, Johnstone A, Kirby M, McStay R, Nair A, Openshaw PJM, Parker G, Reilly G, Robinson G, Roditi G, Rodrigues JCL, Sebire N, Semple MG, Sudlow C, Woznitza N, Joshi Iet al., 2020, Using imaging to combat a pandemic: rationale for developing the UK National COVID-19 Chest Imaging Database, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936

Journal article

Mehta P, Porter JC, Manson JJ, Isaacs JD, Openshaw PJM, McInnes IB, Summers C, Chambers RCet al., 2020, Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities, The Lancet Respiratory Medicine, Vol: 8, Pages: 822-830, ISSN: 2213-2600

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

Journal article

Pritchard M, Dankwa EA, Hall M, Baillie JK, Carson G, Docherty A, Donnelly CA, Dunning J, Fraser C, Hardwick H, Harrison EM, Holden KA, Kartsonaki C, Kennon K, Lee J, McLean K, Openshaw PJM, Plotkin D, Rojek A, Russell CD, Semple MG, Sigfrid L, Horby P, Olliaro P, Merson Let al., 2020, ISARIC Clinical Data Report 4 October 2020

<jats:title>Abstract</jats:title><jats:p>ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) partnerships and outbreak preparedness initiatives enabled the rapid launch of standardised clinical data collection on COVID-19 in Jan 2020. Extensive global uptake of this resource has resulted in a large, standardised collection of comprehensive clinical data from hundreds of sites across dozens of countries. Data are analysed regularly and reported publicly to inform patient care and public health response. This report is a part of a series and includes the results of data analysis on 4 October 2020.</jats:p><jats:p>We thank all of the data contributors for their ongoing support.</jats:p><jats:sec><jats:title>Report highlights include</jats:title><jats:p>ISARIC collaborators recorded symptoms from over 102,000 patients in hospital with COVID-19. Most had fever, cough or shortness of breath. Children and older adults were less likely to display typical symptoms, and over 40% of patients &gt;80 years experienced confusion.</jats:p><jats:p>The ISARIC international database continues to grow. Data have been entered for 102,959 individuals from 566 sites across 42 countries.</jats:p><jats:p>The analysis detailed in this report only includes individuals:</jats:p><jats:list list-type="order"><jats:list-item><jats:p>for whom data collection commenced on or before 14 September 2020. (We have applied a 14-day rule to focus analysis on individuals who are more likely to have a recorded outcome. By excluding patients enrolled during the last 14 days, we aim to reduce the number of incomplete data records and thus improve the generalisability of the results and the accuracy of the outcomes. However, this limits our focus to a restricted cohort despite the much larger volumes of data held in the database.)</jats:p><jats:p>

Journal article

Jha A, Thwaites RS, Tunstall T, Kon OM, Shattock RJ, Hansel TT, Openshaw PJMet al., 2020, Increased nasal mucosal interferon and CCL13 response to a TLR7/8 agonist in asthma and allergic rhinitis., J Allergy Clin Immunol

BACKGROUND: Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with preexisting lung diseases such as asthma. Toll-like receptors are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured. OBJECTIVE: We sought to assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy volunteers and volunteers with allergy. METHODS: We administered the Toll-like receptor 7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA) or saline by nasal spray to healthy participants without allergy (n = 12), those with allergic rhinitis (n = 12), or those with allergic rhinitis with asthma (n = 11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time. RESULTS: R848 was well tolerated and significantly induced IFN-α2a, IFN-γ, proinflammatory cytokines (TNF-α, IL-2, IL-12p70), and chemokines (CXCL10, C-C motif chemokine ligand [CCL]2, CCL3, CCL4, and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3, and CCL13 responses relative to healthy participants; those with asthma had increased induction of IFN-stimulated genes DExD/H-box helicase 58, MX dynamin-like GTPase 1, and IFN-induced protein with tetratricopeptide repeats 3. CONCLUSIONS: Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal IFN and chemokine response to the viral RNA analogue R848. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the

Journal article

Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, Babu S, Barber CM, Barratt S, Bendstrup E, Bianchi S, Villegas DC, Chaudhuri N, Chua F, Coker R, Chang W, Crawshaw A, Crowley LE, Dosanjh D, Fiddler CA, Forrest IA, George P, Gibbons MA, Groom K, Haney S, Hart SP, Heiden E, Henry M, Ho L-P, Hoyles RK, Hutchinson J, Hurley K, Jones M, Jones S, Kokosi M, Kreuter M, MacKay L, Mahendran S, Margaritopoulos G, Molina-Molina M, Molyneaux PL, OBrien A, OReilly K, Packham A, Parfrey H, Poletti V, Porter J, Renzoni E, Rivera-Ortega P, Russell A-M, Saini G, Spencer LG, Stella GM, Stone H, Sturney S, Thickett D, Thillai M, Wallis T, Ward K, Wells AU, West A, Wickremasinghe M, Woodhead F, Hearson G, Howard L, Baillie JK, Openshaw PJM, Semple MG, Stewart I, ISARIC4C Investigators, Jenkins RGet al., 2020, Outcome of hospitalisation for COVID-19 in patients with interstitial lung disease: an international multicentre study., Publisher: bioRxiv

Rationale: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. Objectives: To assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. Methods: An international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 1.98, 1.13−3.46). Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Working paper

Samanta R, Dunning J, Taylor A, Bayliffe AI, Chambers RC, Chilvers ER, Openshaw PJM, Summers Cet al., 2020, Identification of novel mechanistically distinct endotypes of pandemic influenza-associated acute respiratory failure

<jats:p>Respiratory viral pandemics result in large numbers of cases of acute respiratory failure arising from a single etiology, thus reducing the heterogeneity of precepting insult and allowing improved insight into the variation of host responses. In 2009-2011, an influenza pandemic occurred, with pH1N1 infecting millions of people worldwide. Here, we have used novel bioinformatic methods to combine clinical, protein biomarker, and genomic data from patients with influenza-associated acute respiratory failure to identify three mechanistically discrete sub-types with significantly different clinical outcomes. The three endotypes identified can be described as neutrophil-driven (16.3%), adaptive (51.9%), and endothelial leak (31.7%). The neutrophil driven patients display evidence of innate immune activation with associated multi-organ dysfunction and reduced 30-day survival. These patients could be differentiated from the adaptive endotype by an alteration in the GAIT-mechanism, a late transcriptional regulatory response to IFN-gamma; that acts to suppress innate immunity by reducing caeruloplasmin mRNA translation. Patients with the neutrophil-driven endotype had significantly increased IFN-gamma; levels but appeared unable to suppress their innate immune response. The endothelial leak endotype could be distinguished from both the neutrophil driven and adaptive endotypes by alterations in Slit-Robo signalling, a pathway important in the maintenance of endothelial barrier integrity; Although patients with this endotype required mechanical ventilation, they did not develop multi-organ failure in the manner of the neutrophil-driven endotype patients, and had significantly better clinical outcomes. Importantly, the endotypes identified were stable over 48 hours opening up the possibility of stratified interventional clinical trials in the future.</jats:p>

Journal article

Landewe RBM, Machado PM, Kroon F, Bijlsma HWJ, Burmester GR, Carmona L, Combe B, Galli M, Gossec L, Iagnocco A, Isaacs JD, Mariette X, McInnes I, Mueller-Ladner U, Openshaw P, Smolen JS, Stamm TA, Wiek D, Schulze-Koops Het al., 2020, EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2, ANNALS OF THE RHEUMATIC DISEASES, Vol: 79, Pages: 851-858, ISSN: 0003-4967

Journal article

ISARIC clinical characterisation group, 2020, Global outbreak research: harmony not hegemony., Lancet Infect Dis, Vol: 20, Pages: 770-772

Journal article

Pollard AJ, Sauerwein R, Baay M, Neels P, HCT3 speakers and session chairset al., 2020, Third human challenge trial conference, Oxford, United Kingdom, February 6-7, 2020, a meeting report., Biologicals, Vol: 66, Pages: 41-52

The third Human Challenge Trial Meeting brought together a broad range of international stakeholders, including academia, regulators, funders and industry, with a considerable delegation from Low- and Middle-Income Countries. Controlled human infection models (CHIMs) can be helpful to study pathogenesis and for the development of vaccines. As challenge agents are used to infect healthy volunteers, ethical considerations include that the challenge studies need to be safe and results should be meaningful. The meeting provided a state-of-the-art overview on a wide range of CHIMs, including viral, bacterial and parasitic challenge agents. Recommendations included globally aligned guidance documents for CHIM studies; further definition of a CHIM, based on the challenge agent used; standardization of methodology and study endpoints; capacity building in Low- and Middle-Income Countries, in performance as well as regulation of CHIM studies; guidance on compensation for participation in CHIM studies; and preparation of CHIM studies, with strong engagement with stakeholders.

Journal article

Peng Y, Mentzer AJ, Liu G, Yao X, Yin Z, Dong D, Dejnirattisai W, Rostron T, Supasa P, Liu C, Lopez-Camacho C, Slon-Campos J, Zhao Y, Stuart D, Paeson G, Grimes J, Antson F, Bayfield OW, Hawkins DE, Ker D-S, Turtle L, Subramaniam K, Thomson P, Zhang P, Dold C, Ratcliff J, Simmonds P, de Silva T, Sopp P, Wellington D, Rajapaksa U, Chen Y-L, Salio M, Napolitani G, Paes W, Borrow P, Kessler B, Fry JW, Schwabe NF, Semple MG, Baillie KJ, Moore S, Openshaw PJ, Ansari A, Dunachie S, Barnes E, Frater J, Kerr G, Goulder P, Lockett T, Levin R, Cornall RJ, Conlon C, Klenerman P, McMichael A, Screaton G, Mongkolsapaya J, Knight JC, Ogg G, Dong Tet al., 2020, Broad and strong memory CD4 + and CD8 + T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients., bioRxiv

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated wi

Journal article

Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJM, Baillie JK, Semple MGet al., 2020, Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study, BMJ, Vol: 369, Pages: 1-12, ISSN: 1759-2151

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

Journal article

McGrath BA, Brenner MJ, Warrillow SJ, Pandian V, Arora A, Cameron TS, Añon JM, Hernández Martínez G, Truog RD, Block SD, Lui GCY, McDonald C, Rassekh CH, Atkins J, Qiang L, Vergez S, Dulguerov P, Zenk J, Antonelli M, Pelosi P, Walsh BK, Ward E, Shang Y, Gasparini S, Donati A, Singer M, Openshaw PJM, Tolley N, Markel H, Feller-Kopman DJet al., 2020, Tracheostomy in the COVID-19 era: global and multidisciplinary guidance., The Lancet Respiratory Medicine, ISSN: 2213-2600

Global health care is experiencing an unprecedented surge in the number of critically ill patients who require mechanical ventilation due to the COVID-19 pandemic. The requirement for relatively long periods of ventilation in those who survive means that many are considered for tracheostomy to free patients from ventilatory support and maximise scarce resources. COVID-19 provides unique challenges for tracheostomy care: health-care workers need to safely undertake tracheostomy procedures and manage patients afterwards, minimising risks of nosocomial transmission and compromises in the quality of care. Conflicting recommendations exist about case selection, the timing and performance of tracheostomy, and the subsequent management of patients. In response, we convened an international working group of individuals with relevant expertise in tracheostomy. We did a literature and internet search for reports of research pertaining to tracheostomy during the COVID-19 pandemic, supplemented by sources comprising statements and guidance on tracheostomy care. By synthesising early experiences from countries that have managed a surge in patient numbers, emerging virological data, and international, multidisciplinary expert opinion, we aim to provide consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic.

Journal article

Goya S, Galiano M, Nauwelaers I, Trento A, Openshaw PJ, Mistchenko AS, Zambon M, Viegas Met al., 2020, Toward unified molecular surveillance of RSV: A proposal for genotype definition, Influenza and Other Respiratory Viruses, Vol: 14, Pages: 274-285, ISSN: 1750-2640

BackgroundHuman respiratory syncytial virus (RSV) is classified into antigenic subgroups A and B. Thirteen genotypes have been defined for RSV‐A and 20 for RSV‐B, without any consensus on genotype definition.MethodsWe evaluated clustering of RSV sequences published in GenBank until February 2018 to define genotypes by using maximum likelihood and Bayesian phylogenetic analyses and average p‐distances.ResultsWe compared the patterns of sequence clustering of complete genomes; the three surface glycoproteins genes (SH, G, and F, single and concatenated); the ectodomain and the 2nd hypervariable region of G gene. Although complete genome analysis achieved the best resolution, the F, G, and G‐ectodomain phylogenies showed similar topologies with statistical support comparable to complete genome. Based on the widespread geographic representation and large number of available G‐ectodomain sequences, this region was chosen as the minimum region suitable for RSV genotyping. A genotype was defined as a monophyletic cluster of sequences with high statistical support (≥80% bootstrap and ≥0.8 posterior probability), with an intragenotype p‐distance ≤0.03 for both subgroups and an intergenotype p‐distance ≥0.09 for RSV‐A and ≥0.05 for RSV‐B. In this work, the number of genotypes was reduced from 13 to three for RSV‐A (GA1‐GA3) and from 20 to seven for RSV‐B (GB1‐GB7). Within these, two additional levels of classification were defined: subgenotypes and lineages. Signature amino acid substitutions to complement this classification were also identified.ConclusionsWe propose an objective protocol for RSV genotyping suitable for adoption as an international standard to support the global expansion of RSV molecular surveillance.

Journal article

Palmieri C, Palmer D, Openshaw PJM, Baille JK, Semple MG, Turtle Let al., 2020, Cancer datasets and the SARS-CoV-2 pandemic: establishing principles for collaboration, ESMO OPEN, Vol: 5

Journal article

Dunning J, Thwaites RS, Openshaw PJM, Dunning J, Thwaites R, Openshaw Pet al., 2020, Seasonal and pandemic influenza: 100 years of progress, still much to learn, Mucosal Immunology, Vol: https://www.nature.com/articles/s41385-020-0287-5, Pages: 566-573, ISSN: 1935-3456

Influenza viruses are highly transmissible, both within and between host species. The severity of the disease they cause is highly variable, from the mild and inapparent through to the devastating and fatal. The unpredictability of epidemic and pandemic outbreaks is accompanied but the predictability of seasonal disease in wide areas of the Globe, providing an inexorable toll on human health and survival. Although there have been great improvements in understanding influenza viruses and the disease that they cause, our knowledge of the effects they have on the host and the ways that the host immune system responds continues to develop. This review highlights the importance of the mucosa in defence against infection and in understanding the pathogenesis of disease. Although vaccines have been available for many decades, they remain suboptimal in needing constant redesign and in only providing short-term protection. There are real prospects for improvement in treatment and prevention of influenza soon, based on deeper knowledge of how the virus transmits, replicates and triggers immune defences at the mucosal surface.

Journal article

Park M, Thwaites RS, Openshaw PJM, 2020, COVID-19: Lessons from SARS and MERS., European Journal of Immunology, Vol: 50, Pages: 308-311, ISSN: 0014-2980

Journal article

Butler CC, van der Velden AW, Bongard E, Saville BR, Holmes J, Coenen S, Cook J, Francis NA, Lewis RJ, Godycki-Cwirko M, Llor C, Chlabicz S, Lionis C, Seifert B, Sundvall P-D, Colliers A, Aabenhus R, Bjerrum L, Harbin NJ, Lindbaek M, Glinz D, Bucher HC, Kovacs B, Jurgute RR, Lundgren PT, Little P, Murphy AW, De Sutter A, Openshaw P, de Jong MD, Connor JT, Matheeussen V, Ieven M, Goossens H, Verheij TJet al., 2020, Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial, LANCET, Vol: 395, Pages: 42-52, ISSN: 0140-6736

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00104101&limit=30&person=true