Publications by authors named "Tristan W Clark"

33 Publications

Influenza vaccination: protecting the most vulnerable.

Eur Respir Rev 2021 Mar 13;30(159). Epub 2021 Jan 13.

School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Influenza virus infection causes seasonal epidemics and occasional pandemics, leading to huge morbidity and mortality worldwide. Vaccination against influenza is needed annually as protection from constantly mutating strains is required. Groups at high risk of poor outcomes include the elderly, the very young, pregnant women and those with chronic health conditions. However, vaccine effectiveness in the elderly is generally poor due to immunosenescence and may be altered due to "original antigenic sin". Strategies to overcome these challenges in the elderly include high-dose or adjuvant vaccines. Other options include vaccinating healthcare workers and children as this reduces community-level influenza transmission. Current guidelines in the UK are that young children receive a live attenuated nasal spray vaccine, adults aged >65 years receive an adjuvanted trivalent inactivated vaccine and adults aged <65 years with comorbidities receive a quadrivalent inactivated vaccine. The goal of a universal influenza vaccine targeting conserved regions of the virus and avoiding the need for annual vaccination is edging closer with early-phase trials under way.
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http://dx.doi.org/10.1183/16000617.0258-2020DOI Listing
March 2021

Physical distancing in schools for SARS-CoV-2 and the resurgence of rhinovirus.

Lancet Respir Med 2020 12 22;8(12):e92-e93. Epub 2020 Oct 22.

School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, Southampton, UK; NIHR Post-Doctoral Fellowship Programme, UK.

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http://dx.doi.org/10.1016/S2213-2600(20)30502-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581315PMC
December 2020

Clinical impact of a routine, molecular, point-of-care, test-and-treat strategy for influenza in adults admitted to hospital (FluPOC): a multicentre, open-label, randomised controlled trial.

Lancet Respir Med 2021 04 4;9(4):419-429. Epub 2020 Dec 4.

NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Background: Diagnosis of influenza in patients admitted to hospital is delayed due to long turnaround times with laboratory testing, leading to inappropriate and late antiviral treatment and isolation facility use. Molecular point-of-care tests (mPOCTs) are highly accurate, easy to use, and generate results in less than 1 h, but high-quality evidence for their effect on management and clinical outcomes is needed. The aim of this study was to assess the clinical impact of an mPOCT on influenza detection, antiviral use, infection control measures, and clinical outcomes in adults admitted to hospital with acute respiratory illness.

Methods: In this multicentre, pragmatic, open-label, randomised controlled trial (FluPOC), we recruited adults admitted to hospital with acute respiratory illness during influenza seasons from two hospitals in Hampshire, UK. Eligible patients were aged 18 years and older, with acute respiratory illness of 10 days or fewer duration before admission to hospital, who were recruited within 16 h of admission to hospital. Participants were randomly assigned (1:1), using random permuted blocks of varying sizes (4, 6 and 8), to receive mPOCT for influenza or routine clinical care (control group). The primary outcome was the proportion of patients infected with influenza who were treated appropriately with antivirals (neuraminidase inhibitors) within 5 days of admission. Safety was assessed in all patients. Secondary outcomes included time to antivirals, isolation facility use, and clinical outcomes. This study is registered with the ISRCTN registry, ISRCTN17197293, and is now complete.

Findings: Between Dec 12, 2017, and May 3, 2019, over two influenza seasons, 613 patients were enrolled, of whom 307 were assigned to the mPOCT group and 306 to the control group, and all were analysed. Median age was 62 years (IQR 45-75) and 332 (54%) of 612 participants with data were female. 100 (33%) of 307 patients in the mPOCT group and 102 (33%) of 306 in the control group had influenza. 100 (100%) of 100 patients with influenza were diagnosed in the mPOCT group and 60 (59%) of 102 were diagnosed though routine clinical care in the control group (relative risk 1·7, 95% CI 1·7-1·7; p<0·0001). 99 (99%) of 100 patients with influenza in the mPOCT group were given antiviral treatment within 5 days of admission versus 63 (62%) 102 in the control group (relative risk 1·6, 95% CI 1·4-1·9; p<0·0001). Median time to antivirals was 1·0 h (IQR 0·0 to 2·0) in the mPOCT group versus 6·0 h (0·0 to 12·0) in the control group (difference of 5·0 h [95% CI 0·0-6·0; p=0·0039]). 70 (70%) of 100 patients with influenza in the mPOCT group were isolated to single-room accommodation versus 39 (38%) of 102 in the control group (relative risk 1·8 [95% CI 1·4-2·4; p<0·0001]). 19 adverse events occurred among patients with influenza in the mPOCT group compared with 34 events in the control group. No patients with influenza died in the mPOCT group and two (2%) died in the control group (p=0·16).

Interpretation: Routine mPOCT for influenza was associated with improved influenza detection and improvements in appropriate and timely antiviral and isolation facility use. Routine mPOCT should replace laboratory-based diagnostics for acute admissions to hospital during the influenza season.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S2213-2600(20)30469-0DOI Listing
April 2021

SARS-CoV-2 has displaced other seasonal respiratory viruses: Results from a prospective cohort study.

J Infect 2020 12 15;81(6):966-972. Epub 2020 Nov 15.

NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust Southampton, UK; School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Post-Doctoral Fellowship Programme, UK.

Objectives: The effect of SARS-CoV-2 on existing respiratory viruses in circulation and the overall burden of viral respiratory disease remains uncertain. Traditionally, severe viral respiratory disease disproportionally affects those with underlying chronic lung diseases. This study aimed to assess the impact of SARS-CoV-2 on the prevalence and clinical characteristics of respiratory virus disease in hospitalised adults.

Methods: Data for this cohort study were from hospitalised adults who had multiplex PCR testing for respiratory viruses over several seasons in Hampshire, UK. Respiratory virus detection during the first epidemic peak of SARS-CoV-2 was compared to detection during the same time period across previous years.

Results: 856 patients had multiplex PCR for respiratory viruses between March and May over 5 years. Before 2020, a non-SARS-CoV-2 virus was detected in 54% patients (202/371) compared to 4.1% (20/485) in 2020 (p < 0.0001). SARS-CoV-2 was associated with asthma or COPD exacerbations in a smaller proportion of infected patients compared to other viruses (1.0% vs 37%, p < 0.0001).

Conclusions: The emergence of SARS-CoV-2 was associated with substantial reductions in the circulation of seasonal respiratory viruses and large differences in the characteristics of viral-associated disease, including illness in a greater proportion of patients without underlying lung disease.
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http://dx.doi.org/10.1016/j.jinf.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666810PMC
December 2020

Clinical impact of molecular point-of-care testing for suspected COVID-19 in hospital (COV-19POC): a prospective, interventional, non-randomised, controlled study.

Lancet Respir Med 2020 12 8;8(12):1192-1200. Epub 2020 Oct 8.

School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

Background: The management of the COVID-19 pandemic is hampered by long delays associated with centralised laboratory PCR testing. In hospitals, these delays lead to poor patient flow and nosocomial transmission. Rapid, accurate tests are therefore urgently needed in preparation for the next wave of the pandemic.

Methods: We did a prospective, interventional, non-randomised, controlled study of molecular point-of-care testing in patients aged 18 years or older presenting with suspected COVID-19 to the emergency department or other acute areas of Southampton General Hospital during the first wave of the pandemic in the UK. Nose and throat swab samples taken at admission from patients in the point-of-care testing group were tested with the QIAstat-Dx Respiratory SARS-CoV-2 Panel. Samples taken from patients in a contemporaneous control group were tested by laboratory PCR. The primary outcome was time to results in the full cohort. This study is registered with ISRCTN (ISRCTN14966673) and is completed.

Findings: Between March 20 and April 29, 2020, 517 patients were assessed for eligibility, of whom 499 were recruited to the point-of-care testing group and tested by the QIAstat-Dx Respiratory SARS-CoV-2 Panel. 555 contemporaneously identified patients were included in the control group and tested by laboratory PCR. The two groups were similar with regard to the distribution of sex, age, and ethnicity. 197 (39%) patients in the point-of-care testing group and 155 (28%) in the control group tested positive for COVID-19 (difference 11·5% [95% CI 5·8-17·2], p=0·0001). Median time to results was 1·7 h (IQR 1·6-1·9) in the point-of-care testing group and 21·3 h (16·0-27·9) in the control group (difference 19·6 h [19·0-20·3], p<0·0001). A Cox proportional hazards regression model controlling for age, sex, time of presentation, and severity of illness also showed that time to results was significantly shorter in the point-of-care testing group than in the control group (hazard ratio 4023 [95% CI 545-29 696], p<0·0001).

Interpretation: Point-of-care testing is associated with large reductions in time to results and could lead to improvements in infection control measures and patient flow compared with centralised laboratory PCR testing.

Funding: University Hospitals Southampton NHS Foundation Trust.
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http://dx.doi.org/10.1016/S2213-2600(20)30454-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544498PMC
December 2020

Clinical characteristics, symptoms and outcomes of 1054 adults presenting to hospital with suspected COVID-19: A comparison of patients with and without SARS-CoV-2 infection.

J Infect 2020 12 28;81(6):937-943. Epub 2020 Sep 28.

School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS, Foundation Trust, Southampton, UK; NIHR Post Doctoral Fellowship Programme, UK.

Objectives: Most reports describing the characteristics of patients hospitalised with COVID-19 lack a comparator group. We compared clinical characteristics, symptoms, and outcomes of adults presenting to hospital during the pandemic first wave, who tested positive and negative for SARS-CoV-2.

Methods: Detailed patient data was obtained from a large, controlled, non-randomised trial of molecular point-of-care testing versus laboratory RT-PCR for SARS-CoV-2 in adults presenting to a large UK hospital with suspected COVID-19.

Results: 1054 patients were included: 352 (33.4%) tested positive and 702 (66.6%) negative. 13.4% (47/352) COVID-19-positive patients had COPD versus 18.7% (131/702) of COVID-19-negative patients (difference=5.3% [95%CI -9.7% to -0.5%], p = 0.0297). 5.7% (20/352) of COVID-19-positive patients were smokers versus 16.5% (116/702) of negative patients (difference=-10.8% [-14.4% to -7.0%], p = 0.0001). 70.5% (248/352) of COVID-19-positive patients were White-British versus 85.5% (600/702) of negative patients (difference=-15.0% [-20.5% to -9.7%], p<0.0001). 20.9% (39/187) of COVID-19-positive patients were healthcare workers versus 5.2% (15/287) of negative patients (p<0.0001). Anosmia was reported in 33.1% (47/142) versus 8.8% (19/216) of COVID-19-positive and negative patients respectively (p<0.0001). Non-SARS-CoV-2 respiratory viruses or atypical bacteria were detected in 2.5% (5/197) of COVID-19 patients versus 7.9% (24/302) of COVID-19-negative patients (p = 0.0109). Hospitalisation duration and 30-day-mortality were higher in COVID-19 patients and invasive ventilation was more frequent (11.1% vs 2.8%, p<0.0001), and longer (14.5 vs 4.7 days, p = 0.0015).

Conclusions: There were substantial differences between patients with and without COVID-19 in terms of ethnicity, healthcare worker-status, comorbidities, symptoms, and outcomes. These data can inform healthcare planning for the next phase of the pandemic.
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http://dx.doi.org/10.1016/j.jinf.2020.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521430PMC
December 2020

Diagnostic accuracy of the FebriDx host response point-of-care test in patients hospitalised with suspected COVID-19.

J Infect 2020 10 21;81(4):607-613. Epub 2020 Jun 21.

Southampton Clinical Trials Unit, University of Southampton, UK.

Introduction: Management of the COVID-19 pandemic is hampered by long delays associated with centralised laboratory PCR testing. In hospitals this leads to poor patient flow and nosocomial transmission and so rapid, accurate diagnostic tests are urgently required. The FebriDx is a point-of-care test that detects an antiviral host response protein in finger prick blood within 10 min, but its accuracy for the identification of COVID-19 is unknown.

Methods: We performed a real-world diagnostic accuracy study of FebriDx in hospitalised patients during the first wave of the pandemic. Measures of diagnostic accuracy were calculated based on FebriDx results compared to the reference standard of SARS-CoV-2 PCR on combined nose and throat swabs. A multivariable predictive model including FebriDx, age, sex, and clinical characteristics was developed and underwent internal validation.

Results: FebriDx was performed on 251 patients and gave a valid result in 248. 118 of 248 (48%) were PCR positive for COVID-19. FebriDx results were available after 10 min compared with 1.7 (1.6 to 2.1) hours with point-of-care PCR testing and 23.4 (17.2 to 31.1) hours with laboratory PCR testing. Sensitivity of FebriDx for the identification of COVID-19 was 93% (110/118; 95% CI 87 to 97%) and specificity was 86% (112/130; 95%CI 79 to 92%). Positive and negative likelihood ratios were 6.73 (95%CI 4.37 to 10.37) and 0.08 (95%CI 0.04 to 0.15) respectively. In the multivariate model age, sex and other clinical features did not contribute significantly to the effect of the FebriDx result in distinguishing patients with and without COVID-19.

Conclusions: During the first wave of the pandemic, FebriDx had high accuracy for the identification of COVID-19 in hospitalised adults and could be deployed as a front door triage tool.

Trial Registration: ISRCTN14966673.
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http://dx.doi.org/10.1016/j.jinf.2020.06.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306108PMC
October 2020

Rapid syndromic molecular testing in pneumonia: The current landscape and future potential.

J Infect 2020 01 3;80(1):1-7. Epub 2019 Dec 3.

School of Clinical and Experimental Sciences, University of Southampton and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.

Community acquired pneumonia (CAP), hospital-acquired pneumonia (HAP) and ventilator associated pneumonia (VAP) are all associated with significant mortality and cause huge expense to health care services around the world. Early, appropriate antimicrobial therapy is crucial for effective treatment. Syndromic diagnostic testing using novel, rapid multiplexed molecular platforms represents a new opportunity for rapidly targeted antimicrobial therapy to improve patient outcomes and facilitate antibiotic stewardship. In this article we review the currently available testing platforms and discuss the potential benefits and pitfalls of rapid testing in pneumonia.
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http://dx.doi.org/10.1016/j.jinf.2019.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132381PMC
January 2020

Impact of point-of-care testing for respiratory viruses on antibiotic use in adults with exacerbation of airways disease.

J Infect 2019 10 21;79(4):357-362. Epub 2019 Jun 21.

Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, LF101, South Academic block, Southampton General Hospital, Southampton SO16 6YD, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Post-Doctoral Fellowship Programme, UK. Electronic address:

Background: The ResPOC study demonstrated that syndromic molecular point-of-care testing (POCT) for respiratory viruses was associated with early discontinuation of unnecessary antibiotics compared to routine clinical care. Subgroup analysis suggests these changes occur predominantly in patients with exacerbation of airways disease. Use of molecular POCT for respiratory viruses is becoming widespread but there is a lack of evidence to inform the choice between multiplex syndromic panels versus POCT for influenza only.

Materials/methods: We evaluated patients from the ResPOC study with exacerbation of asthma or COPD who were treated with antibiotics. The duration of antibiotics and proportion with early discontinuation were compared between patients testing positive and negative for viruses by POCT, and controls. Patients testing positive for viruses by POCT were compared according to virus types.

Results: 118 patient with exacerbation of airways disease received antibiotics in the POCT group and 111 in the control group. In the POCT group 49/118 (42%) patients tested positive for viruses. Of those testing positive for viruses 17/49 (35%) had early discontinuation of antibiotics versus 9/69 (13%) testing negative and 7/111 (6%) of controls, p<0.0001. Of those positive for viruses by POCT 10/49 (20%) were positive for influenza, 21/49 (43%) for rhinovirus and 18/49 (37%) for other viruses. The proportion with early discontinuation of antibiotics was not different between the virus types (p = 0.34).

Conclusions: This data suggests that syndromic molecular POCT for respiratory viruses should be favoured over POCT for influenza alone in adults with exacerbation of airways disease.
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http://dx.doi.org/10.1016/j.jinf.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112619PMC
October 2019

Hospitalised adults with pneumonia are frequently misclassified as another diagnosis.

Respir Med 2019 04 21;150:81-84. Epub 2019 Feb 21.

Academic Unit of Clinical and Experimental Sciences, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Post-Doctoral Fellowship Programme, UK.

Using data from a large randomised controlled trial of adults hospitalised with acute respiratory illness, we examined the reliability of pneumonia diagnosis on discharge documentation. 50 (28.2%) of 177 patients with a pneumonia diagnosis had no radiological evidence of pneumonia. 67 (34.9%) of 192 patients with clinico-radiological evidence of pneumonia did not have a diagnosis of pneumonia listed; 'COPD exacerbation' or 'lower respiratory tract infection' was often listed instead. These patients more frequently had a respiratory comorbidity and lower oxygen saturations, CRP and temperature at presentation. Pneumonia diagnoses misclassification on discharge documentation may have clinical, financial, and research data implications.
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http://dx.doi.org/10.1016/j.rmed.2019.02.013DOI Listing
April 2019

Molecular Point-of-care Testing for Influenza to Improve Early Neuraminidase Inhibitor Treatment and Outcomes in Hospitalized Adults.

Clin Infect Dis 2019 05;68(12):2154-2155

Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton.

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http://dx.doi.org/10.1093/cid/ciy1042DOI Listing
May 2019

Viral therapeutics: where we are and where we are going.

Curr Opin Infect Dis 2018 12;31(6):512-513

Academic Unit of Clinical and Experimental Sciences, University of Southampton.

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http://dx.doi.org/10.1097/QCO.0000000000000507DOI Listing
December 2018

Treatment of influenza with neuraminidase inhibitors.

Curr Opin Infect Dis 2018 12;31(6):514-519

Academic Unit of Clinical and Experimental Sciences, University of Southampton.

Purpose Of Review: Seasonal and pandemic influenza are major causes of morbidity and mortality globally. Neuraminidase inhibitors (NAIs) are the only class of antiviral agent recommended for the treatment of currently circulating strains of influenza. There has previously been controversy over the level of evidence for patient benefit with NAIs. We review here the current evidence base for the clinical impact of treatment of influenza with NAIs.

Recent Findings: Meta-analysis of pharma-sponsored studies (including previously unpublished data) shows that NAIs reduce the duration of illness in influenza-infected patients, and suggest a possible reduction in the rate of complications and hospitalization. Meta-analysis of observational studies examining oseltamivir use during the H1N1 2009 pandemic, suggest a reduction in hospitalization rate in community-dwelling patients and a reduction in mortality in hospitalized adults treated with NAIs. Current NAI use in the community and hospitals varies widely but in general they are underutilized.

Summary: Although there has been controversy over the level of evidence for patient benefit, a growing body of evidence suggests that treatment of influenza with NAIs is associated with improved outcomes for both patients in the community and more severely unwell patients in hospital. Clinical outcomes are optimal with earlier use and strategies to improve early widespread NAI utilization are needed.
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http://dx.doi.org/10.1097/QCO.0000000000000496DOI Listing
December 2018

Impact of turnaround time on outcome with point-of-care testing for respiratory viruses: a analysis from a randomised controlled trial.

Eur Respir J 2018 08 9;52(2). Epub 2018 Aug 9.

Academic Unit of Clinical and Experimental Sciences, University of Southampton, Southampton, UK.

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http://dx.doi.org/10.1183/13993003.00555-2018DOI Listing
August 2018

Antiviral treatment of severe non-influenza respiratory virus infection.

Curr Opin Infect Dis 2017 Dec;30(6):573-578

aClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General HospitalbNIHR Southampton Biomedical Research CentrecNIHR Post-Doctoral Fellowship Programme, Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Purpose Of Review: Non-influenza respiratory virus infections are a frequent cause of severe acute respiratory infections, especially in infants, the elderly, and the immunocompromised. We review here the current treatment options for non-influenza respiratory viruses and promising candidate antiviral agents currently in development.

Recent Findings: Small molecule antiviral agents active against respiratory syncytial virus (RSV), such as ALS-8176 and GS-5806, show considerable promise in challenge studies and are undergoing late-phase clinical trials in hospitalised adults and children. Monoclonal antibodies (mAbs) active against non-influenza respiratory viruses are broadly at a preclinical stage. Broad-spectrum antivirals, such as favipiravir and nitrazoxanide, have potential utility in treating illness caused by non-influenza respiratory viruses but further definitive clinical trials are needed.

Summary: Severe non-influenza respiratory virus infection is common and current treatment is largely supportive. Ribavirin is used in immunocompromised patients but its use is limited by toxicity and the evidence for its efficacy is weak. Effective antiviral treatment for RSV may shortly become available, pending the results of ongoing clinical trials. For other non-influenza viruses, effective treatments may become available in the medium term. Early detection of respiratory viruses with rapid molecular test platforms will be crucial in differentiating virus types and directing the prompt initiation of novel treatments when available.
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http://dx.doi.org/10.1097/QCO.0000000000000410DOI Listing
December 2017

Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial.

Lancet Respir Med 2017 05 6;5(5):401-411. Epub 2017 Apr 6.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

Background: Respiratory virus infection is a common cause of hospitalisation in adults. Rapid point-of-care testing (POCT) for respiratory viruses might improve clinical care by reducing unnecessary antibiotic use, shortening length of hospital stay, improving influenza detection and treatment, and rationalising isolation facility use; however, insufficient evidence exists to support its use over standard clinical care. We aimed to assess the effect of routine POCT on a broad range of clinical outcomes including antibiotic use.

Methods: In this pragmatic, parallel-group, open-label, randomised controlled trial, we enrolled adults (aged ≥18 years) within 24 h of presenting to the emergency department or acute medical unit of a large UK hospital with acute respiratory illness or fever higher than 37·5°C (≤7 days duration), or both, over two winter seasons. Patients were randomly assigned (1:1), via an internet-based allocation sequence with random permuted blocks, to have a molecular POC test for respiratory viruses or routine clinical care. The primary outcome was the proportion of patients who received antibiotics while hospitalised (up to 30 days). Secondary outcomes included duration of antibiotics, proportion of patients receiving single doses or brief courses of antibiotics, length of stay, antiviral use, isolation facility use, and safety. Analysis was by modified intention to treat, excluding patients who declined intervention or were withdrawn for protocol violations. This study is registered with ISRCTN, number 90211642, and has been completed.

Findings: Between Jan 15, 2015, and April 30, 2015, and between Oct 1, 2015, and April 30, 2016, we enrolled 720 patients (362 assigned to POCT and 358 to routine care). Six patients withdrew or had protocol violations. 301 (84%) of 360 patients in the POCT group received antibiotics compared with 294 (83%) of 354 controls (difference 0·6%, 95% CI -4·9 to 6·0; p=0·84). Mean duration of antibiotics did not differ between groups (7·2 days [SD 5·1] in the POCT group vs 7·7 days [4·9] in the control group; difference -0·4, 95% CI -1·2 to 0·4; p=0·32). 50 (17%) of 301 patients treated with antibiotics in the POCT group received single doses or brief courses of antibiotics (<48 h) compared with 26 (9%) of 294 patients in the control group (difference 7·8%, 95% CI 2·5 to 13·1; p=0·0047; number needed to test=13). Mean length of stay was shorter in the POCT group (5·7 days [SD 6·3]) than in the control group (6·8 days [7·7]; difference -1·1, 95% CI -2·2 to -0·3; p=0·0443). Appropriate antiviral treatment of influenza-positive patients was more common in the POCT group (52 [91%] of 57 patients) than in the control group (24 [65%] of 37 patients; difference 26·4%, 95% CI 9·6 to 43·2; p=0·0026; number needed to test=4). We found no differences in adverse outcomes between the groups (77 [21%] of 360 patients in the POCT group vs 88 [25%] of 354 patients in the control group; -3·5%, -9·7 to 2·7; p=0·29).

Interpretation: Routine use of molecular POCT for respiratory viruses did not reduce the proportion of patients treated with antibiotics. However, the primary outcome measure failed to capture differences in antibiotic use because many patients were started on antibiotics before the results of POCT could be made available. Although POCT was not associated with a reduction in the duration of antibiotics overall, more patients in the POCT group received single doses or brief courses of antibiotics than did patients in the control group. POCT was also associated with a reduced length of stay and improved influenza detection and antiviral use, and appeared to be safe.

Funding: University of Southampton.
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http://dx.doi.org/10.1016/S2213-2600(17)30120-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164815PMC
May 2017

Molecular point-of-care testing for respiratory viruses versus routine clinical care in adults with acute respiratory illness presenting to secondary care: a pragmatic randomised controlled trial protocol (ResPOC).

BMC Infect Dis 2017 02 6;17(1):128. Epub 2017 Feb 6.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Respiratory viruses are associated with a huge socio-economic burden and are responsible for a large proportion of acute respiratory illness in hospitalised adults. Laboratory PCR is accurate but takes at least 24 h to generate a result to clinicians and antigen-based point-of-care tests (POCT) lack sensitivity. Rapid molecular platforms, such as the FilmArray Respiratory Panel, have equivalent diagnostic accuracy to laboratory PCR and can generate a result in 1 h making them deployable as POCT. Molecular point-of-care testing for respiratory viruses in hospital has the potential to improve the detection rate of respiratory viruses, improve the use of influenza antivirals and reduce unnecessary antibiotic use, but high quality randomised trials with clinically relevant endpoints are needed.

Methods: The ResPOC study is a pragmatic randomised controlled trial of molecular point-of-care testing for respiratory viruses in adults with acute respiratory illness presenting to a large teaching hospital in the United Kingdom. Eligible participants are adults presenting with acute respiratory illness to the emergency department or the acute medicine unit. Participants are allocated 1:1 by internet-based randomisation service to either the intervention of a nose and throat swab analysed immediately on the FilmArray Respiratory Panel as a POCT or receive routine clinical care. The primary outcome is the proportion of patients treated with antibiotics. Secondary outcomes include turnaround time, virus detection, neuraminidase inhibitor use, length of hospital stay and side room use. Analysis of the primary outcome will be by intention-to-treat and all enrolled participants will be included in safety analysis.

Discussion: Multiple novel molecular POCT platforms for infections including respiratory viruses have been developed and licensed in the last few years and many more are in development but the evidence base for clinical benefit above standard practice is minimal. This randomised controlled trial aims to close this evidence gap by generating high quality evidence for the clinical impact of molecular POCT for respiratory viruses in secondary care and to act as an exemplar for future studies of molecular POCT for infections. This study has the potential to change practice and improve patient care for patients presenting to hospital with acute respiratory illness.

Trial Registration: This study was registered with ISRCTN, number ISRCTN90211642 , on 14th January 2015.
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http://dx.doi.org/10.1186/s12879-017-2219-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294894PMC
February 2017

Haemagglutinin and neuraminidase sequencing delineate nosocomial influenza outbreaks with accuracy equivalent to whole genome sequencing.

J Infect 2017 04 16;74(4):377-384. Epub 2017 Jan 16.

Microbiology Department, Queen Alexandra Hospital, Portsmouth, England, PO6 3LY, UK.

Objectives: We describe haemagglutinin (HA) and neuraminidase (NA) sequencing in an apparent cross-site influenza A(H1N1) outbreak in renal transplant and haemodialysis patients, confirmed with whole genome sequencing (WGS).

Methods: Isolates were sequenced from influenza positive individuals. Phylogenetic trees were constructed using HA and NA sequencing and subsequently WGS. Sequence data was analysed to determine genetic relatedness of viruses obtained from inpatient and outpatient cohorts and compared with epidemiological outbreak information.

Results: There were 6 patient cases of influenza in the inpatient renal ward cohort (associated with 3 deaths) and 9 patient cases in the outpatient haemodialysis unit cohort (no deaths). WGS confirmed clustered transmission of two genetically different influenza A(H1N1)pdm09 strains initially identified by analysis of HA and NA genes. WGS took longer, and in this case was not required to determine whether or not the two seemingly linked outbreaks were related.

Conclusion: Rapid sequencing of HA and NA genes may be sufficient to aid early influenza outbreak investigation making it appealing for future outbreak investigation. However, as next generation sequencing becomes cheaper and more widely available and bioinformatics software is now freely accessible next generation whole genome analysis may increasingly become a valuable tool for real-time Influenza outbreak investigation.
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http://dx.doi.org/10.1016/j.jinf.2016.12.015DOI Listing
April 2017

Tabes Dorsalis and Argyll Robertson Pupils.

N Engl J Med 2016 Nov;375(20):e40

University of Southampton, Southampton, United Kingdom

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http://dx.doi.org/10.1056/NEJMicm1507564DOI Listing
November 2016

Viral load is strongly associated with length of stay in adults hospitalised with viral acute respiratory illness.

J Infect 2016 12 9;73(6):598-606. Epub 2016 Sep 9.

Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.

Background: Respiratory viruses are detectable in a large proportion of adults hospitalised with acute respiratory illness. For influenza and other viruses there is evidence that viral load and persistence are associated with certain clinical outcomes but it is not known if there is an association between viral load and hospital length of stay.

Methods: 306 adults hospitalised with viral acute respiratory illness were studied. Associations between viral load and length of stay were examined. Multiple linear regression analysis was performed to control for age, comorbidity, influenza vaccine status, duration of illness prior to hospitalisation, bacterial co-infection, clinical group and virus subtype.

Results: High viral load was associated with a longer duration of hospitalisation for all patients (p < 0.0001). This remained significant across all virus types and clinical groups and when adjusted for age, comorbidity, duration of illness prior to hospitalisation, bacterial co-infection and other factors.

Conclusions: High viral loads are associated with prolonged hospital length of stay in adults with viral acute respiratory illness. This further supports existing evidence demonstrating that viral acute respiratory illness is a viral load driven process and suggests that viral load could be used in clinical practise to predict prolonged hospitalisation and prioritise antivirals. International Standard Randomised Controlled Trial Number (ISRCTN): 21521552.
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http://dx.doi.org/10.1016/j.jinf.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112535PMC
December 2016

Severe Enterovirus Infections in Hospitalized Children in the South of England: Clinical Phenotypes and Causative Genotypes.

Pediatr Infect Dis J 2016 07;35(7):723-7

From the *Academic Unit of Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; †Southampton NIHR Wellcome Trust Clinical Research Facility, ‡Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; §Public Health England Microbiology Services, Southampton, United Kingdom; ¶Department of Paediatric Intensive Care, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; ‖Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; **Department of Paediatric Immunology & Infectious Diseases, ††NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; ‡‡Global Health Research Institute, University of Southampton, Southampton, United Kingdom; and §§Department of Paediatrics, The University of Melbourne, Parkville, Australia.

Background: Most enterovirus surveillance studies lack detailed clinical data, which limits their clinical usefulness. This study aimed to describe the clinical spectrum and outcome of severe enterovirus infections in children, and to determine whether there are associations between causative enterovirus genotypes and clinical phenotypes.

Methods: Retrospective analysis of microbiological and clinical data from a tertiary children's hospital in the South of England over a 17-month period (2012-2013).

Results: In total, 30 patients were identified, comprising sepsis (n = 9), myocarditis (n = 8), meningitis (n = 8) and encephalitis (n = 5). Cases with sepsis or myocarditis were significantly younger than those with central nervous system disease (median age 21 and 15 days vs. 79 days; P = 0.0244 and P = 0.0310, respectively). There was considerable diversity in the causative genotypes in each of the clinical phenotypes, with some predominance of echoviruses in the meningitis group, and coxsackie B viruses in the myocarditis group. Thirteen cases required mechanical ventilation, 11 cases inotropic support, 3 cases dialysis and 3 cases extracorporal membrane oxygenation. The overall mortality was 10% (sepsis group, n = 1; myocarditis group, n = 2). Of the survivors, 5 (19%) had long-term sequelae (myocardial dysfunction, n = 2; neurological sequelae, n = 3). Patients with encephalitis had the longest hospital stay (median: 16 days), compared with 9, 6 and 3 days in patients with myocarditis, sepsis and meningitis, respectively (P = 0.005).

Conclusions: Enterovirus infections, particularly enteroviral myocarditis and encephalitis, can cause significant morbidity and mortality. The results show that there are currently no strong associations between clinical phenotypes and particular causative enterovirus genotypes in the South of England.
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http://dx.doi.org/10.1097/INF.0000000000001093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985250PMC
July 2016

Point-of-care testing for respiratory viruses in adults: The current landscape and future potential.

J Infect 2015 Nov 26;71(5):501-10. Epub 2015 Jul 26.

Department of Clinical and Experimental Sciences and Respiratory Biomedical Research Unit, University of Southampton, UK. Electronic address:

Respiratory viruses are responsible for a large proportion of acute respiratory illness in adults as well as children, and are associated with a huge socio-economic burden worldwide. Development of accurate point-of-care tests (POCT) for respiratory viruses has been listed as a priority by the World Health Organisation and replacing the current paradigm of empirical antimicrobial use with directed use is a listed goal of the movement for reduction in antimicrobial resistance. POCTs for respiratory viruses have previously been limited by the poor sensitivity of antigen detection based tests and by a limited range of detectable viruses. Highly accurate molecular platforms are now able to test for a comprehensive range of viruses, can be operated by non-laboratory staff and can generate a result in approximately 1 h, making them potentially deployable as POCTs. The potential clinical benefits of POC testing for respiratory viruses in adults include a reduction in unnecessary antibiotic use, improved antiviral prescribing for influenza and rationalisation of isolation facilities. We review here the burden of disease, the currently available molecular platforms with potential for POCT use and the existing evidence for clinical and economic benefits of testing for respiratory viruses in adults.
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http://dx.doi.org/10.1016/j.jinf.2015.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172689PMC
November 2015

Are C-reactive protein levels associated with bacteria in COPD exacerbations?

Authors:
Tristan W Clark

Eur Respir J 2015 May;45(5):1515-6

Dept of Clinical and Experimental Sciences and Respiratory Biomedical Research Unit, University of Southampton, Southampton, UK Dept of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK

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http://dx.doi.org/10.1183/09031936.00020015DOI Listing
May 2015

C-reactive protein level and microbial aetiology in patients hospitalised with acute exacerbation of COPD.

Eur Respir J 2015 Jan 3;45(1):76-86. Epub 2014 Sep 3.

Dept of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.

Both viruses and bacteria are thought to cause exacerbations of chronic obstructive pulmonary disease (COPD); however, the relative importance of each remains uncertain. C-reactive protein (CRP) levels increase during exacerbations but the relationship with aetiology is not established. We aimed to explore the relationship between serum CRP and the rate of detection of viruses and bacteria. This was a prospectively recruited, observational study of patients hospitalised with exacerbations of COPD. Nasopharyngeal swabs were tested for respiratory viruses by reverse transcriptase-PCR. Sputum and blood were collected for bacterial culture and urine tested for pneumococcal antigen. CRP levels were measured on sera. CRP and other factors associated with viral, bacterial or mixed detection were assessed using multiple logistic regression analysis. 264 patients with exacerbations of COPD were studied: 26% tested positive for respiratory viruses only, 13% had bacteria only, 12% had mixed viral/bacterial detection, and 49% had no pathogens detected. CRP level and temperature were strongly associated with viral detection rate (p<0.001 and p=0.004, respectively) and mixed viral/bacterial detection rate (p=0.02 and p=0.03, respectively) on multivariate analysis. Bacterial detection rate was not associated with CRP level or body temperature. This study supports the role of viruses as important aetiological agents causing exacerbations of COPD.
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http://dx.doi.org/10.1183/09031936.00092214DOI Listing
January 2015

Adults hospitalised with acute respiratory illness rarely have detectable bacteria in the absence of COPD or pneumonia; viral infection predominates in a large prospective UK sample.

J Infect 2014 Nov 6;69(5):507-15. Epub 2014 Aug 6.

Department of Clinical and Experimental Sciences and Respiratory Biomedical Research Unit, University of Southampton, UK; Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.

Objectives: Many adult patients hospitalised with acute respiratory illness have viruses detected but the overall importance of viral infection compared to bacterial infection is unclear.

Methods: Patients were recruited from two acute hospital sites in Leicester (UK) over 3 successive winters. Samples were taken for viral and bacterial testing.

Results: Of the 780 patients hospitalised with acute respiratory illness 345 (44%) had a respiratory virus detected. Picornaviruses were the most commonly isolated viruses (detected in 23% of all patients). Virus detection rates exceeded 50% in patients with exacerbation of asthma (58%), acute bronchitis and Influenza-like-illness (64%), and ranged from 30 to 50% in patients with an exacerbation of COPD (38%), community acquired pneumonia (36%) and congestive cardiac failure (31%). Bacterial detection was relatively frequent in patients with exacerbation of COPD and pneumonia (25% and 33% respectively) but was uncommon in all other groups. Antibiotic use was high across all clinical groups (76% overall) and only 21% of all antibiotic use occurred in patients with detectable bacteria.

Conclusions: Respiratory viruses are the predominant detectable aetiological agents in most hospitalised adults with acute respiratory illness. Antibiotic usage in hospital remains excessive including in clinical conditions associated with low rates of bacterial detection. Efforts at reducing excess antibiotic use should focus on these groups as a priority. Registered International Standard Controlled Trial Number: 21521552.
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http://dx.doi.org/10.1016/j.jinf.2014.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112687PMC
November 2014

Randomised controlled trial and health economic evaluation of the impact of diagnostic testing for influenza, respiratory syncytial virus and Streptococcus pneumoniae infection on the management of acute admissions in the elderly and high-risk 18- to 64-year-olds.

Health Technol Assess 2014 May;18(36):1-274, vii-viii

Health Protection Agency, Centre for Infections, London, UK.

Background: Western industrialised nations face a large increase in the number of older people. People over the age of 60 years account for almost half of the 16.8 million hospital admissions in England from 2009 to 2010. During 2009-10, respiratory infections accounted for approximately 1 in 30 hospital admissions and 1 in 20 of the 51.5 million bed-days.

Objective: To determine the diagnostic accuracy and clinical effectiveness and cost-effectiveness of rapid molecular and near-patient diagnostic tests for influenza, respiratory syncytial virus (RSV) and Streptococcus pneumoniae infections in comparison with traditional laboratory culture.

Methods: We carried out a randomised controlled trial (RCT) to evaluate impact on prescribing and clinical outcomes of point-of-care tests (POCTs) for influenza A and B and pneumococcal infection, reverse transcriptase-polymerase chain reaction (RT-PCR) tests for influenza A and B and RSV A and B, and conventional culture for these pathogens. We evaluated diagnostic accuracy of POCTs for influenza and pneumococcal infection, RT-PCR for influenza and sputum culture for S. pneumoniae using samples collected during the RCT. We did a systematic review and meta-analysis of POCTs for influenza A and B. We evaluated ease and speed of use of each test, process outcomes and cost-effectiveness.

Results: There was no evidence of association between diagnostic group and prescribing or clinical outcomes. Using PCR as 'gold standard', Quidel Influenza A + B POCT detected 24.4% [95% confidence interval (CI) 16.0% to 34.6%] of influenza infections (specificity 99.7%, 95% CI 99.2% to 99.9%); viral culture detected 21.6% (95% CI 13.5% to 31.6%; specificity 99.8%, 95% CI 99.4% to 100%). Using blood culture as 'gold standard', BinaxNOW pneumococcal POCT detected 57.1% (95% CI 18.4% to 90.1%) of pneumococcal infections (specificity 92.5%; 95% CI 90.6% to 94.1%); sputum culture detected 100% (95% CI 2.5% to 100%; specificity 97.2%, 95% CI 94.3% to 98.9%). Overall, pooled estimates of sensitivity and specificity of POCTs for influenza from the literature were 74% (95% CI 67% to 80%) and 99% (95% CI 98% to 99%), respectively. Median intervals from specimen collection to test result were 15 minutes [interquartile range (IQR) 10-23 minutes) for Quidel Influenza A + B POCT, 20 minutes (IQR 15-30 minutes) for BinaxNOW pneumococcal POCT, 50.8 hours (IQR 44.3-92.6 hours) for semi-nested conventional PCR, 29.2 hours (IQR 26-46.9 hours) for real-time PCR, 629.6 hours (IQR 262.5-846.7 hours) for culture of influenza and 84.4 hours (IQR 70.7-137.8 hours) and 71.4 hours (IQR 69.15-84.0 hours) for culture of S. pneumoniae in blood and sputum, respectively. Both POCTs were rated straightforward and undemanding; blood culture was moderately complex and all other tests were complex. Costs and quality-adjusted life-years (QALYs) of each diagnostic strategy were similar. Incrementally, PCR was most cost-effective (78.3% probability at a willingness to pay of £20,000/QALY). Few patients were admitted within a timescale conducive to treatment with a neuraminidase inhibitor according to National Institute for Health and Care Excellence guidance.

Limitations: The accuracy study was limited by inadequate gold standards.

Conclusions: All tests had limitations. We found no evidence that POCTs for influenza or S. pneumoniae, or PCR for influenza or RSV influenced antimicrobial prescribing or clinical outcomes. The total costs and QALYs of each diagnostic strategy were similar, although, incrementally, PCR was the most cost-effective strategy. The analysis does not support routine use of POCTs for either influenza or pneumococcal antigen for adults presenting with acute cardiopulmonary conditions, but suggests that conventional viral culture for clinical diagnosis should be replaced by PCR.

Trial Registration: Current Controlled Trials ISRCTN21521552.

Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 36. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta18360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781605PMC
May 2014

Severe community-acquired adenovirus pneumonia in an immunocompetent 44-year-old woman: a case report and review of the literature.

J Med Case Rep 2011 Jun 30;5:259. Epub 2011 Jun 30.

Department of Infectious Diseases, Leicester Royal Infirmary, Level 6 Windsor Building, Leicester, LE1 5WW, UK.

Introduction: This case report describes a rare condition: community-acquired adenovirus pneumonia in an immunocompetent adult. The diagnosis was achieved by using a multiplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay and highlights the usefulness of these novel molecular diagnostic techniques in patients hospitalized with acute respiratory illness. We also performed a literature search for previously published cases and present a summary of the clinical, laboratory and radiological features of this condition.

Case Presentation: A 44-year-old immunocompetent Caucasian woman was admitted to our hospital with an acute febrile respiratory illness associated with a rash. Her blood tests were non-specifically abnormal, and tests for bacterial pathogens were negative. Her condition rapidly deteriorated while she was in our hospital and required mechanical ventilation and inotropic support. A multiplex real-time RT-PCR assay performed on respiratory specimens to detect respiratory viruses was negative for influenza but positive for adenovirus DNA. The patient recovered on supportive treatment, and antibiotics were stopped after 5 days.

Conclusions: Community-acquired adenovirus pneumonia in immunocompetent adult civilians presents as a non-specific acute febrile respiratory illness followed by the abrupt onset of respiratory failure, often requiring mechanical ventilation. Its laboratory and radiological features are typical of viral infections but also are non-specific. Novel multiplex real-time RT-PCR testing for respiratory viruses enabled us to rapidly make the diagnosis in this case. The new technology could be used more widely in patients with acute respiratory illness and has potential utility for rationalization of the use of antibiotics and improving infection control measures.
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http://dx.doi.org/10.1186/1752-1947-5-259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148995PMC
June 2011

Eumycetoma of the hand caused by Leptosphaeria tompkinsii and refractory to medical therapy with voriconazole.

Mycopathologia 2011 Oct 13;172(4):311-5. Epub 2011 May 13.

Department of Infectious Diseases, Infectious Diseases Unit, Leicester Royal Infirmary, Level 6 Windsor building, Leicester, LE1 5WW, UK.

We report on the first case of eumycetoma caused by the organism Leptosphaeria tompkinsii to be diagnosed and possibly acquired within the United Kingdom. Conventional culture of fungal grains and surgical tissue specimens was negative and the diagnosis was achieved using panfungal polymerase chain reaction and sequencing technology. Despite limited surgical resection and prolonged antifungal therapy with voriconazole, the patient developed progressive disease with mycetoma bone involvement. This case highlights the usefulness of molecular diagnostic techniques in eumycetoma where organisms may fail to grow with conventional culture or be difficult to identify morphologically. It also reminds us that eumycetoma is a difficult infection to treat and despite optimism regarding the efficacy of the newer triazole antifungals in this condition, treatment failures may still occur.
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http://dx.doi.org/10.1007/s11046-011-9432-8DOI Listing
October 2011

Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial.

Lancet Infect Dis 2011 Feb 16;11(2):91-101. Epub 2010 Dec 16.

Infectious Diseases Unit, Vaccine Evaluation Centre, University Hospitals of Leicester NHS Trust and Department of Infection, Immunity, and Inflammation, University of Leicester, UK.

Background: Effective antigen-sparing vaccines are needed to confront pandemic influenza. Whole-virion and oil-in-water adjuvanted vaccines are the most effective formulations against H5N1 avian influenza. We assessed the safety and immunogenicity in adults in the UK of pandemic H1N1 whole-virion vaccine and oil-in-water adjuvanted vaccine purchased by the UK government in 2009.

Methods: In our randomised, observer-blind, parallel-group, controlled trial, healthy adults aged 18-44 years, 45-64 years, and 65 years and older (from Oct 19, to Nov 12, 2009) received two doses of vaccine given 21 days apart: either 7·5 μg of haemagglutinin formulated as whole-virion vaccine, or 3·75 μg of haemagglutinin formulated as split-virion vaccine with AS03(A) oil-in-water adjuvant. Assignment was by a computer-generated code, with random permuted blocks of two, four, and six. All participants and investigators were unaware of vaccine assignments. The trial was done at three hospitals in the UK. We measured antibody titres with a haemagglutination-inhibition assay at baseline; 7, 14, and 21 days after each vaccination; and at 6 months after the first dose. Primary outcome was vaccine immunogenicity of the full analysis set by the EU Committee of Human Medicinal Products licensing criteria. This study is registered with ISRCTN, number ISRCTN92328241.

Findings: At day 0, baseline antibody (titre ≥1/8) was detected in 44 (13%) of 347 participants. Sera from 95% to 98% of participants were assessed for immunogenicity on days 7, 14, 21, 28, 35, and 42, and at 6 months. On day 21 after one dose of adjuvanted AS03(A) or whole-virion vaccine, 63 (94%, 95 CI 85·4-98·4) of 67 and 50 (71%, 59·4-81·6) of 70 participants aged 18-44 years, 51 (77%, 65·3-86·7) of 66 and 26 (39%, 27·1-51·5) of 67 aged 45-64 years, and 19 (51%, 34·4-68·1) of 37 and 11 (32%, 17·4-50·5) of 34 aged 65 years or older had titres of 1:40 or greater. On day 42 (21 days after the second dose), 64 (100%, 94·4-100) of 64 and 49 (73%, 60·9-83·2) of 67 participants aged 18-44 years, 59 (91%, 81·0-96·5) of 65 and 29 (43·9%, 31·7-56·7) of 66 aged 45-64 years, and 28 (76%, 58·8-88·2) of 37 and 12 (36%, 20·4-54·9) of 33 aged 65 years or older had titres of 1/40 or greater. At 6 months, 62 (98%, 91·5-100) of 63 and 54 (78%, 66·7-87·3) of 69 participants aged 18-44 years, 54 (82%, 70·4-90·2) of 66 and 37 (55%, 42·6-67·4) of 67 aged 45-64 years, and 21 (57%, 39·5-72·9) of 37 and 10 (29%, 15·1-47·5) of 34 aged 65 years or older had titres of 1/40 or greater. There were no vaccine-related serious adverse events. Whole-virion vaccine was associated with fewer local and systemic reactions than adjuvanted vaccine.

Interpretation: AS03(A)-adjuvanted vaccine was more immunogenic against pandemic influenza A H1N1 virus than whole-virion vaccine and offers greater antigen-sparing capacity. A two-dose strategy should be considered for older people.

Funding: Department of Health, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre.
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http://dx.doi.org/10.1016/S1473-3099(10)70296-6DOI Listing
February 2011

Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD.

Chest 2011 Jun 28;139(6):1410-1418. Epub 2010 Oct 28.

Institute for Lung Health, University of Leicester, Leicester, England; Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, England. Electronic address:

Background: Antibiotic overuse in respiratory illness is common and is associated with drug resistance and hospital-acquired infection. Biomarkers that can identify bacterial infections may reduce antibiotic prescription. We aimed to compare the usefulness of the biomarkers procalcitonin and C-reactive protein (CRP) in patients with pneumonia or exacerbations of asthma or COPD.

Methods: Patients with a diagnosis of community-acquired pneumonia or exacerbation of asthma or COPD were recruited during the winter months of 2006 to 2008. Demographics, clinical data, and blood samples were collected. Procalcitonin and CRP concentrations were measured from available sera.

Results: Sixty-two patients with pneumonia, 96 with asthma, and 161 with COPD were studied. Serum procalcitonin and CRP concentrations were strongly correlated (Spearman rank correlation coefficient [rs] = 0.56, P < .001). Patients with pneumonia had increased procalcitonin and CRP levels (median [interquartile range] 1.27 ng/mL [2.36], 191 mg/L [159]) compared with those with asthma (0.03 ng/mL [0.04], 9 mg/L [21]) and COPD (0.05 ng/mL [0.06], 16 mg/L [34]). The area under the receiver operating characteristic curve (95% CI) for distinguishing between patients with pneumonia (antibiotics required) and exacerbations of asthma (antibiotics not required), for procalcitonin and CRP was 0.93 (0.88-0.98) and 0.96 (0.93-1.00). A CRP value > 48 mg/L had a sensitivity of 91% (95% CI, 80%-97%) and specificity of 93% (95% CI, 86%-98%) for identifying patients with pneumonia.

Conclusions: Procalcitonin and CRP levels can both independently distinguish pneumonia from exacerbations of asthma. CRP levels could be used to guide antibiotic therapy and reduce antibiotic overuse in hospitalized patients with acute respiratory illness.
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http://dx.doi.org/10.1378/chest.10-1747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109646PMC
June 2011