Publications by authors named "Catherine F Houlihan"

35 Publications

Monkeypox: An old foe, with new challenges.

Infect Prev Pract 2022 Sep 30;4(3):100229. Epub 2022 Jun 30.

Infection Service, Clinical Laboratory Services, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, B15 2GW, UK.

At first glance, a multi-country outbreak of monkeypox in 2022 seems unusual. However, the re-emergence and expansion of this viral disease beyond its endemicity in West and Central Africa had previously been predicted as a possible consequence of a decline in population immunity following smallpox eradication. Since the 13th of May 2022, cases of monkeypox have been reported in at least 28 WHO member states from within 4 regions (the Americans, European, Eastern Mediterranean and Western Pacific regions). This summary describes the multi-country outbreak to date, with an emphasis on patient demographics, common symptoms and signs, clinical management (including infection prevention measures) and clinical outcomes of the cases in the United Kingdom, which has so far reported the largest number of laboratory confirmed cases. The future implications of this outbreak, including preventative measures to curb the current outbreak, prevent future outbreaks and the likelihood of the disease becoming endemic in the UK are also discussed.
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http://dx.doi.org/10.1016/j.infpip.2022.100229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283547PMC
September 2022

Clinical features and management of human monkeypox: a retrospective observational study in the UK.

Lancet Infect Dis 2022 08 24;22(8):1153-1162. Epub 2022 May 24.

Directorate of Infection, Guy's & St Thomas' NHS Foundation Trust, London, UK. Electronic address:

Background: Cases of human monkeypox are rarely seen outside of west and central Africa. There are few data regarding viral kinetics or the duration of viral shedding and no licensed treatments. Two oral drugs, brincidofovir and tecovirimat, have been approved for treatment of smallpox and have demonstrated efficacy against monkeypox in animals. Our aim was to describe the longitudinal clinical course of monkeypox in a high-income setting, coupled with viral dynamics, and any adverse events related to novel antiviral therapies.

Methods: In this retrospective observational study, we report the clinical features, longitudinal virological findings, and response to off-label antivirals in seven patients with monkeypox who were diagnosed in the UK between 2018 and 2021, identified through retrospective case-note review. This study included all patients who were managed in dedicated high consequence infectious diseases (HCID) centres in Liverpool, London, and Newcastle, coordinated via a national HCID network.

Findings: We reviewed all cases since the inception of the HCID (airborne) network between Aug 15, 2018, and Sept 10, 2021, identifying seven patients. Of the seven patients, four were men and three were women. Three acquired monkeypox in the UK: one patient was a health-care worker who acquired the virus nosocomially, and one patient who acquired the virus abroad transmitted it to an adult and child within their household cluster. Notable disease features included viraemia, prolonged monkeypox virus DNA detection in upper respiratory tract swabs, reactive low mood, and one patient had a monkeypox virus PCR-positive deep tissue abscess. Five patients spent more than 3 weeks (range 22-39 days) in isolation due to prolonged PCR positivity. Three patients were treated with brincidofovir (200 mg once a week orally), all of whom developed elevated liver enzymes resulting in cessation of therapy. One patient was treated with tecovirimat (600 mg twice daily for 2 weeks orally), experienced no adverse effects, and had a shorter duration of viral shedding and illness (10 days hospitalisation) compared with the other six patients. One patient experienced a mild relapse 6 weeks after hospital discharge.

Interpretation: Human monkeypox poses unique challenges, even to well resourced health-care systems with HCID networks. Prolonged upper respiratory tract viral DNA shedding after skin lesion resolution challenged current infection prevention and control guidance. There is an urgent need for prospective studies of antivirals for this disease.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(22)00228-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300470PMC
August 2022

Amyloid processing in COVID-19-associated neurological syndromes.

J Neurochem 2022 04 2;161(2):146-157. Epub 2022 Mar 2.

Queen Square Institute of Neurology, University College London, London, UK.

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1β, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10 ), Aβ42 (p = 3.5 × 10 ), and Aβ42/Aβ40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPβ. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPβ. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPβ. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.
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http://dx.doi.org/10.1111/jnc.15585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115071PMC
April 2022

Favorable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases.

Med (N Y) 2021 09 14;2(9):1093-1109.e6. Epub 2021 Aug 14.

Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), University College London Hospitals (UCLH), Great Ormond Street Hospital (GOSH), London, UK.

Background: Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained, and the effect of underlying immune dysfunction or suppression is unknown. Here, we sought to examine the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), and juvenile systemic lupus erythematosus (JSLE) against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group.

Methods: Sera were collected from JIA (n = 118), JDM (n = 49), and JSLE (n = 30) patients and from healthy control (n = 54) children and adolescents prior to the coronavirus disease 19 (COVID-19) pandemic. We used sensitive flow-cytometry-based assays to determine titers of antibodies that reacted with the spike and nucleoprotein of HCoV-OC43 and cross-reacted with the spike and nucleoprotein of SARS-CoV-2, and we compared them with respective titers in sera from patients with multisystem inflammatory syndrome in children and adolescents (MIS-C).

Findings: Despite immune dysfunction and immunosuppressive treatment, JIA, JDM, and JSLE patients maintained comparable or stronger humoral responses than healthier peers, which was dominated by immunoglobulin G (IgG) antibodies to HCoV-OC43 spike, and harbored IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM, and JSLE patients, which argues against increased exposure.

Conclusions: Consequently, autoimmune rheumatic diseases and their treatment were associated with a favorable ratio of spike to nucleoprotein antibodies.

Funding: This work was supported by a Centre of Excellence Centre for Adolescent Rheumatology Versus Arthritis grant, 21593, UKRI funding reference MR/R013926/1, the Great Ormond Street Children's Charity, Cure JM Foundation, Myositis UK, Lupus UK, and the NIHR Biomedical Research Centres at GOSH and UCLH. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust
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http://dx.doi.org/10.1016/j.medj.2021.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363467PMC
September 2021

Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.

EClinicalMedicine 2021 Sep 12;39:101070. Epub 2021 Aug 12.

Francis Crick Institute, London, UK.

Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear.

Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβGPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I βGPI (aD1β2GPI) IgG.

Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups ( < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO =-0.15  = 0.040) and was associated with venous thromboembolism ( = 0.043). In contrast, aCL IgA ( < 0.001) and IgG ( < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO.

Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management.

Funding: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.
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http://dx.doi.org/10.1016/j.eclinm.2021.101070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358233PMC
September 2021

Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes.

Brain Commun 2021 12;3(3):fcab099. Epub 2021 May 12.

Advanced Pathogens Diagnostic Unit, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS ( = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with ( = 94) and without ( = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.
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http://dx.doi.org/10.1093/braincomms/fcab099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194666PMC
May 2021

Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study.

Lancet Infect Dis 2021 09 12;21(9):1246-1256. Epub 2021 Apr 12.

Great Ormond Street Institute of Child Health, University College London, London, UK; Advanced Pathogen Diagnostics Unit, University College London Hospitals NHS Foundation Trust, London, UK; Department of Clinical Virology, University College London Hospitals NHS Foundation Trust, London, UK; The Francis Crick Institute, London, UK. Electronic address:

Background: Emergence of variants with specific mutations in key epitopes in the spike protein of SARS-CoV-2 raises concerns pertinent to mass vaccination campaigns and use of monoclonal antibodies. We aimed to describe the emergence of the B.1.1.7 variant of concern (VOC), including virological characteristics and clinical severity in contemporaneous patients with and without the variant.

Methods: In this cohort study, samples positive for SARS-CoV-2 on PCR that were collected from Nov 9, 2020, for patients acutely admitted to one of two hospitals on or before Dec 20, 2020, in London, UK, were sequenced and analysed for the presence of VOC-defining mutations. We fitted Poisson regression models to investigate the association between B.1.1.7 infection and severe disease (defined as point 6 or higher on the WHO ordinal scale within 14 days of symptoms or positive test) and death within 28 days of a positive test and did supplementary genomic analyses in a cohort of chronically shedding patients and in a cohort of remdesivir-treated patients. Viral load was compared by proxy, using PCR cycle threshold values and sequencing read depths.

Findings: Of 496 patients with samples positive for SARS-CoV-2 on PCR and who met inclusion criteria, 341 had samples that could be sequenced. 198 (58%) of 341 had B.1.1.7 infection and 143 (42%) had non-B.1.1.7 infection. We found no evidence of an association between severe disease and death and lineage (B.1.1.7 vs non-B.1.1.7) in unadjusted analyses (prevalence ratio [PR] 0·97 [95% CI 0·72-1·31]), or in analyses adjusted for hospital, sex, age, comorbidities, and ethnicity (adjusted PR 1·02 [0·76-1·38]). We detected no B.1.1.7 VOC-defining mutations in 123 chronically shedding immunocompromised patients or in 32 remdesivir-treated patients. Viral load by proxy was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold value (mean 28·8 [SD 4·7] vs 32·0 [4·8]; p=0·0085) and genomic read depth (1280 [1004] vs 831 [682]; p=0·0011).

Interpretation: Emerging evidence exists of increased transmissibility of B.1.1.7, and we found increased virus load by proxy for B.1.1.7 in our data. We did not identify an association of the variant with severe disease in this hospitalised cohort.

Funding: University College London Hospitals NHS Trust, University College London/University College London Hospitals NIHR Biomedical Research Centre, Engineering and Physical Sciences Research Council.
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http://dx.doi.org/10.1016/S1473-3099(21)00170-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041359PMC
September 2021

The effect of spike mutations on SARS-CoV-2 neutralization.

Cell Rep 2021 03 6;34(12):108890. Epub 2021 Mar 6.

Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK. Electronic address:

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines show protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, spike. Because new SARS-CoV-2 variants are emerging rapidly, as exemplified by the B.1.1.7, B.1.351, and P.1 lineages, it is critical to understand whether antibody responses induced by infection with the original SARS-CoV-2 virus or current vaccines remain effective. In this study, we evaluate neutralization of a series of mutated spike pseudotypes based on divergence from SARS-CoV and then compare neutralization of the B.1.1.7 spike pseudotype and individual mutations. Spike-specific monoclonal antibody neutralization is reduced dramatically; in contrast, polyclonal antibodies from individuals infected in early 2020 remain active against most mutated spike pseudotypes, but potency is reduced in a minority of samples. This work highlights that changes in SARS-CoV-2 spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their effect on vaccine efficacy.
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http://dx.doi.org/10.1016/j.celrep.2021.108890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936541PMC
March 2021

Clinical outcomes of COVID-19 in long-term care facilities for people with epilepsy.

Epilepsy Behav 2021 02 5;115:107602. Epub 2020 Nov 5.

Department of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Chalfont Centre for Epilepsy (CCE), Chalfont St Peter, Bucks SL9 0RJ, UK.

In this cohort study, we aim to compare outcomes from coronavirus disease 2019 (COVID-19) in people with severe epilepsy and other co-morbidities living in long-term care facilities which all implemented early preventative measures, but different levels of surveillance. During 25-week observation period (16 March-6 September 2020), we included 404 residents (118 children), and 1643 caregivers. We compare strategies for infection prevention, control, and containment, and related outcomes, across four UK long-term care facilities. Strategies included early on-site enhancement of preventative and infection control measures, early identification and isolation of symptomatic cases, contact tracing, mass surveillance of asymptomatic cases and contacts. We measured infection rate among vulnerable people living in the facilities and their caregivers, with asymptomatic and symptomatic cases, including fatality rate. We report 38 individuals (17 residents) who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive, with outbreaks amongst residents in two facilities. At Chalfont Centre for Epilepsy (CCE), 10/98 residents tested positive: two symptomatic (one died), eight asymptomatic on weekly enhanced surveillance; 2/275 caregivers tested positive: one symptomatic, one asymptomatic. At St Elizabeth's (STE), 7/146 residents tested positive: four symptomatic (one died), one positive during hospital admission for symptoms unrelated to COVID-19, two asymptomatic on one-off testing of all 146 residents; 106/601 symptomatic caregivers were tested, 13 positive. In addition, during two cycles of systematically testing all asymptomatic carers, four tested positive. At The Meath (TM), 8/80 residents were symptomatic but none tested; 26/250 caregivers were tested, two positive. At Young Epilepsy (YE), 8/80 children were tested, all negative; 22/517 caregivers were tested, one positive. Infection outbreaks in long-term care facilities for vulnerable people with epilepsy can be quickly contained, but only if asymptomatic individuals are identified through enhanced surveillance at resident and caregiver level. We observed a low rate of morbidity and mortality, which confirmed that preventative measures with isolation of suspected and confirmed COVID-19 residents can reduce resident-to-resident and resident-to-caregiver transmission. Children and young adults appear to have lower infection rates. Even in people with epilepsy and multiple co-morbidities, we observed a high percentage of asymptomatic people suggesting that epilepsy-related factors (anti-seizure medications and seizures) do not necessarily lead to poor outcomes.
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http://dx.doi.org/10.1016/j.yebeh.2020.107602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643621PMC
February 2021

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.

Science 2020 12 6;370(6522):1339-1343. Epub 2020 Nov 6.

Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, Great Ormond Street Hospital (GOSH), London WC1N 3JH, UK.

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.
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http://dx.doi.org/10.1126/science.abe1107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857411PMC
December 2020

The complexities of SARS-CoV-2 serology.

Lancet Infect Dis 2020 12 23;20(12):1350-1351. Epub 2020 Sep 23.

University College London, London, UK; The Francis Crick Institute, London, UK.

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http://dx.doi.org/10.1016/S1473-3099(20)30699-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511169PMC
December 2020

A case of limbic encephalitis associated with asymptomatic COVID-19 infection.

J Neurol Neurosurg Psychiatry 2020 11 13;91(11):1229-1230. Epub 2020 Jul 13.

MRC Centre for Neuromuscular Disease and Department of Molecular Neuroscience, University College London Hospitals NHS Foundation Trust National Hospital for Neurology and Neurosurgery, London, UK.

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http://dx.doi.org/10.1136/jnnp-2020-323839DOI Listing
November 2020

Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers.

Lancet 2020 07 9;396(10246):e6-e7. Epub 2020 Jul 9.

Department of Clinical Virology, University College London Hospitals, London W1T 4EU, UK; Advanced Pathogen Diagnostics Unit, University College London Hospitals, London W1T 4EU, UK; Great Ormond Street Institute of Child Health, University College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)31484-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347344PMC
July 2020

Nosocomial Transmission of Coronavirus Disease 2019: A Retrospective Study of 66 Hospital-acquired Cases in a London Teaching Hospital.

Clin Infect Dis 2021 02;72(4):690-693

Department of Virology, University College London Hospitals NHS Trust, London, United Kingdom.

Coronavirus disease 2019 (COVID-19) can cause deadly healthcare-associated outbreaks. In a major London teaching hospital, 66 of 435 (15%) COVID-19 inpatient cases between 2 March and 12 April 2020 were definitely or probably hospital-acquired, through varied transmission routes. The case fatality was 36%. Nosocomial infection rates fell following comprehensive infection prevention and control measures.
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http://dx.doi.org/10.1093/cid/ciaa816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337682PMC
February 2021

Herpesvirus Infections of the Central Nervous System.

Semin Neurol 2019 06 2;39(3):369-382. Epub 2019 Aug 2.

Division of Infection and Immunity, University College London, London, United Kingdom.

There are over 200 herpesvirus species, of which 10 affect humans. Each of these 10 herpesviruses has a unique clinical syndrome, but common to all is their ability to cause infection and pathology in the central nervous system. In this article, we discuss the epidemiology, clinical presentation, diagnostic modalities, treatment, sequelae, and availability of vaccination of each of the following herpesviruses: herpes simplex virus 1 and 2, varicella zoster virus, human cytomegalovirus, human herpesvirus 6A, 6B, and 7, Epstein-Barr virus, human herpesvirus 8, and simian herpesvirus B.
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http://dx.doi.org/10.1055/s-0039-1687837DOI Listing
June 2019

Advances in molecular diagnostic testing for central nervous system infections.

Curr Opin Infect Dis 2019 06;32(3):244-250

Division of Infection and Immunity, University College London.

Purpose Of Review: Central nervous system (CNS) infections present an ongoing diagnostic challenge for clinicians, with an aetiological agent remaining unidentified in the majority of cases even in high-income settings. This review summarizes developments in a range of diagnostic methods published in the past 18 months.

Recent Findings: Several commercial assays exist for the detection of viral, bacterial and fungal pathogens using single multiplex PCR. Multicentre validation of the Biofire FilmArray panel illustrated high sensitivity for bacterial and fungal pathogens, but poor results for Cryptococcus species detection. The development of microarray cards for bacterial CNS pathogens shows promise but requires further validation. Few developments have been made in proteomics and transcriptomics, contrasted with significant increase in the use of metagenomic (or unbiased) sequencing. Novel viruses causing CNS infection have been described using this technique but contamination, cost, expertise and turnaround time requirements remain restrictive. Finally, the development of Gene Xpert and Ultra has revolutionized tuberculosis meningitis diagnostics with newly released recommendations for their use from the WHO.

Summary: Progress has been made in the clinical validation and international recommendation of PCR-based tests for CNS infections. Sequencing techniques present the most dynamic field, although significant ongoing challenges persist.
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http://dx.doi.org/10.1097/QCO.0000000000000548DOI Listing
June 2019

Outbreak science: recent progress in the detection and response to outbreaks of infectious diseases.

Clin Med (Lond) 2019 03;19(2):140-144

Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

The frequency of reported outbreaks of infectious diseases has increased over the past 3 decades, with predictions that this rise will continue. Outbreak response continues to follow nine basic principles: establish the presence of an outbreak, verify the diagnosis, make a case definition, find cases and contacts, conduct basic epidemiology, test hypotheses, institute control measures, communicate the situation and establish ongoing surveillance. Within each of these areas, significant advances have been made over the past 5 years using progress in digital, laboratory, epidemiology and anthropological equipment or techniques. Irrespective of these, future outbreaks of high-consequence are inevitable, and vigilance and preparation must continue in order to prevent significant mortality, morbidity and socio-economic crisis.
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http://dx.doi.org/10.7861/clinmedicine.19-2-140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454359PMC
March 2019

Human papillomavirus DNA detected in fingertip, oral and bathroom samples from unvaccinated adolescent girls in Tanzania.

Sex Transm Infect 2019 08 13;95(5):374-379. Epub 2019 Jan 13.

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.

Objective: Human papillomavirus (HPV) DNA has been detected in vaginal samples from adolescent girls who report no previous sex and, in high-income settings, from fingertips, raising the possibility of non-sexual transmission. No such studies originate from East Africa which bears among the highest cervical cancer incidence and HPV prevalence worldwide. HPV-related oral cancer incidence is increasing, but oral HPV prevalence data from East Africa are limited. We aimed to describe the HPV DNA prevalence in genital and non-genital sites and in the bathroom of unvaccinated adolescent girls, and examine genotype concordance between sites.

Methods: We nested a cross-sectional study of HPV in genital and extragenital sites within a cohort study of vaginal HPV acquisition. Unvaccinated girls age 16-18 years in Tanzania, who reported ever having had sex, were consented, enrolled and tested for the presence of HPV DNA in vaginal samples collected using self-administered swabs, oral samples collected using an oral rinse, and on fingertips and bathroom surfaces collected using a cytobrush.

Results: Overall, 65 girls were enrolled and 23 (35%, 95% CI 23% to 47%) had detectable vaginal HPV. Adequate (β-globin positive) samples were collected from 36 girls' fingertips and HPV was detected in 7 (19%, 95% CI 6% to 33%). 63 girls provided adequate oral samples, 4 (6%, 95% CI 0% to 13%) of which had HPV DNA detected. In bathroom samples from 58 girls, 4 (7%, 95% CI 0% to 14%) had detectable HPV DNA. Of the 11 girls with extragenital HPV, six had the same genotype in >1 site.

Conclusion: We found a high prevalence of HPV in non-genital sites in adolescent girls and in their bathrooms, in this region with a high cervical cancer incidence. Concordance of genotypes between sites supports the possibility of autoinoculation.
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http://dx.doi.org/10.1136/sextrans-2018-053756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678034PMC
August 2019

The Acceptability of Online Consent in a Self-Test Serosurvey of Responders to the 2014-2016 West African Ebola Outbreak.

Public Health Ethics 2018 Jul 22;11(2):201-212. Epub 2017 Dec 22.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.

Online participation in research is used increasingly to recruit geographically dispersed populations. Obtaining online consent is convenient, yet we know little about the acceptability of this practice. We carried out a serostudy among personnel returning to the UK/Ireland following deployment to West Africa during the 2014-2016 Ebola epidemic. We used an online procedure for consenting returnees and designed a small descriptive study to understand: how much of the consent material they read, how informed they felt and if they preferred online to traditional face-to-face consent. Of 261 returnees, 111 (43 per cent) completed the consent survey. Participants indicated a high level of engagement with the consent materials, with 67 per cent reporting having read all and 20 per cent having read 'most' of the materials. All participants indicated feeling completely (78 per cent) or mostly (22 per cent) informed about the purpose, methods and intended uses of the research, as well as what participation was required and what risks were involved. Only three participants indicated a preference for face-to-face consent. Free-text comments suggested that online consent may be an acceptable modality for uncomplicated and low-risk studies. The study sample was largely composed of health professionals, suggesting acceptability of online consent within this population.
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http://dx.doi.org/10.1093/phe/phx027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093377PMC
July 2018

Use of Whole-Genome Sequencing in the Investigation of a Nosocomial Influenza Virus Outbreak.

J Infect Dis 2018 09;218(9):1485-1489

Department of Population, Policy, and Practice, Great Ormond Street Institute of Child Health, University College London (UCL), London, United Kingdom.

Traditional epidemiological investigation of nosocomial transmission of influenza involves the identification of patients who have the same influenza virus type and who have overlapped in time and place. This method may misidentify transmission where it has not occurred or miss transmission when it has. We used influenza virus whole-genome sequencing (WGS) to investigate an outbreak of influenza A virus infection in a hematology/oncology ward and identified 2 separate introductions, one of which resulted in 5 additional infections and 79 bed-days lost. Results from WGS are becoming rapidly available and may supplement traditional infection control procedures in the investigation and management of nosocomial outbreaks.
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http://dx.doi.org/10.1093/infdis/jiy335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151078PMC
September 2018

Ebola exposure, illness experience, and Ebola antibody prevalence in international responders to the West African Ebola epidemic 2014-2016: A cross-sectional study.

PLoS Med 2017 05 16;14(5):e1002300. Epub 2017 May 16.

Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: Healthcare and other front-line workers are at particular risk of infection with Ebola virus (EBOV). Despite the large-scale deployment of international responders, few cases of Ebola virus disease have been diagnosed in this group. Since asymptomatic or pauci-symptomatic infection has been described, it is plausible that infections have occurred in healthcare workers but have escaped being diagnosed. We aimed to assess the prevalence of asymptomatic or pauci-symptomatic infection, and of exposure events, among returned responders to the West African Ebola epidemic 2014-2016.

Methods And Findings: We used snowball sampling to identify responders who had returned to the UK or Ireland, and used an online consent and questionnaire to determine their exposure to EBOV and their experience of illness. Oral fluid collection devices were sent and returned by post, and samples were tested using an EBOV IgG capture assay that detects IgG to Ebola glycoprotein. Blood was collected from returnees with reactive samples for further testing. Unexposed UK controls were also recruited. In all, 300 individuals consented, of whom 268 (89.3%) returned an oral fluid sample (OFS). The majority had worked in Sierra Leone in clinical, laboratory, research, and other roles. Fifty-three UK controls consented and provided samples using the same method. Of the returnees, 47 (17.5%) reported that they had had a possible EBOV exposure. Based on their free-text descriptions, using a published risk assessment method, we classified 43 (16%) as having had incidents with risk of Ebola transmission, including five intermediate-risk and one high-risk exposure. Of the returnees, 57 (21%) reported a febrile or diarrhoeal illness in West Africa or within 1 mo of return, of whom 40 (70%) were not tested at the time for EBOV infection. Of the 268 OFSs, 266 were unreactive. Two returnees, who did not experience an illness in West Africa or on return, had OFSs that were reactive on the EBOV IgG capture assay, with similar results on plasma. One individual had no further positive test results; the other had a positive result on a double-antigen bridging assay but not on a competitive assay or on an indirect EBOV IgG ELISA. All 53 controls had non-reactive OFSs. While the participants were not a random sample of returnees, the number participating was high.

Conclusions: This is the first study, to our knowledge, of the prevalence of EBOV infection in international responders. More than 99% had clear negative results. Sera from two individuals had discordant results on the different assays; both were negative on the competitive assay, suggesting that prior infection was unlikely. The finding that a significant proportion experienced "near miss" exposure events, and that most of those who experienced symptoms did not get tested for EBOV at the time, suggests a need to review and standardise protocols for the management of possible exposure to EBOV, and for the management of illness, across organisations that deploy staff to outbreaks.
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http://dx.doi.org/10.1371/journal.pmed.1002300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433702PMC
May 2017

Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus.

Lancet Infect Dis 2017 06 28;17(6):645-653. Epub 2017 Feb 28.

Virus Reference Department, Public Health England, London, UK.

Background: The frequency of asymptomatic infection with Ebola virus is unclear: previous estimates vary and there is no standard test. Asymptomatic infection with Ebola virus could contribute to population immunity, reducing spread. If people with asymptomatic infection are infectious it could explain re-emergences of Ebola virus disease (EVD) without known contact.

Methods: We validated a new oral fluid anti-glycoprotein IgG capture assay among survivors from Kerry Town Ebola Treatment Centre and controls from communities unaffected by EVD in Sierra Leone. We then assessed the seroprevalence of antibodies to Ebola virus in a cross-sectional study of household contacts of the survivors. All household members were interviewed. Two reactive tests were required for a positive result, with a third test to resolve any discrepancies.

Findings: The assay had a specificity of 100% (95% CI 98·9-100; 339 of 339 controls tested negative) and sensitivity of 95·9% (89·8-98·9; 93 of 97 PCR-confirmed survivors tested positive). Of household contacts not diagnosed with EVD, 47·6% (229 of 481) had high level exposure (direct contact with a corpse, body fluids, or a case with diarrhoea, vomiting, or bleeding). Among the contacts, 12·0% (95% CI 6·1-20·4; 11 of 92) with symptoms at the time other household members had EVD, and 2·6% (1·2-4·7; 10 of 388) with no symptoms tested positive. Among asymptomatic contacts, seropositivity was weakly correlated with exposure level.

Interpretation: This new highly specific and sensitive assay showed asymptomatic infection with Ebola virus was uncommon despite high exposure. The low prevalence suggests asymptomatic infection contributes little to herd immunity in Ebola, and even if infectious, would account for few transmissions.

Funding: Wellcome Trust ERAES Programme, Save the Children.
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http://dx.doi.org/10.1016/S1473-3099(17)30111-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520246PMC
June 2017

Rapid acquisition of HPV around the time of sexual debut in adolescent girls in Tanzania.

Int J Epidemiol 2016 06 4;45(3):762-73. Epub 2016 Mar 4.

Clinical Research Department, London School of Hygiene and Tropical Medicine, London, UK Mwanza Intervention Trials Unit, Mwanza, Tanzania.

Background: No reports exist on genotype-specific human papillomavirus (HPV) acquisition in girls after first sex in sub-Saharan Africa, despite high HPV prevalence and cervical cancer incidence.

Methods: We followed 503 HP-unvaccinated girls aged 15-16 years in Mwanza, Tanzania, 3-monthly for 18 months with interviews and self-administered vaginal swabs. Swabs were tested for 13 higHRisk and 24 low-risk HPV genotypes. Incidence, clearance and duration of overall HPV and genotype-specific infections were calculated and associated factors evaluated.

Results: A total of 106 participants reported first sex prior to enrolment (N = 29) or during follow-up (N = 77). One was HIV-positive at the final visit. The remaining 105 girls contributed 323 adequate specimens. Incidence of any new HPV genotype was 225/100 person-years (pys), and incidence of vaccine types HPV-6, -11, -16 and -18 were 12, 2, 2 and 7/100 pys, respectively. Reporting sex in the past 3 months and knowing the most recent sexual partner for a longer period before sex were associated with HPV acquisition. Median time from reported sexual debut to first HPVinfection was 5 months, and infection duration was 6 months.

Conclusion: This is the first description of HPV acquisition after first sex in sub-Saharan Africa where the incidence of cervical cancer is amongst the highest in the world. HPV incidence was very high after first sex, including some vaccine genotypes, and infection duration was short. This very high HPV incidence may help explain high cervical cancer rates, and supports recommendations that the HPV vaccine should be given to girls before first sex.
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http://dx.doi.org/10.1093/ije/dyv367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005945PMC
June 2016

The Incidence of Human Papillomavirus in Tanzanian Adolescent Girls Before Reported Sexual Debut.

J Adolesc Health 2016 Mar 22;58(3):295-301. Epub 2015 Dec 22.

Clinical Research Department, London School of Hygiene and Tropical Medicine, London, United Kingdom; Mwanza Intervention Trials Unit, Mwanza, Tanzania.

Purpose: Acquisition of human papillomavirus (HPV) in women occurs predominantly through vaginal sex. However, HPV has been detected in girls reporting no previous sex. We aimed to determine incidence and risk factors for HPV acquisition in girls who report no previous sex in Tanzania, a country with high HPV prevalence and cervical cancer incidence.

Methods: We followed 503 adolescent girls aged 15-16 years in Mwanza, Tanzania, with face-to-face interviews and self-administered vaginal swabs every 3 months for 18 months; 397 girls reported no sex before enrollment or during follow-up; of whom, 120 were randomly selected. Samples from enrollment, 6-, 12-, and 18-month visits were tested for 37 HPV genotypes. Incidence, clearance, point prevalence, and duration of any HPV and genotype-specific infections were calculated and associated factors were evaluated.

Results: Of 120 girls who reported no previous sex, 119 were included, contributing 438 samples. HPV was detected in 51 (11.6%) samples. The overall incidence of new HPV infections was 29.4/100 person-years (95% confidence interval: 15.9-54.2). The point prevalence of vaccine types HPV-6,-11,-16, and -18 was .9%, .9%, 2.0%, and 0%, respectively. Spending a night away from home and using the Internet were associated with incident HPV, and reporting having seen a pornographic movie was inversely associated with HPV incidence.

Conclusions: Incident HPV infections were detected frequently in adolescent girls who reported no previous sex over 18 months. This is likely to reflect under-reporting of sex. A low-point prevalence of HPV genotypes in licensed vaccines was seen, indicating that vaccination of these girls might still be effective.
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http://dx.doi.org/10.1016/j.jadohealth.2015.10.248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762460PMC
March 2016

Authors' reply to Kremer and Van de Perre.

BMJ 2015 Mar 10;350:h1308. Epub 2015 Mar 10.

London School of Hygiene and Tropical Medicine, London, UK.

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http://dx.doi.org/10.1136/bmj.h1308DOI Listing
March 2015

Being ready to treat Ebola virus disease patients.

Am J Trop Med Hyg 2015 Feb 15;92(2):233-237. Epub 2014 Dec 15.

As the outbreak of Ebola virus disease (EVD) in West Africa continues, clinical preparedness is needed in countries at risk for EVD (e.g., United States) and more fully equipped and supported clinical teams in those countries with epidemic spread of EVD in Africa. Clinical staff must approach the patient with a very deliberate focus on providing effective care while assuring personal safety. To do this, both individual health care providers and health systems must improve EVD care. Although formal guidance toward these goals exists from the World Health Organization, Medecin Sans Frontières, the Centers for Disease Control and Prevention, and other groups, some of the most critical lessons come from personal experience. In this narrative, clinicians deployed by the World Health Organization into a wide range of clinical settings in West Africa distill key, practical considerations for working safely and effectively with patients with EVD.
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http://dx.doi.org/10.4269/ajtmh.14-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347319PMC
February 2015

Ebola virus disease.

BMJ 2014 Dec 10;349:g7348. Epub 2014 Dec 10.

London School of Hygiene and Tropical Medicine, London, UK.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707720PMC
http://dx.doi.org/10.1136/bmj.g7348DOI Listing
December 2014
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