Cohort profile: Virus Watch: Understanding community incidence, symptom profiles, and transmission of COVID-19 in relation to population movement and behaviour (preprint)

[bullet] Virus Watch is a national community cohort study of COVID-19 in households in England and Wales, established in June 2020. The study aims to provide evidence on which public health approaches are most effective in reducing transmission, and investigate community incidence, symptoms, and transmission of COVID-19 in relation to population movement and behaviours. [bullet] 28,527 households and 58,628 participants of age (0-98 years, mean age 48), were recruited between June 2020 - July 2022 [bullet] Data collected include demographics, details on occupation, co-morbidities, medications, and infection-prevention behaviours. Households are followed up weekly with illness surveys capturing symptoms and their severity, activities in the week prior to symptom onset and any COVID-19 test results. Monthly surveys capture household finance, employment, mental health, access to healthcare, vaccination uptake, activities and contacts. Data have been linked to Hospital Episode Statistics (HES), inpatient and critical care episodes, outpatient visits, emergency care contacts, mortality, virology testing and vaccination data held by NHS Digital. [bullet] Nested within Virus Watch are a serology & PCR cohort study (n=12,877) and a vaccine evaluation study (n=19,555). [bullet] Study data are deposited in the Office of National Statistics (ONS) Secure Research Service (SRS). Survey data are available under restricted access upon request to ONS SRS.

Assessing the spatial-temporal risks of SARS-CoV-2 infection for healthcare-workers in the hospital using behavioural indices from routine data (preprint)

The COVID-19 pandemic has emphasised the need to rapidly assess infection risks for healthcare workers within the hospital environment. Using data from the first year of the pandemic, we investigated whether an individuals COVID-19 test result was associated with behavioural markers derived from routinely collected hospital data two weeks prior to a test. The temporal and spatial context of behaviours were important, with the highest risks of infection during the first wave, for staff in contact with a greater number of patients and those with greater levels of activity on floors handling the majority of COVID-19 patients. Infection risks were higher for BAME staff and individuals working more shifts. Night shifts presented higher risks of infection between waves of COVID-19 patients. Our results demonstrate the epidemiological relevance of deriving markers of staff behaviour from electronic records, which extend beyond COVID-19 with applications for other communicable diseases and in supporting pandemic preparedness.

Comparison Of New and emerging SARS-CoV-2 variant Transmissibility through Active Contact Testing. A comparative cross-sectional household seroprevalence study. (preprint)

Historically SARS-CoV-2 secondary attack rates (SAR) have been based on PCR positivity on screening symptomatic contacts, this misses transmission events and identifies only symptomatic contacts who are PCR positive at the time of sampling. We used serology to detect the relative transmissibility of Alpha Variant of Concern (VOC) to non-VOC SARS-CoV-2 to calculate household secondary attack rates. We identified index patients diagnosed with Alpha and non-VOC SARS-CoV-2 across two London Hospitals between November 2020 and January 2021 during a prolonged and well adhered national lockdown. We completed a household seroprevalence survey and found that 61.8% of non-VOC exposed household contacts were seropositive compared to 82.1% of Alpha exposed household contacts. The odds of infection doubled with exposure to an index diagnosed with Alpha. There was evidence of transmission events in almost all households. Our data strongly support that estimates of SAR should include serological data to improve accuracy and understanding.

Using routinely collected hospital data to investigate healthcare worker mobility and patient contacts within a UK hospital during the COVID-19 pandemic (preprint)

Movement and contacts are central to the transmission of infectious diseases and, within the hospital setting, healthcare worker (HCW) mobility and their contact with patients play an important role in the spread of nosocomial disease. Yet data relating to HCW behaviours associated with mobility and contacts in the healthcare environment are often limited. This paper proposes a framework for integrating several electronic data sources routinely-collected by modern hospitals, to enable the measurement of HCW behaviours relevant to the transmission of infections. Using data from a London teaching hospital during the COVID-19 pandemic, we demonstrate how, at an aggregate level, electronic medical records (EMRs) and door access logs can be used to establish changes in HCW mobility and patient contacts. In addition, to show the utility of these data sources in supporting infection prevention and control (IPC), we investigate changes in the indirect connectivity of patients (resulting from shared contacts with HCWs) and spatial connectivity of floors (owing to the movements of HCWs). Average daily rates of patient contacts are computed and found to be higher throughout the pandemic compared to that pre-pandemic, while the average daily rates of HCW mobility remained stable until the second wave, where they surpassed pre-pandemic levels. The response of HCW behaviour to the pandemic was not equal between floors, whereby the highest increases in patient contacts and mobility were on floors handling the majority of COVID-19 patients. The first wave of COVID-19 patients resulted in changes to the flow of HCWs between floors, but the interconnectivity between COVID-19 and non COVID-19 wards was evident throughout the pandemic. Daily rates of indirect contact between patients provided evidence for reactive staff cohorting, whereby indirect contact rates between COVID-19 positive and negative patients were lowest during peaks in COVID-19 hospital admissions. We propose that IPC practitioners use these routinely collected data on HCW behaviour to support infection control activities and to help better protect hospital staff and patients from nosocomial outbreaks of communicable diseases.

Evaluating the effectiveness of rapid SARS-CoV-2 genome sequencing in supporting infection control teams: the COG-UK hospital-onset COVID-19 infection study (preprint)

Introduction Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. Methods We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data-collection period, followed by intervention periods comprising 8 weeks of 'rapid' (<48h) and 4 weeks of 'longer-turnaround' (5-10 day) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital onset COVID-19 infections (HOCIs; detected [≥]48h from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on incidence of probable/definite hospital-acquired infections (HAIs) was evaluated. Results A total of 2170 HOCI cases were recorded from October 2020-April 2021, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (IRR 1.60, 95%CI 0.85-3.01; P=0.14) or rapid (0.85, 0.48-1.50; P=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8% and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2% and 11.6% of cases where the report was returned. In a per-protocol sensitivity analysis there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Conclusion While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days.

A Fast Extraction-Free Isothermal LAMP Assay for Detection of SARS-CoV-2 in Resource-Limited Settings (preprint)

Background To retain the spread of SARS-CoV-2, fast, sensitive and cost-effective testing is essential, particularly in resource limited settings (RLS). Current standard nucleic acid-based RT-PCR assays, although highly sensitive and specific, require transportation of samples to specialised laboratories, trained staff and expensive reagents. The latter are often not readily available in low- and middle-income countries and this may significantly impact on the successful disease management in these settings. Various studies have suggested a SARS-CoV-2 loop mediated isothermal amplification (LAMP) assay as an alternative method to RT-PCR.Methods Four previously published primer pairs were used for detection of SARS-CoV-2 in the LAMP assay. To determine optimal conditions, different temperatures, sample input and incubation times were tested. Ninety-two extracted RNA samples from St. George's Hospital, London, 10 non-extracted nasopharyngeal swab samples from Great Ormond Street Hospital for Children, London, and 92 non-extracted samples from Queen Elisabeth Central Hospital (QECH), Malawi, which have previously been tested for SARS-Cov-2 by qRT-PCR, were analysed in the LAMP assay.Results In this study we report the optimisation of an extraction-free colourimetric SARS-CoV-2 LAMP assay and demonstrated that a lower limit of detection between 10-100 copies/µL of SARS-CoV-2 could be readily detected by a colour change of the reaction within as little as 30min. We further show that this assay could be quickly established in Malawi, as no expensive equipment is necessary. We tested 92 clinical samples from QECH and showed the sensitivity and specificity of the assay to be 98.4% and 86.7%, respectively. Some viral transport media, used routinely to stabilise RNA in clinical samples during transportation, caused a non-specific colour-change in the LAMP reaction and therefore we suggest collecting samples in phosphate buffered saline (which did not affect the colour) as the assay allows immediate sample analysis on-site.Conclusion SARS-CoV-2 LAMP is a cheap and reliable assay that can be readily employed in RLS to improve disease monitoring and management.

Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK. (preprint)

Background and aimsTo determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (ALT and HBV viral load). MethodsWe used anonymised electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK NHS Trusts. ResultsWe report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID years, both in terms of the proportion of patients who had [≥]1 measurement annually, and the mean number of measurements per patient. ConclusionsFurther investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.

Symptom profiles and accuracy of clinical definitions for COVID-19 in the community. Results of the Virus Watch community cohort. (preprint)

Background: Understanding the symptomatology and accuracy of clinical case definitions for COVID-19 in the community is important for the initiation of Test, Trace and Isolate (TTI) and may, in future, be important for early prescription of antivirals. Methods: Virus Watch is a large community cohort with prospective daily recording of a wide range of symptoms and self-reporting of swab results (mainly undertaken through the UK TTI System). We compared frequency, severity, timing, and duration of symptoms in test positive and test negative cases. We compared the test performance of the current UK case definition used by TTI (any one of: new continuous cough, high temperature or loss of or change in sense of smell or taste) with a wider definition that also included muscle aches or chills or headache or loss of appetite. Findings: We included results from 8213 swabbed illnesses, 944 of which tested positive for COVID-19. All symptoms were more common in swab positive than swab negative illnesses and symptoms were also more severe and of longer duration. Common symptoms such as cough, headache, fatigue, muscle aches and loss of appetite occurred early in the course of illness but were also very common in test-negative illnesses. Rarer symptoms such as fever or loss or altered sense of smell or taste were often not present but were markedly more common in swab positive compared to swab negative cases. The current UK definition had a sensitivity and specificity of 81% and 47% respectively for symptomatic COVID-19 compared to 93% and 26% for the broader definition. On average cases met the broader case definition one day earlier than current definition. 1.7-fold more illnesses met the broader definition than the current case definition. Interpretation: COVID-19 is difficult to distinguish from other respiratory infections and common ailments on the basis of symptoms. Broadening the list of symptoms used to encourage engagement with TTI could moderately increase the number of infections identified and shorten delays but with a large increase in the number of tests needed and in the number of people and contacts who do not have COVID-19 but might need to self-isolate whilst awaiting results.

Detection of SARS-CoV-2 infection by saliva and nasopharyngeal sampling in frontline healthcare workers: an observational cohort study. (preprint)

Background The SARS-CoV-2 pandemic has caused an unprecedented strain on healthcare systems worldwide, including the UK National Health Service (NHS). During the first wave of SARS-CoV-2 transmission in UK, SARS-CoV-2 NHS diagnostic test availability was limited to self-isolating symptomatic staff. The burden of symptomatic and asymptomatic infection in healthcare workers (HCW) attending work was unknown. Methods We conducted an observational cohort study of SARS-CoV-2 infection in HCW working in an acute NHS Trust during the first wave of the COVID-19 pandemic, using serial self-collected saliva and nasopharyngeal (NP) samples. We also collected self-assessed symptom profiles and isolation behaviours. We retrospectively compared SARS-CoV-2 detection by RT-PCR from saliva (weekly) and NP swabs (twice weekly) from 85 individuals in this cohort and evaluated the association with symptoms. Findings Over a 12-week period from 30th March 2020, 40% (n=34/85, CI95% 31.3-51.8%) HCWs had evidence of SARS-CoV-2 infection by surveillance NP swab and/or saliva RT-qPCR. Agreement between paired saliva and NP swabs was poor (28.6%, CI95% 13.2-48.7%) with both methods detecting symptomatic and asymptomatic infections. Symptoms were reported by 47.1% (n=40) and self-isolation by 25.9% participants (n=22). Only 41.2% (n=14/34) participants with SARS-CoV-2 infection reported any symptoms within 14 days of the infection. Interpretation HCWs are a potential source of SARS-CoV-2 transmission in hospitals and symptom screening will identify the minority of infections in HCW. Saliva is an easily accessible fluid sample for screening for SARS-CoV-2 infection and in addition to NP swab, facilitated ascertainment of symptomatic and asymptomatic cases in this setting. Combined saliva and NP testing would improve detection of SARS-CoV-2 for surveillance. Better understanding of transmissibility from asymptomatic staff using transmission-based infection precautions, is required to inform policy.

Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains (preprint)

We examined the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.7 that arose in the United Kingdom and spread globally. Antibodies elicited by B.1.1.7 infection exhibited significantly reduced recognition and neutralisation of parental strains or of the South Africa B.1.351 variant, than of the infecting variant. The drop in cross-reactivity was more pronounced following B.1.1.7 than parental strain infection, indicating asymmetric heterotypic immunity induced by SARS-CoV-2 variants.

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases (preprint)

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined 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. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured 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, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

Defining Potential Therapeutic Targets in COVID-19: A Cross-Sectional Analysis of a Single Centre Cohort (preprint)

Background: For a targeted therapeutic strategy to show outcome benefit, there needs to be a strong biological and pathogenic rationale to underpin and direct personalised treatments. Relevant biological disease features and biomarkers identify patients for the correct therapeutic, delivered at an appropriate time, dose and duration for maximal efficacy. We evaluated whether serum levels of a wide range of proposed therapeutic targets in COVID-19 discriminated between patients with mild and severe disease or death.Methods: A search of clinicaltrials.gov identified immunological drug targets in COVID-19. We subsequently conducted an observational study investigating the association of serum biomarkers relating to putative therapeutic biomarkers with illness severity and outcome.Results: A search of clinicaltrials.gov identified 477 randomized trials assessing immunomodulatory therapies, including 168 different therapies against 83 different pathways. We measured levels of ten cytokines/signalling proteins including those related to the most common therapeutic targets (GM-CSF, IFN-α2a, IFN-β, IFN-γ, IL-1β, IL-1ra, IL-6, IL-7, IL-8, TNF-α), immunoglobulin G ( IgG) antibodies directed against either the COVID-19 spike protein (S1) or nucleocapsid protein (N), and neutralization titres of antibodies within the first 5 days of hospital admission in 86 patients, 44 (51%) with mild disease and 42 (49%) with severe disease. Six of the ten cytokine/signalling protein markers measured (IL-6, IL-7, IL-8, interferon- a, interferon- b, IL -1ra ) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable S1 or N IgG antibodies with equivalent levels between groups. Neutralization titres were higher among patients with severe disease.Interpretation: Some therapeutic and prognostic biomarkers may be potentially useful in identifying patients who may benefit from specific immunomodulatory therapies in COVID-19 disease, particularly interleukin-6. It is however noteworthy that absolute values of a number of identified biomarkers were either appropriately elevated or within the normal range. This implies that these immunomodulatory treatments may be of limited benefit.Funding: National Institute for Health Research UCLH Biomedical Research Centre (BRC756/HI/MS/101440) and the UCL Coronavirus Response Fund.Declaration of Interests: MeS reports grants and advisory board fees from NewB, grants from the Defence Science and Technology Laboratory, Critical Pressure, Apollo Therapeutics, advisory board and speaker fees (paid to his institution) from Amormed, Biotest, GE, Baxter, Roche, and Bayer, and honorarium for chairing a data monitoring and safety committee from Shionogi. All other authors have nothing to declare. Ethics Approval Statement: Ethical approval was received from the London-Westminster Research Ethics Committee, the Health Research Authority and Health and Care Research Wales (HCRW) on 2nd July 2020 (REC reference 20/HRA/2505, IRAS ID 284088). The SAFER study protocol was approved by the NHS Health Research Authority (ref 20/SC/0147) on 26 March 2020. Ethical oversight was provided by the South- Central Berkshire Research Ethics Committee.

SARS-CoV-2 recruits a haem metabolite to evade antibody immunity (preprint)

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.

The impact of Spike mutations on SARS-CoV-2 neutralization (preprint)

Multiple SARS-CoV-2 vaccines have shown protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, Spike. Antibodies from SARS-CoV-2 infection neutralize the virus by focused targeting of Spike and there is limited serum cross-neutralization of the closely-related SARS-CoV. As new SARS-CoV-2 variants are rapidly emerging, exemplified by the B.1.1.7, 501Y.V2 and P.1 lineages, it is critical to understand if antibody responses induced by infection with the original SARS-CoV-2 virus or the current vaccines will remain effective against virus variants. In this study we evaluate neutralization of a series of mutated Spike pseudotypes including a B.1.1.7 Spike pseudotype. The analyses of a panel of Spike-specific monoclonal antibodies revealed that the neutralizing activity of some antibodies was dramatically reduced by Spike mutations. In contrast, polyclonal antibodies in the serum of patients infected in early 2020 remained active against most mutated Spike pseudotypes. The majority of serum samples were equally able to neutralize the B.1.1.7 Spike pseudotype, however potency was reduced in a small number of samples (3 of 36) by 5-10-fold. This work highlights that changes in the SARS-CoV-2 Spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their impact on vaccine efficacy.

Risk factors, symptom reporting, healthcare-seeking behaviour and adherence to public health guidance: protocol for Virus Watch, a prospective community cohort study (preprint)

Introduction The Coronavirus (COVID-19) Pandemic has caused significant global mortality and impacted lives around the world. Virus Watch aims to provide evidence on which public health approaches are most likely to be effective in reducing transmission and impact of the virus, and will investigate community incidence, symptom profiles, and transmission of COVID-19 in relation to population movement and behaviours. Methods and analysis Virus Watch is a household community cohort study of acute respiratory infections in England & Wales and will run from June 2020 to August 2021. The study aims to recruit 50,000 people, including 12,500 from minority ethnic backgrounds, for an online survey cohort and monthly antibody testing using home finger prick kits. Nested within this larger study will be a sub-cohort of 10,000 individuals, including 3,000 people from minority ethnic backgrounds. This cohort of 10,000 people will have full blood serology taken between October 2020 and January 2021 and repeat serology between May 2021 and August 2021. Participants will also post self-administered nasal swabs for PCR assays of SARS-CoV-2 and will follow one of three different PCR testing schedules based upon symptoms. Ethics and dissemination This study has been approved by the Hampstead NHS Health Research Authority Ethics Committee. Ethics approval number – 20/HRA/2320. We are monitoring participant queries and using these to refine methodology where necessary, and are providing summaries and policy briefings of our preliminary findings to inform public health action by working through our partnerships with our study advisory group, Public Health England, NHS and Government Scientific Advisory panels. Strengths and limitations of this study Virus Watch is a large national household community cohort study of the occurrence and risk factors for COVID-19 infection that aims to recruit 50,000 people, including 12,500 from minority ethnic backgrounds. Virus Watch is designed to estimate incidence of PCR confirmed COVID-19 in those with respiratory and non-respiratory presentations and the incidence of hospitalisation among PCR confirmed COVID-19 cases. Virus Watch will measure effectiveness and impact of recommended COVID-19 control measures including testing, isolation, social distancing, respiratory and hand hygiene measures on risk of respiratory infection. Only households with a lead householder able to speak English were able to take part in the study up until March 2021. Only households of up to six people were eligible for inclusion and they were also required to have access to an internet connection. These restrictions will limit the generalisability to large or multigenerational households, and those without access to the internet.

Estimating the effectiveness of routine asymptomatic PCR testing at different frequencies for the detection of SARS-CoV-2 infections (preprint)

BackgroundRoutine asymptomatic testing using RT-PCR of people who interact with vulnerable populations, such as medical staff in hospitals or care workers in care homes, has been employed to help prevent outbreaks among vulnerable populations. Although the peak sensitivity of RT-PCR can be high, the probability of detecting an infection will vary throughout the course of an infection. The effectiveness of routine asymptomatic testing will therefore depend on testing frequency and how PCR detection varies over time. MethodsWe fitted a Bayesian statistical model to a dataset of twice weekly PCR tests of UK healthcare workers performed by self-administered nasopharyngeal swab, regardless of symptoms. We jointly estimated times of infection and the probability of a positive PCR test over time following infection, we then compared asymptomatic testing strategies by calculating the probability that a symptomatic infection is detected before symptom onset and the probability that an asymptomatic infection is detected within 7 days of infection. FindingsWe estimated that the probability that the PCR test detected infection peaked at 77% (54 - 88%) 4 days after infection, decreasing to 50% (38 - 65%) by 10 days after infection. Our results suggest a substantially higher probability of detecting infections 1-3 days after infection than previously published estimates. We estimated that testing every other day would detect 57% (33-76%) of symptomatic cases prior to onset and 94% (75-99%) of asymptomatic cases within 7 days if test results were returned within a day. InterpretationOur results suggest that routine asymptomatic testing can enable detection of a high proportion of infected individuals early in their infection, provided that the testing is frequent and the time from testing to notification of results is sufficiently fast. FundingWellcome Trust, National Institute for Health Research (NIHR) Health Protection Research Unit, Medical Research Council (UKRI)

Recognition and Treatment of Severe COVID-19 in Pregnancy: Lessons from a Cohort of 69 Infected Women and an Evidence-Based Guideline (preprint)

Objectives: To determine clinical and laboratory features of pregnant woman with COVID-19 who require respiratory support. To recommend a management strategy that optimises maternal and fetal outcomes. Design: An observational cohort study of 7000 maternities between 1st March and 1st July 2020. Setting: Five maternity centres across a maternal medicine network in north-central London, UK Population: 69 pregnant women with confirmed acute SARS-COV2 Methods: Review of electronic healthcare records Main Outcome Measures: Clinical and laboratory features, maternal and fetal outcomes. Results: Respiratory support was needed by 15/69 . This cohort was more likely to present with dyspnoea (10/15 vs 10/54, p<0.001), a lower lymphocyte count (0.90.1 vs 1.40.1 x 109 cells/L; p<0.01) and hypokalaemia (3.80.1 vs 4.00.1 mmol/l, p<0.05). Radiological evidence of lung consolidation did not identify women in need of respiratory support. Women on respiratory support underwent childbirth at an earlier gestation than those who did not (36+4 vs 39+5 weeks, p<0.001), and required emergency c-section (6/15 vs 8/54, p<0.05). Childbirth did not improve respiratory function in those with severe disease, with 3 women remaining on invasive ventilation despite childbirth. Conclusions: Routine clinical data can identify pregnant women at risk of severe COVID-19. Pregnant women should be offered the same treatment as non-pregnant patients but iatrogenic childbirth should not be the default for women with severe disease. We propose a management pathway for pregnant women with severe COVID-19.

Laboratory biomarkers associated with COVID-19 severity and management. (preprint)

The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p[≤]0.001). IL-6 levels of [≥]3.27pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of [≥]37mg/L of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, resource management and potentially the initiation of novel therapies in severe patients.

Standard operating procedures for SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay (preprint)

The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 40,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated standard operating procedure (SOP) for high-throughput SARS- CoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive.