Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study (preprint)

Background: Men and older women have been shown to be at higher risk of adverse COVID-19 outcomes. Animal model studies of SARS-CoV and MERS suggest that the age and sex difference in COVID-19 symptom severity may be due to a protective effect of the female sex hormone estrogen. Females have shown an ability to mount a stronger immune response to a variety of viral infections because of more robust humoral and cellular immune responses. Objectives: We sought to determine whether COVID-19 positivity increases in women entering menopause. We also aimed to identify whether premenopausal women taking exogenous hormones in the form of the combined oral contraceptive pill (COCP) and post-menopausal women taking hormone replacement therapy (HRT) have lower predicted rates of COVID-19, using our published symptom-based model. Design: The COVID Symptom Study developed by Kings College London and Zoe Global Limited was launched in the UK on 24th March 2020. It captured self-reported information related to COVID-19 symptoms. Data used for this study included records collected between 7th May - 15th June 2020. Main outcome measures: We investigated links between COVID-19 rates and 1) menopausal status, 2) COCP use and 3) HRT use, using symptom-based predicted COVID-19, tested COVID-19, and disease severity based on requirement for hospital attendance or respiratory support. Participants: Female users of the COVID Symptom Tracker Application in the UK, including 152,637 women for menopause status, 295,689 for COCP use, and 151,193 for HRT use. Analyses were adjusted for age, smoking and BMI. Results: Post-menopausal women aged 40-60 years had a higher rate of predicted COVID (P=0.003) and a corresponding range of symptoms, with consistent, but not significant trends observed for tested COVID-19 and disease severity. Women aged 18-45 years taking COCP had a significantly lower predicted COVID-19 (P=8.03E-05), with a reduction in hospital attendance (P=0.023). Post-menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P=2.22E-05) for HRT users alone. Conclusions: Our findings support a protective effect of estrogen on COVID-19, based on positive association between predicted COVID-19 and menopausal status, and a negative association with COCP use. HRT use was positively associated with COVID-19 symptoms; however, the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential comorbidities. Trial registration: The App Ethics has been approved by KCL ethics Committee REMAS ID 18210, review reference LRS-19/20-18210

Racial and ethnic determinants of Covid-19 risk (preprint)

BackgroundRacial and ethnic minorities have disproportionately high hospitalization rates and mortality related to the novel coronavirus disease 2019 (Covid-19). There are comparatively scant data on race and ethnicity as determinants of infection risk. MethodsWe used a smartphone application (beginning March 24, 2020 in the United Kingdom [U.K.] and March 29, 2020 in the United States [U.S.]) to recruit 2,414,601 participants who reported their race/ethnicity through May 25, 2020 and employed logistic regression to determine the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for a positive Covid-19 test among racial and ethnic groups. ResultsWe documented 8,858 self-reported cases of Covid-19 among 2,259,841 non-Hispanic white; 79 among 9,615 Hispanic; 186 among 18,176 Black; 598 among 63,316 Asian; and 347 among 63,653 other racial minority participants. Compared with non-Hispanic white participants, the risk for a positive Covid-19 test was increased across racial minorities (aORs ranging from 1.24 to 3.51). After adjustment for socioeconomic indices and Covid-19 exposure risk factors, the associations (aOR [95% CI]) were attenuated but remained significant for Hispanic (1.58 [1.24-2.02]) and Black participants (2.56 [1.93-3.39]) in the U.S. and South Asian (1.52 [1.38-1.67]) and Middle Eastern participants (1.56 [1.25-1.95]) in the U.K. A higher risk of Covid-19 and seeking or receiving treatment was also observed for several racial/ethnic minority subgroups. ConclusionsOur results demonstrate an increase in Covid-19 risk among racial and ethnic minorities not completely explained by other risk factors for Covid-19, comorbidities, and sociodemographic characteristics. Further research investigating these disparities are needed to inform public health measures.

Cancer and risk of COVID-19 through a general community survey (preprint)

Background: Data are limited on the risk of coronavirus disease 2019 (COVID-19) among individuals with cancer and whether cancer-related therapy exacerbates this risk. Methods: We evaluated the risk for coronavirus disease 2019 (COVID-19) among patients living with cancer compared to the general community and whether cancer-related treatments influence this risk. Data were collected from the COVID Symptom Study smartphone application since March 24, 2020 (United Kingdom), March 29 (U.S.), and April 29, 2020 (Sweden) through May 8, 2020. We used multivariate-adjusted odds ratios (aORs) of a positive COVID-19 test as well as predicted COVID-19 infection using a validated symptom model. Results: Among 23,266 participants with cancer and 1,784,293 without cancer, we documented 10,404 reports of a positive COVID-19 test. Compared to participants without cancer, those living with cancer had 62% increased risk of a positive COVID-19 test (95% CI: 1.37-1.91). Among patients with cancer, current treatment with chemotherapy/immunotherapy was associated with a nearly 2.5-fold increased risk of a positive test (aOR: 2.42; 95% CI: 1.81-3.25). The association between cancer and COVID-19+ was stronger among participants >65 years (aOR: 1.93; 95%CI: 1.51-2.46) compared to younger participants (aOR: 1.32; 95%CI: 1.06-1.64; Pinteraction<0.001); and among males (aOR: 1.71; 95%CI: 1.36-2.15) compared to females (aOR: 1.43; 95%CI: 1.14-1.79; Pinteraction=0.02). Conclusions: Individuals with cancer had a significantly increased risk of infection compared to the general community. Those treated with chemotherapy or immunotherapy were particularly at-risk of infection. Trial Registration: ClinicalTrials.gov NCT04331509

Risk of symptomatic Covid-19 among frontline healthcare workers (preprint)

BackgroundData for frontline healthcare workers (HCWs) and risk of SARS-CoV-2 infection are limited and whether personal protective equipment (PPE) mitigates this risk is unknown. We evaluated risk for COVID-19 among frontline HCWs compared to the general community and the influence of PPE. MethodsWe performed a prospective cohort study of the general community, including frontline HCWs, who reported information through the COVID Symptom Study smartphone application beginning on March 24 (United Kingdom, U.K.) and March 29 (United States, U.S.) through April 23, 2020. We used Cox proportional hazards modeling to estimate multivariate-adjusted hazard ratios (aHRs) of a positive COVID-19 test. FindingsAmong 2,035,395 community individuals and 99,795 frontline HCWs, we documented 5,545 incident reports of a positive COVID-19 test over 34,435,272 person-days. Compared with the general community, frontline HCWs had an aHR of 11{middle dot}6 (95% CI: 10{middle dot}9 to 12{middle dot}3) for reporting a positive test. The corresponding aHR was 3{middle dot}40 (95% CI: 3{middle dot}37 to 3{middle dot}43) using an inverse probability weighted Cox model adjusting for the likelihood of receiving a test. A symptom-based classifier of predicted COVID-19 yielded similar risk estimates. Compared with HCWs reporting adequate PPE, the aHRs for reporting a positive test were 1{middle dot}46 (95% CI: 1{middle dot}21 to 1{middle dot}76) for those reporting PPE reuse and 1{middle dot}31 (95% CI: 1{middle dot}10 to 1{middle dot}56) for reporting inadequate PPE. Compared with HCWs reporting adequate PPE who did not care for COVID-19 patients, HCWs caring for patients with documented COVID-19 had aHRs for a positive test of 4{middle dot}83 (95% CI: 3{middle dot}99 to 5{middle dot}85) if they had adequate PPE, 5{middle dot}06 (95% CI: 3{middle dot}90 to 6{middle dot}57) for reused PPE, and 5{middle dot}91 (95% CI: 4{middle dot}53 to 7{middle dot}71) for inadequate PPE. InterpretationFrontline HCWs had a significantly increased risk of COVID-19 infection, highest among HCWs who reused PPE or had inadequate access to PPE. However, adequate supplies of PPE did not completely mitigate high-risk exposures. FundingZoe Global Ltd., Wellcome Trust, EPSRC, NIHR, UK Research and Innovation, Alzheimers Society, NIH, NIOSH, Massachusetts Consortium on Pathogen Readiness RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSThe prolonged course of the coronavirus disease 2019 (COVID-19) pandemic, coupled with sustained challenges supplying adequate personal protective equipment (PPE) for frontline healthcare workers (HCW), have strained global healthcare systems in an unprecedented fashion. Despite growing awareness of this problem, there are few data to inform policy makers on the risk of COVID-19 among HCWs and the impact of PPE on their disease burden. Prior reports of HCW infections are based on cross sectional data with limited individual-level information on risk factors for infection. A PubMed search for articles published between January 1, 2020 and May 5, 2020 using the terms "covid-19", "healthcare workers", and "personal protective equipment," yielded no population-scale investigations exploring this topic. Added value of this studyIn a prospective study of 2,135,190 individuals, frontline HCWs may have up to a 12-fold increased risk of reporting a positive COVID-19 test. Compared with those who reported adequate availability of PPE, frontline HCWs with inadequate PPE had a 31% increase in risk. However, adequate availability of PPE did not completely reduce risk among HCWs caring for COVID-19 patients. Implications of all the available evidenceBeyond ensuring adequate availability of PPE, additional efforts to protect HCWs from COVID-19 are needed, particularly as lockdown is lifted in many regions of the world.

Key predictors of attending hospital with COVID19: An association study from the COVID Symptom Tracker App in 2,618,948 individuals (preprint)

Objectives: We aimed to identify key demographic risk factors for hospital attendance with COVID-19 infection. Design: Community survey Setting: The COVID Symptom Tracker mobile application co-developed by physicians and scientists at Kings College London, Massachusetts General Hospital, Boston and Zoe Global Limited was launched in the UK and US on 24th and 29th March 2020 respectively. It captured self-reported information related to COVID-19 symptoms and testing. Participants: 2,618,948 users of the COVID Symptom Tracker App. UK (95.7%) and US (4.3%) population. Data cut-off for this analysis was 21st April 2020. Main outcome measures: Visit to hospital and for those who attended hospital, the need for respiratory support in three subgroups (i) self-reported COVID-19 infection with classical symptoms (SR-COVID-19), (ii) self-reported positive COVID-19 test results (T-COVID-19), and (iii) imputed/predicted COVID-19 infection based on symptomatology (I-COVID-19). Multivariate logistic regressions for each outcome and each subgroup were adjusted for age and gender, with sensitivity analyses adjusted for comorbidities. Classical symptoms were defined as high fever and persistent cough for several days. Results: Older age and all comorbidities tested were found to be associated with increased odds of requiring hospital care for COVID-19. Obesity (BMI >30) predicted hospital care in all models, with odds ratios (OR) varying from 1.20 [1.11; 1.31] to 1.40 [1.23; 1.60] across population groups. Pre-existing lung disease and diabetes were consistently found to be associated with hospital visit with a maximum OR of 1.79 [1.64,1.95] and 1.72 [1.27; 2.31]) respectively. Findings were similar when assessing the need for respiratory support, for which age and male gender played an additional role. Conclusions: Being older, obese, diabetic or suffering from pre-existing lung, heart or renal disease placed participants at increased risk of visiting hospital with COVID-19. It is of utmost importance for governments and the scientific and medical communities to work together to find evidence-based means of protecting those deemed most vulnerable from COVID-19. Trial registration: The App Ethics have been approved by KCL ethics Committee REMAS ID 18210, review reference LRS-19/20-18210

Detecting SARS-CoV-2 at point of care: Preliminary data comparing Loop-mediated isothermal amplification (LAMP) to PCR (preprint)

Background: The need for a fast and reliable test for COVID-19 is paramount in managing the current pandemic. A cost effective and efficient diagnostic tool as near to the point of care (PoC) as possible would be a game changer in current testing. We tested reverse transcription loop mediated isothermal amplification (RT-LAMP), a method which can produce results in under 30 minutes, alongside standard methods in a real-life clinical setting. Methods: This service improvement project piloted a research RT-LAMP method on nasal and pharyngeal swabs on 21 residents in an NHS Category 1 care home, with two index COVID-19 cases, and compared it to multiplex tandem reverse transcription polymerase chain reaction (RT-PCR). We calculated the sensitivity, specificity, positive and negative predictive values of a single RT-LAMP swab compared to RT-PCR, as per STARD guidelines. We also recorded vital signs of patients to correlate clinical and laboratory information. Findings: The novel method accurately detected 8/10 PCR positive cases and identified a further 3 positive cases. Eight further cases were negative using both methods. Using repeated RT-PCR as a 'gold standard', the sensitivity and specificity of the novel test were 80% and 73% respectively. Positive predictive value (PPV) was 73% and negative predictive value (NPV) was 83%. We also observed hypothermia to be a significant early clinical sign in a number of COVID-19 patients in this setting. Interpretation: RT-LAMP testing for SARS-CoV-2 was found to be promising, fast, easy to use and to work equivalently to RT-PCR methods. Definitive studies to evaluate this method in larger cohorts are underway. RT-LAMP has the potential to transform COVID-19 detection, bringing rapid and accurate testing to the point of care. This method could be deployed in mobile testing units in the community, care homes and hospitals to detect disease early and prevent spread.