Genome-wide Association Study of Long COVID (preprint)

Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

Immune phenotypes that predict COVID-19 severity (preprint)

Severe COVID-19 causes profound immune perturbations, but pre-infection immune signatures contributing to severe COVID-19 remain unknown. Genome-wide association studies (GWAS) identified strong associations between severe disease and several chemokine receptors and molecules from the type I interferon pathway. Here, we define immune signatures associated with severe COVID-19 using high-dimensional flow cytometry. We measured the peripheral immune system from individuals who recovered from mild, moderate, severe or critical COVID-19 and focused only on those immune signatures returning to steady-state. Individuals that suffered from severe COVID-19 showed reduced frequencies of T cell, MAIT cell and dendritic cell (DCs) subsets and altered chemokine receptor expression on several subsets, such as reduced levels of CCR1 and CCR2 on monocyte subsets. Furthermore, we found reduced frequencies of type I interferon-producing plasmacytoid DCs and altered IFNAR2 expression on several myeloid cells in individuals recovered from severe COVID-19. Thus, these data identify potential immune mechanisms contributing to severe COVID-19.

Vaccine after Effects and Post-Vaccine Infection in a Real World Setting: Results from the COVID Symptom Study App (preprint)

Background: The Pfizer-BioNTech (BNT162b2) and the Oxford/AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in Phase III trials. Here we report results from a real world setting on the two most administered vaccines in the UK.Methods: We investigated self-reported systemic and local effects within eight days of vaccination in 387,471 individuals from the COVID Symptom Study app who received one (n=209,251) or two (n=13,478) doses of the BNT162b2 vaccine, or one dose of ChAdOx1 nCoV-19 vaccine (n=178,220) between December 8 and February 15 2021. A subset of individuals subsequently tested for SARS-CoV-2 were studied for infection rates from PCR or lateral flow test results post-vaccination (59,639 vaccinated vs 277,599 controls).Findings: Systemic side effects were reported in 11.8% of participants after the first BNT162b2 dose, 20.3% after the second BNT162b2 dose, and 29.4% after the first ChAdOx1 nCoV-19 dose. Systemic effects were more prevalent among individuals with pre-existing COVID-19 infection (BNT162b2:34.1%; ChAdOx1 nCoV-19:51.6%) than among individuals without known prior infection (BNT162b2:10.6%; ChAdOx1 nCoV-19:28.6%) and among those aged <55 years (BNT162b2:19.9%; ChAdOx1 nCoV-19:45.3%) compared to those aged >55 years (BNT162b2:9.2%, ChAdOx1 nCoV-19: 26.9%). We observed significant reduction in infection risk 12-21 days after the first dose (BNT162b2:-57% [-71%, -38%], ChAdOx1 nCoV-19:-42% [-71%, -17%]). Interpretation: This phase IV-type study assessing both BNT162b2 and ChAdOx1 nCoV-19 vaccines identifies mild systemic side effects affecting 11-30% of individuals post-vaccination, lower than in published Phase III trials. Our data on infection post-vaccine were also reassuring.Funding: Zoe, NIHR, CDRF, NIH, MRCDeclaration of Interests: TDS and AMV are consultants to Zoe Global Ltd (“Zoe”). JW, AM, LP and JC are employees of Zoe Global Limited. ALG is a regional PI on the COV002 trial and the Novavax COVID-19 vaccine trial and as such her organisation has received grants from Novavax. Other authors have no conflict of interest to declare.Ethics Approval Statement: Ethical approval for use of the app for research purposes in the UK was obtained from King’s College London Ethics Committee (review reference LRS-19/20-18210), and all users provided consent for non-commercial use.

Delirium is a presenting symptom of COVID-19 in frail, older adults: a cohort study of 322 hospitalised and 535 community-based older adults (preprint)

BackgroundFrailty, increased vulnerability to physiological stressors, is associated with adverse outcomes. COVID-19 exhibits a more severe disease course in older, co-morbid adults. Awareness of atypical presentations is critical to facilitate early identification. ObjectiveTo assess how frailty affects presenting COVID-19 symptoms in older adults. DesignObservational cohort study of hospitalised older patients and self-report data for community-based older adults. SettingAdmissions to St Thomas Hospital, London with laboratory-confirmed COVID-19. Community-based data for 535 older adults using the COVID Symptom Study mobile application. SubjectsHospital cohort: patients aged 65 and over (n=322); unscheduled hospital admission between March 1st, 2020-May 5th, 2020; COVID-19 confirmed by RT-PCR of nasopharyngeal swab. Community-based cohort: participants aged 65 and over enrolled in the COVID Symptom Study (n=535); reported test-positive for COVID-19 from March 24th (application launch)-May 8th, 2020. MethodsMultivariate logistic regression analysis performed on age-matched samples from hospital and community-based cohorts to ascertain association of frailty with symptoms of confirmed COVID-19. ResultsHospital cohort: significantly higher prevalence of delirium in the frail sample, with no difference in fever or cough. Community-based cohort :significantly higher prevalence of probable delirium in frailer, older adults, and fatigue and shortness of breath. ConclusionsThis is the first study demonstrating higher prevalence of delirium as a COVID-19 symptom in older adults with frailty compared to other older adults. This emphasises need for systematic frailty assessment and screening for delirium in acutely ill older patients in hospital and community settings. Clinicians should suspect COVID-19 in frail adults with delirium.

Self-reported symptoms of covid-19 including symptoms most predictive of SARS-CoV-2 infection, are heritable (preprint)

Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n=2633) completing the C-19 Covid symptom tracker app allowed classical twin studies of covid-19 symptoms including predicted covid-19, a symptom-based algorithm predicting true infection derived in app users tested for SARS-CoV-2. We found heritability for fever = 41 (95% confidence intervals 12-70)%; anosmia 47 (27-67)%; delirium 49 (24-75)%; and predicted covid-19 gave heritability = 50 (29-70)%.

Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection (preprint)

ImportanceA strategy for preventing further spread of the ongoing COVID-19 epidemic is to detect infections and isolate infected individuals without the need of extensive bio-specimen testing. ObjectivesHere we investigate the prevalence of loss of smell and taste among COVID-19 diagnosed individuals and we identify the combination of symptoms, besides loss of smell and taste, most likely to correspond to a positive COVID-19 diagnosis in non-severe cases. DesignCommunity survey. Setting and ParticipantsSubscribers of RADAR COVID-19, an app that was launched for use among the UK general population asking about COVID-19 symptoms. Main ExposureLoss of smell and taste. Main Outcome MeasuresCOVID-19. ResultsBetween 24 and 29 March 2020, 1,573,103 individuals reported their symptoms via the app; 26% reported suffering from one or more symptoms of COVID-19. Of those, n=1702 reported having had a RT-PCR COVID-19 test and gave full report on symptoms including loss of smell and taste; 579 were positive and 1123 negative. In this subset, we find that loss of smell and taste were present in 59% of COVID-19 positive individuals compared to 18% of those negative to the test, yielding an odds ratio (OR) of COVID-19 diagnosis of OR[95%CI]=6.59[5.25; 8.27], P= 1.90x10-59. We also find that a combination of loss of smell and taste, fever, persistent cough, fatigue, diarrhoea, abdominal pain and loss of appetite is predictive of COVID-19 positive test with sensitivity 0.54[0.44; 0.63], specificity 0.86[0.80; 0.90], ROC-AUC 0.77[0.72; 0.82] in the test set, and cross-validation ROC-AUC 0.75[0.72; 0.77]. When applied to the 410,598 individuals reporting symptoms but not formally tested, our model predicted that 13.06%[12.97%;13.15] of these might have been already infected by the virus. Conclusions and RelevanceOur study suggests that loss of taste and smell is a strong predictor of having been infected by the COVID-19 virus. Also, the combination of symptoms that could be used to identify and isolate individuals includes anosmia, fever, persistent cough, diarrhoea, fatigue, abdominal pain and loss of appetite. This is particularly relevant to healthcare and other key workers in constant contact with the public who have not yet been tested for COVID-19. Key pointsO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIThe spread of COVID-19 can be reduced by identifying and isolating infected individuals but it is not possible to test everyone and priority has been given in most countries to individuals presenting symptoms of the disease. C_LIO_LICOVID-19 symptoms, such as fever, cough, aches, fatigue are common in many other viral infections C_LIO_LIThere is therefore a need to identify symptom combinations that can rightly pinpoint to infected individuals C_LI What this study addsO_LIAmong individuals showing symptoms severe enough to be given a COVID-19 RT-PCR test in the UK the prevalence of loss of smell (anosmia) was 3-fold higher (59%) in those positive to the test than among those negative to the test (18%). C_LIO_LIWe developed a mathematical model combining symptoms to predict individuals likely to be COVID-19 positive and applied this to over 400,000 individuals in the general population presenting some of the COVID-19 symptoms. C_LIO_LIWe find that [~]13% of those presenting symptoms are likely to have or have had a COVID-19 infection. The proportion was slightly higher in women than in men but is comparable in all age groups, and corresponds to 3.4% of those who filled the app report. C_LI