SARS-CoV-2 and COVID-19

This wiki is intended for healthcare professionals and should not be considered medical advice.

General
BMJ Best Practice: COVID-19 - expert advice contributions by Nick Beeching from Liverpool School of Hygiene and Tropical Medicine, Tom Fletcher and Robert Fowler : includes criteria/case definitions and treatment algorithm

This page by Nature curates key new research relevant to COVID-19

COVID-19 NICE guidelines and resources hub

Oxford Medicine Online - Coronavirus resources

Cennimo DJ, Bergman SJ and Olsen KM. (Updated 14 Jan 2021 when accessed 19 Jan) Coronavirus Disease 2019 (COVID-19). Medscape (website). Log-in required but free registration.

UK and Global Statistics
Office of National Statistics

UK Government - GOV.UK

Worldometers.info - Global

Coronavirus World Map: Tracking the Global Outbreak - The New York Times - Global

Prevention and Public Health
Haug, N., Geyrhofer, L., Londei, A. et al. Ranking the effectiveness of worldwide COVID-19 government interventions. Nat Hum Behav 4, 1303–1312 (2020). https://doi.org/10.1038/s41562-020-01009-0 Note the findings in Fig. 1

Auger KA, Shah SS, Richardson T, et al. Association Between Statewide School Closure and COVID-19 Incidence and Mortality in the US. JAMA. 2020;324(9):859–870. doi:10.1001/jama.2020.14348

van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17;382(16):1564–7.
 * Aerosol - up to 3 hours
 * Copper - 4 hours
 * Cardboard - 24 hours
 * Plastics, stainless steel - 72 hrs

Chan NC, Li K, Hirsh J. Peripheral Oxygen Saturation in Older Persons Wearing Nonmedical Face Masks in Community Settings. JAMA. 2020;324(22):2323–2324. doi:10.1001/jama.2020.21905

Stephen A. Lauer, Kyra H. Grantz, Qifang Bi, et al. TThe Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med.2020;172:577-582. [Epub ahead of print 10 March 2020]. doi:10.7326/M20-0504

Chu, Derek KChu, Derek K et al. (Jun 2020) Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis The Lancet, Volume 395, Issue 10242, 1973 - 1987

Contact tracing
John Hopkins online coursera course - COVID-19 Contact Tracing

PPE
CDC PPE FAQs

WHO - Personal protective equipment for COVID-19

BOHS, The Chartered Society for Worker Health Protection BOHS – Covid-19: Occupation Risk Rating and Control Options According to Exposure Rank July 2020

Transmission Dynamics
Cheng H, Jian S, Liu D, et al. (May 2020) Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset. JAMA Intern Med. 2020;180(9):1156–1163. doi:10.1001/jamainternmed.2020.2020

Shen Y, Li C, Dong H, et al. Community Outbreak Investigation of SARS-CoV-2 Transmission Among Bus Riders in Eastern China. JAMA Intern Med. 2020;180(12):1665–1671. doi:10.1001/jamainternmed.2020.5225

Pombal R, Hosegood I, Powell D. [https://jamanetwork.com/journals/jama/fullarticle/2771435. Risk of COVID-19 During Air Travel.] JAMA. 2020;324(17):1798. doi:10.1001/jama.2020.19108

Grijalva CG, Rolfes MA, Zhu Y, et al. Transmission of SARS-COV-2 Infections in Households — Tennessee and Wisconsin, April–September 2020. MMWR Morb Mortal Wkly Rep 2020;69:1631–1634. DOI: http://dx.doi.org/10.15585/mmwr.mm6944e1

Lee S, Kim T, Lee E, et al. Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea. JAMA Intern Med. 2020;180(11):1447–1452. doi:10.1001/jamainternmed.2020.3862

Tang JW, Bahnfleth WP, Bluyssen PM et al. Dismantling myths on the airborne transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Journal of Hospital Infection 110 (2021) 89-96 doi: https://doi.org/10.1016/j.jhin.2020.12.022 Summary The coronavirus disease 2019 (COVID-19) pandemic has caused untold disruption throughout the world. Understanding the mechanisms for transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is key to preventing further spread, but there is confusion over the meaning of ‘airborne’ whenever transmission is discussed. Scientific ambivalence originates from evidence published many years ago which has generated mythological beliefs that obscure current thinking. This article collates and explores some of the most commonly held dogmas on airborne transmission in order to stimulate revision of the science in the light of current evidence. Six ‘myths’ are presented, explained and ultimately refuted on the basis of recently published papers and expert opinion from previous work related to similar viruses. There is little doubt that SARS-CoV-2 is transmitted via a range of airborne particle sizes subject to all the usual ventilation parameters and human behaviour. Experts from specialties encompassing aerosol studies, ventilation, engineering, physics, virology and clinical medicine have joined together to produce this review to consolidate the evidence for airborne transmission mechanisms, and offer justification for modern strategies for prevention and control of COVID-19 in health care and the community.

Education Tools
MARIANO ZAFRA, JAVIER SALAS.(29 October 2020) A room, a bar and a classroom: how the coronavirus is spread through the air 2EDICIONES EL PAÍS S.L.
 * This is an article aimed at general public with animations (scroll up and down) showing how aerosol and/or droplet transmission works depending on masks, ventilation, speech etc.

Herd Immunity
Omer SB, Yildirim I, Forman HP. Herd Immunity and Implications for SARS-CoV-2 Control. JAMA. 2020;324(20):2095–2096. doi:10.1001/jama.2020.20892

Aschwanden, C. (Oct 2020) The false promise of herd immunity for COVID-19. Nature News Feature. Nature 587, 26-28 (2020). doi: https://doi.org/10.1038/d41586-020-02948-4

Tobias S. Brett, Pejman Rohani (Oct 2020) Transmission dynamics reveal the impracticality of COVID-19 herd immunity strategies Proceedings of the National Academy of Sciences Oct 2020, 117 (41) 25897-25903; DOI: 10.1073/pnas.2008087117

Presentation and pathophysiology
Kumar R, Lee MH, Mickael C, et al. (Oct 2020) Pathophysiology and potential future therapeutic targets using preclinical models of COVID-19. ERJ Open Res. 2020;6(4):00405-2020. Published 2020 Dec 7. doi:10.1183/23120541.00405-2020

Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. van de Veerdonk FL, van der Meer JW, van de Veerdonk FL, Little R, editors. eLife. 2020 Jul 7;9:e59177.

Symptoms
COVID Symptom Study (17 July 2020) The COVID Symptom Study reveals six distinct ‘types’ of COVID-19. COVID Symptom Study/ZOE/KCL

Sudre C. H. et al. (16 June 2020) Symptom clusters in Covid19: A potential clinical prediction tool from the COVID Symptom study app. MedRxivdoi:https://doi.org/10.1101/2020.06.12.20129056

Dermatology
Galván Casas, C. et al. (29 April 2020) Classification of the cutaneous manifestations of COVID‐19: a rapid prospective nationwide consensus study in Spain with 375 cases. British Journal of Dermatology 2020;183pg.71-77 doi: https://doi.org/10.1111/bjd.19163

Cardiovascular
Maccio U, Zinkernagel AS, Shambat SM, et al. (7 Jan 2021) SARS-CoV-2 leads to a small vessel endotheliitis in the heart EBioMedicine. 2021;63:103182. doi:10.1016/j.ebiom.2020.103182

Findings COVID-19 positive patients showed strong ACE2 / TMPRSS2 expression in capillaries and less in arterioles/venules. The main coronary arteries were virtually devoid of ACE2 receptor and had only mild intimal inflammation. Epicardial capillaries had a prominent lympho-monocytic endotheliitis, which was less pronounced in arterioles/venules. The lymphocytic-monocytic infiltrate strongly expressed CD4, CD45, CD68. Peri/epicardial nerves had strong ACE2 expression and lympho-monocytic inflammation. COVID-19 negative patients showed minimal vascular ACE2 expression and lacked endotheliitis or inflammatory reaction.

Interpretation ACE2 / TMPRSS2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically towards the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries. The inflammatory neuropathy of epicardial nerves in COVID-19 disease provides further evidence of an angio- and neurotrophic affinity of SARS-COV2 and might potentially contribute to the understanding of the high prevalence of cardiac complications such as myocardial injury and arrhythmias in COVID-19.

Varga, Zsuzsanna et al.(20 April 2020) Endothelial cell infection and endotheliitis in COVID-19 The Lancet, Volume 395, Issue 10234, 1417 - 1418 DOI: https://doi.org/10.1016/S0140-6736(20)30937-5

Ratchford SM, Stickford JL, Province VM, et al. Vascular alterations among young adults with SARS-CoV-2 Am J Physiol Heart Circ Physiol. 2021;320(1):H404-H410. doi:10.1152/ajpheart.00897.2020

Abstract [...] This study was the first to investigate the vascular implications of contracting SARS-CoV-2 among young, otherwise healthy adults. Using a cross-sectional design, this study assessed vascular function 3–4 wk after young adults tested positive for SARS-CoV-2. The main findings from this study were a strikingly lower vascular function and a higher arterial stiffness compared with healthy controls. Together, these results suggest rampant vascular effects seen weeks after contracting SARS-CoV-2 in young adults.

Sharon E. Fox, Fernanda S. Lameira, Elizabeth B. Rinker, et al. Cardiac Endotheliitis and Multisystem Inflammatory Syndrome After COVID-19 Ann Intern Med.2020;173:1025-1027. (Epub ahead of print 29 July 2020). doi:10.7326/L20-0882

Background: Endotheliitis and microangiopathy have been identified as key features of the pathophysiology of severe coronavirus disease 2019 (COVID-19). In addition, a multisystem inflammatory syndrome (MIS) similar to Kawasaki disease has been increasingly reported in association with COVID-19 in children and young adults. Although vascular damage seems to be a component of both of these presentations, the pathologic features of MIS remain elusive.

Objective: To provide what we believe to be the first report on the pathologic findings of vasculitis of the small vessels of the heart, which likely represents MIS, leading to death in a young adult after presumed resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Discussion: [...] Our report highlights the potential for serious complications due to endothelial damage and describes potential pathologic characteristics of MIS after COVID-19, a possible mimicker of true myocarditis. Careful monitoring of laboratory markers of inflammation, as well as therapeutic intervention to target this inflammatory process, may improve patient outcomes.

Neurology
Yang, A.C., Kern, F., Losada, P.M. et al. (21 June 2021) Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 595, 565–571 (2021). https://doi.org/10.1038/s41586-021-03710-0 "'Abstract: Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1,2,3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease4,5,6. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans7 and linked to cognitive function8—is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.'"

Gwenaëlle Douaud et al. Brain imaging before and after COVID-19 in UK Biobank [pre-print] (15 June 2021) medRxiv 2021.06.11.21258690; doi: https://doi.org/10.1101/2021.06.11.21258690

"Z"

Thakur KT, Miller EH, Glendinning MD et al. (25 April 2021) COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital Brain, 2021;, awab148, https://doi.org/10.1093/brain/awab148

Conclusion 1. In our single center study of 41 consecutive autopsies of COVID-19 patients we found significant neuropathology in all brains, most commonly diffuse hypoxic/ischemic damage, acute and subacute infarcts, both large and small, the latter often with a hemorrhagic component, and diffuse and focal microglial activation, including neuronophagia, predominantly localized to the brainstem. There was sparse T cell infiltration and no evidence for acute vascular wall damage. qRT-PCR on multiple frozen brain tissues of many brains showed low or absent levels of viral RNA. RNAscope and immunohistochemistry for S and N proteins were negative. Although we cannot conclusively rule out the presence of viral RNA and protein in these brains, we conclude that it is unlikely that viral infection of brain tissue directly accounts for the pathological changes.

2. Our predominantly elder, Hispanic population had multiple comorbidities including those only identified in the postmortem period. Patients died in a range of time periods, with prolonged hospital courses associated with a significant number of hospital related complications. ''Notably, neuropathological findings did not appear to correlate with time of hospitalization, further suggesting that pathology was not closely correlated with hospital interventions like medications or mechanical ventilation.''

Immunology
Ramos-Casals, M., Brito-Zerón, P. & Mariette, X. Systemic and organ-specific immune-related manifestations of COVID-19 Nat Rev Rheumatol (2021). https://doi.org/10.1038/s41584-021-00608-z Abstract

Immune-related manifestations are increasingly recognized conditions in patients with COVID-19, with around 3,000 cases reported worldwide comprising more than 70 different systemic and organ-specific disorders. Although the inflammation caused by SARS-CoV-2 infection is predominantly centred on the respiratory system, some patients can develop an abnormal inflammatory reaction involving extrapulmonary tissues. The signs and symptoms associated with this excessive immune response are very diverse and can resemble some autoimmune or inflammatory diseases, with the clinical phenotype that is seemingly influenced by epidemiological factors such as age, sex or ethnicity. The severity of the manifestations is also very varied, ranging from benign and self-limiting features to life-threatening systemic syndromes. Little is known about the pathogenesis of these manifestations, and some tend to emerge within the first 2 weeks of SARS-CoV-2 infection, whereas others tend to appear in a late post-infectious stage or even in asymptomatic patients. As the body of evidence comprises predominantly case series and uncontrolled studies, diagnostic and therapeutic decision-making is unsurprisingly often based on the scarcely reported experience and expert opinion. Additional studies are required to learn about the mechanisms involved in the development of these manifestations and apply that knowledge to achieve early diagnosis and the most suitable therapy.

Song, E. Bartley, MC. Chow, RD et al Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms Cell Reports Medicine, April 27, 2021 DOI: https://doi.org/10.1016/j.xcrm.2021.100288

Highlights Summary Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.
 * Immune cell scRNA-seq showed divergent T cell activation in the CNS during COVID-19
 * Individuals with COVID-19 had a compartmentalized cytokine response in the CNS
 * All individuals with COVID-19 had anti-SARS-CoV-2 antibodies in their CSF
 * Five of seven individuals with COVID-19 had antineural autoantibodies in their CSF

Files JK, Boppana S, Perez MD, et al. Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection J Clin Invest. 2021;131(1):e140491. https://doi.org/10.1172/JCI140491 Abstract SARS-CoV-2 causes a wide spectrum of clinical manifestations and significant mortality. Studies investigating underlying immune characteristics are needed to understand disease pathogenesis and inform vaccine design. In this study, we examined immune cell subsets in hospitalized and nonhospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared with those of healthy and convalescent individuals, with the exception of an increase in B lymphocytes. Our findings show increased frequencies of T cell activation markers (CD69, OX40, HLA-DR, and CD154) in hospitalized patients, with other T cell activation/exhaustion markers (PD-L1 and TIGIT) remaining elevated in hospitalized and nonhospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization followed by an increase in PD1 frequencies in nonhospitalized individuals. Interestingly, many of these changes were found to increase over time in nonhospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation after SARS-CoV-2 infection. Changes in T cell activation/exhaustion in nonhospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation after SARS-CoV-2 infection, highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.

Thrombo-embolic
Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020 Apr 28;382(20):e60.

Autopsy studies
Sekhawat V, Green A, Mahadeva U. COVID-19 autopsies: conclusions from international studies. Diagn Histopathol (Oxf). 2020 Dec 5. doi: 10.1016/j.mpdhp.2020.11.008. Epub ahead of print. PMID: 33312230; PMCID: PMC7719010.
 * VTE: hypercoagulability, DVT, PE, microvascular injury, immunothrombosis
 * CVS: myocyte necrosis (?direct invasion, not a classic myocarditis?)
 * Resp: Diffuse alveolar damage, acute fibrinous organising pneumonia fibrosis pattern, secondary lung infections, microthrombi, circulating megakaryocytes
 * Neuro: microthrombi, microinfacrts, focal T-lymphocytes/microglia
 * Renal: acute tubular injury, pre-existing disease HTN, DM [there are case reports of collapsing glomerulopathy]
 * Liver: severe passive congestion with centrilobular necrosis and collapse
 * Haematolymphoid: white pulp atrophy, lymphoid depletion, haemophagocytosis, plasmablastic proliferation
 * Muscoskeletal: mononuclear myositis, myocyte necrosis

Dorward DA et al (July 2020). Tissue-specific tolerance in fatal Covid-19. medRxiv 2020.07.02.20145003 doi:10.1101/2020.07.02.20145003.

Youd E, Moore L (2020 Jun 30). COVID-19 autopsy in people who died in community settings: the first series. Journal of Clinical Pathology.

Zhou B, Zhao W, Feng R, Zhang X, Li X, Zhou Y, et al. (2020 Jan) The pathological autopsy of coronavirus disease 2019 (COVID-2019) in China: a review. Pathog Dis. 2020 01;78(3).

Buja LM, Wolf DA, Zhao B, Akkanti B, McDonald M, Lelenwa L, et al. (2020 Oct) The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol. 2020 Oct;48:107233. 23 cases in this study.

Bryce C, Grimes Z, Pujadas E, Ahuja S, Beasley MB, Albrecht R, et al. (2020 May) Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience. medRxiv. 2020 May 22;2020.05.18.20099960.

Wichmann D, Sperhake J-P, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al.(2020 May) Autopsy Findings and Venous Thromboembolism in Patients With COVID-19. Ann Intern Med.

Menter T, Haslbauer JD, Nienhold R, Savic S, Deigendesch H, Frank S, et al. (2020 May) Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology.2020;77(2):198–209.

Jaunmuktane Z, Mahadeva U, Green A, Sekhawat V, Barrett NA, Childs L, et al. (2020 Jul) Microvascular injury and hypoxic damage: emerging neuropathological signatures in COVID-19. Acta Neuropathol. 2020 Jul 8;1–4.

Mental health: pandemic-related, coronaviruses
Taylor, S, Landry, CA, Paluszek, MM, Fergus, TA, McKay, D, Asmundson, GJG. COVID stress syndrome: Concept, structure, and correlates. Depression and Anxiety. 2020; 37: 706– 714. https://doi.org/10.1002/da.23071

Rogers, Jonathan P et al. (1 July 2020) Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. The Lancet Psychiatry, Volume 7, Issue 7, 611 - 627

Host genomics
Pairo-Castineira, E., Clohisey, S., Klaric, L. et al. Genetic mechanisms of critical illness in Covid-19. Nature (2020). https://doi.org/10.1038/s41586-020-03065-y

Virus variants
Please see the virus variants page.

"Omics" Resources
(pulled from this review):

SARS-CoV-2 Genome Sequencing Data, DNA Sequencing Data	https://www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs/

SARS-CoV-2 Transcriptomic Map
 * RNA Sequencing Data	Open Science Framework: accession number doi:10.17605/OSF.IO/8F6N9


 * Kim, D et al. The Architecture of SARS-CoV-2 Transcriptome. Cell, Volume 181, Issue 4, 914 - 921.e10

SARS-CoV-2 and Human Protein Interactions, Mass Spectrometry Raw Data	http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD018117

SARS-CoV-2 Strains	https://nextstrain.org/ncov

Genomic Epidemiology   https://www.gisaid.org/

The COVID-19 Host Genetics Initiative, Host Genetics Data (GWAS, WES, WGS) https://www.covid19hg.org/

COVID-19 Cell Atlas, Single cell transcriptomics data	https://www.covid19cellatlas.org

Tests, viral persistence and immunity
Dan JM et al Immunological memory to SARS-CoV-2 assessed for greater than six months after infection. bioRxiv 2020.11.15.383323; doi: https://doi.org/10.1101/2020.11.15.383323

PCR
Lauren M. Kucirka, Stephen A. Lauer, Oliver Laeyendecker, et al. Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure. Ann Intern Med.2020;173:262-267. [Epub ahead of print 13 May 2020]. doi:10.7326/M20-1495

Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection — Challenges and Implications. New England Journal of Medicine. 2020 Aug 6;383(6):e38.

Isikbay M, Henry TS, Frank JA, Hope MD. When to rule out COVID-19: How many negative RT-PCR tests are needed? Respiratory Medicine Case Reports. 2020 Jan 1;31:101192.

Lateral flow tests
(8 Nov 2020) Preliminary report from the Joint PHE Porton Down & University of Oxford SARS-CoV-2 test development and validation cell: Rapid evaluation of Lateral Flow Viral Antigen detection devices (LFDs) for mass community testing Innova SARS-CoV-2 Antigen Rapid Qualitative Test
 * Specificity 99.68%; False positive rate 0.32% (0.06-0.39%)
 * Kit failure rates ranging from 0.65% to 16.8% with batch differences
 * 248/323 (76.8%) of the PCR positives are positive on lateral flow but also further data shows operator variation in performance
 * laboratory scientists (156/197 LFDs positive [79.2%, 95% CI: 72.8-84.6%])]
 * trained healthcare-workers (92/126 LFDs positive [73.0%, 95% CI: 64.3-80.5%])
 * self-trained members of the public given a protocol (214/372 LFDs positive [57.5%, 95% CI:52.3-62.6%]; p<0.0001 chi2(2)=30.1)

Antibodies and antibody testing
Deeks JJ.et al. (25 June 2020) [https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013652/full '''Antibody tests for identification of current and past infection withSARS-CoV-2 (Review). Cochrane Database of Systematic Reviews'''], Issue 6. Art. No.: CD013652.doi: https://doi.org/10.1002/14651858.CD013652

Lisba Bastos M. et al. (1 July 2020) Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis. BMJ370:m2516 doi:https://doi.org/10.1136/bmj.m2516

Staines H. M. et al. (9 June 2020) Dynamics of IgG seroconversion and pathophysiology of COVID-19 infections. MedRxivdoi:https://doi.org/10.1101/2020.06.07.20124636

Choe PG, Kang CK, Suh HJ, Jung J, Song K-H, Bang JH, et al. Waning antibody responses in asymptomatic and symptomatic SARS-CoV-2 infection. Emerg Infect Dis. 2021 Jan [published online Dec 2020]. https://doi.org/10.3201/eid2701.203515

Viral shedding, live viral culture studies, persistence and reactivation
Gousseff M. et al. (Nov 2020) Clinical recurrences of COVID-19 symptoms after recovery: Viral relapse, reinfection or inflammatory rebound? Journal of Infection, Volume 81, Issue 5, 2020, Pages 816-846, ISSN 0163-4453, https://doi.org/10.1016/j.jinf.2020.06.073.

[https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30172-5/fulltext Lancet Review. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Cevik et al. November 19, 2020] DOI:https://doi.org/10.1016/S2666-5247(20)30172-5 “Our findings suggest that, although patients with SARS-CoV-2 infection might have prolonged RNA shedding of up to 83 days in upper respiratory tract infection, no live virus was isolated from culture beyond day 9 of symptoms despite persistently high viral RNA loads."

[https://www.medrxiv.org/content/10.1101/2020.08.04.20167932v4 '''Viral cultures for COVID-19 infectivity assessment. Systematic review''' Tom Jefferson, Elizabeth Spencer, Jon Brassey, Carl Heneghan medRxiv 2020.08.04.20167932] doi: https://doi.org/10.1101/2020.08.04.20167932

[https://wwwnc.cdc.gov/eid/article/26/11/20-3219_article Perera R, Tso E, Tsang O, et al. SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease. Emerging Infectious Diseases. 2020;26(11):2701-2704.] doi:10.3201/eid2611.203219. Also see this news article which discusses the paper above: https://www.cidrap.umn.edu/news-perspective/2020/08/those-milder-covid-19-may-not-shed-live-virus-long

Roe, K. (2020), Explanation for COVID‐19 infection neurological damage and reactivations. Transbound Emerg Dis, 67: 1414-1415. https://doi.org/10.1111/tbed.13594

Dias De Melo et al. COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system bioRxiv 2020.11.18.388819; doi: https://doi.org/10.1101/2020.11.18.388819

Gaebler et al. Evolution of Antibody Immunity to SARS-CoV-2 bioRxiv 2020.11.03.367391; doi: https://doi.org/10.1101/2020.11.03.367391 "Analysis of intestinal biopsies obtained from asymptomatic individuals 3 months after COVID-19 onset, using immunofluorescence, electron tomography or polymerase chain reaction, revealed persistence of SARS-CoV-2 in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence."

T-cell evidence/Cellular immunity
Snyder et al. Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels medRxiv 2020.07.31.20165647; doi: https://doi.org/10.1101/2020.07.31.20165647 Also see NYTimes article (free but registration required) https://www.nytimes.com/2020/11/10/health/t-cell-test-coronavirus-immunity.html

Schwarzkopf S, Krawczyk A, Knop D, Klump H, Heinold A, Heinemann FM, et al. Cellular immunity in COVID-19 convalescents with PCR-confirmed infection but with undetectable SARS-CoV-2–specific IgG. Emerg Infect Dis. 2021 Jan [original pub date Oct 2020, cited Dec 2020]. https://doi.org/10.3201/eid2701.203772

Reinfection
Ju Zhang, Nan Ding, Lili Ren et al. COVID-19 reinfection in the presence of neutralizing antibodies National Science Review, 11 January 2021, nwab006, https://doi.org/10.1093/nsr/nwab006

Abstract In the face of the coronavirus disease 2019 (COVID-19), strong and long-lasting immunity is required to protect the host from secondary infections. Recent studies revealed potential inadequacy of antibodies against SARS-CoV-2 in some convalescent patients, raising serious concerns about COVID-19 reinfection. Here, from 273 COVID-19 patients, we identified six reinfections based on clinical, phylogenetic, virological, serological, and epidemiological data.

During the second episode, we observed re-emergence of COVID-19 symptoms, new pulmonary lesions on CT images, increased viral load, and secondary humoral immune responses. 'The interval between the two episodes ranged from 19 to 57 days, indicating COVID-19 reinfections could occur after a short recovery period in convalescent patients. More importantly, reinfection occurred not only in patients with inadequate immunity after the primary infection, but also in patients with measurable levels of neutralizing antibodies. This information will aid the implementation of appropriate public health and social measures to control COVID-19, as well as inform vaccine development.

dos Santos LA, de Góis Filho PG, Fantini Silva AM et al. Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers Journal of Infection, 2021, ISSN 0163-4453, doi: https://doi.org/10.1016/j.jinf.2021.01.020

Highlights
 * We describe 33 patients with recurrent COVID19 and a positive PCR.
 * Recurrence is associated with working as a healthcare professional, blood-group A, and low IgG response to infection.
 * Evidence from differential virus sequencing between the first and second episode supports de novo reinfection.
 * Recurrent episodes tended to be more severe, with one fatal infection.

Pregnancy and perinatal
Allotey John, Stallings Elena, Bonet Mercedes, Yap Magnus, Chatterjee Shaunak, Kew Tania et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis BMJ 2020; 370 :m3320

Vitamin D
Overall Vitamin D deficiency or insuffiency prevalence is high and vitamin D is a generally safe supplement (discussion on dose upper limits in literature below).

COVID-19
WHO/COVID-NMA VITAMIN D VS STANDARD CARE/PLACEBO - Tabular summary of vitamin D randomised controlled trials for COVID-19

Jain, A., Chaurasia, R., Sengar, N.S. et al. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep 10, 20191 (2020). https://doi.org/10.1038/s41598-020-77093-z

Please note the expression of concern on the following article: Maghbooli Z, Sahraian MA, Ebrahimi M, Pazoki M, Kafan S, Tabriz HM, et al. (2020) Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS ONE 15(9): e0239799. doi:10.1371/journal.pone.0239799

Martineau AR, Jolliffe DA, Hooper RL, et al. (Feb 2017) Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583

Upper limits
VitaminDWiki. Global Vitamin D recommendations - summer 2018 - A note on safe upper limits: There is not international consensus on the upper safe limit of Vitamin D, here it shows a summary of the different upper limits, with a general disagreement between placing it as 4,000 or 10,000 IU

Prevalence of insufficiency/deficiency
Joshua P. Sutherland, Ang Zhou, Matthew J. Leach, Elina Hyppönen. (Nov 2020) Differences and determinants of vitamin D deficiency among UK biobank participants: A cross-ethnic and socioeconomic study.C linical Nutrition, 2020, ISSN 0261-5614, https://doi.org/10.1016/j.clnu.2020.11.019.
 * "Asian ancestry (57.2% in winter/spring and 50.8% in summer/autumn) followed by those of Black African ancestry (38.5% and 30.8%, respectively), mixed (36.5%, 22.5%), Chinese (33.1%, 20.7%) and White European ancestry (17.5%, 5.9%)."
 * "Participants with higher socioeconomic deprivation were more likely to have 25(OH)D deficiency compared to less deprived participants (P = <1 × 10−300); this pattern was more apparent among those of White European ancestry and in summer (Pinteraction ≤6.4 × 10−5 for both)."
 * "outdoor-time in summer was less effective for Black Africans (OR 0.89, 95% CI 0.70, 1.12) than White Europeans (OR 0.40, 95% CI 0.38, 0.42)."

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761874/ Hossein-nezhad, Arash, and Michael F Holick. “Vitamin D for health: a global perspective.” Mayo Clinic proceedings vol. 88,7 (2013): 720-55. doi:10.1016/j.mayocp.2013.05.011]
 * "It has been estimated that 20% to 80% of US, Canadian, and European men and women are vitamin D deficient"
 * " In the United States, vitamin D deficiency and insufficiency is estimated to be 27% to 91% in pregnant women [USA]... this rate is estimated to be 39% to 65% in Canada, 45% to 100% in Asia, 19% to 96% in Europe, and 25% to 87% in Australia and New Zealand"

RCTs
WHO/COVID-NMA consortium RCTs for pharmacologic treatments of COVID-19 with table of general characteristics of each trial, updated every Friday

Inhaled Budenoside
Department of Health and Social Care et al. (12 April 2021) Interim Position Statement: Inhaled budesonide for adults (50 years and over) with COVID-19. MHRA Alert.

Ramakrishnan, Sanjay et al. (9 April 2021) Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. The Lancet Respiratory Medicine, Volume 0, Issue 0

Severity of COVID-19
Gupta S, Hayek SS, Wang W, et al. Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US. JAMA Intern Med. 2020;180(11):1436–1446. doi:10.1001/jamainternmed.2020.3596

Rodrigues TS et al. (cited Dec 2020) Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2021 Mar 1;218(3):e20201707. doi: 10.1084/jem.20201707. PMID: 33231615; PMCID: PMC7684031.

Obesity
Frasca et al. (Dec 2020) Effects of obesity on serum levels of SARS-CoV-2-specific antibodies in COVID-19 patients medRxiv 2020.12.18.20248483; doi: https://doi.org/10.1101/2020.12.18.20248483

Curtin, K.M., Pawloski, L.R., Mitchell, P. and Dunbar, J. (2020), COVID‐19 and Morbid Obesity: Associations and Consequences for Policy and Practice. World Medical & Health Policy, 12: 512-532. https://doi.org/10.1002/wmh3.361

Michaela R. Anderson, Joshua Geleris, David R. Anderson, et al. Body Mass Index and Risk for Intubation or Death in SARS-CoV-2 Infection: A Retrospective Cohort Study. Ann Intern Med.2020;173:782-790. [Epub ahead of print 29 July 2020]. doi:10.7326/M20-3214

Sara Y. Tartof, Lei Qian, Vennis Hong, et al. Obesity and Mortality Among Patients Diagnosed With COVID-19: Results From an Integrated Health Care Organization. Ann Intern Med.2020;173:773-781. [Epub ahead of print 12 August 2020]. doi:10.7326/M20-3742

Gastroenterology and microbiome
Yeoh YK, Zuo T, Lui GC, et al Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19 BMJ Gut. Published Online First: 11 January 2021. doi: 10.1136/gutjnl-2020-323020

Abstract

Objective Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus.

Methods In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma.

Results Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase.

Conclusion Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Research (open to public)

 * COVID Symptom Study
 * "The COVID Symptom Study app is a not-for-profit initiative that was launched at the end of March 2020 to support vital COVID-19 research. The app was launched by health science company ZOE with scientific analysis provided by King’s College London."
 * COVID Collab
 * "A research study led out of King’s College London (PHIDatalab) investigating the ongoing COVID-19 outbreak - both the disease itself and the impact measures to control it are having on our lives. A key feature of this study is the use of wearable data which will be used to investigate changes in measurements such as heart rate during infection with coronavirus."
 * UCL Virus Watch
 * "We want people of all ages and families from all backgrounds to take part so we can understand how the virus affects different communities. For those who live with others, we need everybody in your household to take part so we can see how much COVID‑19 spreads in the household and how effectively people prevent this."
 * Facebook group: COVID-19 Research Involvement Group [Facebook ]

Other
Other miscellaneous resources