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Viruswatch - Evidence-Based COVID Medicine and Nursing

Your source for short and sweet doses of defense against the dark arts of coronavirus. Viruswatch is brought to you by the BC Pandemic Network, a multidisciplinary collaboration dedicated to sifting through the COVID-19 literature.

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7. Hypercoagulability

Today we’re exploring a COVID-complication that has caught a lot of attention on social media: hypercoagulability. Clinical features Part of the syndrome of immune hyperactivity seen in severe SARS-CoV-2 infection is activation of complement pathways involved in coagulation Termed COVID-associated coagulopathy (CAC) or thromboinflammation Appears distinct from DIC Hallmark is clotting, NOT bleeding! Clinical features include VTE1 Incidence of VTE appears very high in critically ill patients: 25% to 43%, often despite prophylactic anticoagulation2-4 Much lower incidence in ward patients, but data limited2 Outpatients: unknown Arterial thrombosis The incidence of arterial thrombosis in COVID is unknown Two single-center studies of admitted inpatients with COVID report an incidence of 5% and 3.7% respectively4,5 Lay press reports describe the experience of one American physician, who notes that they have seen young patient presenting with stroke (large-vessel occlusions)6,7 Clinical antiphospholipid antibody syndrome (APS) has also been described in case reports, with patients presenting with limb ischemia, cerebral infarcts, and positive antiphospholipid antibodies8,9 Microvascular thrombosis Some studies suggest that multiorgan failure secondary to microvascular damage may be an important cause of death in COVID patients Lab evaluation Patients with severe COVID-19 infections and non-survivors (compared to those with less severe infection) have been found to have: Markedly elevated D-dimer10-12 Patients with D-dimer > 1000 had 20x increased risk of mortality in one study!11 Higher PTT levels11,12 Platelets: typically N/high (unlike DIC); but may be low13 High fibrinogen and factor VIII activity (unlike DIC)14 Potential therapies Anticoagulation It’s been suggested that heparin may be beneficial in COVID-19, given its anticoagulant, anti-inflammatory, endothelial-protective, and antiviral properties In retrospective observational studies, there is a signal for heparin for reduced mortality with heparin, particularly in critically ill patients15,16 Excessive bleeding was low in one study (about 1%)16 Note the potential for bias with these studies! This group has published a nice decision algorithm that may help inform anticoagulation use in COVID patients, taking into consideration risk of VTE, D-dimer levels, and POCUS findings17 Bottom line: still need more evidence here! While awaiting that: individualized decisions in accordance with your group/hospital/health authority policy Prophylactic-dose anticoagulation is strongly recommended in all patients in the absence of very compelling contraindications18 Antiplatelet agents Some of these reports describe therapy for arterial thrombosis with ASA5 No high-quality data; no data on prospective use One group looked at the administration of dipyridamole and its effects on in-vitro cell lines, as well as laboratory coagulation/inflammatory parameters, and on clinical outcomes19 The group cites effects of dipyridamole on viral replication, as well as its antiplatelet and “immune-enhancing” properties Very small size and methodological issues prevent drawing any conclusions from this paper, but it’s hypothesis-generating Thrombolysis tPA has also been trialed in select cases in patients with COVID-19 and ARDS, leading to transient improved oxygenation20 Management of hemorrhage/DIC Bleeding does not seem as common in these patients. Opinion-only (not evidence-based) guidelines have suggestions for management of coagulation parameters in bleeding patients18 If bleeding: target plts > 50, fibrinogen > 2, PT ratio < 1.5 (similar to general management of pts in DIC) Future directions Ongoing trials are looking at the safety and efficacy of anti-platelets and anti-coagulation, including aspirin, clopidogrel, rivaroxaban, tirofiban, fondaparinux and dipyridamole Sources Cui S, Chen S, Li X et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. Apr 2020; doi:10.1111/jth.14830 Middeldorp S, Coppens M, van Haaps TF et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. May 2020; doi: 10.1111/jth.14888 Helms J, Tacquard C, Severac F et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. May 2020; doi:10.1007/s00134-020-06062-x Klok F, Kruip M, van der Meer N et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Res, Apr 2020; doi:10.1016/j.thromres.2020.04.013 Li Y, Zhou Y, Wang M et al. Acute Cerebrovascular Disease Following COVID-19: A Single Center, Retrospective, Observational Study. SSRN, Mar 2020; doi: 10.2139/ssrn.3550025 Cha, A. Young and middle-aged people, barely sick with COVID-19, are dying of strokes. Washington Post online, Apr 25 2020. https://www.washingtonpost.com/health/2020/04/24/strokes-coronavirus-young-patients/ Fox, M. Covid-19 causes sudden strokes in young adults, doctors say. CNN Health (online), Apr 23 2020. https://www.cnn.com/2020/04/22/health/strokes-coronavirus-young-adults/index.html?fbclid=IwAR2s8aUzUcA9N6Vcy02J9eNjYpkkQ2sZUqjmat-00dQpOwEtHcmgUU4eA30 Ma J, Xia P, Li X et al. Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19. Clin Immunol, Apr 2020; doi:10.1016/j.clim.2020.108408 Zhang Y, Xiao M, Zhang S et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. New Eng J Med, Apr 2020; doi:10.1056/NEJMc2007575 Guan W, Ni Z, Hu Y et al. Clinical characteristics of coronavirus disease 2019 in China. New Eng J Med, Feb 2020; doi:10.1056/NEJMoa2002032 11. Zhou F, Yu T, Du R et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet, Mar 2020; doi:1016/S0140-6736(20)30566-3 Tang N, Li D, Wang X et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost, Mar 2020; doi:10.1111/jth.14768 Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clinica Chimica Acta, Mar 2020; doi:10.1016/j.cca.2020.03.022 Panigada M, Bottino N, Tagliabue P et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis. J Thromb Haemost. Mar 2020; doi: 10.1111/jth.14850 Tang N, Bai H, Chen X et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy. J Thromb Haemost, Mar 2020; doi:10.1111/jth.14817 Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. Journal of the American College of Cardiology. May 2020. doi:10.1016/j.jacc.2020.05.001 Atallah B, Mallah SI, Al Mahmeed W. Anticoagulation in COVID-19. European Heart Journal – Cardiovascular Pharmacotherapy. April 2020. doi:10.1093/ehjcvp/pvaa036 Thachil J, Tang N, Gando S et al. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. J Thromb Haemost, Mar 2020; doi: 10.1111/jth.14810 Liu X, Li Z, Liu S et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharmaceutica Sinica B, Apr 2020. doi:10.1016/j.apsb.2020.04.008 Wang J, Hajizadeh N, Moore E et al. Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series. J Thromb Haemost, Apr 2020; doi:10.1111/jth.14828

8mins

15 May 2020

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8. Lopinavir/Ritonavir

Like Voldemort at the end of The Goblet of Fire, lopinavir/ritonavir seems to have come back from the dead…maybe? The background SARS Open-label study showed improved clinical outcomes (combo of ARDS or death) with ribavirin plus lopinavir/ritonavir compared to ribavirin alone1 MERS Case reports suggest that triple-therapy with ribavirin, lopinavir/ritonavir, and interferon led to improved survival and viral clearance2 There is an ongoing clinical trial of combination therapy – stay tuned!3 LOTUS China trial4 Randomized open-label trial (no placebo) at a single hospital in China Methods 199 patients hospitalized with PCR-confirmed COVID-19 Had to have pulmonary involvement: positive chest imaging and hypoxia on room air: sats < 94% or P/F ratio < 300mmHg Randomized to lopinavir/ritonavir plus standard care vs standard care alone Primary endpoint: time to clinical improvement (7-point scale) Results No difference in the primary outcome of time to clinical improvement No difference in subgroup receiving treatment within 12 days of symptom onset No difference in 28-day mortality Note high mortality in both groups (19-25%) No difference in detectable viral RNA at various time points GI side effects were more common in the treatment group Hung et al5 Multi-center prospective open-label phase II RCT at 6 hospitals in Hong Kong Methods Patients: 127 adults (>18yrs) with PCR-confirmed COVID, within 14 days of symptom onset, with NEWS2 scores of at least 1 Treatment: 14 days of lopinavir/ritonavir (BID) and ribavirin (BID) Plus up to 3 doses of interferon beta-1b every other day if within 7d of symptom onset* Control: lopinavir/ritonavir alone Primary outcome: time to a negative RT-PCR NP swab Secondary: time to resolution of symptoms, SOFA scores, hospital length of stay, 30-day mortality Interestingly, their power calculation was based on an estimated 26.4% (!!) improvement in mortality with triple-Tx group based on a prior study1 Results Patients: only very mildly ill Only 11% had dyspnea; and twice as many in control group as Tx group (sicker?) Only 13% required oxygen therapy during their admission Most of these people would NOT have been admitted to hospital here in Canada! Baseline viral load similar between groups Primary outcome: faster time to negative swab in the triple-therapy group (7 vs 12d) Secondary outcomes: many were also improved in the triple-therapy group Improved time to NEWS 0 (4 vs 8 days) Improved time to SOFA score 0 (3 vs 9 days) Shorter hospital length of stay (9 vs 14.5 days) No change in 30 day mortality (0% mortality in both groups) Why the difference? Possible explanations: Timing of medication administration: randomization occurred at median 13 days after symptom onset in LOTUS China Hung: 60% of patients presented within 7 days of symptom onset Subgroup who presented after 7 days: no difference Sicker patients in LOTUS China? Required to be hypoxemic on room air; vs only a small percentage of patients in Hung et al needed oxygen It’s the drugs! Maybe ribavirin or interferon are actually the effective agents? Is there something synergistic and magical about combination therapy? The bottom line This is promising! But… We need more studies With sicker patients: do these actually improve endpoints that we care about? To help tease out the effect of each drug If early administration is the key, we really need to think about how we might deploy this from a public health perspective Sources Chu CM. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. March 2004:252-256. doi:10.1136/thorax.2003.012658 Kim UJ, Won E-J, Kee S-J, Jung S-I, Jang H-C. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α for Middle East respiratory syndrome. Antivir Ther, 2016; 21: 455-9. doi:10.3851/IMP3002 Arabi YM, Alothman A, Balkhy HH et al. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 2018; 19: 81. doi:10.1186/s13063-019-3846-x Cao B, Wang Y, Wen D et al. A trial of lopinaviar/ritonavir in adults hospitalized with severe COVID-19. New Eng J Med, March 2020. doi:10.1056/NEJMoa2001282 Hung IF-N, Lung K-C, Tso EY-K et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet. May 2020. doi:10.1016/s0140-6736(20)31042-4

10mins

15 May 2020

Rank #2

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4. Hydroxychloroquine

Today we’re focusing on a hot topic – the use of chloroquine and hydroxychloroquine for treatment of COVID-19. This drug had a lot of buzz early on, but recent data has been lukewarm at best. Background: why chloroquine? Chloroquine and hydroxychloroquine are old medications generally used for the treatment of malaria, amebiasis, and certain inflammatory conditions like rheumatoid arthritis. These medications have anti-viral activity in vitro, but there is no demonstrated clinical efficacy in treatment of viral illness There are several proposed mechanisms including immunomodulatory/immunosuppressive effects – which, it should be noted, may potentially be harmful in the setting of viral disease Chloroquine isn’t available in Canada. Hydroxycholorquine is, but due to the recent media frenzy, the supply is unstable and there are very real concerns that patients who need these drugs for legitimate indications may have difficulty accessing them In-vitro and animal data There is some in-vitro data of chloroquine and hydroxychloroquine activity against COVID-19; and some data informing potentially effective doses1,2 Animal data is not supportive – one study of chloroquine in mice with SARS was negative3 Human data There was a lot of buzz about this drug early on and hype from some very small/low-quality studies Gautret (2020)4: this was a much-discussed very small French trial of 26 patients hospitalized with COVID-19 (though note that some of them were actually asymptomatic!) They all received hydroxycholorquine; 6 also received azithromycin Non-randomized; control group was patients who refused treatment Their primary endpoint was negative viral PCR on day 6 This was lauded as a positive study as all patients who received both drugs had viral clearance at 6 days; vs 57% of the patients who had hydroxychloroquine only; and 12% of controls HOWEVER – a lot of caveats here: high loss to follow up, high potential for bias, non-clinical endpoint Gao (2020)5: this was a publication stating that “chloroquine use in 100 patient is superior to the control treatment for inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting virus negative conversion, and shortening the disease course” – but no patient data was published Chen (2020)6: randomized trial of hydroxychloroquine use in patients with mild illness 62 patients in a Wuhan hospital with mild illness only Patient were randomized to 200mg BID of hydroxychloroquine vs control Their primary outcome as a time to clinical improvement They reported improved numbers in the treatment group BUT v small numbers, no mention of statistical significance, arguably relevant clinical endpoint Higher-quality data has now emerged showing no benefit to HCQ, and potential harm Magagnoli (2020)7 Retrospective cohort analysis of patients admitted to VA hospitals in the US with exposure to hydroxychloroquine, hydroxychloroquine and azithromycin, or neither drug Adjusted risk of death was higher in the HCQ group (HR 2.61) Unadjusted mortality was higher in both HCQ and HCQ + AZA groups compared to no Tx (27.8% vs 22.1% vs 11.4% respectively) Borba (2020)8 Randomized clinical trial of low vs high-dose hydroxychloroquine for severe COVID 450mg BID on day 1, then daily x 4d vs 600mg BID x 10d Interim analysis recommended early termination of the trial after enrollment of 81 of a pre-planned 440 patients due to increased mortality in the high-dose group (39% vs 15%) More QTc prolongation in high-dose group Tang (2020)9 Open-label RCT for hydroxychloroquine in mild-to-moderate COVID 151 patients Intervention: 1200mg PO daily x 3d load, then 800mg PO daily for 2-3 weeks Primary outcome of viral clearance by 28 days, defined by 2 consecutive negative PCR tests Outcome: no difference (85% vs 81%); increase in adverse events in HCQ group (30% vs 7%) Side effects Have not been investigated in the setting of COVID-19 From experience with malaria and rheumatologic illnesses, hydroxychloroquine is generally well-tolerated Dose of 400mg/d max (generally) Common side effect: GI upset Less common but more potentially worrisome: hypoglycemia, skin reactions, QTc prolongation (especially in combination with other QT-prolonging agents like azithromycin!), hepatotoxicity, bone marrow suppression, and retinal toxicity (related to long-term cumulative use) Bottom line While it’s tempting to jump at any and all possible therapies right now, we need to first do no harm Despite initial promising pre-clinical data and anecdotal reports, more recent evidence on hydroxychloroquine fails to demonstrate a clinical benefit; and suggests the potential for harm, especially at high doses Sources Wang, M., Cao, R., Zhang, L. et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res30, 269–271 (2020). doi: 10.1038/s41422-020-0282-0 Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clinical Infectious Diseases, ciaa237, doi: 10.1093/cid/ciaa237 Barnard D, Day C, Bailey K et al. Evaluation of immunomodulators, interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antiviral Chemistry & Chemotherapy, 2006, 17:275–284. doi: 10.1177/095632020601700505 Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrobial Agents, 2020. doi: 10.1016/j.ijantimicag.2020.105949 Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends, 2020. doi:10.5582/bst.2020.01047 Chen J, Liu L, Liu D et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci), 2020;49(1). doi:10.3785/j.issn.1008-9292.2020.03.03 Magagnoli J, Narendran S, Pereira P et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. MedRxiv pre-print, 2020. doi:10.1101/2020.04.16.20065920 Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open.2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857 Tang W, Cao Z, Han M. Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial. MedRxiv pre-print, 2020. doi: 10.1101/2020.04.10.20060558

8mins

12 May 2020

Rank #3

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6. Vaccines

We’re looking optimistically to the future today and talking about the development of potential vaccines for COVID. All the information below has been amalgamated from the review pieces cited. Vaccine development landscape Researchers across the country are devoting huge amounts of time and energy to the development of a coronavirus vaccine Currently there are 115 vaccine candidates 78 are confirmed active trials Majority (73) are in exploratory or pre-clinical testing phase First vaccine candidate entered human testing on March 16 2020 Majority are in the private/industrial sector (>70%) Many different vaccine types are being investigated, each with advantages and disadvantages mRNA, DNA, viral vector, live attenuated virus, inactivated virus, peptide-based, recombinant protein, etc Trials of vaccine adjuvants are also underway Current phase 1 clinical trials Moderna: mRNA vaccine CanSino Biologicals: recombinant protein Inovio Pharmaceuticals: DNA vaccine Shenzhen Geno-Immune Medical Institute: viral vector (2) Vaccine safety Vaccine safety remains to be a major consideration This is a new viral target with some novel vaccine technology and developmental paradigms There were documented adverse vaccine responses with SARS (ADE) Some concerns in particular about liver damage To combat this, rigorous animal model safety assessment is being undertaken Mouse and macaques (monkeys) have proven to be reliable models for vaccine study Mutations? The virus may mutate and necessitate vaccine reformulations; however, this would be a much shorter process (similar to the yearly flu vaccine) Some research is also underway to create a pan-coronavirus vaccine Timeline Timeline for completion of the clinical trials varies from 2021 to 2023 and beyond The most optimistic estimates are that a vaccine may be ready by early 2021 That does not account for the time it would take to mass-produce the vaccine; nor for any hiccups along the way!! Global perspective Moving forward, there is also a need to ensure that vaccines will be manufactured in sufficient quantities and equitably supplied to all affected areas, particularly low-resourced Sources Le T, Andreadakis Z, Kumar A et al. The COVID-19 vaccine development landscape. Nature Reviews, April 2020. doi:10.1038/d41573-020-00073-5 Zhang J, Zeng H, Gu J et al. Progress and Prospects on Vaccine Development against SARS-CoV-2. Vaccines,2020, 8(2), 153. doi:10.3390/vaccines8020153 Weber B. A look at research being done in Canada for a coronavirus vaccine. Global News, Mar 30 2020. https://globalnews.ca/news/6749536/coronavirus-canada-vaccine-research/

6mins

12 May 2020

Rank #4

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5. Immunity and COVID-19

Today we’re tackling a question with a lot of public health implications as we consider how to move forward in this pandemic (and potentially being to loosen restrictions). A huge part of that equation is the question of immunity: are people who have previously been infected immune to COVID; or could they become re-infected and continue to transmit the virus? And could antibody tests help us determine who has already been infected (perhaps asymptomatically)? Antibody tests for COVID-19 Several different types of tests available1 GICA: gold immunochromatographic assay CLIA: chemiluminescent immunoassay ELISA: enzyme-linked immunosorbent assay Point-of care lateral flow tests ELISA tests are the most common (most studies below use ELISA assays) Plate-based technique for detecting and quantifying peptides, proteins, antibodies, etc May have slightly different targets Several assays available each with slightly varying test characteristics Generally sensitivity is good (>90% for most tests)2 False positives are rare but have been reported3 Some assays show cross-reactivity with other coronaviruses4 Initial antibody response and seroconversion Most studies support a high rate of seroconversion after acute illness One study found 50% of pts had detectable antibodies by day 7 post-Sx onset5 Most pts who seroconvert do so by day 10-156 Seroconversion rates varied but are generally high: 83% to 100% by day 21-353,5,7-11 However - One study classified patients as “strong responders” vs “weak responders” vs “non-responders”12 Strong responders: >2x the cutoff value; weak responders: 1-2x the cutoff value; non-responders: below assay cutoff value The clinical implications of this stratification system have NOT been determined A significant portion of patients were non- or weak-responders by the end of the follow-up period (1 month) 7% (IgM) and 16.7% (IgG) were non-responders 2% (IgM) and 61.1% (IgG) were weak responders Another group found that 30% of patients had very low titers at day 10-15 post-symptom onset – again, the clinical implications of these low levels are unclear13 Patients with more severe disease seem to mount a stronger antibody response (IgG in particular)12,14 Weak antibody responders had a higher rate of viral clearance in one study12 Lasting immunity?   IgM levels decline over time, as expected 33% of pts had no detectable IgM by week 7 in one study15 Some evidence that IgG levels also fall with time One group did weekly serial testing of IgG levels and found that levels decreased with time16 Adams et al reported that IgG levels decreased by 8 weeks (but remained above detection threshold)17 In contrast, another group found stable IgG levels up to 7 weeks after symptom onset15 No one has looked beyond 2 months post-Sx onset yet à we don't know how long immunity might last! UPDATE – May 18/20 An interesting new basic science study has come out looking at the role of T-cells in COVID-1918 Reminder: T-cells are key players in cell-mediated immunity (vs B-cells in humoral immunity discussed above) This group found that SARS-CoV2-reactive CD4+ T cell were detected in 40-60% of healthy historical controls who had never been exposed to COVID They theorize that this may reflect a degree of cross-reactivity between SARS-CoV-2 and other coronaviruses BUT the clinical implications of this re: immunity are not known This is a potentially hopeful study – if there is some degree of cross-reactivity, we may be closer to herd immunity than previously suspected Sources Gao HX, Li YN, Xu ZG et al. Detection of serum immunoglobulin M and immunoglobulin G antibodies in 2019-nCoV-infected cases from different stages. Chinese Medical Journal, Mar 2020. doi:10.1097/CM9.0000000000000820 Lassauniere R, Frische A, Harboe ZB et al. Evaluation of nine commercial SARS-CoV-2 immunoassays. MedRxiv pre-print, Apr 2020. doi: 10.1101/2020.04.09.20056325 Xiang F, Wang X, He X et al. Antibody detection and dynamic characteristics in patients with COVID-19. Clin Infect Dis, Apr 2020. doi: 10.1093/cid/ciaa461/5822173 Okba N, Muller M, Li W et al. Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus Disease 2019 Patients. Emerg Infect Dis, Apr 2020. doi:10.3201/eid2607.200841 Wölfel, R., Corman, V.M., Guggemos, W. et al. Virological assessment of hospitalized patients with COVID-19. Nature, Apr 2020. doi:10.1038/s41586-020-2196-x Wu F, Wang A, Liu M et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.03.30.20047365 Zhang B, Zhou X, Zhu C et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.12.20035048 Zhao J, Yuan Q, Wang H et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis, Mar 2020. doi:10.1093/cid/ciaa344 Lou B, Li T, Zheng S et al. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.23.20041707 Long Q, Deng H, Chen J et al. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.18.20038018v1 To K, Tsang O, Leung W et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infec Dis, Mar 2020. doi:10.1016/S1473-3099(20)30196-1 Tan W, Lu Y, Zhang J et al. Viral kinetics and antibody responses in patients with COVID-19. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.24.20042382v1 Wu F, Wang A, Liu M et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.03.30.20047365 Huang A, Garcia-Carreras B, Hitchings M et al. A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.14.20065771 Xiao A, Gao C, Zhang S. Profile of specific antibodies to SARS-CoV-2: The first report. J Infect, Mar 2020. doi:10.1016/j.jinf.2020.03.012 Du Z, Zhu F, Guo F et al. Detection of antibodies against SARS‐CoV‐2 in patients with COVID‐19. J Med Virol, Apr 2020. doi: 10.1002/jmv.25820 Adams E, Ainsworth M, Anand R et al. Evaluation of antibody testing for SARS-CoV-2 using ELISA and lateral flow immunoassays. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.15.20066407 Grifoni A, Weiskopf D, Ramirez SI et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals, Cell, May 2020, doi:10.1016/j.cell.2020.05.015

8mins

12 May 2020

Rank #5