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By Christian Hoffmann &
Bernd S. Kamps

30 April

Epidemiology

Oliu-Barton M, Pradelski BS, Aghion OP, et al. SARS-CoV-2 elimination, not mitigation, creates best outcomes for health, the economy, and civil liberties. April 28, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00978-8/fulltext

See title. “Living with the virus“ is not a good idea. And will not work. Important comment, good arguments. Evidence suggests that countries that opt for rapid action to eliminate SARS-CoV-2—with the strong back-up of their inhabitants—also better protect their economies and minimize restrictions on civil liberties compared to those that strive for mitigation.

 

Vaccine

Tenforde MW, Olson SM, Self WH. Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years — United States, January–March 2021. MMWR April 28. https://www.cdc.gov/mmwr/volumes/70/wr/mm7018e1.htm?s_cid=mm7018e1_w

In a multi-state network of US hospitals during January–March 2021, receipt of Pfizer/BioNTech or Moderna COVID-19 vaccines was 94% effective against COVID-19 hospitalization among fully vaccinated adults and 64% effective among partially vaccinated adults aged ≥ 65 years. There was no significant effect for receiving the first dose of a 2-dose COVID-19 vaccine series within 14 days prior to illness onset.

 

Diagnostics

McKay SL, Tobolowsky FA, Moritz ED, et al. Performance Evaluation of Serial SARS-CoV-2 Rapid Antigen Testing During a Nursing Home Outbreak. Ann Int Med 27 April 2021. https://www.acpjournals.org/doi/10.7326/M21-0422

Serial antigen testing early and often could be an effective testing strategy to support infection control in nursing homes having a SARS-CoV-2 outbreak.

 

Clinical

Gao M, Piernas C, Astbury NM, et al. Associations between body-mass index and COVID-19 severity in 6·9 million people in England: a prospective, community-based, cohort study. Lancet Diab Endoc April 28, 2021. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00089-9/fulltext

At a BMI of more than 23 kg/m², there was a linear increase in risk of severe COVID-19 leading to admission to hospital and death, and a linear increase in admission to an ICU across the whole BMI range, which was not attributable to excess risks of related diseases. The relative risk due to increasing BMI was particularly notable people younger than 40 years and of Black ethnicity.

 

Co-morbidities

Saadoun D, Vieira M, Vautier M, et al. SARS-CoV-2 outbreak in immune-mediated inflammatory diseases: the Euro-COVIMID multicentre cross-sectional study. Lancet Rheumatology April 28, 2021. https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00112-0/fulltext

Among 122 patients with a clinical diagnosis of diseases like rheumatoid arthritis and systemic lupus erythematosus, factors associated with symptomatic COVID-19 were higher numbers of recent disease flares (Odds ratio 1.27), whereas use of biological therapy was associated with a reduced risk (OR 0.51).

 

29 April

Variants

Resende PC, Bezerra JF, Vasconcelos RHT, Arantes I, Appolinario L, Mendonça AC, et al. Severe acute respiratory syndrome coronavirus 2 P.2 lineage associated with reinfection case, Brazil, June–October 2020. Emerg Infect Dis April 21, 2021 Jul [date cited] https://wwwnc.cdc.gov/eid/article/27/7/21-0401_article

Case report of a 37-year-old healthcare worker from the northeastern region of Brazil who experienced two clinical episodes, 116 days apart. The two infections were caused by the most prevalent lineage in Brazil, B.1.1.33, and the emerging lineage P.2.

 

Vaccine

MacNeil JR, Su JR, Broder KR, et al. Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients — United States, April 2021. MMWR Morb Mortal Wkly Rep. ePub: 27 April 2021. DOI: https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e4.htm?s_cid=mm7017e4_w

On April 23, the Advisory Committee on Immunization Practices concluded that the benefits of resuming Janssen’s vaccination in persons aged ≥ 18 years outweigh the risks. Up to now, there are 15 cases of cerebral venous sinus thrombosis (CVST), mostly among women aged 18−49 years. Two occurred among women aged ≥ 50 years; no cases post-authorization were reported among men. Reporting rates were 7.0 cases per million doses administered to women aged 18−49 years and 0.9 per million to women aged ≥ 50 years.

 

Menni C, Klaser K, May A, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Inf Dis April 27, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00224-3/fulltext

Between Dec 8, and March 10, 2021, 627,383 individuals reported being vaccinated: 282,103 received one dose of BNT162b2, of whom 28,207 received a second dose, and 345,280 received one dose of ChAdOx1 nCoV-19. Systemic side effects were reported by 13.5%, 22.0%, and by 33.7%, respectively. Local side effects were reported by 71.9%, 68.5% and 58.7%. Systemic side effects were more common (1.6 times after the first dose of ChAdOx1 nCoV-19 and 2.9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection.

 

Vaccine/Co-morbidities

Monin L, Laing AG, Muñoz-Ruiz M, et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Inf Dis April 27, 2021. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00213-8/fulltext

Better not wait too long with the second shot in cancer patients? In this prospective observational study of 151 patients with solid and hematological cancers, one 30 μg dose of the BNT162b2 vaccine yielded poor efficacy, as measured by seroconversion rates, viral neutralization capacity, and T cell responses, at 3 weeks and 5 weeks following the first inoculum. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose.

 

Diagnostics

Jalkanen P, Pasternack A, Maljanen S, et al. A combination of N and S antigens with IgA and IgG measurement strengthens the accuracy of SARS-CoV-2 serodiagnostics. J Inf Dis April 27, 2021, jiab222, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab222/6255671?searchresult=1

Using both N and S1/RBD antigens in SARS-CoV-2, antibody detection is beneficial. By combining anti-N and anti-RBD IgA with IgM or IgG EIA measurement, a rather high sensitivity (77–80%) was reached within the first two weeks of SARS-CoV-2 infection.

 

28 April

Immunology

Zhou X, Ma F, Xie J, et al. Diverse immunoglobulin gene usage and convergent epitope targeting in neutralizing antibody responses to SARS-CoV-2. Cell Rep April 23, 2021. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00443-5

Employing a high-throughput system combining isolation of receptor binding domain (RBD)-binding memory B cells, in vitro single cell culture, and functional screening, 54 potent neutralizing antibodies for SARS-CoV-2 were isolated. Fifty-two of them target the ACE2 binding surface on the RBD of the SARS-CoV-2 spike protein, while the other two recognize epitopes that do not appear to overlap as extensively with the ACE2 binding site, among them 47D1 that binds a site on the backside of the receptor binding surface of the SARS-CoV-2 RBD (less susceptible to mutations?). mAb 47D1 was able to protect hamsters.

 

Transmission

Amorim MR, Souza WM, Barros ACG Jr, Toledo-Teixeira DA, Bispo-dos-Santos K, Simeoni CL, et al. Respiratory viral shedding in healthcare workers reinfected with SARS-CoV-2, Brazil, 2020. Emerg Infect Dis. 2021 June [date cited]. https://doi.org/10.3201/eid2706.210558

Four cases of SARS-CoV-2 reinfection among HCWs. In each HCW, shedding of infectious viral particles was observed during both infection episodes.

 

Gonzalo EM, Martinez PP, Mahmud AS, et al. Socioeconomic status determines COVID-19 incidence and related mortality in Santiago, Chile. Science 27 Apr 2021: eabg5298. DOI: https://science.sciencemag.org/content/early/2021/04/26/science.abg5298

Data from the capital of Chile, a highly segregated city: people living in municipalities with low socioeconomic status did not reduce their mobility during lockdowns as much as those in more affluent municipalities. Both test positivity rates and testing delays were much higher in one group. There was a strong association between socioeconomic status and mortality, measured either by COVID-19 attributed deaths or excess deaths. Finally, infection fatality rates in young people were (1.7 – 3.1 fold) higher in low-income municipalities.

Treatment

Huang L, Yuen TT, Ye Z et al. Berbamine inhibits SARS-CoV-2 infection by compromising TRPMLs-mediated endolysosomal trafficking of ACE2. Sig Transduct Target Ther 6, 168 April 24, 2021. https://www.nature.com/articles/s41392-021-00584-6

Berbamine compromises the endolysosomal trafficking of ACE2 via inhibition of TRPMLs, and this leads to an increase in the secretion of ACE2 via exosomes and a concomitant decrease in the levels of ACE2 at the cell surface, thereby preventing SARS-CoV-2 from entering the host cells. Before ordering (and drinking) barberry tea, however, let’s wait for clinical data!

 

Reis G, Moreira Silva EA, Medeiros Silva DC, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19The TOGETHER Randomized Clinical Trial. JAMA Netw Open April 22, 2021;4(4):e216468. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044?resultClick=1

In this large trial from Brazil, rates of COVID-19–associated hospitalization in 685 patients treated with hydroxychloroquine or lopinavir/ritonavir were not significantly different compared with those who received placebo. The trial was stopped after an interim analysis for futility.

 

Derington CG, Cohen JB, Mohanty AF, et al. Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans. PLOS April 23, 2021 https://doi.org/10.1371/journal.pone.0248080

One of the first observational studies to show a protective association among out-patients between current users of an ARB compared to ACEI on COVID-19-related outcomes. In this retrospective cohort study of 4969 veterans with treated hypertension (and without compelling indications), current users of an ARB in the outpatient cohort had a 9% lower relative risk of all-cause hospitalization or mortality and 16% lower relative risk of ICU admission compared to ACEI users.

 

27 April

Epidemiology

Somekh I, Boker KL, Shohat T, et al. Comparison of COVID-19 Incidence Rates Before and After School Reopening in Israel. JAMA Netw Open April 26, 2021. 2021; 4(4):e217105. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778940?resultClick=1

This study suggests that children aged 0 to 9 years did not have substantial rates of SARS-CoV-2 infection during school attendance periods, and it may be assumed that they did not have a substantial role in COVID-19 spread either during this period. Therefore, resuming school for this age group when lockdown was relaxed appears to have been safe for them.

 

Immunology

Wu Y, Ma L, Cai S, et al. RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-κB hyper-activation and inflammation. Sig Transduct Target Ther 6, 167 (2021). https://www.nature.com/articles/s41392-021-00575-7

How does SARS-CoV-2 trigger dysfunctional inflammatory responses? Here, it is shown that the SARS-CoV-2 N protein promotes the activation of Nuclear Factor κB (NF-κB) signaling, which is one of the key transcription factors of IL-6 in both immune cells and non-immune cells.

 

Scheid JF, Barnes CO, Eraslan B, et al. B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV. Cell April 23, 2021. DOI:https://doi.org/10.1016/j.cell.2021.04.032

It is important to learn more about transcriptional pathways involved in the generation of efficient antiviral antibody (Ab) responses and the roles of different B cell sub-populations. This in-depth analysis of SARS-CoV-2 binding B cells from convalescent individuals show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations such as Ab secreting and activated B cells but also mature naïve B cells.

 

Asarnow D, Wang B, Lee WH, et al. Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia. Cell April 23, 2021. DOI: https://doi.org/10.1016/j.cell.2021.04.033

An important paper that shows bivalent binding and receptor blockade are not sole determinants of potent neutralization. In addition to blocking ACE2, antibodies either inhibit or enhance spike-mediated membrane fusion and formation of syncytia, associated with lung tissue damage. These findings suggest that potentiation of cell-cell fusion by antibodies may compromise the effectiveness of viral neutralization in the treatment of severe COVID-19.

 

Co-morbidities

Bastard P, Orlova E, Sozaeva L, et al. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1. J Exp Med April 23m, 2021, 218 (7): e20210554. https://rupress.org/jem/article/218/7/e20210554/212019/Preexisting-autoantibodies-to-type-I-IFNs-underlie?searchresult=1

Patients with biallelic loss-of-function variants of the autoimmune regulator suffer from autoimmune polyendocrine syndrome type-1 (APS-1). They produce a broad range of autoantibodies, including circulating auto-Abs neutralizing most type I interferons. In this small cohort of 22 APS-1 patients with COVID-19 from seven countries, aged between 8 and 48 years, 19 (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an ICU, 11 (50%) who required mechanical ventilation, and four (18%) who died.

 

26 April

Epidemiology

Mallapaty S. India’s massive COVID surge puzzles scientists. Nature NEWS, April 21, 2021. https://www.nature.com/articles/d41586-021-01059-y

The virus is spreading faster than ever before in the country despite previous high infection rates in megacities, which should have conferred some protection. Smriti Mallapaty summarizes the current knowledge. It remains unclear whether the surge is due to the new variant B.1.617 or due to a fully open society where people were mixing and moving and travelling. Or both.

Brief summary on B.1.617: https://www.sciencemediacentre.org/expert-reaction-to-cases-of-variant-b-1-617-the-indian-variant-being-investigated-in-the-uk/

 

Watson OJ, Alhaffar M, Mehchy Z, et al. Leveraging community mortality indicators to infer COVID-19 mortality and transmission dynamics in Damascus, Syria. Nat Commun 12, 2394 (2021). https://www.nature.com/articles/s41467-021-22474-9

What about Syria? By 2 September, the authors estimate that by September 2, 2020, 4380 (95% CI: 3250 – 5550) COVID-19 deaths in Damascus may have been missed, with 39.0% (95% CI: 32.5% – 45.0%) of the population in Damascus estimated to have been infected.

 

Variants

Funk T, Pharris A, Spiteri G, et al. Characteristics of SARS-CoV-2 variants of concern B.1.1.7, B.1.351 or P.1: data from seven EU/EEA countries, weeks 38/2020 to 10/2021. Euro Surveill 2021;26(16):pii=2100348. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.16.2100348

This analysis outlines the characteristics of SARS-CoV-2 variants of concern (VOC) infections in seven EU/EEA countries, including 19,995 VOC and 3348 non-VOC cases, suggesting a higher risk for hospitalization, and also for ICU admission in age groups < 60 years for B.1.1.7, B.1.351 and P.1. The matched multivariable analysis found that VOC had significantly higher odds of hospitalization than non-VOC cases (aOR: 1.6–4.2).

 

Diagnostics

Jungnick S, Hobmaier B, Mautner L, et al. Detection of the new SARS-CoV-2 variants of concern B.1.1.7 and B.1.351 in five SARS-CoV-2 rapid antigen tests (RATs), Germany, March 2021. Euro Surveill. 2021;26(16):pii=2100413. https://doi.org/10.2807/1560-7917.ES.2021.26.16.2100413

Detection of B.1.1.7 and B.1.351 by RATs (based on detection of the nucleocapsid protein) was comparable to that of the non-VOC strain.

 

Clinical

Rubin GA, Desai AD, Chai Z, et al. Cardiac Corrected QT Interval Changes Among Patients Treated for COVID-19 Infection During the Early Phase of the Pandemic. JAMA Netw Open April 23, 2021;4(4):e216842. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779053

In this cohort study of 965 patients with at least two ECGs, COVID-19 infection was independently associated with significant mean QTc prolongation at days 2 and 5 of hospitalization compared with day 0. The distinctive aspect of this analysis was the inclusion of patients who had negative COVID-19 swabs but continued to receive HCQ and/or azithromycin treatment, which permitted independent analysis of the electrocardiographic association of COVID-19 itself. Of note, 25% of COVID-19 patients receiving neither drug still had a QTc interval of 500 milliseconds or greater.

 

Broccia MM, de Knegt VE, Mills EH, et al. Household exposure to SARS-CoV-2 and association with COVID-19 severity: a Danish nationwide cohort study. Clinical Infectious Diseases April 24, ciab340, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab340/6248492

Large cohort study from Denmark, revealing that the presence of SARS-CoV-2 positive individuals within households did not pose a higher risk of ‘critical COVID-19’ infection among subsequently infected household members.

 

25 April

Epidemiology

Moghadas SM, Fitzpatrick MC, Shoukat A, et al. Simulated Identification of Silent COVID-19 Infections Among Children and Estimated Future Infection Rates With Vaccination. JAMA Netw Open April 23, 2021; 4(4):e217097. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779052?resultClick=1

In this simulation modeling study of a synthetic US population, in the absence of vaccine availability for children, a targeted approach to rapidly identify silent COVID-19 infections in this age group was estimated to significantly mitigate disease burden. Without these measures, vaccination of adults is unlikely to contain outbreaks in the near term.

 

Vaccine

Shimabukuro TT, Kim SY, Myers TR. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. NEJM April 22, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2104983?query=featured_home

Data on more than 35,000 pregnant women receiving mRNA vaccines (BioNTech or Moderna) indicate no safety signals. However, as this was a participant-reported surveillance system, more data is needed.

 

Vasileiou E, Simpson CR, Shi T, et al. Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. Lancet April 23, 2021. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2900677-2

Paper of the day! Between Dec 8, 2020, and Feb 22, 2021, a total of 1,331,993 people were vaccinated in Scotland. The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85–94) for reduced COVID-19 hospital admission at 28–34 days post-vaccination. Vaccine effect for the ChAdOx1 vaccine was 88% (95% CI: 75–94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar the analysis was restricted to those aged 80 years and older (83%, 95% CI: 72–89).

 

Clinical

Tu TM, Seet CY, Koh JS, et al. Acute Ischemic Stroke During the Convalescent Phase of Asymptomatic COVID-2019 Infection in Men. JAMA Netw Open April 22 2021;4(4):e217498. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779040?resultClick=1

This small cohort from Singapore describes 18 adults 50 years or younger who presented with AIS in the convalescent period of COVID-19 infection. The median (range) time from a positive serological test result to AIS was 54.5 (0-130) days. The findings suggest an increased risk of AIS for these patients even months after a serological diagnosis.

 

Co-morbidities

Agrawal M, Zhang X, Brenner EJ, et al. The impact of vedolizumab on COVID-19 outcomes among adult IBD patients in the SECURE-IBD registry. Journal of Crohn’s and Colitis April 22, 2021, jjab071, https://academic.oup.com/ecco-jcc/advance-article/doi/10.1093/ecco-jcc/jjab071/6245085?searchresult=1

Of 3647 adult patients on any IBD medication in the registry, 457 (12.5%) patients were on vedolizumab (VDZ), a gut-selective anti-integrin. COVID-19 outcomes among IBD patients on VDZ were comparable to those on all other therapies.

 

24 April

Epidemiology

Panovska-Griffiths J, Kerr CC, Waites W et al. Modelling the potential impact of mask use in schools and society on COVID-19 control in the UK. Sci Rep April 22, 2021, 11, 8747. https://www.nature.com/articles/s41598-021-88075-0

This modelling study from the UK shows that mandating the use of masks in secondary schools would not be sufficient to prevent a COVID-19 resurgence in late 2020. Assuming test-trace-isolate (TTI) levels from August 2020 and no changes in the virus’s transmissibility, adoption of masks would have reduced the predicted size of a second wave, but preventing it would have required 68% or 46% of those with symptoms to seek testing (assuming masks’ effective coverage 15% or 30% respectively). With masks in community settings but not secondary schools, the required testing rates increase to 76% and 57%.

 

Transmission

Mack CD, DiFiori J, Tai CG, et al. SARS-CoV-2 Transmission Risk Among National Basketball Association Players, Staff, and Vendors Exposed to Individuals With Positive Test Results After COVID-19 Recovery During the 2020 Regular and Postseason. JAMA Intern Med April 22, 2021. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2779287?resultClick=1

A negative PCR is not necessary for ending up quarantine. In this large retrospective cohort study of the 2020 NBA closed campus occupational health program, none of the 36/3648 (1%) participants who continued to test positive for SARS-CoV-2 (cycle threshold range 30-37) following discontinuation of isolation were infectious to others. Of note, this included 29 individuals who were engaged in at least 1480 person-days of indoor, unmasked contact events or situations during the period of persistent positive test results, supporting a time-based approach to discontinuation of isolation.

 

Long COVID-19

Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequalae of COVID-19. Nature April 22, 2021. https://www.nature.com/articles/s41586-021-03553-9

High-dimensional is correct. This incredible work, the largest post-acute COVID-19 study to date, included 73,435 non-hospitalized and 13,654 hospitalized patients with COVID-19, 4,990,835 controls, and 13,997 patients hospitalized with seasonal influenza. The results suggest that beyond the first 30 days of illness, people with COVID-19 are at higher risk of death, health care resource utilization, and exhibit a broad array of incident pulmonary and extrapulmonary clinical manifestations.

 

Treatment

Sasisekharan R. Preparing for the Future — Nanobodies for Covid-19? NEJM April 22, 2021, 384:1568-1571. https://www.nejm.org/doi/full/10.1056/NEJMcibr2101205?query=featured_home

Intravenously administered antibody drugs are facing several problems, including the narrow therapeutic window, the relative paucity of infusion centers and medical staff professionals, and the emergence of mutations that affect the spike protein. This brief review focusses on nanobodies that may offer a cheap alternative, possibly formulated for aerosol or subcutaneous administration.

 

Pediatrics

Villar J, Ariff S, Gunier RB. Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection. JAMA Pediatr April 22, 2021. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2779182?resultClick=1

This prospective, multinational study compared 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19. The risk of maternal mortality was 1.6%, ie, 22 times higher in the group of women with a COVID-19 diagnosis. Of note, these deaths were concentrated in institutions from less developed regions. Data also indicate an association between COVID-19 and higher rates of preeclampsia/eclampsia/HELLP syndrome.

 

23 April

Today, we present papers focusing only on vaccines: Johnson & Johnson’s Phase III study, data on a new recombinant spike vaccine and some reports on the growing evidence that breakthrough infections may occur after vaccination.

Vaccine

Sadoff J, Gray G, Vandebosch A, et al. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. NEJM Apr 22, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2101544?query=featured_home

Paper of the day. In this large Phase III study, Johnson & Johnson’s Ad26.COV2.S vaccine protected 67% (66%) against moderate to severe/critical COVID-19 with onset at least 14 (28) days after administration. Vaccine efficacy was higher against severe/critical disease (85% for onset at ≥ 28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 82% against severe/critical COVID-19 with onset at least 28 days after administration.

 

Chappell KJ, Mordant FL, Li Z, et al. Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Inf Dis April 19, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00200-0/fulltext

This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilized recombinant spike protein elicits strong immune responses with a promising safety profile. However, as the glycoprotein 41 peptide present in the clamp created HIV cross-reactivity, this specific vaccine design will not be progressed further.

 

Cavanaugh AM, Fortier S, Lewis P, et al. COVID-19 Outbreak Associated with a SARS-CoV-2 R.1 Lineage Variant in a Skilled Nursing Facility After Vaccination Program — Kentucky, March 2021. MMWR Morb Mortal Wkly Rep. ePub: 21 April 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e2.htm?s_cid=mm7017e2_w#suggestedcitation

In a COVID-19 outbreak at a Kentucky skilled nursing facility involving a newly introduced variant (characterized by E484K and other mutations within the spike protein) to the region, 26/83 residents (18/75 fully vaccinated with BioNTech) and 20/116 HCP (4/61 vaccinated) became infected. Vaccine was 86.5% protective against symptomatic illness among residents and 87.1% protective among HCP. Three residents died, two of whom were unvaccinated (vaccine effectiveness 94%).

 

Teran RA, Walblay KA, Shane EL, et al. Postvaccination SARS-CoV-2 Infections Among Skilled Nursing Facility Residents and Staff Members — Chicago, Illinois, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 21 April 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e1.htm?s_cid=mm7017e1_w#suggestedcitation

During the investigation period, an estimated 7931 skilled nursing facility residents and 6834 staff members received two doses of the COVID-19 vaccine. Among 12 possible breakthrough SARS-CoV-2 infections among fully vaccinated residents ≥ 14 days after their second dose of COVID-19 vaccine, 8 were asymptomatic.

 

Hacisuleyman E, Hale H, Saito Y, et al. Vaccine Breakthrough Infections with SARS-CoV-2 Variants. NEJM April 21, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2105000?query=featured_home

Two breakthrough cases. Despite evidence of vaccine efficacy in both women, symptoms of COVID-19 developed, and they tested PCR positive 19 and 36 days after the second MODERNA shot. Rapid identification of sequence variants by targeted PCR amplification showed that neither sequence precisely fit any known clade.

 

22 April

Vaccine

Goepfert PA, Fu B, Chabanon AL, et al. Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1–2, dose-ranging study. Lancet Inf Dis April 19, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00147-X/fulltext

Recombinant protein vaccines offer the advantages of fewer potential safety concerns and lower production costs than other traditional (eg, attenuated or inactivated) vaccines. However, they often require the use of an adjuvant to enhance the magnitude and quality of the immune response. In this first-in-human evaluation, CoV2 preS dTM (a stabilized pre-fusion spike protein vaccine produced in a baculovirus expression system) had suboptimal immunogenicity and greater than expected reactogenicity, requiring optimization of the antigen formulation.

 

Variants

Munitz A, Yechezkel M, Dickstein Y. BNT162b2 Vaccination Effectively Prevents the Rapid Rise of SARS-CoV-2 Variant B.1.1.7 in high risk populations in Israel. Cell Rep Med April 17, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00080-X

Good news. Although B.1.1.7 is 45% more transmissible than the wild type strain, becoming the dominant lineage in Israel within a few weeks, focused RT-PCR testing and prioritized vaccination programs can prevent the spread of the B.1.1.7 variant in the elderly.

 

Deng X, Garcia-Knight MA, Khalid MM, et al. Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant. Cell April 20, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00505-5

The “California” variant named B.1.427/B.1.429 to denote its 2 lineages, with 3 mutations, including L452R, emerged in May 2020 and increased from 0% to > 50% of sequenced cases from September 2020 to January 2021, showing a 19-24% increased transmissibility. Antibody neutralization assays revealed modest decreases (4.0 to 6.7-fold and 2.0-fold) in neutralizing titers from convalescent patients and vaccine recipients, respectively.

 

Clinical

Lebreton G, Schmidt M, Ponnaiah M, et al. Extracorporeal membrane oxygenation network organisation and clinical outcomes during the COVID-19 pandemic in Greater Paris, France: a multicentre cohort study. Lancet Resp Med April 19, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00096-5/fulltext

Of 302 patients on ECMO during the first wave in Paris, 46% were alive at 90 days. During ECMO, 43% had a major bleeding event, 27 of whom had intracranial hemorrhage. Among other well-known factors, treatment in centers that manage at least 30 venovenous ECMO cases annually was independently associated (odds ratio 2.98) with improved 90-day survival.

 

Dy LF, Lintao RC, Cordero CP, et al. Prevalence and prognostic associations of cardiac abnormalities among hospitalized patients with COVID-19: a systematic review and meta-analysis. Sci Rep 11, 8449 (2021). https://www.nature.com/articles/s41598-021-87961-x

Despite significant heterogeneity in most comparisons, there is a trend towards a definite increase in mortality or severity risk among COVID-19 patients with any cardiac abnormality. Much more long-term prognostic studies are needed as well as to formalize definitive criteria of “COVID-19 associated cardiomyopathy”.

 

21 April

Virology

Hamed SM, Elkhatib WF, Khairalla AS et al. Global dynamics of SARS-CoV-2 clades and their relation to COVID-19 epidemiology. Sci Rep April 19, 2021, 11, 8435. https://www.nature.com/articles/s41598-021-87713-x

In this study, the metadata of 408,493 SARS-CoV-2 genomes submitted to GISAID EpiCoV database as of January 25, 2021 were analyzed. Most of the genomes belonged to one of seven major clades, namely L, S, V, G, GH, GR or GV. Clade GR was the most frequently identified followed by GV and GH. Earlier in January, clade G characterized by spike D614G mutation was identified and rapidly predominated in the pandemic. Some more data on distribution by geography, age, and gender.

Vaccine

Rossman H, Shilo S, Meir T, et al. COVID-19 dynamics after a national immunization program in Israel. Nat Med April 19, 2021. https://www.nature.com/articles/s41591-021-01337-2

No doubt – Paper of the day. The early effect of the national vaccination campaign in Israel on the pandemic dynamics. A little over 2 months after the initiation of the campaign, with 85% of individuals older than 60 years already vaccinated with two doses (24 February 2021), there was an approximate 77% drop in cases, a 45% drop in positive test percentage, a 68% drop in hospitalizations and a 67% drop in severe hospitalizations compared to peak values. Larger and earlier decreases in COVID-19 cases and hospitalization were observed in individuals older than 60 years, followed by younger age groups, in the order of vaccination prioritization. This pattern was not observed in the previous lockdown and was more pronounced in early vaccinated cities.

 

Diagnostics

Zacharias M, Stangl V, Thüringer A, et al. Rapid antigen test for postmortem evaluation of SARS-CoV-2 carriage. Emerg Infect Dis. 2021 April 13 [date cited]. https://doi.org/10.3201/eid2706.210226

This prospective cohort study compared a rapid antigen test (RAT) with PCR in 30 consecutive deceased COVID-19 patients. 80% (24/30) of cases were PCR positive, whereas 56.7% (17/30) were RAT-positive. RAT sensitivity was high in patients with low Ct values (high viral load) and all cases with disease courses > 17 days were RAT-negative. Findings indicate the rapid test’s usability as a tool to guide autopsy practice.

 

Clinical

Rossen LM, Branum AM, Ahmad FB, Sutton PD, Anderson RN. Notes from the Field: Update on Excess Deaths Associated with the COVID-19 Pandemic — United States, January 26, 2020–February 27, 2021. MMWR Morb Mortal Wkly Rep 2021;70:570–571. https://www.cdc.gov/mmwr/volumes/70/wr/mm7015a4.htm?s_cid=mm7015a4_w

Best Figure of the day. During January 26, 2020–February 27, 2021, an estimated 545,600–660,200 more persons than expected died in the United States from all causes. Approximately 75%–88% of excess deaths were directly associated with COVID-19. Using weekly historical and provisional mortality data from 2013 through 2021, expected numbers of deaths were estimated using over-dispersed Poisson regression models with spline terms to account for seasonal patterns.

Treatment

Taylor PC, Adams AC, Hufford MM, et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol April 17, 2021. https://doi.org/10.1038/s41577-021-00542-x

Excellent review. Early clinical trial data is encouraging, but many unanswered questions set a pressing research agenda. Which at-risk individuals would benefit most from prophylactic neutralizing mAbs? What is the duration of protection? Is there any potential impact of mAb therapy on subsequent vaccination? It will also be important to determine the optimum timing for administration of neutralizing mAbs on the basis of viral load, serology and other potential clinical factors.

 

20 April

Epidemiology

Gettings JR, Gold JA, Kimball A, et al. SARS-CoV-2 transmission in a Georgia school district — United States, December 2020–January 2021. Clinical Infectious Diseases, April 17, 2021, ciab332. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab332/6232104?searchresult=1

During December 1, 2020–January 22, 2021, 86 index cases and their close contacts in schools were identified. Of 679 contacts, 59 (9%) tested positive. Highest secondary attack rates were observed in indoor, high-contact sports settings (24%) and staff meetings/lunches (18%).

 

Di Domenico L, Sabbatini CE, Pullano G, et al. Impact of January 2021 curfew measures on SARS-CoV-2 B.1.1.7 circulation in France. Euro Surveill. 2021;26(15):pii=2100272. https://doi.org/10.2807/1560-7917.ES.2021.26.15.2100272

Curfew alone is not enough. The authors estimate that curfew measures allowed hospitalizations to plateau by decreasing transmission of the historical strains while B.1.1.7 continued to grow. Without progressively strengthened social distancing, a rapid surge of hospitalizations is expected, despite the foreseen increase in vaccination rhythm.

Transmission

Allen JG, Ibrahim AM. Indoor Air Changes and Potential Implications for SARS-CoV-2 Transmission. JAMA April 16, 2021. https://jamanetwork.com/journals/jama/fullarticle/2779062

Some thoughts on far-field airborne transmission (defined as within-room but beyond 6 feet) of SARS-CoV-2. Air changes per hour and air filtration is a simple but important concept that could be deployed to help reduce risk from within-room but distant airborne transmission of SARS-CoV-2 and other respiratory infectious diseases. Healthy building controls like higher ventilation and enhanced filtration are a fundamental, but often overlooked, part of risk reduction strategies that could have benefit beyond the current pandemic.

 

Vaccine and co-morbidities

Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia. Blood April 16, 2021. https://ashpublications.org/blood/article/doi/10.1182/blood.2021011568/475742/Efficacy-of-the-BNT162b2-mRNA-COVID-19-Vaccine-in?searchresult=1

Antibody response to BNT162b2 mRNA COVID-19 vaccine in CLL patients is markedly impaired and affected by disease activity and treatment. In a total of 167 patients with CLL who received two doses, the antibody response rate was only 39.5%. In patients treated with either Bruton’s tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, responses were particularly low (16% and 14%).

 

Severe COVID-19

Luo H, Liu D, Liu W, et al. Germline variants in UNC13D and AP3B1 are enriched in COVID-19 patients experiencing severe cytokine storms. Eur J Hum Genet Apr 19, 2021. https://www.nature.com/articles/s41431-021-00886-x

Whole-exome sequencing in 233 hospitalized COVID-19 patients identified four primary immunodeficiency gene variants significantly enriched in patients experiencing severe cytokine storms. The percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical hemophagocytic lymphohistiocytosis genes, was dramatically higher in the high level cytokine group than in the low level group (33.3% vs 5.7%, p < 0.001).

 

19 April

Vaccine

Blain H, Tuaillon E, Gamon L, et al. Spike Antibody Levels of Nursing Home Residents With or Without Prior COVID-19 3 Weeks After a Single BNT162b2 Vaccine Dose. JAMA April 15, 2021. https://jamanetwork.com/journals/jama/fullarticle/2778926?resultClick=1

One shot may be enough in people with previous COVID-19. What had already been described in HCW (https://jamanetwork.com/journals/jama/fullarticle/2777171?resultClick=1) may also be true for nursing home residents: all 36 residents (100%) with prior COVID-19 were seropositive for S protein IgG after one mRNA vaccine dose vs only 29 of 60 residents (49.2%) without prior COVID-19.

 

Transmission

Braun KM, Moreno GK, Buys A, et al. Viral sequencing reveals US healthcare personnel rarely become infected with SARS-CoV-2 through patient contact. Clinical Infectious Diseases April 15, 2021, ciab281. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab281/6226897?searchresult=1

Katarina Braun and colleagues from Madison, Wisconsin, US investigated SARS-CoV-2 infection clusters involving 95 HCP and 137 possible patient contact sequences. Strikingly, only 4/95 of HCP infections could be traced back to a patient source.

 

Diagnostics

Essler JL, Kane SA, Nolan P, et al. Discrimination of SARS-CoV-2 infected patient samples by detection dogs: A proof of concept study. PLOS April 14, 2021. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250158

Dogs successfully discriminated between infected and uninfected urine samples, regardless of the inactivation protocol, as well as heat-treated saliva samples. But it’s not that easy. Generalization to novel samples was limited, particularly after intensive training with a restricted sample set.

 

Long COVID

Moulson N, Petek BJ, Drezner JA, et al. SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes. Circulation 17 Apr 2021. https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.054824

Cardiac involvement is rare among young competitive athletes. Among 3018 athletes who tested positive for SARS-CoV-2 infection (mean age 20 years, 32% female), abnormal findings suggestive of cardiac involvement were detected by ECG (0.7%), cardiac troponin (0.9%), and TTE (0.9%). Clinical predictors of cardiac involvement included cardiopulmonary symptoms (such as chest pain or shortness of breath) during acute infection or upon return to exercise and any abnormality on triad testing. Findings suggest that asymptomatic or mildly symptomatic athletes who have fully recovered from SARS-CoV-2 infection may return to sport without cardiac testing.

 

Treatment

Rosenke K, Hansen F, Schwarz B, et al. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model. Nat Commun 12, 2295 (2021). https://doi.org/10.1038/s41467-021-22580-8

A new post-exposure prophylaxis? Molnupiravir (MK-4482), an orally administered nucleoside analog, inhibited SARS-CoV-2 replication in the Syrian hamster model. An inhibitory effect was observed in animals when the drug was administered either beginning 12 h before or 12 h after infection in a high-risk exposure model. Large clinical trials are planned (or ongoing). However, the potential treatment window for molnupiravir may be small. Direct acting antivirals seem to be most effective in modifying disease outcome when administered as early as possible following infection.

 

18 April

Vaccine

Scully M, Sing D, Lown R, et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19. NEJM April 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2105385

This case series of 23 patients from London who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). All patients had D-dimer levels at presentation much higher than what would be expected in patients with acute venous thromboembolism.

 

Muir KL, Kallam A, Koepsell SA, et al. Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination. NEJM April 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2105869

First case seen with the Ad26.COV2.S vaccine from Johnson & Johnson. A 48-year-old White woman presenting with extensive thrombosis associated with severe thrombocytopenia and disseminated intravascular coagulation. The patient remained critically ill at the time of this report.

 

Sadoff J, Davis K, Douoguih M. Thrombocytopenia after Ad26.COV2.S Vaccination — Response from the Manufacturer. NEJM April 16, 2021, https://www.nejm.org/doi/full/10.1056/NEJMc2106075

Response from Janssen: Their ongoing safety surveillance received reports of six cases of CVST with thrombocytopenia occurring 7 to 14 days after vaccination, including the above case. These cases were reported among more than 7.2 million persons who had been vaccinated with Ad26.COV2.S globally as of April 14. Janssen argues (and surely hopes) that their numbers are lower, due to substantial vector and spike differences between their vaccine and Astra Zeneca’s. Their vaccine uses a human Ad26–based vector (vs the chimpanzee one for ChAdOx1 nCoV-19) with different host cell receptors and is likely to have different phylogenetic and biologic characteristics. Let’s hope.

 

Ledford H. COVID vaccines and blood clots: five key questions. Nature News April 16, 2021. https://www.nature.com/articles/d41586-021-00998-w

Heidi Ledford summarizes the key questions (but has no definite answers): What could the connection be between blood clots and vaccines? Are other COVID-19 vaccines linked to blood clotting disorders? How rare are they and are certain groups of people more at risk? What impact will fears over potential side effects have on global vaccination efforts? Answers needed.

Immunology

Alshukairi AN, Zhao J, Al-Mozaini MA, Wang Y, Dada A, Baharoon SA, et al. Longevity of Middle East respiratory syndrome coronavirus antibody responses in humans, Saudi Arabia. Emerg Infect Dis April 14, 2021. https://wwwnc.cdc.gov/eid/article/27/5/20-4056_article

Learning from MERS? Antibody responses in 48 human MERS-CoV infection survivors who had variable disease severity in Saudi Arabia, MERS-CoV–specific neutralizing antibodies were detected for 6 years post-infection. Positive neutralizing antibodies were found in 21/31 survivors with mild disease, 12/12 moderate disease, and 5/6 survivors with severe disease.

Transmission

Sickbert-Bennett EE, Samet JM, Prince SE, et al. Fitted Filtration Efficiency of Double Masking During the COVID-19 Pandemic. JAMA Intern Med. 2021; https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2778913

Anthony Fauci is doing right when wearing two masks. This study compared the fitted filtration efficiency (FFE) of commonly available masks worn alone, doubled, or in combinations. Wearing a medical procedure mask underneath a cloth mask provided the best improvement to FFE of all the combinations evaluated.

 

17 April

Immunology

Letizia AG, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study. Lancet Resp Med April 15, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00158-2/fulltext

84% protection. In this large prospective cohort study of new US Marine recruits (18–20 years old, mostly male) without active infection, a lower proportion of participants who had baseline serum antibodies (n = 225) became infected during the 6-week study period than of those without detectable antibodies (n = 2851). After adjusting for the effects of race, age, and sex, the hazard ratio comparing seropositive participants and seronegative participants was 0.16 (95% CI: 0.10–0.25; p < 0·001). The risk of subsequent infection in seropositive individuals was associated with lower IgG antibody titers and absent or lower neutralizing antibody activity.

 

Alrubayyi A, Peppa D. Seeing SARS-CoV-2 variants through the eyes of T cells. Nat Rev Immunol April 14, 2021. https://www.nature.com/articles/s41577-021-00551-w

Best paper title of the day. It’s time to look at the T cells. They will do their job, irrespective as to what variant is present. The authors discuss a pre-print indicating a negligible impact of the SARS-CoV-2 variant mutations on global CD4+ and CD8+ T cell responses in COVID-19 convalescent donors and COVID-19 mRNA vaccine recipients. It’s not all about antibodies. Hopefully.

 

Transmission

Cheng VC, Fung SC, Siu GT, et al. Nosocomial outbreak of COVID-19 by possible airborne transmission leading to a superspreading event. Clinical Infectious Diseases 14 April 2021. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab313/6225253?searchresult=1

A superspreading event involving 12 patients and 9 healthcare workers (HCWs) occurred within 4 days in 3 of 6 cubicles at an old-fashioned general hospital ward with no air exhaust system within the cubicles. Some evidence (however, no proof) that transmission was airborne.

 

Diagnostics

Tsang NN, So HC, Ng KY, et al. Diagnostic performance of different sampling approaches for SARS-CoV-2 RT-PCR testing: a systematic review and meta-analysis. Lancet Inf Dis April 12, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00146-8/fulltext

Incredible work. Of the 5577 studies identified, 23 studies that included 7973 participants with 16,762 respiratory samples were included. Compared with the gold standard of nasopharyngeal swabs, pooled nasal and throat swabs offered the best diagnostic performance. Saliva and nasal swabs gave comparable and very good diagnostic performance and are clinically acceptable alternative specimen collection methods. Throat swabs gave a much lower sensitivity and positive predictive value and should not be recommended.

 

Treatment

Keating SM, Mizrahi RA, Adams MS, et al. Generation of recombinant hyperimmune globulins from diverse B-cell repertoires. Nat Biotechnol April 14, 2021. https://www.nature.com/articles/s41587-021-00894-8

This paper describes a new technology (a microfluidics and molecular genomics strategy) for generating recombinant hyperimmune globulins that combines the advantages of recombinant antibodies (purity, consistency, potency) with the advantages of plasma-derived antibodies (proven efficacy, diversity, polyvalence, in vivo affinity maturation).

 

Other facts to consider

Marshall CR, Latorre DV, Wilson CJ, et al. Absolute abundance and preservation rate of Tyrannosaurus rex. Science 16 Apr 2021: Vol. 372, Issue 6539, pp. 284-287. https://science.sciencemag.org/content/372/6539/284

How many Tyrannosaurus rex terrorized the Earth at any one time? 20,000. Multiplying the plausible population densities by the plausible geographic areas yielded an average population size of 20,000 animals, with a 95% confidence interval from 1300 to 328,000 (ie, 3800 per area the size of the state of California, 2 / Washington, DC).

 

16 April

 

Variants

Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 14 Apr 2021: eabh2644. https://science.sciencemag.org/content/early/2021/04/13/science.abh2644

The second wave of infection in Manaus was associated with the emergence and rapid spread of lineage P.1. that occurred mid-November 2020 and had acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. P.1 may be 1.7–2.4-fold more transmissible, and previous (non-P.1) infection provides 54–79% of the protection against infection with P.1 that it provides against non-P.1 lineages.

 

Vaccines

Anichini G, Terrosi C Gandolfo C, et al. SARS-CoV-2 Antibody Response in Persons with Past Natural Infection. NEJM April 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2103825?query=featured_coronavirus

This study indicates a significantly lower neutralizing antibody titer after administration of a second dose of vaccine in previously uninfected patients than the titer after only a single dose of vaccine in previously infected participants.

Transmission

Dietrich WL, Bennett JS, Jones BW, Hosni MH. Laboratory Modeling of SARS-CoV-2 Exposure Reduction Through Physically Distanced Seating in Aircraft Cabins Using Bacteriophage Aerosol — November 2020. MMWR Morb Mortal Wkly Rep. ePub: 14 April 2021. DOI: https://www.cdc.gov/mmwr/volumes/70/wr/mm7016e1.htm?s_cid=mm7016e1_w

Boeing, listen up! Based on laboratory modelling of exposure (not transmission!) to SARS-CoV-2 on single-aisle and twin-aisle aircraft, exposures in scenarios in which the middle seat was vacant were reduced by 23% to 57%, compared with full aircraft occupancy, depending upon the model.

 

Spinelli MA, Rutherford G, Gandhi M. Lowering SARS-CoV-2 viral load might affect transmission but not disease severity in secondary cases – Authors’ reply. Lancet April 14, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00210-3/fulltext

Some comments about a potential relationship between non-pharmaceutical interventions (NPIs) and the viral inoculum as well as the impact of reduced inoculum on COVID-19 severity.

 

Pediatrics

Ramaswamy A, Brodsky NN, Sumida TS. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity April 13, 2021. https://www.cell.com/action/showPdf?pii=S1074-7613%2821%2900165-5

This comprehensive analysis of 23 MIS-C patients using single-cell RNA sequencing, antigen receptor repertoire analysis, serum proteomics, and in vitro assays provides in-depth data on disease immunopathology. Data implicate innate and adaptive immune triggering with direct relevance for tissue destruction during acute MIS-C.

 

15 April

Variants

Graham MS, Sudre CH, May A, et al. Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study. Lancet Public Health April 12, 2021. https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(21)00055-4/fulltext

From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36,920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. There were no changes in reported symptoms or disease duration associated with B.1.1.7.

 

Betton M, Livrozet M, Planas D, et al. Sera neutralizing activities against SARS-CoV-2 and multiple variants six month after hospitalization for COVID-19. Clinical Infectious Diseases 14 April 2020, ciab308, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab308/6225251?searchresult=1

This prospective study analyzed sera of 107 patients hospitalized with COVID-19 at 3 and 6 months post-infection. Decrease of IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Sera collected at 6 months showed efficient neutralizing effects against the D614G, B.1.1.7 and P.1 variants but a significantly weaker activity against the B.1.351 variant.

 

Immunology

Suryamohan K, Diwanji D, Seshagiri S. Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2. Communications Biology 4 , 1–11, 12 April 2021. https://www.nature.com/articles/s42003-021-02030-3

ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting interaction. The authors analyzed over 290,000 samples from public genomic datasets and identified several ACE2 protein-altering variants. Some experiments indicate that ACE2 variants can modulate susceptibility to SARS-CoV-2.

 

Severe COVID-19

de la Morena-Barrio ME, Bravo-Pérez C, Miñano A. et al. Prognostic value of thrombin generation parameters in hospitalized COVID-19 patients. Sci Rep 08 April 2021, 11, 7792 (2021). https://www.nature.com/articles/s41598-021-85906-y

More on the pathogenesis of severe COVID-19. The severe “storm” of pro-inflammatory cytokines, combined with cell lysis, particularly at the endothelium, constitute insults leading to a significant hypercoagulable state that, despite antithrombotic prophylaxis, cause a consumptive and diffuse coagulopathy reflected by the increase of D-dimer, independent of the hypofibrinolysis that is also present in these patients. Patients with lower capacity of thrombin generation and higher D-dimer levels have poor prognosis.

 

Collateral damages

Pirkis J, John A, Shin S, et al. Suicide trends in the early months of the COVID-19 pandemic: an interrupted time-series analysis of preliminary data from 21 countries. Lancet Psychiatry April 13, 2021. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(21)00091-2/fulltext

Was there an early effect of the COVID-19 pandemic on suicide rates around the world? Probably not. In high-income and upper-middle-income countries, suicide numbers have remained largely unchanged or declined in the early months of the pandemic compared with the expected levels based on the pre-pandemic period.

 

Education

Caessens Am Keita-Perse O, Berthier F, et al. Self-Illusion and Medical Expertise in the Era of COVID-19. Open Forum Infectious Diseases, Volume 8, Issue 4, 13 April 2021, ofab058, https://academic.oup.com/ofid/article/8/4/ofab058/6224992?searchresult=1

This was a survey among 2487 participants (from Monaco, May/June 2020) looking at public perception of one’s knowledge regarding COVID-19. Results confirm the concept of “over average syndrome”. In other words: a high level of self-confidence contrasted with low performance on the test. Level of medical literacy obviously altered quality of response. Physicians had the best ratings but other health care professionals (nurses, etc) did not perform well.

 

14 April

Variants

Frampton D, Rampling R, Cross A, et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Inf Dis April 12, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00170-5/fulltext

It will be interesting to see whether this elegant study will gain as much media attraction as the studies showing the opposite: comparing 198 patients with B.1.1.7 infection and 143 with non-B.1.1.7 infection, the authors found NO evidence of an association between severe disease and death and lineage in unadjusted analyses or in analyses adjusted for hospital, sex, age, co-morbidities, and ethnicity. Viral load by proxy was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold value.

 

Ong SW, Young BE, Lye DC. Lack of detail in population-level data impedes analysis of SARS-CoV-2 variants of concern and clinical outcomes. Lancet Inf Dis April 12, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00201-2/fulltext

Comment on the previous study, followed by a nice overview. What do we know about the effects of B.1.1.7 on disease severity? Not enough. Confounding factors including health care resource use, demographic changes, and socio-behavioral trends affect clinical outcomes, including mortality, and are difficult to adjust for without detailed, robust, patient-level data. According to the authors, “careful epidemiologic and clinical assessment, coupled with a healthy skepticism, is important when assessing claims of the effect of these variants”. Agreed.

 

Immunology

Yang F, Nielsen SC, Hoh RA, et al. Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues. Science 12 Apr 2021: eabf6648. https://science.sciencemag.org/content/early/2021/04/09/science.abf6648

Pre-pandemic children had class-switched convergent clones to SARS-CoV-2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. The authors hypothesize that previous HCoV exposures may stimulate cross-reactive memory, and that such clonal responses may have their highest frequencies in childhood.

 

Clinical

Wiegele PN, Kabar I, Kerschke L, Froemmel C, Hüsing-Kabar A, Schmidt H, Vorona E, et al. Symptom diary–based analysis of disease course among patients with mild coronavirus disease, Germany, 2020. Emerg Infect Dis. 2021 May [date cited]. https://doi.org/10.3201/eid2705.204507

Daily prevalence of symptoms in 313 mildly ill COVID-19 outpatients in the first 20 days of illness. Fatigue (91%), cough (85%), and headache (78%) were the most common symptoms and occurred a median of 1 day from symptom onset. Neurological symptoms, such as loss of taste (66%) and anosmia (62%), and dyspnea (51%) occurred considerably later (median 3–4 days after symptom onset).

 

Long COVID-19

Nayagam JS, Jeyaraj R, Mitchell T, et al. Persistent cholestasis in survivors of SARS-CoV-2. J Infection April 03, 2021. DOI: https://doi.org/10.1016/j.jinf.2021.03.029

A considerable proportion of patients with SARS-CoV-2 infection do not normalize their liver blood tests during follow-up, particularly those with highly elevated GGT. Of 397 patients who survived to 60 days, 216 had abnormal liver blood tests. Repeat blood tests at day 60 were performed in 43 of these patients, and a persistent abnormality in liver blood tests was detected in 24/43 patients (55.8%), predominantly in a cholestatic pattern: 3/38 (7.9%) AST abnormal; 12/43 (27.9%) ALP abnormal; and 23/43 (53.5%) GGT abnormal.

 

Treatment

Gaziano L, Giambartolomei C, Pereira AC, et al. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nat Med. 2021 Apr 9. https://www.nature.com/articles/s41591-021-01310-z

Genetic variants acting in ‘cis’ on druggable protein levels or gene expression that encode druggable proteins may mimic the beneficial (or harmful) effects observed by pharmacological modification. This large-scale MR analysis of protein and gene expression data for 1263 actionable druggable genes revealed evidence for drug targets of type I IFNs (IFNAR2) and ACE2 modulators (ACE2) as priority drug candidates for evaluation.

 

13 April

Transmission

Park M, Pawliuk C, Nguyen T, et al. Determining the communicable period of SARS-CoV-2: A rapid review of the literature, March to September 2020. Euro Surveill. 2021;26(14):pii=2001506. https://doi.org/10.2807/1560-7917.ES.2021.26.14.2001506

After reviewing 160 studies, the authors conclude (not surprisingly) significant heterogeneity in reported data. The median duration after symptom onset that virus was successfully isolated was 9 days (IQR: 2.25; range: 2–21), while the corresponding median value for longest duration until viral clearance by RT-PCR was 26 days (IQR: 16.8; range: 8–63).

 

Immunology

Ferreira-Gomes M, Kruglov A, Durek P, et al. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat Commun 12, 1961, March 30, 2021. https://www.nature.com/articles/s41467-021-22210-3

In 60 patients with severe COVID-19, the initial immune reaction (reflected by egress of antibody-secreting plasmablasts into the blood and antibody class switching to IgG1 and IgA1) was controlled by IFNs, IL-21, and TGF-β. At later time points (when IFN is no longer involved), the immune reactions are controlled by TGF-β (and IL-21), which drives cells to switch to the terminal antibody class IgA2. At these later time points, the immune reaction is no longer directed to SARS-CoV-2. Such cells do not relocate to the lung, are not specific for the spike protein and contribute little to humoral immunity to SARS-CoV-2.

 

Diagnostics

Ogbe A, Kronsteiner B, Skelly DT, et al. T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses. Nat Commun April 6, 2021, 12, 2055. https://www.nature.com/articles/s41467-021-21856-3

According to this study, distinct T cell assay platforms (ELISPOT, proliferation assay) should be used across the same individuals to characterize the differences between T cell responses associated with recent SARS-CoV-2 infection and long-term cross-reactive memory T cell responses in unexposed populations.

 

Co-morbidities

Haffner MR, Le HV, Saiz Jr AM, et al. Postoperative In-Hospital Morbidity and Mortality of Patients With COVID-19 Infection Compared With Patients Without COVID-19 Infection. JAMA Netw Open April 12, 2021;4(4):e215697. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778455?resultClick=1

A total of 5470 surgical patients with positive COVID-19 test results were matched with 5470 surgical patients with negative COVID-19 test results during the same study period. COVID-19 infection was an independent risk factor for increased perioperative mortality but not complications. Specifically, the overall mortality rate was more than double in the cohort with COVID-19 (14.8% vs 7.1%).

 

Pediatrics

Perl SH, Uzan-Yulzari A, Klainer H, et al. SARS-CoV-2–Specific Antibodies in Breast Milk After COVID-19 Vaccination of Breastfeeding Women. JAMA April 12, 2021. https://jamanetwork.com/journals/jama/fullarticle/2778766?resultClick=1

Robust secretion of SARS-CoV-2 specific IgA and IgG antibodies in breast milk for 6 weeks after vaccination. In 84 women providing 504 breast milk samples, IgA secretion was evident as early as 2 weeks after vaccination followed by a spike in IgG after 4 weeks (a week after the second vaccine).

 

12 April

Sunday evening: Cold, heavy rain. Curfew. Exponential growth of infections. ICUs to the limit, vaccines are still in shortage. Politicians quarrel over lockdown rules. Everyone tired. Johnson & Johnson’s vaccine may bear the same clotting risk as Astra Zeneca’s Vaxzevria®: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-6-9-april-2021

Depressed? Well, here is some good news.

 

Epidemiology

Matthias J, Charboneau T, Schaffer C, et al. Notes from the Field: COVID-19 Case Investigation and Contact Tracing Program — Spirit Lake Tribe, North Dakota, September–November 2020. MMWR Morb Mortal Wkly Rep 2021;70:533–534. https://www.cdc.gov/mmwr/volumes/70/wr/mm7014a4.htm?s_cid=mm7014a4_w

The Spirit Lake sovereign nation in North Dakota is home to approximately 7,500 members of the Spirit Lake Tribe. From September 29–November 20, 2020, a total of 317 infected persons and 667 close contacts were reported; 129 (19.3%) of these close contacts received a subsequent COVID-19 diagnosis. A tribally managed COVID-19 case investigation and contact tracing program effectively reached tribal members and contributed to timely case and contact management. Good news, because control of the pandemic may be possible, even in hard-to-reach populations (if you involve them).

 

Virology

Abdalhamid B, Iwen PC, Wiley MR, et al. Genome Analysis for Sequence Variants in SARS-CoV-2 Among Asymptomatic Individuals in a Long-term Care Facility. JAMA Netw Open April 9, 2021. 2021;4(4):e217939. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778345?resultClick=1

Early evidence of a reduced pathogenicity of the virus? In this small cohort of 7 individuals aged 75 years and older, 5 recovered without illness. In all cases, a new mutation in the spike protein was found (S:K854N) that could have reduced replication capacity. K854 may lead to a reduction of S protein binding ability to the ACE2 receptor. Good news, because we would highly welcome viruses of lower fitness.

 

Variants

Shen X, Tang H, Pajon R, et al. Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351. NEJM April 7, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2103740?query=featured_home

Vaccine-elicited neutralizing antibodies are likely to remain effective against the B.1.429 variant (“California”). The modestly lower value in neutralization titers was similar to B.1.1.7, using serum from recipients of the mRNA-1273 (Moderna) and NVX-CoV2373 (Novavax). The magnitude of resistance seen with the B.1.351 variant is of greater concern. However, this is good news, because immune escape seems to be limited in most variants.

 

Immunology

Hall VJ; Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). The Lancet April 09, 2021. DOI: https://doi.org/10.1016/S0140-6736(21)00675-9

In this large study on 25,661 HCW, previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection (93% lower risk of symptomatic infection), with median protective effect observed 7 months following primary infection. Of the 155 reinfections, 50% were symptomatic. This is good news because the levels of prevention of symptomatic infection seem to be similar to the new licensed vaccines and also work well against reinfection with the B.1.1.7 variant.

 

Treatment

Ramakrishnan S, Nicolau Jr DV, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Resp Med April 09, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00160-0/fulltext

In this open-label, phase 2 RCT in 146 adults with mild COVID-19 symptoms, early administration of inhaled budesonide within 7 days reduced the likelihood of needing urgent medical care (1% vs 14%) and reduced time to recovery after early COVID-19. The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. According to the authors, their findings “require urgent validation and dissemination”. However, this encouraging early data is good news, the difference in the primary endpoint impressive. Inhaled budesonide is a simple, safe, well studied, inexpensive, and widely available treatment. A game changer – if confirmed by a phase 3 RCT.

 

11 April

Epidemiology

Pathela P, Crawley A, Weiss D, et al. Seroprevalence of SARS-CoV-2 following the largest initial epidemic wave in the United States: Findings from New York City, May 13-July 21, 2020. J Inf Dis 09 April 2021, jiab200, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab200/6219118?searchresult=1

In this large serosurvey of 45,367 adult NYC residents during the first wave, seroprevalence was high, reaching 23.6% (95% CI: 23.2%-24.0%). As this was a convenience sample, however, it is possible that people who sought out testing perceived themselves to have been more likely to have been exposed to SARS-CoV-2. High seroprevalence (> 30%) was observed among Black and Hispanic individuals, people from high poverty neighborhoods, and people in health care or essential worker industry sectors.

 

Vaccine

Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. NEJM April 9, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2104840?query=featured_home

A case series of 11 patients (9 women) from Germany and Austria in whom thrombosis or thrombocytopenia developed after vaccination with ChAdOx1 nCov-19. All had moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites beginning 5-16 days after first vaccination. All had platelet-activating antibodies directed against platelet factor 4 (PF4)–heparin.

 

Schultz NH, Sørvoll ICH, Michelsen AE, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. NEJM April 9, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2104882?query=featured_home

Another five patients (four women) from Norway. Same findings.

 

Diagnostics

Ogbe A, Kronsteiner B, Skelly DT, et al. T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses. Nat Commun April 6, 2021, 12, 2055. https://www.nature.com/articles/s41467-021-21856-3

In this study, distinct T cell assay platforms (ELISPOT and a proliferation assay) were used across the same individuals to characterize the differences between T cell responses associated with recent SARS-CoV-2 infection and long-term cross-reactive memory T cell responses in unexposed populations.

 

Brown L, Byrne RL, Fraser A, et al. Self-sampling of capillary blood for SARS-CoV-2 serology. Sci Rep 08 April 2021, 11, 7754 (2021). https://www.nature.com/articles/s41598-021-86008-5

Large-scale testing is limited by the need for in-person blood collection by staff trained in venepuncture, and the limited sensitivity of lateral flow tests. This study shows that capillary blood self-sampling and postage to laboratories for analysis could provide a reliable alternative. Storage of capillary blood at room temperature for up to 7 days post-sampling and collection on filter paper (dry spots) did not affect the sensitivity.

 

Pediatrics

Preston LE, Chevinsky JR, Kompaniyets L, et al. Characteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-19. JAMA Netw Open April 9, 2021. 2021;4(4):e215298. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778347?resultClick=1

In this large cohort of 2430 pediatric patients (from 869 US medical facilities) who were hospitalized with COVID-19, 756 (31.1%) experienced severe COVID-19. An increased association of severe COVID-19 was observed in patients with 1 or more chronic conditions vs those with none, in male vs female patients, and in children aged 2 through 5 years or 6 through 11 years vs children aged 12 through 18 years.

 

10 April

Vaccine

Van Praet JT, Vandecasteele S, de Roo A, et al. Humoral and cellular immunogenicity of the BNT162b2 mRNA Covid-19 Vaccine in nursing home residents. Clin Inf Dis, ciab300, April 7, 2021. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab300/6213866?searchresult=1

Four weeks after the first dose, the humoral and cellular immunogenicity of the BNT162b2 mRNA vaccine (BioNTech/Pfizer) was suboptimal in COVID-19-naïve nursing home residents in comparison to COVID-19-naïve healthcare workers.

 

Vaccine/Variants

Moyo-Gwete T, Madzivhandila M, Makhado Z, et al. Cross-Reactive Neutralizing Antibody Responses Elicited by SARS-CoV-2 501Y.V2 (B.1.351). NEJM April 7, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2104192?query=featured_home

Infection with B.1.351 (South Africa) elicits robust neutralizing antibody responses against P.1 (Brazil) and the original variants, which indicates high levels of cross-reactivity. Vaccines built on the spike protein of B.1.351 may be promising candidates for the elicitation of cross-reactive responses.

 

Lustig Y, Nemet I, Kliker L, et al. Neutralizing Response against Variants after SARS-CoV-2 Infection and One Dose of BNT162b2. NEJM April 7, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2104036?query=featured_home

In six HCW who had been infected with the original virus, one shot of BNT162b2 (BioNTech/Pfizer) induced robust neutralizing antibody responses against all variants of concern, including B.1.351 from South Africa.

 

Diagnostics

Corman VM, Haage VC, Bleicker T, et al. Comparison of seven commercial SARS-CoV-2 rapid point-of-care antigen tests: a single-centre laboratory evaluation study. Lancet Microbe April 07, 2021 https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00056-2/fulltext

Antigen point-of-care tests (AgPOCTs) can accelerate SARS-CoV-2 testing. Detection range of most AgPOCTs was found to range between around 2 million and 9 million copies per swab. This corresponds to a concentration that can be expected to yield a virus isolation success rate of around 20% in cell culture (typically reached by the end of the first week of symptoms). Thus, AgPOCTs might not have the power to exclude infection in the very early or later phases of COVID-19.

 

Clinical

Finelli L, Gupta V, Petigara T, et al. Mortality Among US Patients Hospitalized With SARS-CoV-2 Infection in 2020. JAMA Netw Open April 8 2021; 4(4):e216556. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778237?resultClick=1

A learning curve? In this large, nationally representative cohort study on 503,409 (!) patients, in-hospital mortality increased from March to April (10.6% to 19.7%), then decreased significantly to November (9.3%), with significant decreases in all older age groups (> 50 years). The authors speculate that the reasons “may include increased clinical experience in caring for and ventilating patients and use of prone positioning, systemic corticosteroids, and remdesivir”.

 

Long COVID-19

Havervall S, Rosell A, Phillipson M, et al. Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers. JAMA April 7, 2021, https://jamanetwork.com/journals/jama/fullarticle/2778528?resultClick=1

Probably one of the best longitudinal studies on long COVID-19 to date, comparing 323 seropositive (with mild disease) vs 1072 seronegative HCW. At 8 months, 15% vs 3% (at 2 months: 26% vs 9%) reported at least one moderate to severe symptom. Symptoms disrupted work, social, and home life.

 

9 April

Vaccine

Doria-Rose N, Suthar MS, Makowski M, et al. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19. N Engl J Med. 2021 Apr 6. PubMed: https://pubmed.gov/33822494. https://www.nejm.org/doi/10.1056/NEJMc2103916

In 33 healthy adult participants in an ongoing Phase I trial, antibodies that were elicited by mRNA-1273 (Moderna) persisted through 6 months after the second dose, as detected by three distinct serologic assays.

 

Transmission

Katelaris AL, Wells J, Clark P, Norton S, Rockett R, Arnott A, et al. Epidemiologic evidence for airborne transmission of SARS-CoV-2 during church singing, Australia, 2020. Emerg Infect Dis. 2021 Jun. https://wwwnc.cdc.gov/eid/article/27/6/21-0465_article

An outbreak among church attendees after an infectious chorister sang at multiple services. 12 secondary case patients. Video recordings showed that case patients were seated in the same section, > 15m from the primary case patient, without close physical contact, suggesting airborne transmission. Thank god there were no deaths, although 3 case patients were hospitalized, including 2 who required intensive care.

 

Westhölter D, Taube C. SARS-CoV-2 outbreak in a long-term care facility after vaccination with BNT162b2. Clin Inf Dis April 7, 2021, ciab299. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab299/6213878?searchresult=1

What a disaster. In early January 2021, 73/76 (96%) residents and about 90% of the employees in an elderly care home in North-Rhine Westfalia, Germany, received a first dose of BNT162b2 (BioNTech/Pfizer). SARS-CoV-2 rapid antigen tests were all negative among residents and participating employees the day before. However, a member of the mobile vaccination team as well as an employee reported respiratory symptoms one and four days after vaccination respectively and tested positive for SARS-CoV-2 by PCR. Overall case fatality rate was 9/26 (35%).

 

Diagnostics

Lagerqvist N, Maleki KT, Verner-Carlsson J, et al. Evaluation of 11 SARS-CoV-2 antibody tests by using samples from patients with defined IgG antibody titers. Sci Rep 11, April 7, 2021, 7614. https://doi.org/10.1038/s41598-021-87289-6

The evaluated antibody tests showed a heterogeneity in their performances and only a few, namely two platform-based tests, in-house RV and Wantai, showed satisfactory performances using samples with low IgG titers. With the exception of Euroimmun, the platform-based assays with S-based antigens had higher sensitivity compared to Abbott and Epitope, which are based on the N protein.

 

Long COVID-19

Taquet M, Geddes JR, Husain M, et al. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry April 06, 2021. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(21)00084-5/fulltext

Did we ever mention that COVID-19 is not the flu? Among 236,379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 34%, with 13% receiving their first such diagnosis. Most diagnostic categories were more common in patients who had COVID-19 than in those who had influenza (hazard ratio 1.44 for any diagnosis; 1.78 for any first diagnosis) and those who had other respiratory tract infections (1.16 and 1.32). Risks were greatest in, but not limited to, patients who had severe COVID-19.

 

8 April

Variants

Wang GL, Wang ZY, Duan LJ, et al. Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization. NEJM April 6, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2103022?query=featured_coronavirus

B.1.1.7 showed little resistance to the neutralizing activity of convalescent or vaccinee serum (inactivated-virus vaccines from Sinopharm and Sinovac were used), whereas B.1.351 showed more resistance to the neutralization of both convalescent serum (by a factor of 2) and vaccinee serum (by a factor of 2.5 – 3.3) than to the wild-type virus. Results are in line with previous studies with mRNA vaccines.

 

De Oliveira T, Lutucuta S, Nkengasong J, et al. A novel variant of interest of SARS-CoV-2 with multiple spike mutations is identified from travel surveillance in Africa. https://www.medrxiv.org/content/10.1101/2021.03.30.21254323v1

Not peer reviewed: a new variant was found in Angola in three travelers arriving from Tanzania who were tested together at the airport in mid-February. The variant, named A.VOI.V2, has 31 amino acid substitutions (11 in spike) and three deletions (all in spike). According to the authors, this warrants urgent investigation as the source country has a largely undocumented epidemic and few public health measures in place to prevent spread either within or outside of the country.

 

Transmission

Sami S, Turbyfill CR, Daniel-Wayman S, et al. Community Transmission of SARS-CoV-2 Associated with a Local Bar Opening Event — Illinois, February 2021. MMWR Morb Mortal Wkly Rep. ePub: 5 April 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7014e3.htm?s_cid=mm7014e3_w

February 2021 (no, not 2020): an opening event at a 2800-sq-ft bar in a rural Illinois county, accommodating approximately 100 persons. The event occurred indoors, with no air flow from outside. Cheers! The results: 46 cases, hospitalization of a long-term facility resident, and a school closure affecting 650 children. Two lessons learnt: first, an outbreak in a bar not only affects patrons and employees but can affect an entire community. Second, please forget “living with the virus” (before the event, average daily COVID-19 incidence had been 41 cases per 100,000 persons in the county).

 

Diagnostics

Assis R, Jain A, Nakajima R, et al. Distinct SARS-CoV-2 antibody reactivity patterns in coronavirus convalescent plasma revealed by a coronavirus antigen microarray. Sci Rep April 6, 2021, 11, 7554 (2021). https://doi.org/10.1038/s41598-021-87137-7

A coronavirus antigen microarray (COVAM) was constructed containing 11 SARS-CoV-2, 5 SARS-1, 5 MERS, and 12 seasonal coronavirus recombinant proteins. The array measures immunoglobulin isotype and subtype levels in serum or plasma samples against each of the individual antigens printed on the array. The array can be used to characterize the antibody profile to qualify convalescent plasma samples as well as immunogenicity and performance of vaccine pre-clinical and clinical studies.

 

Immunology

Pati A, Padhi S, Panda D, et al. A cluster of differentiation 14 (CD14) polymorphism (C-159T rs2569190) is associated with SARS-CoV-2 infection and mortality in the European population. J Inf Dis April 2, 2021. jiab180 https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab180/6209441?searchresult=1

Some early suggestions about a possible role of CD14 promoter variant with the predisposition and disease outcome of SARS-CoV-2 infections. Patients with this gene variant possibly produce elevated sCD14 and exacerbated inflammatory molecules.

 

Clinical

Anderson JL, May HT, Knight S, et al. Association of Sociodemographic Factors and Blood Group Type With Risk of COVID-19 in a US Population. JAMA Netw Open April 5, 2021;4(4):e217429. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778155?resultClick=1

Maybe it’s time to forget the blood group story. In this large, prospective case-control study that included more than 11,000 individuals who were newly infected with SARS-CoV-2, there were no ABO associations with either disease susceptibility or severity. According to the authors, “the smaller sample sizes and retrospective, observational nature of many prior studies, in addition to their striking heterogeneity of ABO associations with disease susceptibility and severity, could be due to chance variations, publication bias, differences in genetic background, geography and environment, and viral strains”.

 

7 April

Epidemiology

Hippich M, Sifft P, Zapardiel-Gonzalo J, et al. A Public Health Antibody Screening Indicates a Marked Increase of SARS-CoV-2 Exposure Rate in Children during the Second Wave. Med April 02, 2021. https://www.cell.com/med/fulltext/S2666-6340(21)00121-5

In this large monitoring study from Bavaria, Germany, antibody frequencies in 2021 were eight-fold higher than those observed at the end of the first wave and remained three- to four-fold higher than the cumulative reported PCR positive frequencies in both pre-school and school children. Among the 413 PCR-positive children who completed questionnaires regarding symptoms, no symptoms were reported in 68% of antibody-positive pre-school children and in 52% of school children.

 

Variants

Hoffmann M, Zhang L, Krüger N, et al. SARS-CoV-2 mutations acquired in mink reduce antibody-mediated neutralization. Cell Report, April 2, 2021. 109017. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00331-4

Mutations frequently found in the S proteins of SARS-CoV-2 from mink were mostly compatible with efficient entry into human cells and its inhibition by soluble ACE2. In contrast, mutation Y453F reduced neutralization by casirivimab and by sera/plasma from COVID-19 patients. Infection of mink and other animal species should be prevented and it should be continuously monitored whether SARS-CoV-2 amplification in other wild or domestic animals occurs and changes critical biological properties of the virus.

 

Immunology

Mazzitelli I, Bleichmar L, Ludueña MG, et al. IgG immune complexes may contribute to neutrophil activation in the course of severe COVID-19. J Inf Dis 02 April 2021, jiab174, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab174/6208275

Whole blood assays revealed that neutrophils from severe COVID-19 patients show a clear association with IgG immune complexes. Sera from severe patients contained high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Results indicate that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils to worsen the course of COVID-19.

 

Clinical

Roubinian NH, Dusendang JR, Mark DG, et al. Incidence of 30-Day Venous Thromboembolism in Adults Tested for SARS-CoV-2 Infection in an Integrated Health Care System in Northern California. JAMA Intern Med April 5, 2021. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2778371?resultClick=1

VTE incidence outside of the hospital is not significantly increased with SARS-CoV-2 infection. This important cohort study includes 220,588 adult members of the Kaiser Permanente Northern California health plan who were tested for SARS-CoV-2 from February 25 through August 31, 2020. Within 30 days of testing, a VTE was diagnosed in 198 (0.8%) positive patients and 1008 (0.5%) patients with a negative result (p < 0.001). Findings argue against the routine use of outpatient thromboprophylaxis as a measure outside of clinical trials.

 

Lunn MP, Carr AX, Keddie S, et al. Reply: Guillain-Barré syndrome, SARS-CoV-2 and molecular mimicry and Ongoing challenges in unravelling the association between COVID-19 and Guillain-Barré syndrome and Unclear association between COVID-19 and Guillain-Barré syndrome and Currently available data regarding the potential association between COVID-19 and Guillain-Barre syndrome. Brain April 3, 2021. awab070. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab070/6209732?searchresult=1

Is there a link between GBS and COVID-19? Michael P. Lunn and colleagues are not convinced. They kill their critics with kindness: “We appreciate being cautioned to making a definitive statement of ‘no link’ but would also equally strongly caution against the misuse of small, single studies that are likely to reflect significant well-recognized ascertainment and publication bias. In our view, the dangers of over-feeding the medical literature with unsubstantiated claims about an alarming disease are greater than our self-acknowledged cautionary analysis of COVID-19 causality for GBS.”

 

Treatment

Wadvalla BA. Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments. BMJ April 1, 2021; 373. https://www.bmj.com/content/373/bmj.n747

Excellent feature on how a debate has reached fever pitch, concluding that doctors “are just as susceptible to the availability heuristic as anyone else and use the experience of ‘n-of-1’ experiments (on a single patient) to signify more importance than what observations might warrant.”

 

6 April

Epidemiology

Hershow RB, Segaloff HE, Shockey AC, et al. Rapid Spread of SARS-CoV-2 in a State Prison After Introduction by Newly Transferred Incarcerated Persons — Wisconsin, August 14–October 22, 2020. MMWR Morb Mortal Wkly Rep April 2, 2021;70:478–482. https://www.cdc.gov/mmwr/volumes/70/wr/mm7013a4.htm?s_cid=mm7013a4_x

Limited testing resources and limited space for quarantine and medical isolation in a state prison: in 9 weeks (August 14–October 22), 869 (79.4%) of 1095 incarcerated persons and 69 (22.6%) of 305 staff members received positive test results for SARS-CoV-2.

 

Lewis NM, Salmanson AP, Price A, et al. Community-Associated Outbreak of COVID-19 in a Correctional Facility — Utah, September 2020–January 2021. MMWR Morb Mortal Wkly Rep April 2, 2021;70:467–472. https://www.cdc.gov/mmwr/volumes/70/wr/mm7013a2.htm?s_cid=mm7013a2_w

Same issue: a prison in Utah. An outbreak was introduced by a dental health care provider (DHCP) who had treated incarcerated persons (wearing an N95 mask as well as gown, gloves, and goggles) while asymptomatic. Outbreak spread was incredibly rapid, eventually affecting 1368 (52%!) of 2632 residents (with 31 hospitalizations and 12 deaths) as well as to an estimated 88 (16%) of 550 staff members. As of March 2, 2021, the outbreak was ongoing. According to the authors, screening of non-facility HCPs with rapid antigen tests (as well as testing incarcerated persons after receiving treatment) would have been a good idea.

 

Variants

Schuit M, Biryukov J, Beck K, et al. The stability of an isolate of the SARS-CoV-2 B.1.1.7 lineage in aerosols is similar to three earlier isolates. J Inf Dis April 2, 2021, jiab171, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab171/6209391?searchresult=1

The stability of SARS-CoV-2 in aerosols does not vary greatly among the currently circulating lineages, including B.1.1.7, suggesting that the increased transmissibility associated with recent SARS-CoV-2 lineages is not due to enhanced survival in the environment.

 

Starr TN, Greaney AJ, Dingens AS, et al. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. Cell Rep Med April 01, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00071-9

Future efforts should diversify the epitopes targeted by antibodies to make them more resilient to antigenic evolution. Individual mutations that escape binding by bamlanivimab (BAM) and etesevimab (ESV) are combined in the B.1.351 and P.1 lineages (E484K escapes BAM, K417N/T escapes ESV). Additionally, the L452R mutation in the B.1.429 lineage escapes BAM. The authors also identified single amino acid changes that escape the combined BAM/ESV cocktail.

 

Transmission

Reukers DF, van Boven M, Meijer A, et al. High infection secondary attack rates of SARS-CoV-2 in Dutch households revealed by dense sampling. Clin Inf Dis April 2, 2021, ciab237, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab237/6209401?searchresult=1

In this Dutch study conducted in March/April 2020, estimated infection of SARs were higher than reported in earlier household studies, presumably owing to a dense sampling protocol: 35% (95%CI: 24%-46%) in children and 51% (95%CI: 39%-63%) in adults.

 

Immunology

Shuwa HA, Shaw TN, Knight SB, et al. Alterations in T and B cell function persist in convalescent COVID-19 patients. Med March 31, 2021. https://www.sciencedirect.com/science/article/pii/S266663402100115X

Alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type-1 cytokines and IL-17.

 

Long COVID-19

Hosp JA, Dressing A, Blazhenets G, et al. Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain April 3, 2021, awab009, https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab009/6209743?searchresult=1

Cognitive deficits are present in many COVID-19 patients requiring in-patient treatment. Of 15 patients undergoing extended neuropsychological testing, only two patients performed entirely normally. Orientation and language abilities were in the range of healthy subjects, while memory and executive items were most severely affected, making general deterioration unlikely. There was no decline in general attention or speed of processing. This specific pattern can hardly be explained by non-specific factors like fatigue. It also differs from cognitive impairment post-sepsis. Many patients displayed frontoparietal cognitive dysfunctions and 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism.

 

5 April

Epidemiology

Codreanu TA, Ngeh S, Trewin A, Armstrong PK. Successful control of an onboard COVID-19 outbreak using the cruise ship as a quarantine facility, Western Australia. Emerg Infect Dis 2021 May https://wwwnc.cdc.gov/eid/article/27/5/20-4142_article

Do you remember the Diamond Princess outbreak in early 2020? These guys here probably have done a better job, reporting on the successful use of a ship as a quarantine facility during the response to the outbreak on the MS Artania, docked in Western Australia. The 14-day quarantine regimen was based on established principles of outbreak management and experiences of outbreaks on cruise ships elsewhere. The attack rate in the crew was 3.3% (28/832) before quarantine commencement and 4.8% (21/441) during quarantine on board (remember Diamond Princess: 17%).

 

Variants

The SARS-CoV-2 variant with lineage B.1.351 clusters investigation team. Linked transmission chains of imported SARS-CoV-2 variant B.1.351 across mainland France, January 2021. Euro Surveill 2021;26(13):pii=2100333. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.13.2100333

Two cases had travelled in mid-December 2020 with a group to Mozambique where they participated in a religious gathering and returned with the B.1.351 variant. A joint team of epidemiologists, public health workers and clinical and virological specialists co-operated across France to urgently investigate and initiate control measures. A total of 36 cases were analyzed. Believe it or not: “Another challenge was that some members of the clusters did not agree to answer questions”.

 

Immunology

Lv J, Yu P, Wang Z, et al. ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques. Cell Mol Immunol, April 1, 2021. https://www.nature.com/articles/s41423-021-00672-1

The cytoplasmic transcription factor aryl hydrocarbon receptor AhR is able to bind the promoter of the ACE2 gene, thus promoting ACE2 expression and augmenting the subsequent pathology in SARS-CoV-2-infected lungs.

 

Vaccine

Rottenstreich A, Zarbiv G, Oiknine-Dijan E, et al. Efficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination. Clinical Infectious Diseases 03 April 2021, ciab266. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab266/6209876?searchresult=1

In 20 pregnant women, two doses of BNT162b2 mRNA vaccine (median time between the second dose until delivery was 11 days) induced an adequate maternal serologic response that had the potential to provide neonatal protection through transplacental transfer of vaccine-stimulated maternally-derived antibodies.

Clinical

Woolf SH, Chapman DA, Sabo RT. Excess Deaths From COVID-19 and Other Causes in the US, March 1, 2020, to January 2, 2021. JAMA April 2, 2021. https://jamanetwork.com/journals/jama/fullarticle/2778361?resultClick=1

Between March 1, 2020, and January 2, 2021, the US experienced 2,801,439 deaths, 22.9% more than expected, representing 522,368 excess deaths. The 22.9% increase in all-cause mortality reported here far exceeds annual increases observed in recent years (≤ 2.5%). Deaths attributed to COVID-19 accounted for 72.4% of US excess deaths.

 

4 April

Virology

Günther S, Reinke PY, Fernández-García Y, et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science 02 Apr 2021: eabf7945. https://science.sciencemag.org/content/early/2021/03/31/science.abf7945

High-throughput X-ray crystallographic screen, revealing 43 compounds binding to M^pro, with seven compounds (calpeptin, ifenprodil, pelitinib, etc) showing antiviral activity against SARS-CoV-2. Structural evidence for interaction of these compounds at active and allosteric sites of M^pro is presented. Two allosteric binding sites represent attractive targets for drug development.

 

Variants

Graham C, Seow J, Huettner I, et al. Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant. Immunity April 01, 2021. https://www.cell.com/immunity/fulltext/S1074-7613(21)00135-7

To understand how mutations affect Spike antigenicity, the authors isolated and characterized > 100 monoclonal antibodies targeting epitopes on SARS-CoV-2 spike receptor-binding domain (RBD), N-terminal domain (NTD) and S2 from SARS-CoV-2-infected individuals. Mutations present in B.1.1.7 spike frequently conferred neutralization resistance to NTD-specific antibodies. Neutralization by RBD-specific nAbs remained largely unchanged.

 

Vaccine

Cobey S, Larremore DB, Grad YH. et al. Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination. Nat Rev Immunol April 2, 2021. https://www.nature.com/articles/s41577-021-00544-9

See title. Marc Lipsitch and colleagues argue that as long as vaccination provides some protection against escape variants, the corresponding reduction in prevalence and incidence should reduce the rate at which new variants are generated and the speed of adaptation.

 

Malhotra HS, Gupta P, Prabhu V. COVID-19 vaccination-associated myelitis. QJM 31 March 2021, hcab069, https://academic.oup.com/qjmed/advance-article/doi/10.1093/qjmed/hcab069/6206408?searchresult=1

A rare case of myelitis, seen with the ChAdOX1 nCoV-19 vaccine. On the 8th day post-vaccination, this 38-yr-old man presented with abnormal sensations in both lower limbs.

 

Co-morbidities/Vaccine

Waissengrin B, Agbarya A, Safadi E, et al. Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors. Lancet Oncology April 01, 2021. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00155-8/fulltext

Do mRNA vaccines provoke or enhance immune-related side-effects in cancer patients who are being treated with immune checkpoint inhibitors? Probably not. In 134 patients treated with these drugs, the side-effect profile was similar compared to healthy controls (apart from muscle pain).

 

Co-morbidities

Aveyard O, Gao M, Lindson N, et al. Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study. Lancet Resp Medicine April 01, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00095-3/fulltext

The next large population cohort study showing that the risk of severe COVID-19 in people with asthma is relatively small (hazard ratio 1.18). People with COPD and interstitial lung disease appear to have a modestly increased risk of severe disease (1.54 and 1.66, respectively).

 

3 April

Variants

Peng J, Liu J, Mann SA, et al. Estimation of secondary household attack rates for emergent spike L452R SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco. Clinical Infectious Diseases 31 March 2021, ciab283, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab283/6206738?searchresult=1

The new lineages B.1.427 and B.1.429 (the “California” or “West Coast” variants) share S gene non-synonymous mutations at sites 13, 152, 452, and 614 and were seen during the December 2020 to February 2021 period when California was experiencing a huge peak. Whereas no instances of B.1.1.7, or independent N501Y mutations were detected in the sample population, the authors found a modest transmissibility increase of the West Coast variants. Household contacts exposed to these variants were at higher risk of infection compared to those exposed to lineages lacking these variants (0.36 vs 0.29, RR = 1.28; 95% CI: 1.00-1.64). Ct values did not differ.

 

Immunology

Sermet-Gaudelus I, Temmam S, Huon C, et al. Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020. Euro Surveill. 2021;26(13):pii=2001782. https://doi.org/10.2807/1560-7917.ES.2021.26.13.2001782

See title. No evidence of cross-protective immunity linked to previous infection with seasonal HCoV. The seasonal HCoV prevalence in SARS-CoV-2-positive and -negative patients was similar. There was no significant correlation between SARS-CoV-2 and antibody levels of any HCoV, whatever the antigen considered (S or N), while SARS-CoV-2 antibodies to N and S correlated as expected.

 

Clinical

Ahmad FB, Cisewski JA, Miniño A, Anderson RN. Provisional Mortality Data — United States, 2020. MMWR 31 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7014e1.htm?s_cid=mm7014e1_w

In 2020, COVID-19 was the third leading underlying cause of death in the US, replacing suicide as one of the top 10 leading causes of death. The COVID-19 death rate was highest among Hispanics.

 

Long COVID-19

Ayoubkhani D, Khunti K, Nafilyan V, et al. Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ 2021;372: n693. 31 March 2021. https://www.bmj.com/content/372/bmj.n693

47,780 hospitalized patients (mean age 65) discharged alive by 31 August 2020 were exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics. Over a mean follow-up of 140 days, nearly a third were readmitted and more than 1 in 10 died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of multi-organ dysfunction after discharge were raised compared to the matched control group, suggesting extrapulmonary pathophysiology. As shown in the Figure, diabetes and major adverse cardiovascular event were particularly common.

 

Treatment

Bharat A, Machuca TN, Querrey M, et al. Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries. Lancet Resp Medicine March 31, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00077-1/fulltext

Twelve cases. The transplant procedures were technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. However, there was no recurrence of SARS-CoV-2 in the allografts and 11/12 were alive at a median of 80 days after transplantation.

 

 

2 April

Epidemiology

Naimark D, Mishra S, Barrett K. Simulation-Based Estimation of SARS-CoV-2 Infections Associated With School Closures and Community-Based Nonpharmaceutical Interventions in Ontario, Canada. JAMA March 31, 2021. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777976?resultClick=1

The magnitude of the effect of schools being open on COVID-19 cases was substantially lower than the effect of community-based NPIs. These findings suggest that school closure be considered the last resort in the face of a resurgence of COVID-19, and that efforts should instead focus on widespread reduction of community transmission.

 

Vaccine

Jentsch PC, Anand M, Bauch CT. Prioritising COVID-19 vaccination in changing social and epidemiological landscapes: a mathematical modelling study. Lancet Inf Dis March 31, 2021. https://www.thelancet.com/action/showPdf?pii=S1473-3099%2821%2900057-8

The oldest-first strategy is not always the best option. This modelling study shows that in populations in which SARS-CoV-2 seropositivity is high, a contact-based strategy allocating vaccines according to the relative role played by different age groups in transmission may be more effective that targeting vulnerable groups.

 

Variants

Dejnirattisai W, Zhou D, Supasa P, et al. Antibody evasion by the P.1 strain of SARS-CoV-2. Cell March 30, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00428-1

All new strains (P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK) have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, conferring similar increased affinity for ACE2. Surprisingly, P.1 was significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain impact neutralization.

 

Clinical

Mehta HB, Li S, Goodwin JS. Risk Factors Associated With SARS-CoV-2 Infections, Hospitalization, and Mortality Among US Nursing Home Residents. JAMA Netw Open Mar 31, 2020. 2021;4(3):e216315. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777972?resultClick=1

Retrospective longitudinal cohort study in long-stay residents aged 65 years or older with fee-for-service Medicare insurance residing in 15,038 US nursing homes. Among 137,119 residents (28.4%) diagnosed with SARS-CoV-2 during follow up, 29,204 of them (21.3%) were hospitalized, and 26,384 (19.2%) died within 30 days. For many resident characteristics, there were substantial differences in risk of hospitalization vs mortality, probably representing resident preferences, triaging decisions, or inadequate recognition of risk of death.

 

Yuan L, Zhu H, Zhou M. et al. Gender associates with both susceptibility to infection and pathogenesis of SARS-CoV-2 in Syrian hamster. Sig Transduct Target Ther March 30, 6, 136 (2021). https://www.nature.com/articles/s41392-021-00552-0

A gender effect in hamsters: in contrast to males, female animals show much lower shedding viral titers, more moderate symptoms, and relatively mild lung pathogenesis.

 

1 April

Vaccine

Paper of the Day

Emary KR, Gulobchik T, Aley PK. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet March 30, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00628-0/fulltext

This post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), revealed that laboratory virus neutralization activity by vaccine-induced antibodies was lower against B.1.1.7. However, clinical vaccine efficacy against symptomatic NAAT positive infection was good, with 70% (95% CI 44–85) for B.1.1.7 and 82% (68–89) for other lineages.

 

Severe COVID-19

Järhult JD, Hultström M, Bergqvist A. et al. The impact of viremia on organ failure, biomarkers and mortality in a Swedish cohort of critically ill COVID-19 patients. Sci Rep March 31, 11, 7163 (2021). https://www.nature.com/articles/s41598-021-86500-y

In this cohort from Sweden, RNAemia was found in 31/92 patients (34%). Extra-pulmonary organ failure biomarkers and the extent of organ failure were similar in patients with and without RNAemia. RNAemia was not an independent predictor of death at 30 days after adjustment for age.

 

Co-morbidities

Khunti K, Knighton P, Zaccardi F, et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diab Endocrin March 30, 2021. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00050-4/fulltext

A nationwide observational cohort study in England, showing some evidence of (weak) associations between prescription of some glucose-lowering drugs and COVID-19-related mortality. As findings were likely to be due to confounding by indication, the authors summarize that there is no clear indication to change prescribing of glucose-lowering drugs in people with type 2 diabetes.

 

Treatment

Jagannathan P, Andrews JR, Bonilla H, et al. Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nat Commun March 30, 2021, 12, 1967. https://www.nature.com/articles/s41467-021-22177-1

Next disappointment: in this well-conducted, placebo-controlled RCT, a single dose of subcutaneous peg-interferon lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in out-patients with uncomplicated COVID-19.

 

Ho JS, Mok BW, Campisi L, et al. TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation. Cell March 30, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00382-2

Therapeutic treatment with two doses of topotecan, an FDA-approved topoisomerase inhibitor, suppressed infection-induced inflammation in hamsters. Treatment as late as four days post-infection reduces morbidity and mortality in a transgenic mouse model.