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By C. Hoffmann & B. S. Kamps
Copy-editor: Rob Camp

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.

Kaplan–Meier graph of cumulative incidence for testing PCR-positive in the seropositive group at different baseline full-length spike protein IgG titers

 

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.

(A) Dark solid line shows the 7-day rolling average of the COVID-19 confirmed and suspected daily time series of hospitalisations in Manaus. Green dots represent daily severe acute respiratory mortality records. The arrow denotes 6 December 2020, the date of the first P.1 case identified in Manaus by our study. (B) Maximum likelihood tree (n=962) with B.1.1.28, P.1 and P.2 sequences, with collapsed views of P.1 and P.2 clusters and highlighting other sequences from Manaus, Brazil. Ancestral branches leading to P.1 and P.2 are shown as dashed lines. (C) Number of air travel passengers from Manaus to all states in Brazil (D) Number of genome sequences from Manaus belonging to lineages of interes; spike mutations of interest are denoted.

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.

Figure: Regional plots of the frequency of reporting of each symptom in users reporting positive test results over time from Sept 28 to Dec 27, 2020 Symptom occurrence per 1-week window is shown smoothed over three timepoints as a function of time. The drop in reporting of fever in early November was caused by a change in the wording of the question; this wording was subsequently reverted a week later.

 

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 Mpro, 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 Mpro 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.

 

31 March

Vaccine

Thompson MG, Burgess JL, Naleway AL, et al. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 29 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm

In this prospective cohort of 3950 health care personnel, first responders, and other essential and frontline workers who completed weekly SARS-CoV-2 testing for 13 consecutive weeks, mRNA vaccine effectiveness of full immunization (≥ 14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥ 14 days after first dose but before second dose) was 80%.

Variants

Francisco MA, Zavascki AP, Lamb WP, et al. Detection of SARS-CoV-2 lineage P.1 in patients from a region with exponentially increasing hospitalisation rate, February 2021, Rio Grande do Sul, Southern Brazil. Euro Surveill Accepted: 25 Mar 2021, 2021. Full text: https://doi.org/10.2807/1560-7917.ES.2021.26.12.2100276

From epidemiological week 6, starting on 7 February 2021, until 6 March, the number of hospitalizations for COVID-19 in Rio Grande do Sul, the southernmost state of Brazil in the South region, increased from 1738 inpatients to 6995 (3.8-fold). This resulted in the collapse of the state healthcare system. The overwhelming increase in hospitalizations temporally coincided with the finding that lineage P.1 became predominant (although a small number of specimens was taken).

 

Immunology

Rendeiro AF, Ravichandran H, Bram Y, et al. The spatial landscape of lung pathology during COVID-19 progression. Nature March 29, 2021. https://www.nature.com/articles/s41586-021-03475-6

A comprehensive examination of the response of the human lung to infection from macroscopic to single-cell level.

 

Daamen AR, Bachali P, Owen KA, et al. Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway. Sci Rep March 29, 2021. 11, 7052 (2021). https://doi.org/10.1038/s41598-021-86002-x

More on the pathogenesis of COVID-19 driven by populations of myeloid-lineage cells with highly inflammatory but distinct transcriptional signatures in each compartment. The authors found a systemic, but compartmentalized immune/inflammatory response with specific signs of cellular activation in blood, lung and airways.

 

Diagnostics

Parikh BA, Wallace MA, McCune BT. The Effects of “Dry Swab” Incubation on SARS-CoV-2 Molecular Testing. The Journal of Applied Laboratory Medicine 29 March 2021 https://academic.oup.com/jalm/advance-article/doi/10.1093/jalm/jfab010/6149478?searchresult=1

In this study, all dry swabs tested on days 1, 2, and 7 provided results that were within 2 cycle thresholds of the average values for swabs hydrated in the same media and tested on day 0. There was no statistical difference in Ct values between swabs incubated in liquid media versus dry swabs incubated at room temperature prior to hydration in liquid media. The ability to obtain robust Ct values from dry swabs stored for a week at room temperature despite culture negativity has important implications for SARS-CoV-2 testing.

 

30 March

One year ago, we published the first edition of COVID Reference. It was a document on the fulminant accumulation of clinical knowledge about an emergent infectious disease in the previous three months. At that time, treatment strategies were tentative, the unutterable hydroxychloroquine was still en vogue, the multisystem inflammatory syndrome in children (MISC) as yet unheard of, and nobody knew about Long COVID or variants.

>>> more

 

29 March

Article of the Day

Kupferschmidt K, Vogel G. A rare clotting disorder may cloud the world’s hopes for AstraZeneca’s COVID-19 vaccine. Science 2021, published 27 March. Full text: https://www.sciencemag.org/news/2021/03/rare-clotting-disorder-may-cloud-worlds-hopes-astrazenecas-covid-19-vaccine

VIPIT – vaccine-induced prothrombotic immune thrombocytopenia – is a preliminary explanation for the unusual strokes and clotting disorders recorded in at least 30 recipients of the AstraZeneca vaccine. A summary.

Transmission

Moschovis PP, Yonker LM, Shah J, et al. Aerosol transmission of SARS-CoV-2 by children and adults during the COVID-19 pandemic. Pediatric Pulmonology 2021. Full text: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.25330

The authors outline the major methods of transmission of SARS-CoV-2 focusing on aerosol transmission and reviewing the principles of aerosol science and discussing their implications for mitigating the spread of SARS-CoV-2.

 

Clinical

Bamidis AD, Koehler P, di Cristanziano V, et al. First manifestation of adult-onset Still’s disease after COVID-19. Lancet Rheumatol 2021, published 26 March. Full text: https://doi.org/10.1016/S2665-9913(21)00072-2

First report of adult-onset Still’s disease (AOSD) showing that long COVID can mimic AOSD and delay diagnosis. The patient was treated with the IL-1 receptor antagonist anakinra (subcutaneous, 100 mg/day).

 

Klein J, Brito AF, Trubin P, et al. Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient. medRxiv 2021, posted 26 March. Full text: https://doi.org/10.1101/2021.03.24.21253992

Patients with solid organ transplantation or those who are otherwise immunosuppressed who recover from infection with SARS-CoV-2, may not develop sufficient protective immunity and are at risk of reinfection.

 

Beyond Corona

Boyoglu-Barnum S, Ellis D, Gillespie RA, et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature (2021). Full text: https://doi.org/10.1038/s41586-021-03365-x

A supra-seasonal flu vaccine? Computationally designed, two-component nanoparticle immunogens induced potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. Unlike current influenza vaccines, the nanoparticle vaccines also protected against diverse viruses NOT in the vaccine formulation (including distant avian viruses like H5N1 and H7N9). This ‘mosaic’ vaccine is now being manufactured for a Phase I clinical trial through the Vaccine Research Center at the NIH.

 

28 March

Vaccines

ANSM 20210326. Point de situation sur la surveillance des vaccins contre la COVID-19 – Période du 12/03/2021 au 18/03/2021. Agence nationale pour la sécurité du médicament et des produits de Santé 2021, published 26 March 2021. Full text: https://ansm.sante.fr/actualites/point-de-situation-sur-la-surveillance-des-vaccins-contre-la-covid-19-periode-du-12-03-2021-au-18-03-2021

On 26 March, the French National Medicine Safety Agency (Agence nationale pour la sécurité du médicament et des produits de Santé – ANSM) declared that there is a risk of atypical thrombosis associated with the AstraZeneca vaccine. The Agency reports 9 cases of big vein thromboses that are atypical by their location (mostly cerebral, but also digestive) and associated with thrombocytopenia and coagulation disorders. With some 1,430,000 injections of the AstraZeneca vaccine as of 18 March 2021, this is one case per 158,000 injections. These cases occurred within a median time of 8.5 days after vaccination in persons without particular risk factors (7 patients under 55 years of age, 2 more than 55 years). Between 12 and 18 March, two deaths were reported, including that of a medical student who died several days after being vaccinated. In the coming months of relative vaccine abundance, the AstraZeneca vaccine does not have a good star.

 

McEllistrem MC, Clancy CJ, Buehrle DJ, et al. Single dose of a mRNA SARS-CoV-2 vaccine is associated with lower nasopharyngeal viral load among nursing home residents with asymptomatic COVID-19. Clin Infect Dis 2021, published 26 March. Full text: https://doi.org/10.1093/cid/ciab263

In nursing home residents with asymptomatic COVID-19 diagnosed through twice-weekly surveillance testing, single dose BNT162b2 vaccination (Pfizer-BioNTech) was associated with -2.4 mean log10 lower nasopharyngeal viral load than that detected in absence of vaccination (p = 0.004).

 

Irwin A. What it will take to vaccinate the world against COVID-19. Nature 2021, published 25 March. Full text: https://www.nature.com/articles/d41586-021-00727-3

Within just a few months, pharmaceutical firms have produced hundreds of millions of doses of COVID-19 vaccine. But the world needs billions — and as fast as possible. This situation is fuelling a campaign to temporarily waive intellectual-property rights so that manufacturers in poorer countries can make the vaccines more quickly themselves.

 

Variants

Abbasi J. How the US Failed to Prioritize SARS-CoV-2 Variant Surveillance. JAMA. 2021 Mar 24. PubMed: https://pubmed.gov/33760030. Full-text: https://doi.org/10.1001/jama.2021.3368

Until late last fall, public health departments had no federal mandate or additional funding to sequence samples, although new variants were an inevitability.

 

Clinical

Molteni E, Astley CM, Ma W, et al. Symptoms and syndromes associated with SARS-CoV-2 infection and severity in pregnant women from two community cohorts. Sci Rep 11, 6928 (2021). https://doi.org/10.1038/s41598-021-86452-3

Pregnant and non-pregnant women positive for SARS-CoV-2 infection were not different in syndromic severity, except for gastrointestinal symptoms.

 

Avouac J, Drumez E, Hachulla E, et al. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study. Lancet Rheumatol 2021, published 25 March. Full text: https://doi.org/10.1016/S2665-9913(21)00059-X

Rituximab therapy is associated with more severe COVID-19 (defined in this study as admission to an ICU or death). Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases.

 

Beyond Corona

Gray  GE, Bekker LG, Laher F, et al. Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120–MF59 in Adults. N Engl J Med 2021, publishd 25 March. Full text: https://doi.org/10.1056/NEJMoa2031499

Most of the 75.7 million persons with human immunodeficiency virus (HIV) infection worldwide are in sub-Saharan Africa, where subtype C of HIV type 1 (HIV-1) is prevalent. The ALVAC–gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity.

 

27 March

Variants

McCormick KD, Jacobs JL, Mellors JW. The emerging plasticity of SARS-CoV-2. Science 2021, published 26 March. Full text: https://doi.org/10.1126/science.abg4493

Another excellent summary and extension of our Variants chapter. By John Mellors and colleagues.

 

Epidemiology

Salyer S, Maeda J, Sembuche S, et al. The first and second waves of the COVID-19 pandemic in Africa: a cross-sectional study. Lancet 2021, published 24 March. Full text: https://doi.org/10.1016/S0140-6736(21)00632-2

Although the first wave of the COVID-19 pandemic progressed more slowly in Africa than the rest of the world, by December 2020, the second wave appeared to be much more aggressive with many more cases.

 

Vaccines

Hughes MM, Wang A, Grossman MK, et al. County-Level COVID-19 Vaccination Coverage and Social Vulnerability — United States, December 14, 2020–March 1, 2021. MMWR Morb Mortal Wkly Rep 2021;70:431–436. Full text:  http://dx.doi.org/10.15585/mmwr.mm7012e1

In the first 2.5 months of the US vaccination program, high social vulnerability counties had lower COVID-19 vaccination coverage than did low social vulnerability counties. Although vaccination coverage estimates by county-level social vulnerability varied widely among states, disparities in vaccination coverage were observed in the majority of states.

 

Diagnosis

Chakraborty D, Agrawal A, Maiti S. Rapid identification and tracking of SARS-CoV-2 variants of concern. Lancet 2021, published 22 March. Full text: https://doi.org/10.1016/S0140-6736(21)00470-0

Detecting SARS-CoV-2 variants with CRISPR for less than $15 in less than 90 minutes?

 

Clinical

Lefrancq N, Paireau J, Hozé N, et al. Evolution of outcomes for patients hospitalised during the first 9 months of the SARS-CoV-2 pandemic in France: A retrospective national surveillance data analysis. Lancet Regional Health, March 2021. Full-text: https://doi.org/10.1016/j.lanepe.2021.100087

Better get COVID-19 between waves when hospital capacities are not stretched to the limit. The authors find that both the probability of death and the probability of entering ICU were significantly correlated with COVID-19 ICU occupancy.

 

Fernández-Prada M, Rivero-Calle I, Calvache-González A, Martinón-Torres F. Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021. Euro Surveill. 2021;26(10). Full text: https://doi.org/10.2807/1560-7917.ES.2021.26.10.2100193

The authors describe a series of 20 clinical cases with acute onset of single supraclavicular lymphadenopathy coinciding with the ipsilateral intramuscular administration of a dose of an mRNA vaccine.

 

Beyond COVID-19

Kirtane AR, Verma M, Karandikar P, et al. Nanotechnology approaches for global infectious diseases. Nat. Nanotechnol. 2021, published 22 March. Full-text: https://doi.org/10.1038/s41565-021-00866-8

The formulation of new and existing drugs into nano-sized carriers promises to overcome several challenges associated with the treatment of malaria, tuberculosis and HIV infection, including low on-target bioavailability, sub-therapeutic drug accumulation in microbial sanctuaries and reservoirs, and low patient adherence due to drug-related toxicities and extended therapeutic regimens.

 

26 March

Variants

Volz E, Mishra S, Chand M, et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature (2021). Full text: https://doi.org/10.1038/s41586-021-03470-x

The preprint we presented on 13 January now published in Nature: the authors describe the new SARS-CoV-2 lineage B.1.1.7 (AKA VOC 202012/01) which originated in England, late Summer to early Autumn 2020. The data indicate a transient shift in the age composition of reported cases, with a larger share of under-20-year-olds among B.1.1.7 cases than among historical cases. B.1.1.7 has a substantial transmission advantage with a 50% to 100% higher reproduction number.

 

Transmission

Forbes H, Morton CE, Bacon S, et al. Association between living with children and outcomes from covid-19: OpenSAFELY cohort study of 12 million adults in England. BMJ 2021; 372. Full text: https://doi.org/10.1136/bmj.n628

Does the risk of SARS-CoV-2 infection and outcomes of COVID-19 differ between adults living with and without children? In the second UK wave (1 September to 18 December 2020), the authors found an increased risk of SARS-CoV-2 infection and COVID-19-related hospital admission for adults living with children of all age groups in the second wave. For adults aged over 65 years, they also found an increased risk of infection associated with living with children of any age and of ICU admission and death from COVID-19 for those living with children aged 0-18 years.

 

Huang N, Pérez P, Kato T, et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med (2021). https://doi.org/10.1038/s41591-021-01296-8

The oral cavity is an important site for SARS-CoV-2 infection. The authors discuss saliva as a potential transmission route.

 

Vaccines

Stamatatos L, Czartoski J, Wan YH, et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 2021, published 25 March. Full text: https://science.sciencemag.org/content/early/2021/03/24/science.abg9175

The preprint we presented on 10 February now published in Science. The study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.

 

Desmond a, Offit PA. On the Shoulders of Giants — From Jenner’s Cowpox to mRNA Covid Vaccines. N Engl J Med 2021; 384:1081-1083. Full text: https://doi.org/10.1056/NEJMp2034334

mRNA vaccines will change the course of the COVID-19 pandemic and the impact of other infectious diseases. Their development goes back to 2008 when Katalin Karikó, Drew Weissman, and colleagues modified messenger RNA (mRNA) using nucleoside analogues. These modifications stabilized the molecule and eliminated its capacity for inducing innate immunity, thereby making mRNA a vaccination tool (Karikó K 2008). A short vaccine history for the weekend.

 

Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants — Clinical, Public Health, and Vaccine Implications. N Engl J Med 2021, published 24 March. Full text: https://doi.org/10.1056/NEJMc2100362

An excellent summary of our Variants chapter by @ProfAbdoolKarim and @Tuliodna.

 

Bradley T, Grundberg E, Selvarangan R, et al. Antibody Responses after a Single Dose of SARS-CoV-2 mRNA Vaccine. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2102051

Three weeks after a single vaccination, persons with recent SARS-CoV-2 infection or seropositive status had higher levels of antibody to four SARS-CoV-2 antigens and higher levels of antibodies with neutralizing characteristics than did those with no history of infection.

 

25 March

Variants

Edara VV, Norwood C, Floyd K, et al. Infection and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant. Cell Host Microbe 2021, published 20 March. Full text: https://doi.org/10.1016/j.chom.2021.03.009

Despite reduced antibody titers against the B.1.351 variant (first detected in South Africa), sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351. The authors conclude that protective humoral immunity may be retained against this variant.

 

Transmission

Plesner Lyngse F, Mølbak K, Træholt Frank K, et al. Association between SARS-CoV-2 Transmission Risk, Viral Load, and Age: A Nationwide Study in Danish Households. medRxiv 2021, posted 5 March. Full-text: https://doi.org/10.1101/2021.02.28.21252608

Should age have a higher impact than Ct value on the risk of SARS-CoV-2 transmission? This is the conclusion of a study by Frederik Lyngse et al. who found an almost linearly increasing transmission risk with age of the primary cases for adults (≥ 20 years) and negatively for children (< 20 years). They also found that the risk of SARS-CoV-2 transmission was negatively associated—approximately linear—with the Ct values of the tested primary cases. However, even for relatively high Ct values, the risk of transmission was not negligible, e.g. for primary cases with a Ct value of 38, the authors found a transmission risk of 8%.

 

Immunology

Thakkar A. Pradhan K, Jindal S, et al. Patterns of seroconversion for SARS-CoV-2 IgG in patients with malignant disease and association with anticancer therapy. Nat Cancer 2021, published 22 March. Full-text:  https://doi.org/10.1038/s43018-021-00191-y

Two hundred and sixty-one patients with a cancer diagnosis underwent SARS-CoV-2 IgG testing and demonstrated a high rate of seroconversion (92%). Significantly lower seroconversion was seen in patients with hematological malignancies (82%), patients who received anti-CD-20 antibody therapy (59%) and stem cell transplant (60%). Notably, all 17 patients who received immunotherapy, including 16 that received anti-PD-1/PD-L1 monoclonal antibodies, developed SARS-CoV-2 IgG antibodies (100% seroconversion).

 

Stertz S, Hale BG. Interferon system deficiencies exacerbating severe pandemic virus infections. Trends Microbiol 2021, published 20 March. Full-text: https://doi.org/10.1016/j.tim.2021.03.001

An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled viral replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with auto-antibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19. The authors discuss key questions surrounding how such auto-antibodies develop and function, as well as the general implications of diagnosing interferon deficiencies for personalized therapies.

 

Vaccines

Keehner J, Pfeffer MA, Longhurst CA, et al. SARS-CoV-2 Infection after Vaccination in Health Care Workers in California. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2101927

COVID-19 infection after complete vaccination? Possible, but rare. At the University of California, San Diego (UCSD) and the University of California, Los Angeles (UCLA) health systems, 379 persons (/36,659 who received the first dose, and /28,184 of whom received the second dose) tested positive for SARS-CoV-2 at least 1 day after vaccination, the majority (71%) of whom tested positive within the first 2 weeks after the first dose. After receiving both vaccinations, 37 health care workers tested positive; of these workers, 22 had positive test results 1 to 7 days after the second dose. Only 8 health care workers tested positive 8 to 14 days after the second vaccination, and 7 tested positive 15 or more days after the second vaccination.

 

Daniel W, Nivet M, Warner J, Podolsky KD. Early Evidence of the Effect of SARS-CoV-2 Vaccine at One Medical Center. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2102153

Vaccine efficacy among employees of a medical center. Daniel et al. report 234 SARS-CoV-2 infections in 8969 non-vaccinated employees, 112 in 6144 partially vaccinated employees, and 4 among 8121 fully vaccinated employees, p < 0.01 for all pairwise comparisons. Next problem: vaccine hesitancy. Only 78% of employees were vaccinated by March 5.

 

Clinical

Altibi AM, Pallavi B, Liaqat H, et al. Characteristics and comparative clinical outcomes of prisoner versus non-prisoner populations hospitalized with COVID-19. Sci Rep 11, 6488 (2021). https://doi.org/10.1038/s41598-021-85916-w

Prisons in the United States have become a hotbed for spreading COVID-19 within said institutions. What about the clinical outcome after hospitalization for COVID-19? You know the answer: prisoner status was associated with more severe clinical presentation, higher rates of ICU admissions, vasopressors requirement, intubation, in-hospital mortality, and 30-day mortality.

 

24 March

Transmission

Paper of the Day

Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol 2021, published 22 March. Full text: https://doi.org/10.1038/s41579-021-00535-6

Excellent summary.

 

Prevention

Kiang MV, Chin ET, Huynh BQ, et al. Routine asymptomatic testing strategies for airline travel during the COVID-19 pandemic: a simulation study. Lancet Infect Dis 2021, published 22 March. Full-text: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00134-1/fulltext

Large-scale computer simulation to provide a comprehensive comparison of possible SARS-CoV-2 testing and quarantine strategies to facilitate safe airline travel. First message: the strategy of a rapid antigen test on the day of travel might give similar results to the pre-travel PCR test strategy. However, a significant proportion of infectious individuals will not be identified. Second message: an abbreviated quarantine with post-travel testing is probably needed to reduce population-level transmission due to importation of infection when travelling from a high to low incidence setting. Without vaccines, air travel will not return to pre-COVID-19 levels.

 

Virology

Jackson B, Rambaut A, Pybus OG, et al. Recombinant SARS-CoV-2 genomes involving lineage B.1.1.7 in the UK. Virological 2021, posted 17 March. Full text: https://virological.org/t/recombinant-sars-cov-2-genomes-involving-lineage-b-1-1-7-in-the-uk/658

The authors report SARS-CoV-2 genome sequences with some sections carrying mutations characteristic of B.1.1.7, while other sections carried mutations specific to another lineage. The timing, location, and genetic composition of the mosaic sequences provide evidence that they originated through recombination in co-infected individuals in the UK.

 

Immunology

McCallum M, De Marco a, Lempp FA, et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell 2021, published 16 March. Full text: https://doi.org/10.1016/j.cell.2021.03.028

McCallum et al. describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultra-potently. The authors underline the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.

 

Greaney AJ, Starr TN, Barnes CO, et al. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. bioRxiv 2021, posted 18 March. Full text: https://doi.org/10.1101/2021.03.17.435863

Although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is dominated by a single class of antibodies targeting an epitope that is already undergoing rapid evolution. These “class 2” antibodies target the face of the receptor-binding ridge that is accessible in both “up” and “down” RBD conformations. A mutation (E484K) that escapes this antibody class is present in many emerging viral lineages, including B.1.351, P.1, P.2, and B.1.526​.

 

Benedict C, Cedernaes J. Could a good night’s sleep improve COVID-19 vaccine efficacy? Lancet Respir Med. 2021 Mar 12:S2213-2600(21)00126-0. PubMed: https://pubmed.gov/33721558. Full text: https://doi.org/10.1016/S2213-2600(21)00126-0

Could the timing of vaccination affect the immune response to COVID-19 vaccines? Should we all take a nap after vaccination? It wouldn’t do any harm.

 

Long COVID

Arnold DT, Milne A, Samms E, et al. Are vaccines safe in patients with Long COVID? A prospective observational study. bioRxiv 2021, posted 14 March. Full text: https://doi.org/10.1101/2021.03.11.21253225

Observational study of 44 vaccinated participants and 22 matched unvaccinated participants. Most were highly symptomatic of Long COVID at 8 months (82% in both groups had at least 1 persistent symptom), with fatigue (61%), breathlessness (50%) and insomnia (38%) predominating. When compared to matched unvaccinated participants from the same cohort, those who had received a vaccine had a small overall improvement in Long COVID symptoms, with a decrease in worsening symptoms (5.6% vaccinated vs 14.2% unvaccinated) and increase in symptom resolution (23.2% vaccinated vs 15.4% unvaccinated) (p = 0.035). Placebo effect? Hopefully not.

 

23 March

Long COVID

Paper of the Day

Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med 2021, published 22 March. Full-text: https://doi.org/10.1038/s41591-021-01283-z

The authors provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae, and discuss relevant considerations for the multidisciplinary care of COVID-19 survivors.

 

Variants

Hoffmann M, Arora P, Groß R, et al. SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell 2021, accepted 16 March. Full-text: https://doi.org/10.1016/j.cell.2021.03.036

The authors show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1 and EK-1-C4. In contrast, entry of B.1.351 and P.1 was partially (casirivimab) or fully (bamlanivimab) resistant to monoclonal antibodies. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from individuals vaccinated with the Pfizer-BioNTech vaccine.

 

Transmission

Couthinho M, Darcie Marquitti FM, Souto Ferreira L, et al. Model-based estimation of transmissibility and reinfection of SARS-CoV-2 P.1 variant. medRxiv 2021, posted 9 March. Full-text: https://doi.org/10.1101/2021.03.03.21252706

From December, 2020 to February, 2021, Manaus was devastated by four times more COVID-19 cases compared to its previous peak (April, 2020). The probable culprit: the new P.1 variant. In this pre-print, the authors describe the transmissibility of P.1. to be about 2.5 times higher compared to the historical variant in Manaus. The probability of re-infection by P.1 seems to be low, though: 6.4% (95% CI: 5.7–7.1%).

 

Ferasin L, Fritz M, Ferasin H, et al. Myocarditis in naturally infected pets with the British variant of COVID-19. bioRxiv 2021, posted 18 March. Full-text: https://doi.org/10.1101/2021.03.18.435945

Given the enhanced infectivity and transmissibility of the B.1.1.7 variant, is there a risk that companion animals may play a more significant role in SARS-CoV-2 outbreak dynamics than previously appreciated? The authors report the first cases of infection of domestic cats and dogs by the British B.1.1.7 variant. They also discovered that many owners and handlers of these pets had developed COVID-19 respiratory symptoms 3-6 weeks before their pets became ill.

 

Vaccines

Khoury DS, Cromer D, Reynaldi A, et al. What level of neutralising antibody protects from COVID-19? medRxiv 2021, posted 11 March. Full-text: https://doi.org/10.1101/2021.03.09.21252641

Predictive models of immune protection are useful to identify immune correlates of protection to assist in the future deployment of vaccines. Here, the authors modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. They report that neutralisation level is highly predictive of immune protection. Attention: this is a pre-print, so don’t take the data for granted. However, in the future, with vaccines abundantly available, we will use figures such as Figure 1 to decide whether to prefer product A over product B.

 

Tauzin A, Nayrac M, Benlarbi M, et al. A single BNT162b2 mRNA dose elicits antibodies with Fc-mediated effector functions and boost pre-existing humoral and T cell responses. bioRxiv 2021, posted 18 March. Full-text: https://doi.org/10.1101/2021.03.18.435972

No neutralising activity in SARS-CoV-2 naïve individuals three weeks after a single dose of the Pfizer-BioNTech vaccine. However, the authors detected strong anti-receptor binding domain (RBD) and spike antibodies with Fc-mediated effector functions and cellular responses dominated by the CD4+ T cell component. These data provide support to spacing the doses of two-vaccine regimens to vaccinate a larger pool of the population in the context of vaccine scarcity against SARS-CoV-2.

 

22 March

Epidemiology

Rennert L, McMahan C, Kalbaugh CA, et al. Surveillance-based informative testing for detection and containment of SARS-CoV-2 outbreaks on a public university campus: an observational and modelling study. Lancet Child Adolescent Health March 19, 2021. https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00060-2/fulltext

There is a strong need for testing strategies for mitigating SARS-CoV-2 spread on college and university campuses. The authors implemented a novel surveillance-based informative testing (SBIT) strategy for SARS-CoV-2 detection. In this setting, random testing is done to detect potential cluster outbreaks (eg, residence hall outbreaks). Upon detection of an outbreak, a portion of available tests the following day are allocated to the entire cluster. SBIT was effective in detecting and containing COVID-19 outbreaks and mitigating SARS-CoV-2.

 

Immunology

Clark SA, Clark LE, Pan J, et al. SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms. Cell March 16, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00355-X

Viral evolution in a persistently infected immunocompromised individual: mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies. Resistance extends to the polyclonal serum immunoglobulins healthy convalescent donors and to monoclonal antibodies in clinical use. This case shows how SARS-CoV-2 can evolve solutions to bind ACE2 while escaping neutralization by major classes of human neutralizing antibodies.

 

Collateral damage

Adlhoch C, Mook P, Lamb F, et al. Very little influenza in the WHO European Region during the 2020/21 season, weeks 40 2020 to 8 2021. Eurosurveillance 18 March 2021, Volume 26, Issue 11. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.11.2100221

Almost no flu this year. This 2020/21 influenza season is exceptional since the creation of the Global Influenza Surveillance and Response System (GISRS) network in 1952. Positivity was 0.1% (33/25,606) this season compared to an average positivity of 38% (14,966/39,407) between week 40 year X and week 8 the following year. Yes, this was statistically significant.

 

Treatment

Driouich JS, Cochin M, Lingas G. et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat Commun March 19, 2021, 12, 1735. https://www.nature.com/articles/s41467-021-21992-w

In hamsters, favipiravir has a strong dose effect, when treatment is initiated before or simultaneously with infection. This led to reduction of infectious titers in lungs and clinical alleviation of the disease.

 

Solaymani-Dodaran M, Ghanei M, Bagheri M, et al. Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. Int Immunopharmacol. 2021 Mar 11;95:107522. PubMed: https://pubmed.gov/33735712. Full-text: https://doi.org/10.1016/j.intimp.2021.107522

In humans, this may be different. A large RCT from Iran, 380 patients randomly allocated into favipiravir and lopinavir/ritonavir, found no clinical benefit of favipiravir. Though the trial was hampered by some methodological issues (as well as its open label design), it seems obvious that patients who are hospitalized due to pneumonia and have passed the viral replication phase, are unlikely to benefit from antiviral treatment.

 

21 March

Epidemiology

Sandmann FG, Davies NG, Vassall A, et al. The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation. Lancet Inf Dis March 18, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00079-7/fulltext

In a modelling study from the UK, highlighting the substantial health and economic value of introducing SARS-CoV-2 vaccination. Without the initial lockdown, vaccination, and increased physical distancing, the authors estimate that 3.1 million (0.84–4.5) deaths would occur in the UK over the next 10 years.

 

Vaccine

Hassan AO, Feldmann F, Zhao H, et al. A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques. Cell Rep Med March 17, 2021. https://www.cell.com/action/showPdf?pii=S2666-3791%2821%2900046-X

The future? An intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) worked well in macaques. A single intranasal dose induced neutralizing antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after a SARS-CoV-2 challenge.

 

Immunology

Wang Z, Yang X, Zhong J, et al. Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection. Nat Commun March 19, 2021, 12, 1724. https://www.nature.com/articles/s41467-021-22036-z

Close contacts who are SARS-CoV-2-exposed are often both PCR- and antibody-negative, indicating that SARS-CoV-2 failed to establish a successful infection in these individuals, presumably due to their exposure to limited numbers of viral particles or a short time of exposure. This interesting study has evaluated T cell responses in 90 recovered COVID-19 patients and 69 close contacts. 58% of close contacts had virus-specific memory CD4+ and 14% of close contacts had virus-specific memory CD8+ T cells. Pool sizes and quality of T memory cells from close contacts were around half of those from COVID-19 patients.

 

Severe COVID-19

INSPIRATION Investigators. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit. JAMA March 18, 2021. doi:10.1001/jama.2021.4152. https://jamanetwork.com/journals/jama/fullarticle/2777829?resultClick=1

No need to increase the dose of prophylactic anticoagulation: a large RCT indicates no clinical benefit of intermediate dose compared with standard dose prophylactic anticoagulation in 452 patients with COVID-19 admitted to the intensive care unit (ICU).

 

Co-morbidities

Salter A, Fox RJ, Newsome SD, et al. Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis. JAMA Neurol March 19, 2021; Full-text: https://doi.org/10.1001/jamaneurol.2021.0688

Huge cross-sectional study of 1626 North American patients with MS and COVID-19. Increased disability was independently associated with worse clinical severity, as well as older age, Black race, cardiovascular co-morbidities, and recent treatment with corticosteroids.

 

20 March

Epidemiology

Pekar J, Worobey M, Moshiri N, et al. Timing the SARS-CoV-2 index case in Hubei province. Science  18 Mar 2021: eabf8003. DOI: 10.1126/science.abf8003. https://science.sciencemag.org/content/early/2021/03/17/science.abf8003

Shit happened in October/November 2019: employing a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations, the authors determine here how long SARS-CoV-2 could have been circulating prior to its “official” recognition. Results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province.

 

Variants

Grint DJ, Wing K, Williamson E, et al. Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February. Volume 26, Issue 11, 18 March 2021. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.11.2100256

Evidence grows that B.1.1.7 is more dangerous. In this data drawn from the OpenSAFELY electronic health records secure research platform (covering 40% of England’s population registered with a general practitioner), there was a consistently higher (about two thirds) absolute risk of death by 28 days after a SARS-CoV-2-positive test in all groups stratified by age, sex and presence of co-morbidities.

 

Immunology

He Z, Ren L, Yang J, et al. Seroprevalence and humoral immune durability of anti-SARS-CoV-2 antibodies in Wuhan, China: a longitudinal, population-level, cross-sectional study. Lancet March 20, 2021 Volume 397, ISSUE 10279, P1075-1084, March 20, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00238-5/fulltext

This cross-sectional study from Wuhan suggests durable protection against SARS-CoV-2. Among 3599 randomly selected families with 9702 individuals, baseline adjusted seroprevalence was 6.9%. Although titers of IgG decreased over the 9-month study period, the proportion of individuals who had IgG antibodies did not decrease substantially. Neutralizing antibodies were found in 39·8% of the seropositive subgroup; encouragingly, this proportion was also sustained. Of note, more than 80% of those surveyed who were seropositive were asymptomatic.

 

Andolfo I, Russo R, Larorsa, et al. Common variants at 21q22.3 locus influence MX1 and TMPRSS2 gene expression and susceptibility to severe COVID-19. iScience March 17, 2021. https://www.cell.com/action/showPdf?pii=S2589-0042%2821%2900290-X

Analyzing the genome of 7970 individuals hospitalized for COVID-19, this Italian group found some host genetic factors to influence the course of COVID-19. Five SNPs within TMPRSS2/MX1 locus (chromosome 21) were associated with severe COVID-19. The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and a high level of MX1 expression in blood (note that the odds ratios were not that dramatic, ranging from 0.5 to 1.5).

 

Vaccine

Moore S, Hill EM, Tildesley MJ, et al. Vaccination and non-pharmaceutical interventions for COVID-19: a mathematical modelling study. Lancet Inf Dis March 18, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00143-2/fulltext

Vaccination alone is not enough. This modeling study from UK indicates that in the absence of non-pharmaceutical interventions (NPIs), even with the most optimistic assumption that the vaccine will prevent 85% of infections, R is estimated to be 1.58 (95% CI 1.36–1.84) once all eligible adults have been offered both doses of the vaccine. Under the default uptake scenario, removal of all NPIs once the vaccination program is complete is predicted to lead to 21,400 deaths due to COVID-19 for a vaccine that prevents 85% of infections, although this number increases to 96,700 deaths if the vaccine only prevents 60% of infections.

 

19 March

Variants

Paper of the Day

Wu K, Werner AP, Koch M. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. NEJM March 17, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2102179

What about Moderna’s mRNA vaccine and the new variants? This study saw a decrease in titers of neutralizing antibodies against the P.1 variant, the B.1.427/B.1.429 variant, the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. Protection against these lineages remains “to be determined”.

 

Clinical

Hansen CH, Michlmayr D, Gubbels SM. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet March 17, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00575-4/fulltext

This large study from Denmark probably provides the best data to date on protection against re-infection. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0.65%) tested positive again during the second surge compared to 16,819 (3.27%) of 514,271 who tested negative during the first surge. Protection against repeat infection was 80.5% (95% CI: 75.4–84.5). Of note, there was no evidence of waning protection over time.

 

Long COVID-19

The Writing Committee for the COMEBAC Study Group. Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19. JAMA. March 17, 2021. https://jamanetwork.com/journals/jama/article-abstract/2777787

How is it going after four months? Not so well. This study included 142 of 172 ICU patients and 336 of 662 non-ICU patients from Paris. During a telephone interview, 244/478 patients (51%) declared at least one symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. CT lung scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 (19%).

 

Treatment

Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatology March 17, 2021. DOI: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00070-9/fulltext

Mavrilimumab is a monoclonal antibody that binds to the GM-CSF receptor and blocks intracellular signalling of GM-CSF. Based on this mechanism of action, the putative role of increased GM-CSF in adverse outcomes from COVID-19, and encouraging results from an observational study, the authors initiated a small RCT of 40 patients to evaluate whether mavrilimumab works in severe COVID-19. It didn’t.

 

Jevalikar G, Mithal A, Singh A, et al. Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19. Sci Rep 11, 6258 (2021). https://www.nature.com/articles/s41598-021-85809-y

Oh, again, no effect of vitamin D. In this prospective observational study on 404 patients, serum 25-OHD levels at admission did not correlate with inflammatory markers, clinical outcomes, or mortality in hospitalized COVID-19 patients. Treatment of vitamin D deficiency with cholecalciferol did not make any difference to the outcomes.

 

18 March

Vaccine/Variants

Mahdi SA, Baillie C, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. NEJM, March 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2102214

No protection from mild-to-moderate COVID-19 with AstraZeneca in this large RCT on young (median age 30 years), HIV-negative patients in South Africa. Infections were seen in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% CI, −49.9 to 59.8). Main caveat: as there were no cases of hospitalization in the study, it remains unclear whether ChAdOx1 nCov-19 may protect against severe infection with the B.1.351 variant.

 

Krutikov M, Hayward A, Shallcrosse L. Spread of a Variant SARS-CoV-2 in Long-Term Care Facilities in England March 16, 2021. NEJM March 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2035906

Rapid spread in staff and residents of long-term care facilities in the UK. Within a few weeks (between November 16 and December 13), the proportion of positive samples with S gene target failure (a proxy for B.1.1.7) increased from 70 of 582 (12.0%) to 491 of 813 (60.4%). This increase was associated with a decrease in median Ct values (from 27 to 21).

 

Immunology

Abayasingam A,  Balachandran H, Agapiou D, et al. Long-term persistence of RBD-positive memory B cells encoding neutralising antibodies in SARS-CoV-2 infection. Cell Rep Med March 14, 2021. https://www.cell.com/action/showPdf?pii=S2666-3791%2821%2900044-6

Good news. The loss of neutralising antibodies (NAb) in plasma may be countered by the maintenance of neutralising capacity in the memory B cell repertoire. Despite  the  declining  NAb  titers, in the great majority  of participants,  memory  B  cells against RBD were maintained and even increased in numbers at four to six months following infection in 12/13 participants.

 

Co-morbidities

Desai A, Gainor JF, Hegde A. et al. COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials. Nat Rev Clin Oncol March 15, 2021. https://doi.org/10.1038/s41571-021-00487-z

Continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility. This important perspective provides operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

 

Treatment

Yuan S, Yin X, Meng X, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature March 16, 2021). https://www.nature.com/articles/s41586-021-03431-4

Clofazimine, an anti-leprosy drug with a favorable safety profile, appears to possess pan-coronaviral inhibitory activity by inhibiting viral spike-mediated cell fusion and viral helicase activity. In hamsters, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and also mitigated inflammation.

 

17 March

Variants

Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 2021 Mar 9;372:n579. PubMed: https://pubmed.gov/33687922. Full-text: https://doi.org/10.1136/bmj.n579

Is B.1.1.7 more lethal? In this large study from the UK, mortality hazard ratio associated with infection with “B.1.1.7” (S gene negative) was 1.64 (95% CI: 1.32 to 2.04) in the community, compared with previously circulating variants. However, even though the authors controlled for some biases, their matched control approach bears several limitations. Let’s take it as a first hint, but not as proof.

 

Clinical

Sheehan MM, Reddy AJ, Rothberg MB, et al. Reinfection Rates among Patients who Previously Tested Positive for COVID-19: a Retrospective Cohort Study. Clinical Infectious Diseases March 15, 2021, ciab234. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab234/6170939

Previous infection appears to offer high levels of protection against symptomatic infection, as well as severe disease, for at least 8 months: in this retrospective cohort study of one multi-hospital health system in Ohio and Florida, protection against symptomatic infection was 84.5% (95% CI: 77.9 to 89.1).

 

Lambrecq V, Hanin A, Munoz-Musat E, et al. Association of Clinical, Biological, and Brain Magnetic Resonance Imaging Findings With Electroencephalographic Findings for Patients With COVID-19. JAMA Netw Open March 15, 2021. 2021; 4(3):e211489. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777441?resultClick=1

In this retrospective study from Paris, 9/664 (1%) of hospitalized patients presented with brain injury that was defined as COVID-19-related encephalopathy. Six had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter–enhancing lesions.

 

Vaccine

Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA March 15, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777685?resultClick=1

In this multicenter study on 436 solid organ transplant recipients taking different immunosuppressive agents, only 76 (17%) had detectable antibodies (anti-S1 or anti–receptor-binding domain) at a median of 20 days after the first dose of vaccine. These results contrast with the robust early immunogenicity observed in mRNA vaccine trials.

 

Britton A, Jacobs Slifka KM, Edens C, et al. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks — Connecticut, December 2020–February 2021. MMWR Morb Mortal Wkly Rep. ePub: 15 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7011e3.htm

Retrospective study in a total of 463 residents of two skilled nursing facilities, estimating effectiveness of partial vaccination in preventing SARS-CoV-2 infection to be 63% (95% CI: 33%–79%).

 

16 March

Top 5 instead of Top 10

We started working on covidreference.com a year ago. Since then, we have selected, evaluated and discussed almost 3500 Top 10 papers every day of the week (from a total of 112,586 papers listed in PubMed on March 14 – don’t blame us too much if we missed one or two). However, during the last months we’ve gotten the impression that 5 important papers per day should be enough. We will be as rigorous as ever in our selection.

 

Diagnostics

Paltiel DA, Zheng A, Sax PA. Clinical and Economic Effects of Widespread Rapid Testing to Decrease SARS-CoV-2 Transmission. Annals Int Medicine 9 March 2021, https://www.acpjournals.org/doi/10.7326/M21-0510

High-frequency home testing for SARS-CoV-2 with an inexpensive, imperfect test could contribute to pandemic control at justifiable cost. Large reductions in infections, mortality, and hospitalizations were seen under different behavioral assumptions and testing frequencies.

 

Immunology

Szabo PA, Dogra P, Gray JI, et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity March 11, 2021. DOI: https://www.cell.com/action/showPdf?pii=S1074-7613%2821%2900117-5

More insights into the immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract. The authors have identified a key role for airway myeloid cells, primarily macrophages and monocytes, in driving and perpetuating immune cell recruitment and lung inflammation, consistent with their associations with older age and mortality.

 

Variants

Garcia-Beltran WF, Lam EC, Denis KS, et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell March 12, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00298-1

Among 99 individuals who received one or two doses of mRNA vaccines, most individuals receiving a single dose did not raise sufficient antibody titers to provide detectable cross neutralization to B.1.351. This supports the importance of 2-dose regimens to acheive protective titers.

 

Altman DM, Boyton RJ, Beale R. Immunity to SARS-CoV-2 variants of concern. Science  12 Mar 2021: Vol. 371, Issue 6534, pp. 1103-1104. https://science.sciencemag.org/content/371/6534/1103

Brilliant brief review about not only immunity to variants but also on methodological issues. Assessment of variants on neutralization are complicated by the variability of pseudotype assays used.

 

Li Y, Ma ML, Lei Q, et al. Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients. Cell Reports March 12, 2021. DOI:https://doi.org/10.1016/j.celrep.2021.108915

What part of the spike protein is highly immunogeneic? By analyzing the serum IgG response of 1051 COVID-19 patients with a peptide microarray, the authors built a comprehensive epitope landscape that covers the entire sequence of the SARS-CoV-2 spike protein. A set of 16 highly immunogenic epitopes outside of the RBD region were identified. The antibody responses against several epitopes are associated with severity. Little neutralization activity was observed for the antibodies against the highly immunogenic epitopes.

 

Long COVID-19

Perlis RH, Ognyanova K, Santillana M, et al. Association of Acute Symptoms of COVID-19 and Symptoms of Depression in Adults. JAMA Netw Open. 2021; 4(3):e213223. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777421?resultClick=1

Depression may be considered as potential neuropsychiatric sequelae. Among more than 3900 individuals with prior COVID-19 surveyed between May 2020 and January 2021, 52.4% met criteria for moderate or greater symptoms of major depression. Symptoms were more prevalent in younger and in male patients.

 

15 March

Co-morbidities

Paper of the Day

Elliott A, Saul M, Zeng J, et al. Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes. Sci Rep 11, 5639 (2021). https://www.nature.com/articles/s41598-021-84731-7

What are the biologic underpinnings of increased COVID-19 morbidity in cancer patients? This study showed significant differences in ACE2 and protease expression in normal and malignant tissues with a subgroup expressing very high levels of ACE2 RNA (in particular in NSCLC and gastrointestinal cancer). These findings, together with the increased presence of inflammatory cells in tumors displaying high ACE2 levels might explain why cancer patients are more severely affected by COVID-19.

 

Arnold J, Winthrop K, Emery P, et al. COVID-19 vaccination and antirheumatic therapy. Rheumatology 12 March 2021, keab223, https://doi.org/10.1093/rheumatology/keab223

Some evidence indicates immunosuppressive therapy inhibits humoral response to the influenza, pneumococcal and hepatitis B vaccines. The degree to which this will translate to impaired COVID-19 vaccine responses is unclear. This article outlines the existing data on the effect of anti-rheumatic therapy on vaccine responses in patients with inflammatory arthritis and formulates a possible pragmatic management strategy for COVID-19 vaccination.

 

Epidemiology

van den Berg P, Schechter-Perkins EM, Jack RS, et al. Effectiveness of three versus six feet of physical distancing for controlling spread of COVID-19 among primary and secondary students and staff: A retrospective, state-wide cohort study. Clinical Infectious Diseases 10 March 2021, ciab230, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab230/6167856?searchresult=1

Incident cases of SARS-CoV-2 in students and staff in Massachusetts public schools among districts with different physical distancing requirements did not differ, suggesting that the less physical distancing recommendation can be adopted in school settings without negatively impacting safety.

 

Transmission

Jordan I, Fernandez de Sevilla M, Bassat Q, et al. Transmission of SARS-CoV-2 infection among children in summer schools applying stringent control measures in Barcelona, Spain. Clinical Infectious Diseases, 12 March 2021, ciab227, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab227/6168543

Among the more than 2000 repeatedly screened participants, the transmission rate of SARS-CoV-2 infection among children attending school-like facilities under strict prevention measures was lower than that reported for the general population.

 

Soriano-Arandes A, Gatell A, Serrano P, et al. Household SARS-CoV-2 transmission and children: a network prospective study. Clinical Infectious Diseases 12 March 2021, ciab228, https://doi.org/10.1093/cid/ciab228

Same direction: children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic even if attending school. Among 1040 COVID-19 patients < 16 years, more than 70% (756) were secondary to an adult infection, while only 7.7% (80) were index cases.

 

Immunology

Flynn RA, Belk JA, Qi Y, et al. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. Cell March 11, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00297-X

Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), Ryan A. Flynn and colleagues identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Their work provides a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which can inform studies to understand the host-virus interface.

 

Clinical

Brehm TT, van der Meirschen M, Hennigs A, et al. Comparison of clinical characteristics and disease outcome of COVID-19 and seasonal influenza. Sci Rep 11, 5803 (2021). https://www.nature.com/articles/s41598-021-85081-0

Again, it’s no flu. Thomas Theo Brehm and colleagues from Hamburg compared 166 patients with COVID-19 diagnosed between February and June 2020, and 255 patients with seasonal influenza diagnosed during the 2017–18 season at the same hospital. Although patients with COVID-19 were younger and had fewer comorbidities, they had a longer duration of hospitalization, a more frequent need of invasive ventilation and were more frequently admitted to the intensive care unit.

 

Almadhi MA, Abdulrahman A, Alawadhi A, et al. The effect of ABO blood group and antibody class on the risk of COVID-19 infection and severity of clinical outcomes. Sci Rep 11, 5745 (2021). https://doi.org/10.1038/s41598-021-84810-9

In this large study from Bahrein, no association between antibodies and either risk of infection or susceptibility to severe infection was found, possibly indicating that an unexplored underlying factor may be causing the association, not necessarily the blood group or type of antibodies present.

 

Severe COVID-19

Lin X, Fu B, Yin S, et al. ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway. iScience March 09, 2021. https://www.cell.com/iscience/fulltext/S2589-0042(21)00261-3

SARS-CoV-2 coding protein open reading frame 8 (ORF8) acts as a contributing factor to the cytokine storm during COVID-19 infection. ORF8 activated the IL-17 signaling pathway and promoted the expression of pro-inflammatory factors. Treatment of IL17RA antibody protects mice from ORF8-induced inflammation.

 

Collateral damage (and benefits)

Li L, Neuroth LM, Valachovic E, et al. Association Between Changes in Social Distancing Policies in Ohio and Traffic Volume and Injuries, January Through July 2020. JAMA March 9, 2021;325(10):1003-100. https://jamanetwork.com/journals/jama/fullarticle/2777228

Better stay home, it’s better for everybody. Compared to 2019, the period between the stay-at-home order and retail reopening (March 23 through May 11, 2020) in Ohio saw 55% fewer motor vehicle crash involvements, 47% fewer injuries, 34% fewer severe/fatal injuries, and 44% lower traffic volume.

 

Treatment

Bertoglio F, Meier D, Langreder N, et al. SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface. Nat Commun March 11, 2021, 12, 1577. https://www.nature.com/articles/s41467-021-21609-2

Successful isolation and characterization of a fully human, recombinant anti-spike neutralizing monoclonal antibody from a universal, human naïve antibody gene library that was constructed before the emergence of SARS-CoV-2. This work shows how neutralizing antibodies can be efficiently selected rapidly without the need of convalescent patient material.

 

14 March

Immunology

Paper of the Day

Amanat F, Thapa M, Lei T, et al. The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies that target both the NTD and the RBD. medRxiv 2021, posted 9 March. Full-text: https://doi.org/10.1101/2021.03.07.21253098

Florian Krammer, Fatima Amanat and colleagues studied the plasmablast response to SARS-CoV-2 mRNA-based vaccination. The authors demonstrate that the antibody responses to SARS-CoV-2 mRNA vaccination comprise a large proportion of non-neutralizing antibodies and are co-dominated by NTD and RBD antibodies. The NTD portion of the spike represents, therefore, an important vaccine target. Since all viral variants of concern are heavily mutated in this region, these observations warrant further attention to optimize SARS-CoV-2 vaccines. Finally, broadly cross-reactive mAbs to β-coronavirus spike proteins are induced after vaccination and suggest a potential development path for a pan-β-coronavirus vaccine.

 

Ellebedy A, Turner J, O’halloran J, et al. SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans. Research Square 2021, posted 9 March. Full-text: https://doi.org/10.21203/rs.3.rs-310773/v1

Did you feel that your arm is on “fire” after getting your SARS-CoV-2 mRNA vaccine? Did you get some fine needle aspirates of your draining axillary lymph nodes? You could have investigated the dynamics of antibody secreting plasmablasts (PBs) and germinal center (GC) B cells induced by these vaccines in SARS-CoV-2 naïve and antigen-experienced humans. Ellebedy et al did just that. They demonstrated that SARS-CoV-2 mRNA-based vaccination of humans induces a robust and persistent GC B cell response that engages pre-existing as well as new B cell clones. High-affinity, broad, and durable humoral immunity on the horizon?

 

Muecksch F, Weisblum Y, Barnes CO, et al. Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies. bioRxiv 2021, posted 8 March. Full-text: https://doi.org/10.1101/2021.03.07.434227

Might affinity maturation generate antibodies that are resilient to viral evolution? Paul Bieniasz, Frauke Muecksch and colleagues think so. After analyzing six independent antibody lineages, they found that for certain ones, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. The authors conclude that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.

 

Epidemiology

CMMID 202103. European COVID-19 Forecast hub. London School of Hygiene & Tropical Medicine and ECDC 2021. Website: https://covid19forecasthub.eu

The European COVID-19 Forecast hub aims to collate and meaningfully combine short-term forecasts of COVID-19 from across Europe in order to 1) improve situational awareness and 2) quantify the current trajectory of COVID-19 everywhere whilst acknowledging uncertainty.

Graphic

 

Mallapaty S. The search for animals harbouring coronavirus — and why it matters. Nature 2021, published 2 March. Full-text: https://www.nature.com/articles/d41586-021-00531-z

Monitoring pets, livestock and wildlife to see where SARS-CoV-2 could hide, and whether it might resurge.

Graphic

 

Transmission

Hensley MK, Bain WG, Jacobs J, et al. Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study. Clin Infect Dis 2021. Full-text: https://doi.org/10.1093/cid/ciab072

Prolonged transmission from immunosuppressed patients is possible. A chimeric antigen receptor-modified T cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting > 2 months. Deep sequencing revealed multiple sequence variants consistent with intra-host viral evolution.

 

Virology

Braun KM, Moreno GK, Halfmann PJ, et al. Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck. PLOS Pathogens 2021, published 26 February. Full-text: https://doi.org/10.1371/journal.ppat.1009373

How is genetic variation generated and selected within and between individual hosts? Using domestic cats as a model, Thomas Friedrich, Katarina Braun and colleagues show that within-host SARS-CoV-2 genetic variation is predominantly influenced by genetic drift and purifying selection. In particular, they identified a notable variant at amino acid position 655 in spike (H655Y), which was previously shown to confer escape from human monoclonal antibodies. This variant arises rapidly and persists at intermediate frequencies in index cats.

 

Variants

Grint DJ, Wing K, Williamson E, et al. Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England. MedRxiv 2021, posted 8 March. Full-text: https://doi.org/10.1101/2021.03.04.21252528

The authors draw data from a research platform that covers 40% of England’s population registered with a general practitioner. B.1.1.7 status was known for 184,786 people. The B.1.1.7 group was younger with a lower proportion of older cases (80+: 0.9% VOC vs. 1.6% non-B.1.1.7 cases), with fewer co-morbidities (2+ co-morbidities: 2.9% vs. 3.8%). After controlling for co-morbidities, age, week, region & other sociodemographics, the authors found an increased risk of death for B.1.1.7 compared with non-B.1.1.7 cases (HR: 1.67; 95% CI: 1.34 – 2.09; P < 0.0001).

 

Tablizo FA, Kim KM, Lapid CM, et al. Genome sequencing and analysis of an emergent SARS-CoV-2 variant characterized by multiple spike protein mutations detected from the Central Visayas Region of the Philippines. medRxiv 2021, posted 6 March. Full-text: https://doi.org/10.1101/2021.03.03.21252812

The authors describe the emergence of a new SARS-CoV-2 lineage, mainly from the Central Visayas region of the Philippines: 13 lineage-defining mutations, including the co-occurrence of the E484K, N501Y, and P681H mutations at the spike protein region, as well as three additional radical amino acid replacements towards the C-terminal end of the said protein. A three amino acid deletion at positions 141 to 143 (LGV141_143del) in the spike protein is reminiscent of a region preceding the 144Y deletion found in the B.1.1.7 variant. See also the ‘P.3’ proposition by Andrew Rambaut: https://github.com/cov-lineages/pango-designation/issues/27.

 

Vaccines

Shah A, Gribben C, Bishop J, et al. Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households. GitHub preprint, posted 12 March. Full-text: https://github.com/ChronicDiseaseEpi/hcw/blob/master/vaccine_manuscript.pdf

Household members of vaccinated healthcare workers have a lower risk for being infected with SARS-CoV-2 (rate per 100 person-years 9∙40 versus 5∙93; HR 0∙70, 95% CI: 0∙63 to 0∙78). This is the result of a Scottish cohort comprised of 194,362 household members (mean age 31∙1 ± 20∙9 years) and 144,525 healthcare workers (mean age 44∙4 ± 11∙4 years). As household members of healthcare workers can also be infected by other people, this 30% risk reduction is probably an underestimate of the effect vaccination will have on transmission of SARS-CoV-2.

 

Fischer R, van Doremalen N, Adney D, et al. ChAdOx1 nCoV-19 (AZD1222) protects against SARS-CoV-2 B.1.351 and B.1.1.7. bioRxiv 2021, posted 11 March. Full-text: https://doi.org/10.1101/2021.03.11.435000

Thinking of maybe not getting the vaccine because of the new variants? Think again! Here, Robert Fischer, Neeltje van Doremalen and colleagues show a lack of disease in Syrian hamsters vaccinated with the AstraZeneca vaccine when infected with B.1.1.7 or B.1.351 (first detected in the UK and South Africa, respectively). The authors observed a 9.5-fold reduction of virus-neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 did not lose weight compared to control animals. Interesting data from a pre-print paper that need to be confirmed in clinical vaccine practice.

 

Public Health England 20210222. PHE monitoring of the early impact and effectiveness of COVID-19 vaccination in England. UK Government 2021, 22 February; accessed 5 March 2021. Full-text: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/963532/COVID-19_vaccine_effectiveness_surveillance_report_February_2021_FINAL.pdf

Public Health England reports on 11,860 confirmed cases of COVID in those aged over 80 years. The Pfizer-BioNTech vaccine effectiveness was 57% (95% CI: 48-63%) from 28 days after the first dose of vaccination. In 8119 individuals aged over 80 years with a confirmed PCR positive test and followed for at least 21 days, the case fatality ratio was lower in cases vaccinated at least 14 days before onset than in unvaccinated cases. This would indicate that within vaccinated individuals who do become symptomatic the vaccine confers additional protection against death.

 

Ghebreyesus TA. A ‘me first’ approach to vaccination won’t defeat Covid. The Guardian 2021, published 5 March. Full-text: https://www.theguardian.com/commentisfree/2021/mar/05/vaccination-covid-vaccines-rich-nations

Of the 225m vaccines administered so far, most have been in a handful of rich nations. This has to change, for all our sakes, says Tedros Adhanom Ghebreyesus, director general of WHO. The normal rules of business that protect the profits of vaccine manufacturers will have to be set aside if that is what it takes to ensure everybody is immunized against SARS-CoV-2. See also Boseley S. A ‘me first’ approach to vaccination won’t defeat Covid. The Guardian 2021, published 5 March. Full-text: https://www.theguardian.com/world/2021/mar/05/covid-vaccines-who-chief-backs-patent-waiver-to-boost-production

 

Boseley S, Brooks L. UK will diverge from EU and US on approving tweaked Covid vaccines. The Guardian 2021, published 4 March. Full-text: https://www.theguardian.com/society/2021/mar/04/vaccines-tweaked-for-covid-variants-will-be-fast-tracked-safely-says-uk-regulator

The UK will adopt a different standard from Europe and the US when it considers approval for coronavirus vaccines that have been tweaked to deal with variants, the UK regulator has said.

 

Clinical

Wohlfahrt J, Fonager J, Albertsen M, et al. Increased Risk of Hospitalisation Associated with Infection with SARS-CoV-2 Lineage B.1.1.7 in Denmark. Lancet Preprints 2021, posted 2 March. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3792894

Infection with B.1.1.7 was associated with an increased risk of hospitalization compared with other lineages (adjusted odds ratio: 1.64).

 

13 March

Variants

Paper of the Day

Collier DA, De Marco A, Ferreira IA, et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature March 11, 2021. https://www.nature.com/articles/s41586-021-03412-7

A pseudovirus bearing S protein with the full set of mutations present in the B.1.1.7 variant did result in a small reduction in neutralization by sera from vaccinees that was more marked following the first dose vs the second dose. Worryingly, Dami A. Collier and colleagues measured further reduction in neutralization titers by vaccine sera when E484K was present alongside the B.1.1.7 S mutations. They conclude that “E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b”.

 

Borges V, Sousa C, Menezes L, et al. Tracking SARS-CoV-2 lineage B.1.1.7 dissemination: insights from nationwide spike gene target failure (SGTF) and spike gene late detection (SGTL) data, Portugal, week 49 2020 to week 3 2021. Eurosurveillance Mar 11, 2021, Article Volume 26, Issue 10.  https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.10.2100130

Dissemination of the B.1.1.7 lineage in Portugal. Both SGTF and SGTL (a proxy for monitoring trends of B.1.1.7) samples had significantly lower median Ct values of N and ORF1ab gene targets (ca 3.5 and 1.8 Ct units, respectively) compared with samples where the S gene was unbiasedly detected.

 

Epidemiology

Sartorius B, Lawson AB, Pullan RL. Modelling and predicting the spatio-temporal spread of COVID-19, associated deaths and impact of key risk factors in England. Sci Rep 11, March 8, 2021, 5378. https://doi.org/10.1038/s41598-021-83780-2

This high resolution spatial–temporal model highlights differences in epidemic dynamics across small areas in England, emphasizing the importance of monitoring at a granular sub-national scale. A geographically staggered approach combined with enhanced community surveillance will be increasingly important.

 

Boffetta P, Violante F, Durando P, et al. Determinants of SARS-CoV-2 infection in Italian healthcare workers: a multicenter study. Sci Rep March 11, 2021, 5788. https://www.nature.com/articles/s41598-021-85215-4.pdf

The prevalence of infection ranged from 3% to 22%, and was correlated with that of the respective areas within Italy. Of note, there was a lack of a clear pattern in risk according to job categories.

 

Vaccine

Krammer F, Srivastava K, Alshammary H, et al. Antibody Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine. March 10, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2101667

In 110 vaccinees, the antibody titers of those with pre-existing infection were 10 to 45 times higher than those of vaccinees without pre-existing immunity at the same time points after the first mRNA vaccine dose. The problem with all these studies: until we know whether this translates into similar protection, the one-shot strategy will not gain widespread acceptance. When we do know one day, this will largely not matter (there will be enough vaccine available) and will only be interesting for cost reasons.

 

Steinberg J, Thomas A, Iravavi A. 18Fluorodeoxyglucose PET/CT findings in a systemic inflammatory response syndrome after COVID-19 vaccine. Lancet March 08, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00464-5/fulltext

Julie Steinberg and colleagues from St. Louis describe an interesting case of a (self-resolving) systemic inflammatory response syndrome in a 65-year-old woman, starting one day after Moderna’s mRNA vaccine. PET/CT showed uptake in the fat stranding posterior to the right deltoid, moderately increased uptake within multiple right axillary lymph nodes and diffusely increased splenic uptake.

 

Fernández-Prada M, Rivero-Calle I, Calvache-González A, Martinón-Torres F. Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021. Euro Surveill. 2021;26(10):pii=2100193. https://doi.org/10.2807/1560-7917.ES.2021.26.10.2100193

María Fernández-Prada and colleagues report on 20 female HCWs with acute onset of a single supraclavicular lymphadenopathy coinciding with the ipsilateral intramuscular administration of an mRNA vaccine. Of note, 17 reported that the injection point had been unusually high. All lymphadenopathies had inflammatory symptoms (pain, swelling), were rounded and mobile, and all but one appeared in the first 24 h to 9 days after vaccine administration. All improved clinically, and 15 completely resolved between 5 and 16 days from onset.

 

Transmission

Klompas M, Baker MA, Griesbach D, et al. Transmission of SARS-CoV-2 from asymptomatic and presymptomatic individuals in healthcare settings despite medical masks and eye protection. Clinical Infectious Diseases, 11 March 2021. ciab218, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab218/6168040?searchresult=1

Three instances of SARS-CoV-2 transmission in Boston, despite medical masks and eye protection, including one transmission despite both parties being masked. Whole genome sequencing confirmed perfect homology between source and exposed persons’ viruses in all cases. These findings teach the importance of not relying upon medical masks and eye protection alone.

 

Pan X, Li X, Kong P, et al. Assessment of Use and Fit of Face Masks Among Individuals in Public During the COVID-19 Pandemic in China. JAMA Netw Open March 11, 2021, 4(3):e212574. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777405?resultClick=1

“Wear a mask.” If it were only that simple, even in China! For this study, during July and August 2020, 6003 (!) people wearing masks were assessed at public places, such as markets, train stations, airports, hospitals, and schools in Beijing, Yunnan, Shanxi, and Jiangsu. Face mask airtightness was commonly suboptimal, mostly secondary to gaps at the upper face mask edge. Sealing the upper face mask edge with an adhesive tape was associated with significantly improving the airtightness of commonly used face masks.

 

Long COVID-19

Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med March 10, 2021. https://www.nature.com/articles/s41591-021-01292-y

Is it possible to predict long COVID-19? Among 4182 people who self-reported their symptoms prospectively in the COVID Symptom Study app, a total of 558 (13.3%) reported symptoms lasting ≥ 28 days, 189 (4.5%) for ≥ 8 weeks and 95 (2.3%) for ≥ 12 weeks. Experiencing more than five symptoms during the first week of illness was associated with long COVID in all sexes and age groups (odds ratio = 3.5). Main caveat: the population was limited by being confined to app contributors (disproportionately female patients). May not be generalizable.

 

12 March

Vaccine

Paper of the Day

Stephenson KE, Le Gars M, Sadoff J, et al. Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19. JAMA March 11, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777598

The COVID-19 vaccine from Janssen (Johnson & Johnson) is the fourth vaccine recommended in the EU for preventing COVID-19. Ad26.COV2.S is a recombinant, replication-incompetent Ad26 vector encoding the full length and stabilized SARS-CoV-2 S protein derived from the first Wuhan strain. This phase I study (in 25 recipients from Boston) shows that a single immunization induced rapid binding and neutralization antibody responses as well as cellular immune responses, including induction of RBD-specific binding antibodies in 90% of vaccine recipients by day 8.

 

Vijayasingham L, Bischof E, Wolfe J. Sex-disaggregated data in COVID-19 vaccine trials. Lancet March 05, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00384-6/fulltext

Lavanya Vijayasingham and colleagues argue that sex factors, including sex-disaggregated analysis and reporting, are still neglected in COVID-19 trial data reporting.

 

Epidemiology

Richard Q, Alizon S, Choisy M, et al. Age-structured non-pharmaceutical interventions for optimal control of COVID-19 epidemic. PLOS Computational Biology March 4, 2021. https://doi.org/10.1371/journal.pcbi.1008776

Complex models, trying to elucidate that countries with contrasted population age-structures and social or physical contacts may need different NPIs.

 

Bokharaie VS. A study on the effects of containment policies and vaccination on the spread of SARS-CoV-2. PLOS March 4, 2021. https://doi.org/10.1371/journal.pone.0247439

Same direction. A method to predict the spread of the SARS-CoV-2 in a population with a known age-structure, and then, to quantify the effects of various containment policies, including those policies that affect each age-group differently.

 

Mulenga LB, Hines JZ, Fwoloshi S, et al. Prevalence of SARS-CoV-2 in six districts in Zambia in July, 2020: a cross-sectional cluster sample survey. Lancet Global Health March 09, 2021. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00053-X/fulltext

Almost 1 in 100 diagnosed: According to this first large cross-sectional cluster-sample survey of households in Africa (performed in July), the number of laboratory-confirmed cases reported in official statistics in Zambia underestimated SARS-CoV-2 infections by a factor of 92.

 

Virology

Lythgoe KA, Hall M, Ferretti L, et al. SARS-CoV-2 within-host diversity and transmission. Science 09 Mar 2021: eabg0821 Full-text: https://doi.org/10.1126/science.abg0821

Katrina A. Lythgoe and colleagues deep-sequenced 1313 clinical samples from the UK. Interestingly, most samples harbored few intrahost variants, and estimated transmission bottleneck sizes were very small, with maximum likelihood estimates between 1 and 8 among household transmission pairs, meaning that if mutations do arise they will be prone to loss at the point of transmission. The results suggest that transmission-enhancing and/or immune-escape variants are likely to arise infrequently, but could spread rapidly if successfully transmitted.

 

Clinical

Poletti P, Tirani M, Cereda D, et al. Association of Age With Likelihood of Developing Symptoms and Critical Disease Among Close Contacts Exposed to Patients With Confirmed SARS-CoV-2 Infection in Italy. JAMA Netw Open March 10, 2021;4(3):e211085. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777314

Of 5484 quarantined case contacts who were monitored daily for symptoms for at least 2 weeks, 2824 (51.5%) tested positive. The proportion of infected persons who developed symptoms ranged from 18.1% (95% CI, 13.9%-22.9%) among participants younger than 20 years to 64.6% (95% CI, 56.6%-72.0%) for those aged 80 years or older.

 

Long COVID

Weng J, Li Y, Li J, et al. Gastrointestinal sequelae 90 days after discharge for COVID-19. Lancet Gastroenterology Hepatology March 9, 2021. https://www.thelancet.com/journals/langas/article/PIIS2468-1253(21)00076-5/fulltext

In this retrospective study from Hubei and Guangdong provinces, 52 (44%) of 117 patients reported gastrointestinal symptoms after discharge at a 90 day telephone interview: loss of appetite (24%), nausea (18%), acid reflux (18%), and diarrhoea (15%). Of note, severe illness during hospitalisation was not associated with post-discharge gastrointestinal sequelae.

 

Collateral damage (and benefits)

Maselli-Schoueri JH, Werneck de Carvalho LE, Affonso Fonseca FL, et al. Hospital Admissions Associated With Noncommunicable Diseases During the COVID-19 Outbreak in Brazil. JAMA Netw Open March 8, 2021; 4(3):e210799. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777139 Reduction in hospital admissions for NCDs from January to June 2020 compared with the corresponding period in each of the 3 previous years in São Paulo, Brazil. Decrease was 68% for musculoskeletal diseases, 44% for metabolic diseases, 38% for CVDs, and 35% for neoplasms.

 

Treatment

Ozaki K, Reinhard CT. The future lifespan of Earth’s oxygenated atmosphere. Nat. Geosci. 14, 138–142 (2021). https://doi.org/10.1038/s41561-021-00693-5

We’d prefer to present other papers in this section. However, there is some good news: we’ll get some more weeks to find a potent treatment for SARS-CoV-2. Using a combined biogeochemistry and climate model to examine the likely timescale of oxygen-rich atmospheric conditions on Earth, these authors estimate that the mean future lifespan of Earth’s atmosphere, with oxygen levels more than 1% of the present atmospheric level, is 1.08 ± 0.14 billion years.

 

11 March

Variants

Paper of the Day

Tegally H, Wilkinson E, Giovanetti M. et al. Emergence of a SARS-CoV-2 variant of concern with mutations in spike glycoprotein. Nature March 9, 2021. https://www.nature.com/articles/s41586-021-03402-9_reference.pdf

The future “reference” paper on the detection of B.1.351 (or 501Y.V2), characterized by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y). This lineage was identified in South Africa after the first epidemic wave in a severely affected metropolitan area, and spread rapidly. The genomic data, showing the rapid expansion and displacement of other lineages in multiple regions, suggest that this lineage is associated with a selection advantage, most plausibly as a result of increased transmissibility or immune escape. Nevertheless, congrats to co-author Wolfgang Preiser!

 

Epidemiology

Agrawal S, Orschler L, Lackner S. Long-term monitoring of SARS-CoV-2 RNA in wastewater of the Frankfurt metropolitan area in Southern Germany. Sci Rep 11, 5372 (2021). https://www.nature.com/articles/s41598-021-84914-2

After monitoring the time course of the SARS-CoV-2 RNA concentration in raw sewage in the Frankfurt metropolitan area for several months, Shelesh Agrawal and colleagues believe that wastewater-based epidemiology has the potential to serve as an early warning system for SARS-CoV-2 infections and as a monitoring system to identify global hotspots.

 

Brault V, Mallein B, Rupprecht JF, et al. Group testing as a strategy for COVID-19 epidemiological monitoring and community surveillance. PLOS Computational Biology, March 4, 2021. https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008726

Group testing could provide the means for regular and massive screenings. In this paper, the authors do not address any diagnostic problems—e.g. how to use a minimal number of tests to obtain an individual diagnostic—but rather focus on population-scale application of pooling.

 

Immunology

Grzelak L, Velay A, Madec Y, et al. Sex differences in the evolution of neutralizing antibodies to SARS-CoV-2. Journal of Infectious Diseases 07 March 2021, jiab127, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab127/6161322?searchresult=1

More robust humoral responses in women than in men? In 308 healthcare workers with mild disease, anti-S and anti-N antibodies were detected in 99% and 59% of individuals at 3-6 months, respectively. Anti-S antibodies and NAbs declined faster in males than in females, independently of age and BMI, suggesting an association of sex with evolution of the humoral response.

 

Vaccine

Saad-Roy CM, Morris SE, Metcalf JE, et al. Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes. Science 09 Mar 2021: eabg8663. https://science.sciencemag.org/content/early/2021/03/08/science.abg8663

Delaying the second dose? Maybe easier said than done. Chadi Saad-Roy and colleagues urge caution. According to their models, a vaccine strategy with a very long inter-dose period could lead to marginal short-term benefits at the cost of a higher infection burden in the long term and substantially more potential for viral evolution and the development of new variants. However, current uncertainties surrounding the strength and duration of adaptive immunity in response to natural infection or vaccination lead to very broad range of possible outcomes of various dosing regimens.

 

Capetti AF, Stangalini CA, Borgonovo F, et al. Impressive boosting of anti-S1/S2 IgG production in COVID-19-experienced patients after the first shot of the BNT162b2 mRNA COVID-19 Vaccine.  Clinical Infectious Diseases 06 March 2021, ciab214, https://doi.org/10.1093/cid/ciab214

But is one shot enough after infection? The next study, comparing COVID-19 naïve people versus asymptomatic/pauci-symptomatic (A/P) people versus symptomatic/hospitalized (S/H) COVID-19 patients. Titers (logarithmic scale!) before and after the first dose of the BNT162b2 vaccine.

 

Virology

Baggen J, Persoons L, Vanstreels E, et al. Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nat Genet March 8, 2021. https://www.nature.com/articles/s41588-021-00805-2.pdf

Jim Baggen and colleagues from Belgium have identified two new host factors required for coronavirus infection. The lysosomal protein TMEM106B serves as an essential specific host factor for SARS-CoV-2 infection in multiple human cell lines. The phosphoinositide 3-kinase (PI3K) type 3 appears to be a common host factor for SARS-CoV-2 that could be targeted by small molecules.

 

Diagnostics

Shrotri M, Harris RJ, Rodger A, Planche T, Sanderson F, Mahungu T, et al. Persistence of SARS-CoV-2 N-antibody response in healthcare workers, London, UK. Emerg Infect Dis. 2021 Apr [date cited]. https://wwwnc.cdc.gov/eid/article/27/4/20-4554_article

Nucleocapsid (N) antibodies appear more stable than Spike (S) antibodies in the short term. N antibody titers were stable and sustained for < 12 weeks in 312 seropositive participants. This was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning.

 

Van Elslande J, Gruwier L, Godderis P. Estimated half-life of SARS-CoV-2 anti-spike antibodies more than double the half-life of anti-nucleocapsid antibodies in healthcare workers. Clinical Infectious Diseases 08 March 2021, ciab219, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab219/6162856?searchresult=1

Oops, the opposite? See title. We would like to attend a Zoom meeting between Madhumita Shrotri and Jan Van Elslande. Different time periods, methods, participants? The debate goes on.

 

Noh JY, Kwak JE, Yang JS, et al. Longitudinal assessment of anti-SARS-CoV-2 immune responses for six months based on the clinical severity of COVID-19. Journal of Infectious Diseases 04 March 2021, jiab124, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab124/6158870?searchresult=1

Ji Yun Noh and colleagues from Seoul have investigated the longitudinal profile of anti-SARS-CoV-2 antibodies in patients who recovered from COVID-19. Neutralizing antibodies were detected in 86.9% until six months after diagnosis of SARS-CoV-2 infection. Patients with pneumonia had significantly higher titers (and stronger T cell immunity) than patients without.

 

10 March

Variants

Paper of the Day

Wang P, Nair MS, Liu L, et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature March 8, 2021. https://www.nature.com/articles/s41586-021-03398-2

For younger readers: once upon a time, in the stone age (c. 1996), David Ho from the Aaron Diamond Center was deemed “man of the year” (Time Magazine), after explaining the dynamics of HIV replication to the world. Today he explains why B.1.351 is so worrisome. While B.1.1.7 is refractory to neutralization by many mAbs but not more resistant to convalescent plasma (CP) or vaccinee sera (VS), B.1.351 is not only refractory to neutralization by almost all mAbs but also by CP (9.4 fold) and VS (10.3-12.4 fold). SARS-CoV-2 “is traveling in a direction that could ultimately lead to escape from our current therapeutic and prophylactic interventions directed to the viral spike”.

 

Epidemiology

Chen X, Chen Z, Azman AS, et al. Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis. Lancet March 08, 2021. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00026-7/fulltext

After reviewing 404 (!) studies, the authors conclude that antibody-mediated herd immunity is far from being reached in most settings. Of note, the pooled infection-to-case ratio was similar between the region of the Americas (6.9, 95% CI: 2.7–17.3) and the European region (8.4, 95% CI: 6.5–10.7), but higher in India (56.5, 95% CI: 28.5–112.0), the only country in the South-East Asia region with data.

 

Leung K, Wu JT, Leung GM. Real-time tracking and prediction of COVID-19 infection using digital proxies of population mobility and mixing. Nat Commun 12, 1501 (2021). https://www.nature.com/articles/s41467-021-21776-2

Big Brother is watching you. However, sometimes he can be helpful. Using digital transactions made on Octopus cards (which are ubiquitously used by the Hong Kong population), the authors describe a framework that integrates digital proxies of human mobility and physical mixing into conventional epidemic models. At the end of the day, real-time estimates of Rt (accurate nowcast and short-term forecast of the epidemic) was obtained in Hong Kong.

 

Vaccine

Ella R, Reddy S, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. Lancet March 08, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00070-0/fulltext

Inactivated vaccines have the advantage of being easily stored and shipped. BBV152 (COVAXIN) is a whole-virion inactivated SARS-CoV-2 vaccine adjuvanted with Algel-IMDG. An imidazoquinoline molecule (IMDG), a TLR7/8 agonist, is added to augment cell-mediated responses. According to the Phase I/II data from India presented here, BBV152 has shown the potential to provide durable humoral and cell-mediated immune responses (even against variants of concern). The Algel-IMDG formulation was selected for the ongoing Phase III efficacy trial, which involves 25,800 volunteers. BBV152 has received emergency use authorisation in India.

 

Rapaka RR, Hammershaimb EA, Neuzil KM. Are some COVID vaccines better than others? Interpreting and comparing estimates of efficacy in trials of COVID-19 vaccines. Clinical Infectious Diseases 06 March 2021, ciab213, https://doi.org/10.1093/cid/ciab213

Do you have colleagues who still “prefer” the BioNTech vaccine? Give him this viewpoint to read. Rekha Rapaka and colleagues from Maryland discuss the caveats of cross-trial comparisons. And why it matters how point estimates of efficacy were determined, in what epidemiologic setting, and against what endpoints.

 

Blumenthal KG, Robinson LB, Camargo Jr CA, et al. Acute Allergic Reactions to mRNA COVID-19 Vaccines. JAMA  March 8, 2021; https://jamanetwork.com/journals/jama/fullarticle/2777417?resultClick=1

Of 64,900 vaccine recipients in Massachusetts, anaphylaxis was confirmed in 16 (0.025%). Of note, 15/16 were female, 10 had a prior history of allergies and 5 had a history of anaphylaxis. Mean time to anaphylaxis onset was 17 minutes (range, 1-120). All recovered.

 

Transmission

Paul LA, Daneman N, Brown KA, et al. Characteristics associated with household transmission of SARS-CoV-2 in Ontario, Canada: A cohort study. Clinical Infectious Diseases 05 March 2021, ciab186, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab186/6159706

Among 26,714 cases of COVID-19 residing in 21,226 households, longer testing delays (≥ 5 days versus 0 days, OR = 3.02) and male gender (OR = 1.28) were associated with greater odds of household secondary transmission, as well as (not surprisingly) larger average family size and a higher proportion of households with multiple persons per room.

 

Clinical

Kompaniyets L, Goodman AB, Belay B, et al. Body Mass Index and Risk for COVID-19–Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death — United States, March–December 2020. MMWR Morb Mortal Wkly Rep. ePub: 8 March 2021.  https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e4.htm

Among 148,494 US adults with COVID-19, a non-linear “dose response” relationship was found between body mass index and COVID-19 severity, with lowest risks at BMIs near the threshold between healthy weight and overweight in most instances, then increasing with higher BMI. Overweight and obesity were risk factors for invasive mechanical ventilation. Obesity was a risk factor for hospitalization and death, particularly among adults aged < 65 years.

Graphic

 

Lugon JC, Smit M, Salamun J, et al. Novel outpatient management of mild to moderate COVID-19 spares hospital capacity and safeguards patient outcome: The Geneva PneumoCoV-Ambu study. PLOS One, March 4, 2021. https://doi.org/10.1371/journal.pone.0247774

Calling patients every 48 hours for the first 10 days following diagnosis, with a standardized interview about self-reported symptoms or every 24 hours if patients presented a worsening clinical condition: this small study in relatively young patients shows that such an outpatient management of mild to moderate COVID-19-related pneumonia is possible. Costly and unnecessary hospitalizations were avoided and hospital capacity was spared.

Treatment

Loffredo M, Lucero H, Chen DY, et al. The in-vitro effect of famotidine on sars-cov-2 proteases and virus replication. Sci Rep March 8, 2021, 11, 5433. https://www.nature.com/articles/s41598-021-84782-w

In silico studies have proposed one of the two SARS-CoV-2 proteases, 3CLpro or PLpro, as potential molecular targets of famotidine activity. Somewhat disappointing: Madeline Loffredo and colleagues show here that the drug neither binds with nor inhibits the functions of these proteases.

 

9 March

Immunology

Paper of the Day

Huang L, Shi Y, Gong B, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Sig Transduct Target Ther March 6, 2021, 6, 110. https://doi.org/10.1038/s41392-021-00526-2

More details on pathogenesis, mainly the host immune process, imbalances and pathways. In this incredible work, Lulin Huang and colleagues obtained single-cell mRNA sequencing data of 341,420 (!) peripheral blood mononuclear cells and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies.

 

Gao L, Zhou J, Yang S, et al. The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity. Sig Transduct Target Ther 6, 113 (2021). https://doi.org/10.1038/s41392-021-00525-3

Specific B-cell and T-cell responses in 74 symptomatic patients with various disease severity: B cell responses were only transiently induced in early infection phase in asymptomatic or mild patients. In keeping with this, sustained GC responses that give rise to long-term memory B cells and IgG-secreting plasma cells were almost absent in these patients. This may explain that asymptomatic patients often fail to generate long-term SARS-CoV-2-specific IgG response. in contrast to humoral immunity, the virus-specific TH1 and CD8+ T cell immune responses were rapidly induced and sustained in asymptomatic or mild symptomatic patients as compared to patients with moderate or severe disease.

 

Casado JL, Häemmerle J, Vizcarra P, et al. SARS CoV-2 infections in health care workers with pre-existing T cell response: a prospective cohort study. March 02, 2021. https://doi.org/10.1016/j.cmi.2021.02.020

José L. Casado and colleagues from Madrid looked at pre-existing T-cell responses. Twenty of 38 HCWs included (53%) had a previous specific CD8+ T cell response that does not seems to reduce incident SARS-CoV-2 infections, but may contribute to asymptomatic or mild disease, rapid viral clearance and differences in seroconversion.

 

Epidemiology

Guy GP Jr., Lee FC, Sunshine G, et al. Association of State-Issued Mask Mandates and Allowing On-Premises Restaurant Dining with County-Level COVID-19 Case and Death Growth Rates — United States, March 1–December 31, 2020. MMWR Morb Mortal Wkly Rep. ePub: 5 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e3.htm

Mask mandates were associated with statistically significant decreases in county-level daily COVID-19 case and death growth rates within 20 days of implementation. Allowing on-premises restaurant dining was associated with increases in county-level case and death growth rates within 41–80 days after reopening. It will be a while until we can finally go to the restaurant again (does anyone else know how to order a dish?)

 

Virology

Liu Y, Hu G, Wang Y, et al. Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2. PNAS March 23, 2021 118 (12) e2025373118; https://www.pnas.org/content/118/12/e2025373118

SARS-CoV-2 has the potential to infect a broad range of mammalian hosts, including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria.

 

Variants

Alexandre G, Bosetti P, Feri A, et al. Early assessment of diffusion and possible expansion of SARS-CoV-2 Lineage 20I/501Y.V1 (B.1.1.7, variant of concern 202012/01) in France, January to March 2021. Euro Surveill. 2021;26(9):pii=2100133. https://doi.org/10.2807/1560-7917.ES.2021.26.9.2100133

Spread of B.1.1.7. in France, in January. The authors estimate the population-level effective reproduction number will be respectively 39% (95%: 33–45%) and 56% (95%: 50–62%) higher on 1 March and 1 April 2021 than what would be expected if only the classical lineages were circulating.

 

Vaccine

Nawwar AA, Searle J, Singh R, Lyburn ID. Oxford-AstraZeneca COVID-19 vaccination induced lymphadenopathy on [18F]Choline PET/CT-not only an FDG finding. Eur J Nucl Med Mol Imaging. 2021 Mar 4:1-2. PubMed: https://pubmed.gov/33661328. Full-text: https://doi.org/10.1007/s00259-021-05279-2

Lymphadenopathy is seen in some people after vaccination. In this case report of a cancer patient who underwent PET/CT 3 days after vaccination, nodal uptake was reactive in the axilla. Nice pictures.

 

Clinical

Wongvibulsin S, Garibaldi BT, Antar AAR, et al. Development of Severe COVID-19 Adaptive Risk Predictor (SCARP), a Calculator to Predict Severe Disease or Death in Hospitalized Patients With COVID-19. Ann Intern Med. 2021 Mar 2. PubMed: https://pubmed.gov/33646849. Full-text: https://doi.org/10.7326/M20-6754

Using longitudinal data from more than 3000 patients hospitalized with COVID-19, the authors have developed a novel tool that can provide dynamic risk predictions for progression from moderate disease to severe illness or death in patients with COVID-19 at any time within the first 14 days of their hospitalization – on the basis of readily available clinical information. Check this out: https://rsconnect.biostat.jhsph.edu/covid_trajectory

 

Comorbidities

Ardestani A, Azizi Z. Targeting glucose metabolism for treatment of COVID-19. Sig Transduct Target Ther March 6, 2021, 6, 112. https://doi.org/10.1038/s41392-021-00532-4

Some thoughts on how dysregulated glucose metabolism in people with diabetes may explain the increased susceptibility to SARS-CoV-2 and why uncontrolled diabetes can lead to excessive adaptive immune reactions in patients with critical COVID-19 symptoms.

 

Long COVID

Subbaraman N. US health agency will invest $1 billion to investigate ‘long COVID’. Nature News 04 March 2021. https://www.nature.com/articles/d41586-021-00586-y

Nidhi Subbaraman reports that the US will spend big on research into ‘long COVID’ — the long-lasting health effects of a SARS-CoV-2 infection (see our recent review) for which experts have coined a new term: post-acute sequelae SARS-CoV-2 infection (PASC).

 

Treatment

Vimaleswaran KS, Frouhi NG, Khunti K. Vitamin D and covid-19. BMJ 04 March 2021; 372 doi: https://doi.org/10.1136/bmj.n544

Is there a role of vitamin D in prevention and management of COVID-19? The authors of this editorial believe that “existing evidence supports a compelling case for further research”.

 

French

If you read French, read Les hôpitaux et cliniques d’Ile-de-France vont déprogrammer 40 % de leurs activités. Le Monde 2021, published 8 March. Full-text : https://www.lemonde.fr/sante/article/2021/03/08/covid-19-les-hopitaux-et-cliniques-d-ile-de-france-vont-deprogrammer-40-de-leurs-activites_6072352_1651302.html

L’agence régionale de santé d’Ile-de-France a donné « l’ordre ferme » aux hôpitaux franciliens de déprogrammer 40 % de leurs activités, afin d’augmenter le nombre de lits de réanimation réservés aux personnes atteintes du Covid-19.

 

8 March

Variants

Firestone MJ, Lorentz AJ, Meyer S, et al. First Identified Cases of SARS-CoV-2 Variant P.1 in the United States — Minnesota, January 2021. MMWR Morb Mortal Wkly Rep. ePub: 3 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e1.htm

The arrival of P.1 in the US. Both guys had returned from southeastern Brazil. According to the authors, this “underscores the importance of community prevention strategies to slow transmission of SARS-CoV-2 including use of well-fitting masks, physical distancing, washing hands, quarantine, testing of persons who have had contact with a person with laboratory-confirmed COVID-19, isolating persons with symptoms of COVID-19 or with diagnosed COVID-19 and” (comment: last but not least) “adhering to CDC recommendations to delay travel”. Maybe it’s not the best idea to vacation in Brazil right now.

 

Ojelade M, Rodriguez A, Gonzalez D, et al. Travel from the United Kingdom to the United States by a Symptomatic Patient Infected with the SARS-CoV-2 B.1.1.7 Variant — Texas, January 2021. MMWR Morb Mortal Wkly Rep. ePub: 3 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e2.htm?s_cid=mm7010e2_w

Another jerk who traveled from UK to US after experiencing COVID-19–compatible symptoms,  infected with the B.1.1.7 variant. “Persons should not travel if they are experiencing symptoms compatible with COVID-19 or if they have received a positive SARS-CoV-2 test result and have not met criteria to discontinue isolation, have had close contact with a person with suspected or confirmed COVID-19 and have not subsequently met criteria to end quarantine, or have a pending SARS-CoV-2 viral test result”. Fully agreed.

 

Fujino T, Nomoto H, Kutsuna S, Ujiie M, Suzuki T, Sato R, et al. Novel SARS-CoV-2 variant identified in travelers from Brazil to Japan. Emerg Infect Dis. 2021 Apr [date cited]. https://doi.org/10.3201/eid2704.210138

A family of four, traveling in early January to Tokyo, Japan, from Amazonas state in Brazil via Istanbul, Turkey (by the way, wouldn’t it have been shorter heading west?). Souvenir: A new lineage, resembling P.1, but with some interesting new mutations.

 

Maggi F, Novazzi F, Genoni A, Baj A, Spezia PG, Focosi D, et al. Imported SARS-CoV-2 variant P.1 detected in traveler returning from Brazil to Italy. Emerg Infect Dis. 2021 Apr [date cited]. https://doi.org/10.3201/eid2704.210183

A family of three, flying from São Paulo/Brazil to Madrid, Spain, and from there to Milan Malpensa Airport in Italy, in mid-January. In the luggage: P.1.

 

Diagnostics

Ott IM, Strine MS, Watkins AE, Boot M, Kalinich CC, Harden CA, et al. Stability of SARS-CoV-2 RNA in nonsupplemented saliva. Emerg Infect Dis. 2021 Apr [date cited]. https://wwwnc.cdc.gov/eid/article/27/4/20-4199_article

Use saliva and simple plastic tubes! For this important study, saliva from COVID-19 inpatients and at-risk healthcare workers was collected into sterile wide-mouth containers without preservatives (nonsupplemented) to evaluate the temporal stability of SARS-CoV-2 RNA at different holding temperatures. Of note, SARS-CoV-2 RNA from saliva was consistently detected at similar levels regardless of the holding time and temperatures tested.

 

Clinical

Nguyen NT, Chinn J, Nahmias J, et al. Outcomes and Mortality Among Adults Hospitalized With COVID-19 at US Medical Centers. JAMA Netw Open March 5, 2021;4(3):e210417. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777028

The largest US cohort of hospitalized COVID-19 adults to date. Among 192,550 adults hospitalized with COVID-19, 55,593 (28.9%) were admitted to the ICU and 26,221 (13.6%) died during the index hospitalization. Not surprisingly, in-hospital mortality increased with increasing age; 179 of 12 644 patients (1.4%) aged 18 to 29 years died, and 8277 of 31135 patients (26.6%) 80 years or older died. Of the patients admitted to the ICU, 15 431 of 55 593 (27.8%) died. The median hospital length of stay among patients who were not admitted to the ICU was 6 days, with a median cost per admission of $10 520. The median hospital length of stay for those admitted to the ICU was 15 days, with a median cost per admission of $39 825. Of note, mortality declined over the course of the 6-month period, from 22.1 % in March to 6.5 % in August.

 

Karagiannidis C, Windisch W, McAuley DF, et al. Major differences in ICU admissions during the first and second COVID-19 wave in Germany. Lancet Resp Med March 05, 2021. https://doi.org/10.1016/S2213-2600(21)00101-6

According to Christian Karagiannidis and colleagues who have analysed the data from the federal German hospital payment institute, their data “clearly suggests a dramatic improvement in the management of patients with COVID-19”. Compared with in the first wave, 50% less of all hospitalised patients were admitted to the ICU during the second wave of the pandemic. By contrast, the prognosis of ICU patients, those requiring mechanical ventilation and those not, remained unimproved.

 

Comorbidities

Attauabi M, Seidelin J, Burisch J; Danish COVID-IBD Study Group. Association between 5-aminosalicylates in patients with IBD and risk of severe COVID-19: an artefactual result of research methodology? Gut. 2021 Mar 3:gutjnl-2021-324397. PubMed: https://pubmed.gov/33658323. Full-text: https://doi.org/10.1136/gutjnl-2021-324397

Discussion whether use mesalamine/sulfasalazine is associated with an increased risk of severe COVID-19 in people with inflammatory bowel disease (IBD). And how to adjust for any potential effect modifiers and confounders in order to determine the granular effect of IBD-related medications. No definitive answer yet.

Ungaro RC, Brenner EJ, Gearry RB, et al. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut. 2020 Oct 20:gutjnl-2020-322539. PubMed: https://pubmed.gov/33082265. Full-text: https://doi.org/10.1136/gutjnl-2020-322539

 

Treatment

PRINCIPLE Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet March 04, 2021. https://doi.org/10.1016/S0140-6736(21)00461-X

Azithromycin makes no sense. This UK-based, open-label, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE) randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. In total, 402 (80%) of 500 participants in the azithromycin group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days.

 

Pediatrics

LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol March 5, 2021. doi:10.1001/jamaneurol.2021.0504. https://jamanetwork.com/journals/jamaneurology/fullarticle/2777392?resultClick=1

In this study of 1.695 patients 21 years or younger hospitalized at 61 US hospitals for acute COVID-19 or multisystem inflammatory syndrome, 365 (22%) had neurologic involvement. Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), CNS infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4).

 

Spanish

If you read Spanish, read Zafra M, Linde P, López JV. Así puede pasar el aire (y el coronavirus) de unas viviendas a otras a través del baño. El País 2021, published 7 March. Full-text: https://elpais.com/sociedad/2021-03-06/asi-puede-pasar-el-aire-y-el-coronavirus-de-unas-viviendas-a-otras-a-traves-del-bano.html

Los conductos de ventilación de los baños en edificios antiguos conectan los pisos y, en circunstancias muy concretas, se sospecha que pueden ser una vía de contagio de la covid.

 

French

If you read French, read Covid-19 : l’appel des ordres de santé à tous les soignants, « faites-vous vacciner », c’est un « devoir déontologique ». Le Monde 2021, published 7 March. Full-text : https://www.lemonde.fr/planete/article/2021/03/07/faites-vous-vacciner-l-appel-des-ordres-de-sante-a-tous-les-soignants_6072226_3244.html

Ils sont fous, les Gaulois? Seul un tiers des soignants sont actuellement vaccinés en France. « Ce n’est pas tolérable », estime Alain Fischer, le coordinateur de la campagne de vaccination. Les soignants sont « les plus exposés au virus, tout en étant au contact des populations les plus fragiles », estiment les organisations signataires. Ils doivent se faire vacciner « parce que cela relève de leur devoir déontologique, protéger leurs patients en toutes circonstances, et parce qu’il est impératif qu’ils puissent eux-mêmes se protéger contre le virus, ainsi que leurs proches, et freiner la propagation de l’épidémie », poursuivent-elles. Soyons plus clair encore (the CR Editors): Si vous êtes incapables de vous faire vacciner, changez de métier.

 

7 March

Variants

Paper of the Day

De Souza WM, Amorm MR, Sesti-Costa R, et al. Levels of SARS-CoV-2 Lineage P.1 Neutralization by Antibodies Elicited after Natural Infection and Vaccination. Lancet Preprints 2021, posted 1 March. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3793486

William de Souza and colleagues isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar lavage samples of patients in Manaus, Brazil. They found that the immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B lineage. Moreover, five months after booster immunization with the Chinese CoronaVac vaccine, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates.

 

Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. MedRxiv 2021, posted 3 March. Full-text: https://doi.org/10.1101/2021.02.26.21252554

Using a combination of genomic and epidemiological data, Nuno Faria and colleagues characterize the emergence and characteristics of P.1 that acquired 17 mutations, including the trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. The authors show that P.1 emerged around early November 2020. They estimate that P.1 could be 1.4–2.2 times more transmissible and able to evade 25-61% of protective immunity elicited by previous infection with non-P.1 lineages.

 

Wang P, Wang M, Yu J, et al. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. bioRxiv 2021, posted 2 March. Full-text: https://doi.org/10.1101/2021.03.01.433466

David D. Ho, Pengfei Wang and colleagues report that P.1 is not only refractory to multiple neutralizing monoclonal antibodies, but also more resistant to neutralization by convalescent plasma (6.5-fold) and vaccinee sera (2.2-2.8-fold).

 

Cele S, Gazy I, Jackson L, et al. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. MedRxiv 2021, posted 27 February. Full-text: https://doi.org/10.1101/2021.01.26.21250224
We already knew that people previously infected with the non-B.1.351 variant don’t neutralize B.1.351 very effectively. Now Alex Sigal, Tulio de Oliveira, Sandile Cele and colleagues show that people infected with B.1.351 can neutralize both B.1.351 and (to a slightly lesser extent) ‘regular’ non-B.1.351 viruses (Cele 2021). If these data are confirmed, a variant B.1.351-targeted booster vaccine could be a solution for countries where B.1.351 is the dominant strain.

 

Starr TN, Greaney AJ, Dingens AS, Bloom JD. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. bioRxiv 2021, posted 21 February. Full-text: https://doi.org/10.1101/2021.02.17.431683

Jesse Bloom, Tyler Starr and colleagues completely map all mutations to the SARS-CoV-2 spike receptor binding domain (RBD) that escape binding by LY-CoV555 (bamlanivimab, a monoclonal antibody manufactured by Lilly), and its cocktail combination with LY-CoV016. Individual mutations that escape binding are present in B.1.351 and P.1 (E484K escapes LY-CoV555, K417N/T escape LY-CoV016). Additionally, the L452R mutation in the B.1.429 lineage escapes LY-CoV555.

 

Transmission

Dinklage F, Ehmann A, Erdmann E, et al. Why Is the Risk of Coronavirus Transmission so High Indoors? Die Zeit 2020, published 26 November. Full-text: https://www.zeit.de/wissen/gesundheit/2020-11/coronavirus-aerosols-infection-risk-hotspot-interiors

Whenever people gather in closed spaces, the infection risk climbs. This interactive tool shows how the coronavirus spreads. Find out how safe your environment is. See also the German version.

 

Immunology

Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv 2021, posted 1 March. Full-text: https://doi.org/10.1101/2021.02.27.433180

Good news from the T cell front. Alessandro Sette, Alba Grifoni, Shane Crotty, Alison Tarke and colleagues did a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or the Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. The comfortable result: CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.

 

Vaccines

Vasileiou E, Simpson CR, Robertson C, et al. Effectiveness of First Dose of COVID-19 Vaccines Against Hospital Admissions in Scotland: National Prospective Cohort Study of 5.4 Million People. Lancet Preprints 2021, posted 19 February. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3789264

A single dose of the Pfizer-BioNTech or AstraZeneca vaccine results in substantial reductions in the risk of COVID-19 related hospitalization. In a study from Scotland, the first vaccine dose protected well over 80% of vaccinees against COVID-19 related hospitalization at 28-34 days post-vaccination (Pfizer-BioNTech:  85%; AstraZeneca: 94%). Comparable results (81%) were seen in people aged ≥ 80 years (Vasileiou 2021).

 

Hall VJ, Foulkes S, Saei A, et al. Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study) Victoria Jane Hall. Lancet Preprints 2021, published 22 February. Full-text:  https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3790399

These data from the SIREN (Sarscov2 Immunity and REinfection EvaluatioN) study suggest that the Pfizer-BioNTech vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults. (The SIREN study is a prospective cohort study among staff working in publicly funded hospitals.) The vaccine was 72% effective (95% CI 58-86) 21 days after first dose and 86% effective (95% CI 76-97) seven days after two doses in the antibody negative cohort (Hall 2021).

 

French

If you read French, read Covid-19 : « A court terme, l’effet positif des vaccins risque de ne pas suffire pour compenser l’impact délétère des variants ». Le Monde 2021, published 6 March. Full-text : https://www.lemonde.fr/planete/article/2021/03/06/covid-19-a-court-terme-l-effet-positif-des-vaccins-risque-de-ne-pas-suffire-pour-compenser-l-impact-deletere-des-variants_6072159_3244.html

Simon Cauchemez, modélisateur à l’Institut Pasteur, doute que les mesures actuelles permettent une amélioration à la mi-avril, comme espéré par le gouvernement.

 

Mandard S. Covid-19 : les pics de pollution aux particules fines soupçonnés de jouer un rôle dans le rebond épidémique. Le Monde 2021, published 6 March. Full-text : https://www.lemonde.fr/planete/article/2021/03/06/covid-19-les-pics-de-pollution-aux-particules-fines-soupconnes-de-jouer-un-role-dans-le-rebond-epidemique_6072189_3244.html

Pour l’épidémiologiste Antoine Flahault, les épisodes de pollution liés aux sables du Sahara pourraient expliquer la reprise des contaminations et des hospitalisations.

 

Editorial. Covid-19 : changer le regard sur le vaccin. Le Monde 2021, published 5 March. Full-text : https://www.lemonde.fr/idees/article/2021/03/05/covid-19-changer-le-regard-sur-le-vaccin_6072064_3232.html

Cinq semaines après avoir exclu le reconfinement général du pays que de nombreux médecins appelaient de leurs vœux, Emmanuel Macron peut se targuer de deux résultats. A ce jour, l’épidémie n’a pas connu de hausse exponentielle, comme certains modèles le laissaient craindre. Et aucun de ses opposants politiques ne lui fait grief d’avoir fait ce choix risqué. Compte tenu de la fragilité économique et psychologique du pays, il existe désormais un quasi-consensus pour rejeter cette solution radicale. La partie, cependant, est encore loin d’être gagnée.

 

6 March

Variants

Paper of the Day

Shen X, Tang H, McDanal C, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines. Cell Host Microbe March 03, 2021. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00102-5

Good news. Using a lentivirus-based pseudovirus assay, Xiaoying Shen and colleagues from Duke, Durham, US, show that B.1.1.7 is probably not a neutralization escape variant of concern for COVID-19 vaccines. Moreover, B.1.1.7 is unlikely to increase the risk of SARS-CoV-2 re-infection.

 

Wibmer CK, Ayres F, Hermanus T, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nature Medicine 02 March 2021. https://www.nature.com/articles/s41591-021-01285-x

B.1.351 is a bigger problem. This study (for months available as a pre-print only, now as a beautiful paper in Nature Medicine) shows that this lineage completely escapes three classes of therapeutically relevant antibodies. The B.1.351 pseudovirus also exhibited substantial to complete escape from neutralization, but not binding, by convalescent plasma. The overwhelming majority of monoclonal antibodies already on the path to licensure target residues K417 or E484 and are therefore likely to be futile against this variant.

 

Virology

Schroeder S, Pott F, Niemeyer D, et al. Interferon antagonism by SARS-CoV-2: a functional study using reverse genetics. Lancet Microbe March 04, 2021. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00027-6/fulltext

Do differences in receptor usage determine all the differences in disease presentation between SARS-CoV and SARS-CoV-2? This work by Christian Drosten and colleagues shows that SARS-CoV-2 suppresses cytokine induction and interferon signaling with lower efficiency than SARS-CoV, despite the shared genome architecture and expression of homologous viral proteins. Gene encoding protein 6 as a genetic marker of virulence varied between SARS-CoV and SARS-CoV-2, thus providing a target for genome-based surveillance of circulating strains of SARS-CoV-2. The authors recommend to monitor sequence evolution of SARS-CoV ORF6.

 

Immunology

Bost P, De Sanctis F, Canè S et al. Deciphering the state of immune silence in fatal COVID-19 patients. Nat Commun March 4, 2021 12, 1428. https://www.nature.com/articles/s41467-021-21702-6#citeas

This study shows innate and adaptive immune dysfunction, including loss of immune suppression by blood myeloid cells and the replacement of lung memory CD8+ T cells by naive T cells, suggesting a state of “immune silence” that correlates with a severe clinical manifestation and fatal outcome.

 

Diagnostics

Azzolini C, Donati S, Premi E, et al. SARS-CoV-2 on Ocular Surfaces in a Cohort of Patients With COVID-19 From the Lombardy Region, Italy. JAMA Ophthalmology March 4, 2021. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2777178

SARS-CoV-2 was present on the ocular surface in 52 of 91 COVID-19 patients, showing a wide variability in the viral load. Some had positive conjunctival swabs while having a negative nasopharyngeal swab. However, the authors did not determine the infectivity of the viral material detected. Clinical relevance remains unclear.

 

Moshe M, Daunt A, Flower B, et al. SARS-CoV-2 lateral flow assays for possible use in national covid-19 seroprevalence surveys (React 2): diagnostic accuracy study. BMJ. 2021 Mar 2;372:n423. PubMed: https://pubmed.gov/33653694 . Full-text: https://doi.org/10.1136/bmj.n423

In contrast to routine serology assays, the use of lateral flow immunoassays (LFIAs) does not require the support of central laboratories and offers a rapid and affordable method of testing. This study shows that LFIA sensitivity is variable on serum and finger prick testing, and often differs from that stated by the manufacturer. Specificity of all LFIAs was high. However, none showed sufficient sensitivity and specificity to be considered for routine clinical use. One further LFIA (Surescreen) was identified as suitable for use in seroprevalence studies because it showed comparable performance to the LFIA currently used in the React 2 seroprevalence studies (Fortress). However, the performance of Surescreen was not significantly better than Fortress.

 

Clinical

Martinez MW, Tucker AM, Bloom J, et al. Prevalence of Inflammatory Heart Disease Among Professional Athletes With Prior COVID-19 Infection Who Received Systematic Return-to-Play Cardiac Screening. JAMA Cardiol March 4 2021; https://jamanetwork.com/journals/jamacardiology/fullarticle/2777308

“The virus challenged me and I defeated it.” That’s what Zlatan Ibrahimovic, famous Swedish soccer player who caught COVID-19 last September, posted on Instagram (you don’t know him? Then please take 94 seconds: https://www.youtube.com/watch?v=GcCVfNA7otY).

“But you are not Zlatan. Do not challenge the virus. Use your head, respect the rules. Social distancing and masks, always. We will win.”

Zlatan was right! But should we have been worried about him? Probably not. In this multicenter, retrospective cross-sectional study of RTP cardiac testing performed on 789 professional athletes with COVID-19 (58% symptomatic, 42% asymptomatic or pauci-symptomatic), imaging evidence of inflammatory heart disease (performed around 3 weeks after positive testing) that resulted in restriction from play was identified in 5 athletes (0.6%) only. No adverse cardiac events occurred in the athletes who underwent cardiac screening and resumed professional sport participation. Thus, with regard to mild COVID-19, there were many Zlatans. On the field, however, there is only one.

 

Comorbidities

Bloom CI, Drake TM, Docherty AB, et al. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Resp Med March 04, 2021. https://doi.org/10.1016/S2213-2600(21)00013-8

Analyzing 75,463 patients from the UK, Chloe Bloom and colleagues show that patients with chronic pulmonary disease had a high level of mortality, with a prevalence of 40% for in-hospital death. Of patients with asthma, only those with severe asthma had increased mortality compared to those without an underlying respiratory condition. Patients with asthma (aged ≥ 50 years) had a lower mortality risk if they had used inhaled corticosteroids within 2 weeks of admission.

 

Treatment

López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA March 4, 2021; doi: 10.1001/jama.2021.3071. https://jamanetwork.com/journals/jama/fullarticle/2777389

The next hydroxychloroquine? Because of some evidence of activity in vitro, ivermectin has attracted huge interest. Several countries have included ivermectin in their treatment guidelines, leading to a surge in the demand for the drug by the general population and even alleged distribution of veterinary formulations. In this RCT that included 476 patients from Cali, Colombia, the duration of symptoms was not significantly different for patients who received either a 5-day course of ivermectin or placebo (median time to resolution of symptoms, 10 vs 12 days; hazard ratio for resolution of symptoms, 1.07).  This is consistent with PK models showing that ivermectin levels do not reach the IC50 even for a dose level 10-times higher than the approved dose.

Graphic

 

Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Resp Med March 04, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00099-0/fulltext

This large placebo-controlled multinational Phase III trial evaluated two doses of sarilumab, an interleukin-6 receptor inhibitor, in 416 patients with severe or critical COVID-19. At day 29, no significant differences were seen between the arms. The authors bravely suggest several potential reasons for why sarilumab was not effective (IL-6 insufficient to quell the inflammatory phase of the disease, patient selection not based on inflammation markers, dosage too low, use of confounding concomitant steroids, etc).  However, this strategy seems not be a game changer in this pandemic.

 

French

If you read French, read HerzbergN, Aeberhardt C. Covid-19 : comment la lutte contre les variants pourrait modifier les stratégies vaccinales. Le Monde 2021, published 25 February. Full-text : https://www.lemonde.fr/planete/article/2021/02/25/covid-19-la-lutte-contre-les-variants-s-organise_6071122_3244.html

L’apparition de nouvelles mutations du virus contraint les laboratoires à adapter leurs vaccins, les agences sanitaires à inventer de nouvelles procédures réglementaires, et les Etats à réexaminer leur stratégie vaccinale.

 

5 March

Variants

Paper of the Day

Davies NG, Abbott S, Barnard RS, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science  03 Mar 2021: eabg3055. Full-text:  https://science.sciencemag.org/content/early/2021/03/03/science.abg3055

Difficult months ahead: the B.1.1.7 variant emerged in southeast England in November 2020 and is rapidly spreading toward dominance. In this brilliant article, Nicholas Davies and colleagues from London estimate that this variant has a 43–90% (range of 95% credible intervals 38–130%) higher reproduction number than pre-existing variants. A fitted two-strain dynamic transmission model shows that B.1.1.7. will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalizations and deaths across England in 2021 will exceed those in 2020.

 

Virology

Murray CJ, Piot P. The Potential Future of the COVID-19 Pandemic. JAMA March 3, 2021. Full-text: https://jamanetwork.com/journals/jama/fullarticle/2777343

Will SARS-CoV-2 become a recurrent seasonal Infection? Peter Piot and Christopher Murray don’t know, how could they? According to their nice viewpoint, there is too much uncertainty about the probability and frequency of emergence of new variants, the reduction in vaccine efficacy for each variant, the critical question of cross-variant immunity, and the consistency of safe human behavior. However, the prospect of persistent and seasonal COVID-19 is real.

 

Immunology

Le Bert N, Clapham HE, Tan AT. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J Exp Med March 1, 2021. 218 (5): e20202617. https://doi.org/10.1084/jem.20202617

Nina Le Bert and colleagues from Singapore studies T cells longitudinally in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. Important findings: asymptomatic SARS-CoV-2-infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.

 

Vaccine

Kimberly G. Blumenthal KG, Freeman EE, Saff RR. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. NEJM, March 3, 2021. DOI: 10.1056/NEJMc2102131. https://www.nejm.org/doi/full/10.1056/NEJMc2102131

Case series of 12 delayed large but varying local reactions to the mRNA-1273 vaccine, with a median onset on day 8 after the first dose. After the second shot, 6 had no recurrence, 3 had similar and 3 had recurrent reactions that were of a lower grade than those after the initial dose.

 

Kadire SR, Wachter RM, Lurie N. Delayed Second Dose versus Standard Regimen for Covid-19 Vaccination. N Engl J Med March 4, 2021; 384:e28. DOI: 10.1056/NEJMclde2101987. https://www.nejm.org/doi/full/10.1056/NEJMclde2101987

Nice case vignette on the question of whether we delay the second dose. Robert M. Wachter says yes, Nicole Lurie says no. No clear winner.

 

Transmission

Shumsky RA, Debo L, Lebeaux RM, et al. Retail store customer flow and COVID-19 transmission. PNAS February 26, 2021. https://doi.org/10.1073/pnas.2019225118

Nice modelling study on how customer flows in retail stores affect the rate of COVID-19 transmission. The model calculates the disease transmission rate in a retail environment and determines how the rate depends on the customer flow policy (one-way versus two-way), the travel speed distribution, and store size. Restricting customer flow to one-way movement is highly effective if direct exposure is the dominant mode of transmission. However, it is not effective if more indirect (“wake”) exposure dominates.

 

Schumm MA, Hadaya JE, Mody N, et al. Filtering Facepiece Respirator (N95 Respirator) Reprocessing: A Systematic Review. JAMA. March 3, 2021; doi: 10.1001/jama.2021.2531.  https://jamanetwork.com/journals/jama/fullarticle/2777342?resultClick=1

Max A. Schumm and colleagues have reviewed 42 studies (through January 31, 2021) that examined 65 types of masks. Ultraviolet germicidal irradiation, vaporized hydrogen peroxide, moist heat, and microwave-generated steam processing effectively sterilized N95 respirators and retained filtration performance. Ultraviolet irradiation and vaporized hydrogen peroxide damaged respirators the least.

 

Collateral damage

Knudsen AK, Stene-Larsen K, Gustavson K, et al. Prevalence of mental disorders, suicidal ideation and suicides in the general population before and during the COVID-19 pandemic in Norway: A population-based repeated cross-sectional analysis. Lancet Regional Health February 27, 2021. Volume 4, 100071, May 01, 2021DOI: https://doi.org/10.1016/j.lanepe.2021.100071

Credible data from Norway: except for a decrease in mental disorders in the first pandemic period, the findings suggest stable levels of mental disorders, suicidal ideation and suicide deaths during the first six months of the COVID-19 pandemic compared to pre-pandemic levels.

 

Treatment

Touafchia A, Bagheri H, Carrié D, et al. Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns. Clin Microbiol Infection February 26, 2021. DOI: https://doi.org/10.1016/j.cmi.2021.02.013

Oops: this post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids.

 

Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021 Mar 1;372:n526. PubMed: https://pubmed.gov/33649077. Full-text: https://doi.org/10.1136/bmj.n526

This is the first version of a living (up-to-date, evolving and EBM) guideline, focusing on the evidence for hydroxychloroquine. 53 authors from 45 centers say on 12 pages, “Do not use it!”

 

4 March

Vaccine

Paper of the Day

Oliver SE, Gargano JW, Scobie H, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen COVID-19 Vaccine — United States, February 2021. MMWR Morb Mortal Wkly Rep. ePub: 2 March 2021. DOI: https://www.cdc.gov/mmwr/volumes/70/wr/mm7009e4.htm

The Janssen COVID-19 vaccine is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector vaccine, encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2. On February 27, 2021, the FDA issued an Emergency Use Authorization (EUA). This is an interim recommendation for use in persons aged ≥ 18 years for the prevention of COVID-19, discussing the available data and the question who to vaccinate and when. Answer: everybody, ASAP. Of note, the Janssen vaccine seems to work in the B.1.351 lineage from South Africa as well in the P.2 lineage from Brazil.

 

Epidemiology

Van Loon W, Hommes F, Theuring S, et al. Renewed absence of SARS-CoV-2 infections in the day care context in Berlin, January 2021. Clinical Infectious Diseases March 2.  Full-text: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab199/6155930

The second round of a longitudinal study in 12 randomly selected kindergartens across Berlin including 156 children, 80 staff, and 488 household members of children and staff. According to the authors, repeated absence of SARS-CoV-2 infection four months apart, at weekly community incidences of 38 (first round in September) and 110/100,000, support the initial interpretation that kindergartens are not silent transmission reservoirs.

 

Virology

Phuong HVM, Tung TS, Trang UTH, et al. Novel mutation of SARS-CoV-2, Vietnam, July 2020. Emerg Infect Dis. 2021 May [date cited]. https://doi.org/10.3201/eid2705.210013

Now that the whole world is sequencing the virus, we are likely to see many such studies. A cluster in Danang, Vietnam, began July 25, 2020, and resulted in 551 confirmed cases and 35 deaths. The authors analyzed 26 sequences from this cluster and identified a novel shared mutation in non-structural protein 9, suggesting a single introduction into Vietnam. The single-nucleotide polymorphism, C835T, was not reported in any other sequences collected globally. However, it has no known associations with virulence or transmissibility.

 

Variants

Plante JA, Mitchell BM, Plante KS, et al. The Variant Gambit: COVID’s Next Move. Cell Host Microbe March 01, 2021. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00099-8

Nice review that outlines factors driving SARS-CoV-2 variant evolution, explores the potential impact of specific mutations and examines the risk of further mutations. Jessica A. Plante and colleagues from the World Reference Center for Emerging Viruses and Arboviruses consider also the experimental studies needed to understand the threat these variants pose.

 

Transmission, Prevention

Lubrano R, Bliose S, Testa A, et al. Assessment of Respiratory Function in Infants and Young Children Wearing Face Masks During the COVID-19 Pandemic. JAMA Netw Open March 2, 2021. 4(3):e210414. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776928

Are surgical masks associated with episodes of oxygen desaturation or respiratory distress among children? This study from Italy says no. Among 47 children (22 aged 24 months or younger!) the use of facial masks was not associated with significant changes in Sao2 or Petco2.

 

Wilmes P, Zimmer J, Schulz J, et al. SARS-CoV-2 transmission risk from asymptomatic carriers: Results from a mass screening programme in Luxembourg. Lancet Regional Health February 27, 2021. DOI: https://doi.org/10.1016/j.lanepe.2021.100056

To accompany the lifting of COVID-19 lockdown measures, Luxembourg implemented a mass screening (MS) program. Based on a participation of 49% amongst the resident population and 22% amongst cross-border workers, the MS program allowed identification of 1099 cases corresponding to 26% of positive cases related to an early summer epidemic wave. Among the index cases, 567 (67%) reported symptoms at the time of being informed of their positive test result (these may have been pre-symptomatic at the time of the test), whereas 283 (33%) were asymptomatic. Asymptomatic individuals had significant secondary attack rates, both in households and among close contacts, but these were lower compared to those for symptomatic cases.

 

Clinical

Van den Hurk K, Merz EM, Prinsze FJ, et al. Low awareness of past SARS-CoV-2 infection in healthy plasma donors. Cell Reports Med February 25, 2021. https://doi.org/10.1016/j.xcrm.2021.100222

See title. They know nothing. Katja van den Hurk and colleagues asked individuals donating plasma across the Netherlands between May 11th and 18th 2020. Among 3676 with antibody and questionnaire data, 239 (6.5%) were positive for SARS-CoV-2 antibodies. Of those, 48% did not suspect COVID-19 despite the majority reporting symptoms. 11% of seropositive individuals reported no symptims and 27% very mild symptoms at any time during the first peak of the epidemic. Anosmia/ageusia and fever were most strongly associated with seropositivity. Almost 13% of the individuals who tested negative for SARS-CoV-2 did suspect a SARS-CoV-2 infection, a large majority (84%) because of symptoms indicative of COVID-19.

 

Baldassarri M, Picchiotti N, Fava F, et al. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males. EBioMedicine. 2021 Feb 26;65:103246. PubMed: https://pubmed.gov/33647767. Full-text: https://doi.org/10.1016/j.ebiom.2021.103246

A genetic polymorphism predisposing some men to develop a more severe disease irrespective of age: in a cohort of 1178 men and women with COVID-19, Margherita Baldassarri from Siena, Italy, and colleagues used a supervised Machine Learning approach on a synthetic representation of genetic variability due to poly-amino acid repeats. Comparing the genotype of patients with extreme manifestations (severe vs. asymptomatic), they found an association between the poly-glutamine repeat number of the androgen receptor (AR) gene, serum testosterone concentrations, and COVID-19 outcome in male patients. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the fact that polyQ ≥ 23 becomes dominant to testosterone levels for the clinical outcome.

 

Strålin K, Wahlström E, Walther S, et al. Mortality trends among hospitalised COVID-19 patients in Sweden: A nationwide observational cohort study. Lancet Regional Health February 26, 2021 DOI: https://doi.org/10.1016/j.lanepe.2021.100054

There was a gradual decline in mortality during the spring of 2020 in Swedish hospitalised COVID-19 patients. The results remained after adjustment for age, sex, co-morbidities, level of care dependency, country of birth, healthcare region, and SAPS3 (ICU treated patients). Read about the many explanations for this phenomenon. However, the bottom line is that in studies using mortality as an endpoint, the timing of inclusion may play a crucial role regarding outcome. The results of before-and-after studies on specific interventions should be interpreted with caution.

 

Collateral damage (today: benefit)

Shepherd JP, Moore SC, Long A, et al. Association Between COVID-19 Lockdown Measures and Emergency Department Visits for Violence-Related Injuries in Cardiff, Wales. JAMA March 2, 2021. 2021; 325(9):885-887. https://jamanetwork.com/journals/jama/article-abstract/2776868

Less violence during lockdown. In Cardiff, Wales, the average weekly number of violent injury admissions dropped from 28.4 to 16.5 during lockdown. There was also a 92% reduction in weapon use. This may reflect closure of city center pubs and clubs where most violence takes place. Cheers.

 

3 March

Vaccine

Paper of the Day

Saadat S, Tehrani ZR, Logue J, et al. Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2. JAMA. March 1, 2021. doi:10.1001/jama.2021.3341. https://jamanetwork.com/journals/jama/fullarticle/2777171?resultClick=1

Health care workers with previous COVID-19, based on laboratory-confirmed serology testing, had higher antibody titer responses to a single dose of mRNA vaccine (Pfizer-BioNTech or Moderna, depending on personal preference and availability) than those who were not previously infected. Although the groups were small and only 59 volunteers were enrolled (17 in the Ab-negative, 16 in the asymptomatic, and 26 in the symptomatic group), this data indicates that one shot is enough in people with prior infection. Of note, titers did not differ between asymptomatic and symptomatic disease.

 

Virology

Tse H, Lung CD, Wong SC, et al. Emergence of a Severe Acute Respiratory Syndrome Coronavirus 2 virus variant with novel genomic architecture in Hong Kong. Clinical Infectious Diseases 02 March 2021, ciab198, https://doi.org/10.1093/cid/ciab198

SARS-CoV-2 lineages have emerged continuously, mostly through the genomic accumulation of substitutions. Herman Tse and colleagues highlight the considerable evolutionary potential of SARS-CoV-2. They report three infections caused by a variant with a novel genomic architecture resulting from deletion of an 882-nucleotide region spanning ORF6 to ORF8 together with duplication and transposition of a 57-nucleotide segment from the 5’-untranslated region (UTR). The tolerance of a major and unusual genomic arrangement led to the formation of ORF6x, which involved recruitment of typically non-coding sequences into the open reading frame. These events greatly increased the genetic diversity of SARS-CoV-2, thereby accelerating the evolution of new potentially advantageous genotypes and compensating for the relatively low mutation rates in coronaviruses. On a more immediate note, caution is warranted when using diagnostic assays targeting only accessory genes or proteins such as Orf8, given the risk of false-negative results.

 

Clinical

Rodebaugh TL, Frumkin MR, Reiersen AM, et al.  Acute symptoms of mild to moderate COVID-19 are highly heterogeneous across individuals and over time. Open Forum Infectious Diseases March 1, ofab090, https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab090/6154666

Thomas L. Rodebaugh from St. Louis, US, and colleagues asked 162 participants with acute COVID-19 to respond to surveys up to 31 times for up to 17 days. Several statistical methods were used to characterize the temporal dynamics of these symptoms. Results: the course of symptoms during the initial weeks of COVID-19 is highly heterogeneous and is neither predictable nor easily characterized using typical survey methods. However, the pattern of symptoms over time suggested a fluctuating course for many patients. Participants who showed clinical deterioration were more likely to present with higher reports of severity of cough and diarrhea.

 

Cavanaugh AM, Thoroughman D, Miranda H, Spicer K. Suspected Recurrent SARS-CoV-2 Infections Among Residents of a Skilled Nursing Facility During a Second COVID-19 Outbreak — Kentucky, July–November 2020. MMWR Morb Mortal Wkly Rep 2021;70:273–277. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008a3.htm?s_cid=mm7008a3_w#suggestedcitation

Five residents of a skilled nursing facility received positive PCR results in two separate COVID-19 outbreaks separated by 3 months. Residents received at least four negative test results between the two outbreaks, suggesting the possibility of reinfection. Severity of disease in the five residents during the second outbreak was worse than that during the first outbreak and included one death.

 

Long COVID

Gacci M, Coppi M, Baldi E, et al. Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19. Human Reproduction March 1, 2021. Full-text: https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deab026/6125160

Mauro Gacci from Florence, Italy, and colleagues performed a large prospective cross-sectional study on 43 sexually active men who were known to have recovered from SARS-CoV-2 (3-6 weeks after negative swab). One patient had a positive PCR in semen (21 days after the second negative swab). Of note, 11/43 were oligo-crypto-azoospermic and all azoospermic patients reported a previous unimpaired fertility status suggesting that semen impairment was due to COVID-19. However, a main limitation of the study is the lack of samples obtained prior to COVID-19.

 

Severe COVID-19

Yang P, Zhao Y, Li J. et al. Downregulated miR-451a as a feature of the plasma cfRNA landscape reveals regulatory networks of IL-6/IL-6R-associated cytokine storms in COVID-19 patients. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-021-00652-5

Cell-free circulating RNAs (cfRNAs) in plasma carry information from pathologic sites, and they have been reported to play important roles in disease development. Compared with healthy donors, significantly higher mRNA expression of IL-6R was observed; miR-451a, a known negative regulator of IL-6R translation, was down-regulated, which may promote IL-6R expression at the protein level.

 

Co-morbidities

Jee J, Stonestrom AJ, Devlin S, et al. Oncologic immunomodulatory agents in patients with cancer and COVID-19. Sci Rep March 1, 2021, 11, 4814 (2021). https://doi.org/10.1038/s41598-021-84137-5. https://www.nature.com/articles/s41598-021-84137-5

A large single-center, retrospective analysis of 820 cancer patients with COVID-19 treated with various immunomodulatory agents within 90 days prior to SARS-CoV-2 diagnosis, mainly anti-CD20 therapies (rituximab, ofatumumab, or obinutuzumab) and immunotherapy (PD-1, PDL-1, or CTLA-4 blockade). Of note, whereas cytotoxic chemotherapy itself was not a risk for worse outcomes, pre-COVID-19 neutropenia was associated with worse COVID-19. In assessing whether certain oncologic medications are associated with worse COVID-19 outcomes, considering cancer type, degree of effect (i.e. neutropenia or other bone marrow suppression) and other patient-specific factors is crucial.

 

Treatment

Janiaud P, Axfors C, Ioannidis JP, et al. Recruitment and Results Reporting of COVID-19 Randomized Clinical Trials Registered in the First 100 Days of the Pandemic. JAMA Netw Open March 1, 2021;4(3):e210330. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776802

All RCTs (n = 516) registered in ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform between January 1 and April 9, 2020, were included. Overall, 30% of COVID-19 RCTs initiated in the first 100 days of the pandemic did not begin recruitment, and only 10% had results reported by mid-October, suggesting the possibility of substantial research waste.

 

Li S, Liu S, Jiang Z, et al. Study on the promotion of lymphocytes in patients with COVID-19 by broad-spectrum chemokine receptor inhibitor vMIP-II and its Mechanism of signal transmission in vitro. Sig Transduct Target Ther March2, 2012. 6, 104. https://doi.org/10.1038/s41392-021-00516-4

Viral macrophage inflammatory protein (vMIP) is a homologue of a chemokine derived from the recombinant natural human herpes virus 8 gene. It has been proved that vMIP can effectively inhibit the process of HIV infecting target cells through chemokine receptors. In this pilot study, 10 patients and 35 uninfected volunteers from Wuhan were treated with vMIP (given as injection). vMIP-II significantly improved the lymphocyte decrease of COVID-19. It was shown that vMIP-II inhibits multiple chemokine receptors and their related phosphorylation signaling pathways. In other words, this study shows that vMIP-II can reconstruct the cellular immune function lost in acute SARS-CoV-2 infection. The elucidation of the molecular mechanism of vMIP-II increasing CD8+ TCM provides a new strategy for the treatment of COVID-19.

 

Pediatric

Takefuji Y. Besançon L, Steadson D, Flahault A. Ludvigsson JF. Open Schools, Covid-19, and Child and Teacher Morbidity in Sweden. NEJM March 1, 2021, DOI: 10.1056/NEJMc2101280. https://www.nejm.org/doi/full/10.1056/NEJMc2101280?query=featured_home

Ludvigsson JF. The first eight months of Sweden’s COVID-19 strategy and the key actions and actors that were involved. Acta Paediatr 2020;109:2459-2471. https://doi.org/10.1111/apa.15582

Controversial discussion about the Swedish approach. Sweden allowed COVID-19 to spread in the hope that the population would develop “herd immunity.” The younger the patients, the fewer deaths due to COVID-19 were reported by Ludvigsson et al. (Feb. 18 issue). The authors of the correspondence letters don’t believe that this was a good idea.

 

2 March

Immunology

Paper of the Day

Shen B, Tasdogan A, Ubellacker JM, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature, February 24, 2021. https://doi.org/10.1038/s41586-021-03298-5

Exercise will boost your immune system! What we all “knew” already, can now be explained. A specialized type of bone cell progenitor has been identified in the bone marrow and shown to support the generation of lymphocytes in response to movement. Bo Shen and colleagues have identified a role for movement in stimulating communication between one type of stromal cell and immune progenitors in mice, ultimately helping the animals to fight infection. The discovery that mechanosensitive osteogenic progenitors have a role in fighting infections is exciting.

 

Balz K, Kaushik A, Chen M, et al. Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Sci Rep February 25, 2021, 11, 4792. https://doi.org/10.1038/s41598-021-84320-8

Different systematic bioinformatic approaches were used to identify potentially cross-reactive allergen- and SARS-CoV-2-T cell epitopes. Numerous candidate epitope pairs were identified, highlighting an important role of MHC class I inhalant allergens. According to Kathrin Balz and colleagues, findings generate further hypotheses in how the adaptive immune system responds differentially with respect to the atopy status of the host. Their study warrants an immediate investigation of these predicted T cell epitopes to link their possible role in driving the immune response against SARS-CoV-2 and eventually shape the COVID-19 outcome.

 

Epidemiology

Lim T, Delorey M, Bestul N, et al. Changes in SARS CoV-2 Seroprevalence Over Time in Ten Sites in the United States, March – August, 2020. Clin Infect Dis. 2021 Feb 26:ciab185. PubMed: https://pubmed.gov/33639620. Full-text: https://doi.org/10.1093/cid/ciab185

In a well-designed large-scale seroprevalence study, Travis Lim and colleagues tested 78,990 specimens from ten US sites that experienced different epidemic curves, over multiple time points between March and August 2020. During this period, less than 10% of the population had detectable antibodies to SARS-CoV-2 at all sites except New York (23.2%) and Florida (13.3%).

 

Virology

Zhou D, Chan JF, Zhou B, et al. Robust SARS-CoV-2 Infection in Nasal Turbinates after Treatment with Systemic Neutralizing Antibodies. Cell Host Microbe February 24, 2021. Full-text:  https://www.sciencedirect.com/science/article/pii/S1931312821000986?via%3Dihub

Viral infection in nasal turbinate may outcompete antibody treatment. Using a Syrian hamster model, the authors show that ZDY20, ZB8 and 2-15 (three of the most promising classes of RBD-specific human neutralizing Abs) prophylactic intraperitoneal or intranasal injection of individual HuNAb or DNA vaccination significantly reduced infection in the lungs but not in the nasal turbinates of hamsters intranasally challenged with SARS-CoV-2. Although post-challenge HuNAb therapy suppresses viral loads and lung damage, robust infection is observed in nasal turbinates treated within 1-3 days. This has significant implications for sub-protection, reinfection and vaccine.

 

Vaccines

Rinott E, Youngster I, Lewis YE. Reduction in COVID-19 Patients Requiring Mechanical Ventilation Following Implementation of a National COVID-19 Vaccination Program — Israel, December 2020–February 2021. MMWR Morb Mortal Wkly Rep, 26 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7009e3external icon.

Again, encouraging data from Israel. The percentage of COVID-19 patients aged ≥ 70 years requiring mechanical ventilation fluctuated during October–December 2020 but has considerably and consistently decreased after implementation of the vaccination campaign prioritizing older adults. The decline in the ratio of persons aged ≥ 70 years to those < 50 years requiring mechanical ventilation began around the time of start of administration of the second dose of vaccine (January 10, 2021).

 

Clinical

Cuevas AM, Clark JM, Potter JJ. Increased TLR/MyD88 signaling in patients with obesity: is there a link to COVID-19 disease severity? Int J Obes (Lond). 2021 Feb 26. PubMed: https://pubmed.gov/33637950. Full-text: https://doi.org/10.1038/s41366-021-00768-8

Why is obesity a risk factor for severe COVID-19? The authors review current knowledge and hypothesize that people with obesity, especially excess abdominal/visceral fat and associated metabolic complications, have over-expression of MyD88 in the adipose tissue and perhaps in other cells and tissues (like immune cells) that triggers an exaggerated inflammatory response of the immune system.

 

Severe COVID-19

Deinhardt-Emmer S, Böttcher S, Häring C, et al. SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction. J Virol 2021 Feb 26:JVI.00110-21. PubMed: https://pubmed.gov/33637603. Full-text: https://doi.org/10.1128/JVI.00110-21

To elucidate the viral effects on the barrier integrity and immune reactions, Stefanie Deinhardt-Emmer and colleagues from Jena, Germany used mono-cell culture systems and a complex human chip model composed of epithelial, endothelial, and mononuclear cells. SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including interferon expression. By contrast, the adjacent endothelial layer was not infected nor did it show productive viral replication or release of interferon. With prolonged infection, both cell types were damaged, and the barrier function was deteriorated, allowing the viral particles to have to carry too much.

 

Althaus K, Marini I, Zlamal J, et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood February 25, 2021, 137 (8): 1061–1071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791311/

Severe COVID-19 is associated with antibody-mediated up-regulation of platelet apoptosis. In addition, Karina Althaus and colleagues from Tübingen, Germany found a correlation between platelet apoptosis markers and SOFA score, plasma levels of D-dimer, and the incidence of thromboembolic complications in severe COVID-19 patients. These data indicate that platelet apoptosis may contribute to sustained inflammation and increased thromboembolic risk in COVID-19 patients and could potentially present a potential therapeutic target.

 

Treatment

Piepenbrink MS, Park JG, Oladunni FS, et al. Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters. Cell Reports February 24, 2021. DOI: https://doi.org/10.1016/j.xcrm.2021.100218

Antibodies delivered via inhalation for the prevention and treatment of SARS-CoV-2: Michael S. Pipenbrink from Birmingham, US shows that this works. Fully human monoclonal antibodies (hmAbs) potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, exhibited in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhaled treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung-deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration.

 

Bugin K, Woodcock J. Trends in COVID-19 therapeutic clinical trials. Nature Reviews Drug Discovery, 25 February 2021. https://www.nature.com/articles/d41573-021-00037-3

Janet Woodcock and Kevin Bugin have comprehensively assessed the ongoing COVID-19 therapeutic clinical development efforts worldwide. Surveying the clinical trial landscape, their most important finding is that the vast majority of trials of therapeutics for COVID-19 are not designed to yield actionable information; low randomization rates and underpowered outcome data render matters of safety and efficacy generally uninterpretable.

 

Milic J, Novella A, Meschiari M, et al. Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia. AIDS Res Hum Retroviruses. 2021 Feb 23. PubMed: https://pubmed.gov/33619997. Full-text: https://doi.org/10.1089/AID.2020.0305

The HIV protease inhibitor darunavir doesn’t work in COVID. Didn’t we know this already? In this retrospective study in HIV-negative patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy, patients on darunavir/c (c=cobicistat is a pharmacoenhancer) had higher rates of mortality (25% vs 10%, p < 0.0001) and of mechanical ventilation and death (37% vs. 25%, p = 0.03). Multiple serious interactions associated with darunavir/c were observed in the 19 patients who died. According to the authors, darunavir/c “should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials”. The question is: why did the authors study this now?

 

1 March

Virology

Paper of the Day

Zhou B, Thi Nhu Thao T, Hoffmann D, et al. SARS-CoV-2 spike D614G change enhances replication and transmission. Nature 26 February 2021. https://www.nature.com/articles/s41586-021-03361-1

Extensive study on the first update of SARS-CoV-2, namely the mutation at codon 614 (already partially dominant last spring in many countries). It is shown that the S-614G variant has enhanced binding to human host cell surface receptor ACE2, increased replication in primary human bronchial and nasal airway epithelial cultures as well as markedly increased replication and transmissibility in hamsters and ferrets. It will be interesting to see data on such in vivo competitive advantages with the new variants.

 

Epidemiology

Mensah AA, Sinnathamby M, Zaidi A, et al. SARS-CoV-2 infections in children following the full re-opening of schools and the impact of national lockdown: prospective, national observational cohort surveillance, July-December 2020, England. J Infection February 24, 2021. https://doi.org/10.1016/j.jinf.2021.02.022

In England, childhood cases closely followed adult infection rates and national lockdown whilst keeping schools open was associated with large declines in SARS-CoV-2 infection rates, first in adults and then in school-aged children. There was a strong correlation in weekly infection rates between adults and all three educational cohorts during periods of both low and high community infection rates. Two messages from this paper: Schools are not the drivers but low community infection rates are required to allow schools to remain open safely.

 

Hyde Z. Difference in SARS-CoV-2 attack rate between children and adults may reflect bias. Clinical Infectious Diseases 26 February 2021, ciab183, https://doi.org/10.1093/cid/ciab183

In her brief review, Zoë Hyde from Perth, Australia argues that lower secondary attack rates in children compared to adults may reflect lower testing in children and reduced exposure, rather than a genuine difference in biological susceptibility. Additionally, children may shed infectious virus for a shorter period than adults and their antibody response may be less broad, with implications for both polymerase chain reaction and serological testing. After reviewing the data available so far, she thinks it likely that children are more susceptible to SARS-CoV-2 infection than first thought, and they probably play an important role in community transmission.

 

Immunology

Pawlowski C, Puranik A, Bandi H. et al. Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations. Sci Rep 11, 4741 (2021). https://doi.org/10.1038/s41598-021-83641-y

Do existing vaccines afford protection against SARS-CoV-2 infection through trained immunity? By analyzing immunization records from 137,037 individuals, Colin Pawlowski and colleagues from Cambridge found that several vaccines such as polio, MMR, flu or hepatitis A/hepatitis B vaccines administered in the past 1-5 years were associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, co-morbidities, and number of other vaccinations. But can we believe this? Can we control for the “healthy user effect” (that persons who have recently had other vaccines may engage in general health-seeking behaviors which decrease their risk of SARS-CoV-2 infection)? The authors say yes. In a “negative control” experiment on patients who have recently taken cancer screens (who may also have lower rates due to the “healthy user effect”), their propensity score matching method was able to correct for confounding.

 

Transmission

Metlay JP, Haas JS, Soltoff AE, Armstrong KA. Household Transmission of SARS-CoV-2. JAMA Netw Open. 2021 Feb 1;4(2):e210304. PubMed: https://pubmed.gov/33635324. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0304

In this large hospital and ambulatory care network based in Boston, US, 7262 index cases were linked to 17,917 additional at-risk individuals assigned to the same addresses. Overall household infection risk was 10.1%. Independent factors significantly associated with higher transmission risk included age greater than 18 years and multiple comorbid conditions (adjusted OR for individuals with hypertension, 1.93). In sensitivity analyses limiting the maximum size of the household to as small as 2 persons, the calculated transmission risk increased to only 13.8%.

 

Kraay ANM, Hayashi MAL, Berendes DM, Sobolik JS, Leon JS, Lopman BA. Risk for fomite-mediated transmission of SARS-CoV-2 in child daycares, schools, nursing homes, and offices. Emerg Infect Dis. February 24, 2021. https://wwwnc.cdc.gov/eid/article/27/4/20-3631_article

SARS-CoV-2 can persist on surfaces, suggesting possible surface-mediated transmission of this pathogen. Using a transmission model to explore the potential for fomite transmission without other pathways, Alicia N.M. Kraay from Atlanta and colleagues found that fomites might be a substantial source of transmission risk, particularly in schools and child daycares. Combining surface cleaning and decontamination with mask wearing can help mitigate this risk.

 

Clinical

van Westen-Lagerweij NA, Meijer E, Meeuwsen EG, et al. Are smokers protected against SARS-CoV-2 infection (COVID-19)? The origins of the myth. npj Primary Care Respiratory Medicine February 26, 2021, volume 31, Article number: 10. https://www.nature.com/articles/s41533-021-00223-1

Do you believe that alcohol disinfects the stomach? Ok, then you don’t need to read any further. For the rest of us, this commentary dispels a few myths (or, if you will, bullsh*t studies) about smoking and COVID-19.

 

Struyf T, Deeks JJ, Dinnes J, et al. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19. Cochrane Database Syst Rev. 2021 Feb 23;2:CD013665. PubMed: https://pubmed.gov/33620086. Full-text: https://doi.org/10.1002/14651858.CD013665.pub2

Are there signs and symptoms predicting COVID-19? This Cochrane review says no.

 

Treatment

Janiaud P, Axfors C, Schmitt AM, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021 Feb 26. PubMed: https://pubmed.gov/33635310. Full-text: https://doi.org/10.1001/jama.2021.2747

This review of all RCTs published until January 29 showed that compared with placebo or standard of care, convalescent plasma was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes.

 

Gupta A, Madhavan MV, Poterucha TJ, et al. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Nat Commun 12, 1325 (2021). https://doi.org/10.1038/s41467-021-21553-1

Better take your statins! Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use was significantly associated with lower odds of in-hospital mortality within 30 days in the propensity-matched cohort (OR 0.47, 95% CI: 0.36–0.62, p < 0.001). The potential benefits from statins extend beyond cholesterol-lowering properties, as there is a robust literature supporting the anti-inflammatory properties of statins, suggesting that these drugs can stabilize and restore endothelial function. Randomized clinical trials are ongoing (and needed).

 

Herrett E, Williamson E, Brack K, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ. 2021 Feb 24;372:n135. PubMed: https://pubmed.gov/33627334. Full-text: https://www.bmj.com/content/372/bmj.n135

And for those patients who supposedly can’t tolerate a statin, it’s probably not the case. In this nice study among 151 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms, no difference in muscle symptom scores was found between the statin and placebo periods. Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long-term treatment with statins.

 

28 February

Variants

Paper of the Day

WHO 20210223. Weekly epidemiological update – 23 February 2021. WHO 2021, published 23 February. Full-text: https://www.who.int/publications/m/item/weekly-epidemiological-update—23-february-2021

If you are interested in variants, read the Special Focus: Update on SARS-CoV-2 Variants of Concern on page 7 to 13 with an excellent table on the current information we have on B.1.1.7, B.1.351 and P.1.

 

Naveca F, Nascimento V, Souza V, et al. COVID-19 epidemic in the Brazilian state of Amazonas was driven by long-term persistence of endemic SARS-CoV-2 lineages and the recent emergence of the new Variant of Concern P.1. Research Square 2021, posted 25 February. Full-text: https://doi.org/10.21203/rs.3.rs-275494/v1

The second wave in the Northern Brazilian state of Amazonas coincides with the emergence of the P.1 variant in late November 2020. P.1 replaced the parental lineage in less than two months. The authors report that successive lineage replacements in Amazonas were driven by a complex combination of variable levels of social distancing measures and the emergence of a more transmissible VOC P.1 virus. They provide insights to understanding the mechanisms that underlie COVID-19 waves and the risk of disseminating P.1 in Brazil and potentially worldwide.

 

Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus. GitHub 2021, posted 27 February. Full-text: https://github.com/CADDE-CENTRE/Novel-SARS-CoV-2-P1-Lineage-in-Brazil/blob/main/manuscript/FINAL_P1_MANUSCRIPT_25-02-2021_combined.pdf

Using a combination of genomic and epidemiological data, Nuno Faria and colleagues characterize the emergence and characteristics of P.1 that acquired 17 mutations, including the trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. The authors show that P.1 emerged around early November 2020. They estimate that P.1 could be 1.4–2.2 times more transmissible and able to evade 25-61% of protective immunity elicited by previous infection with non-P.1 lineages. These data need to be confirmed by further studies.

 

Epidemiology

Global.health 2021. Link: https://global.health/

This initiave by people from Oxford, Harvard, Northeastern, Boston Children’s Hospital, Georgetown, University of Washington, and Johns Hopkins is meant to be an easy-to-use global data repository and visualization platform that collects anonymized information about individual cases from around the world in one place. The goal: open access to real-time epidemiological anonymized data. See also Maxmen A. Massive Google-funded COVID database will track variants and immunity. Nature. 2021 Feb 24. PubMed: https://pubmed.gov/33627862. Full-text: https://doi.org/10.1038/d41586-021-00490-5

 

Virology

FT 2021026. The same covid-19 mutations are appearing in different places. Financial Times 2021, published 26 February. Link: https://www.economist.com/graphic-detail/2021/02/27/the-same-covid-19-mutations-are-appearing-in-different-places

Excellent ancestry tree of SARS-CoV-2. The Financial Times argues that convergent evolution might make travel restrictions redundant.

 

Transmission

Davis AC, Zee M, Clark AD, et al. Computational Fluid Dynamics Modeling of Cough Transport in an Aircraft Cabin. medRxiv 2021, posted 17 February. Full-text: https://doi.org/10.1101/2021.02.15.431324

Track particles released by coughing from a passenger seated in different seats on a Boeing 737 aircraft. The authors report that 80% of the particles were removed from the cabin in 1.3 to 2.6 minutes, depending on conditions, and 95% of the particles were removed in 2.3 to 4.5 minutes. We know from other reports that this is not sufficient to prevent SARS-CoV-2 transmission onboard aircraft. Remember the paper we presented on 23 February: Wang Z, Galea ER, Grandison A, et al. Inflight Transmission of COVID-19 Based on Experimental Aerosol Dispersion Data. Journal of Travel Medicine, February 19, 2021. taab023, https://doi.org/10.1093/jtm/taab023

 

Vaccine

WHO 20210223. Weekly epidemiological update – 23 February 2021. WHO 2021, published 23 February. Full-text: https://www.who.int/publications/m/item/weekly-epidemiological-update—23-february-2021

Three pages about WHO’s current COVID-19 vaccine policy recommendations (page 4 to 6): age requirements, pregnant women, breastfeeding mothers, people with compromised immune system, living with HIV, or previously infected with SARS-CoV-2, people with a history of severe allergic reaction.

 

FDA 20210226. Vaccines and Related Biological Products Advisory Committee February 26, 2021 Meeting Announcement. FDA 2021, published 26 February. Documents: https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-february-26-2021-meeting-announcement#event-materials

Find here the documents that will lead to the approval of vaccine #4 – the one-shot adenovirus vector vaccine by Johnson & Johnson. The best news of the day: the vaccine had only a slightly reduced overall efficacy rate in South Africa (64% vs 72% in the US). Most importantly, the J&J vaccine showed 86% and 82% efficacy against severe disease of COVID-19 in the US and South Africa, respectively.

 

Diagnostics

Carreño JM, Mendu DR, Simon V, et al. Longitudinal analysis of SARS-CoV-2 seroprevalence using multiple serology platforms. medRxiv 2021, posted 26 February. Full-text: https://doi.org/10.1101/2021.02.24.21252340

Florian Krammer, Juan Manuel Carreño and colleagues look at longitudinal SARS-CoV-2 seroprevalence using multiple serology platforms. Good correlation was observed between the MS and Kantaro RBD ELISAs and between the MS and Kantaro spike ELISAs. By contrast, modest correlations were observed between the Abbott Architect and both RBD and spike-based assays.

 

27 February

Treatment

Paper of the Day

Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 – Cooling the Inflammatory Soup. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631064. Full-text: https://doi.org/10.1056/NEJMe2103108

In their nice editorial, Eric Rubin, Dan Longo, and Lindsey Baden discuss how we can make sense of these disparate results between COVACTA and the REMAP-CAP data. Differences among the trials (enrolment criteria, timing of therapy, primary outcome, and background care, especially steroid use) may account for the discrepancy. In addition, inflammation may not be the same: patients with severe disease at initial presentation may have a different pathogenesis than those in whom inflammatory disease develops later, which suggests that the timing of treatment may be crucial in understanding responses. However, according to the authors, these points raise thorny issues. Is the value of interleukin-6 inhibition dependent on the timing of treatment, being beneficial only if proximate to an acute late inflammatory decompensation event? We rely on clinical trials to either endorse or reject possible interventions. But what if the results of trials change as the underlying therapies improve, a particular problem with platform trials, which always need to include contemporaneous controls? For now, we are left with evidence of benefit from interleukin-6 inhibitors, but how to best use them remains unclear.

 

Transmission

Marcus JE, Frankel DN, Pawlak MT, et al. Risk Factors Associated With COVID-19 Transmission Among US Air Force Trainees in a Congregant Setting. JAMA Netw Open. 2021 Feb 1;4(2):e210202. PubMed: https://pubmed.gov/33630090. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0202

Basic military training is the first step in the transition of a civilian to an enlisted member of the US Air Force. It brings together more than 39,000 trainees every year from around the US and represents an “ideal” setting to assess symptoms and lab values of a young, healthy population living in congregant-setting cohorts in a controlled environment. Among 10,613 US Air Force basic trainees in 263 cohorts, 403 trainees (3%) received a COVID-19 diagnosis in 129 cohorts (49%). Of these, 204 (51%) were symptomatic, and 199 (49%) were asymptomatic. Median cycle threshold values were lower in symptomatic trainees compared with asymptomatic trainees (21.2 vs 34.8). Cohorts with infection clusters were predominantly men, had more symptomatic trainees, and had more symptoms per patient compared with cohorts without clusters.

 

Immunology

Zhou S, Butler-Laporte G, Nakanishi T, et al. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nat Medicine February 25, 2021. https://www.nature.com/articles/s41591-021-01281-1

OAS proteins are part of the innate immune response against RNA viruses. They are induced by interferons and activate latent RNase L, resulting in direct viral and endogenous RNA destruction, as demonstrated in in vitro studies. In this large-scale study of 931 proteins assessed for COVID-19 outcomes in > 14,000 cases and 1.2 million controls of European ancestry, Sirui Zhou and colleagues from Montreal, Canada provide evidence that increased OAS1 levels in the non-infectious state are strongly associated with reduced risks (22-46%) of severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection.

 

Vaccines

Prendecki M, Clarke C, Brown J, et al. Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine. Lancet February 25, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00502-X/fulltext

Early evidence for vaccine responses following previous natural infection. Maria Prendecki and colleagues looked at 72 HCWs from Imperial College Healthcare NHS Trust in London who were vaccinated, among them 21 (29%) participants with evidence of previous SARS-CoV-2 infection. Immune responses were analyzed 21-25 days after the first shot. In almost all individuals with previous SARS-CoV-2 infection, strong humoral and cellular responses to one dose of BNT162b2 vaccine, with evidence of high titers of virus neutralization were seen. In contrast, most infection-naive individuals generated only weak T cell responses and low titers of neutralizing antibodies.

 

Manisty C, Otter AD, Treibel TA, et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet February 25, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00501-8/fulltext

Same direction: in this nested case-control analysis of 51 participants of COVIDsortium (24 seropositive) seronegative individuals had anti-S titers after one dose of vaccine comparable to peak anti-S titers in individuals with a previous natural infection who had not yet been vaccinated. Among those with a previous SARS-CoV-2 infection, vaccination increased anti-S titers more than 140-fold from peak pre-vaccine levels. This increase appears to be at least one order of magnitude greater than reported after a conventional prime-boost vaccine strategy in previously uninfected individuals.

 

Ozonoff A, Nanishi E, Levy O. Bell’s palsy and SARS-CoV-2 vaccines. The Lancet Infectious Diseases, February 24, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00076-1/fulltext

Bell’s palsy is a type of facial paralysis that results in a temporary inability to control the facial muscles on the affected side of the face. Al Ozonoff and colleagues say that observed incidence of Bell’s palsy following mRNA vaccination is 3-7 times higher than would be expected in the general population. According to their comment, this signals a potential safety phenomenon and suggests inaccurate reporting to the public. However, it is also noted that Bell’s palsy usually self-resolves and that the mRNA vaccines offer a substantial net benefit to public health.

 

Co-morbidities

Kwan JY, Lin LT, Bell R, et al. Elevation in viral entry genes and innate immunity compromise underlying increased infectivity and severity of COVID-19 in cancer patients. Sci Rep 11, 4533 (2021). https://doi.org/10.1038/s41598-021-83366-y

What is the potential biological rationale behind the enhanced risk of COVID-19 among cancer patients? Jennifer Yin Yee Kwan from Toronto and colleagues suggest an increased expression of SARS-CoV-2 viral entry genes in the cancer state, particularly in respiratory, gastrointestinal, and genitourinary tract tissues. Elevation of ACE2, TMPRSS2, and CTSL in cancer vs. normal tissue was observed in many of the tissues examined. Moreover, it appeared that some entry genes have transient elevation with radiotherapy or chemotherapies.

 

Treatment

REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631065. Full-text: https://doi.org/10.1056/NEJMoa2100433

Two weeks ago, encouraging (but not peer-reviewed) results from the RECOVERY trial revitalized the strategy of blocking interleukin-6 in patients with severe COVID-19 (https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19). Now we are getting some more evidence, provided by REMAP-CAP. REMAP-CAP is an international, adaptive platform trial designed to determine effective treatment strategies for patients with severe pneumonia in both pandemic and non-pandemic settings. Patients eligible for the platform are assessed for eligibility to potentially undergo randomization to multiple interventions across multiple domains. Adult patients with COVID-19, within 24 hours after starting organ support in the ICU, were randomly assigned to receive tocilizumab (8 mg per kg of body weight), sarilumab (400 mg), or standard care (control). Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 in the tocilizumab group, 11 (0 to 16) in the sarilumab group, and 0 in the control group. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08).

 

Rosas IO, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631066. Full-text: https://doi.org/10.1056/NEJMoa2028700

But can we trust these platform data? In COVACTA, a large randomized Phase III trial, 438 patients who were hospitalized with severe pneumonia were randomized 2:1 to receive TCZ or placebo, the use of TCZ did not result in significantly better clinical status or lower mortality (19.7% versus 19.4%) at 28 days.

 

Pediatrics

Cheong RCT, Jephson C, Frauenfelder C, et al. Otolaryngologic Manifestations in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19. JAMA Otolaryngol Head Neck Surg. 2021 Feb 25. PubMed: https://pubmed.gov/33630068. Full-text: https://doi.org/10.1001/jamaoto.2020.5698

Single-center exploratory observational cohort study focusing on otolaryngologic manifestations of 50 children 18 years or younger presenting with PIMS-TS. Elevated rates of otolaryngology manifestations, such as dysphonia, dysphagia, and anosmia/hyposmia that persisted for longer than 6 weeks.

 

26 February

Vaccines

Paper of the Day

Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. NEJM February 24, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2101765

No doubt, paper of the day! Encouraging real-life data from Israel: Estimated vaccine effectiveness (> 1 M people vaccinated) during the follow-up period starting 7 days after the second dose was 92% for documented infection, 94% for symptomatic COVID-19, 87% for hospitalization, and 92% for severe COVID-19. Estimated effectiveness days 14 through 20 (after one dose) and days 21 through 27 (gradual shifting between the first and second vaccine doses) was 46% and 60% for documented infection, 57% and 66% for symptomatic COVID-19, 74% and 78% for hospitalization, 62% and 80% for severe COVID-19, and 72% and 84% for COVID-19–related death, respectively.

 

Kyriakidis NC, López-Cortés A, González EV, et al. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. npj Vaccines 6, 28 (2021). https://www.nature.com/articles/s41541-021-00292-w

Comprehensive is right. A fantastic review discusses different strategies used for vaccine development and provides an overview of the current leading vaccine candidates against SARS-CoV-2.

 

Epidemiology

Lendacki FR, Teran RA, Gretsch S, Fricchione MJ, Kerins JL. COVID-19 Outbreak Among Attendees of an Exercise Facility — Chicago, Illinois, August–September 2020. MMWR Morb Mortal Wkly Rep. ePub: 24 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7009e2

Have you recently met your personal trainer from the local gym? Did he tell you how he disagrees with the lockdown and the closing of the gym, after all they had worked so hard to develop wonderful hygiene management concepts? That all classes would be held at ≤ 25% capacity (i.e., 10–15 persons)? That mask use, temperature checks, symptom screenings would be required on entry (ok, patrons were allowed to remove masks during exercise) and that patrons would bring their own mats and weights and would be stationed ≥ 6 ft apart? Then show him this report. During August 24–September 1, 2020, an exercise facility at Chicago did exactly this. The results: 55 COVID-19 cases were identified among 81 attendees of indoor high-intensity classes. Twenty-two (40%) persons with COVID-19 attended on or after the day symptoms began. Most attendees (76%) wore masks infrequently, including persons with (84%) and without COVID-19 (60%).

 

Harvey RA, Rassen JA, Kabelac CA, et al. Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection. JAMA Intern Med February 24, 2021. Full-text: https://doi.org/10.1001/jamainternmed.2021.0366

Seropositivity is associated with protection from infection. In this cohort study of more than 3.2 million US patients with a SARS-CoV-2 antibody test, 0.3% of those indexed with positive test results had evidence of a positive nucleic acid amplification test beyond 90 days after index, compared with 3.0% indexed with negative antibody test results. During the follow-up periods, the ratio (95% CI) of positive PCR results among individuals who had a positive antibody test at index vs those with a negative antibody test at index was 2.85 (95% CI: 2.73-2.97, consistent with prolonged RNA shedding!) at 0 to 30 days, 0.67 at 31 to 60 days, 0.29 at 61 to 90 days, and 0.10 at more than 90 days.

 

Katz MH. How to Advise Persons Who Are Antibody Positive for SARS-CoV-2 About Future Infection Risk. JAMA Intern Med February 24, 2021. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2776809

In his comment, Mitchell H. Katz still believes that vaccination against SARS-CoV-2 is recommended regardless of antibody status (as nobody knows how long antibody protection due to natural infection will last).

 

Davido B, Mascitti H, Fortier-Beaulieu M, et al. Blue toes’ following vaccination with the BNT162b2 mRNA COVID-19 vaccine. Journal of Travel Medicine, 23 February 2021, taab024, https://doi.org/10.1093/jtm/taab024

COVID toes-like syndrome linked to COVID-19 vaccine: This interesting case report describes a young Caucasian female (aged 41) who presented with chilblain-like skin changes on her toes that appeared 4 days after the first injection with the Pfizer-BioNTech-162b2 vaccine.

 

Epidemiology

Groves LM, Usagawa L, Elm J, et al. Community Transmission of SARS-CoV-2 at Three Fitness Facilities — Hawaii, June–July 2020. MMWR Morb Mortal Wkly Rep. ePub: 24 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7009e1

Twenty-one COVID-19 cases were linked to an index case in a fitness instructor, who, along with a patient who was also an instructor, taught classes < 1 day, 1 to < 2 days, and ≥ 2 days before symptom onset; aggregate attack rates were 95% (20 of 21), 13% (one of eight), and 0% (zero of 33). Of note, use of masks was not required in the fitness facilities.

 

Clinical

Folgueira MD, Luczkowiak J, Lasala F, et al. Prolonged SARS-CoV-2 cell culture replication in respiratory samples from patients with severe COVID-19. Clin Microbiology Inf February 22, 2021. Full-text: https://doi.org/10.1016/j.cmi.2021.02.014

See title. This study from Madrid found a completely different pattern of SARS-CoV-2 viability in upper respiratory tract samples from mild cases, in which viral replication occurs for a short period (10 days), compared with hospitalized patients with severe COVID-19, in whom viable virus can frequently be demonstrated during prolonged periods of up to 4 weeks, both in their upper and lower respiratory tract samples, even in the presence of high levels of neutralizing activity.

 

Blain H, Gamon L, Tuaillon E, et al. Atypical symptoms, SARS-CoV-2 test results, and immunization rates in 456 residents from eight nursing homes facing a COVID-19 outbreak. Age and Ageing, February 23, 2021, afab050, https://doi.org/10.1093/ageing/afab050

A retrospective longitudinal study in eight NHs with at least ten rRT-PCR-positive residents. Among 456 residents, 161 residents had a positive rRT-PCR (35%), 17% of whom were asymptomatic before testing. Temperature > 37.8°C, oxygen saturation < 90%, unexplained anorexia, behavioral change, exhaustion, malaise, and falls before testing were independent predictors of a further positive rRT-PCR. Hubert Blain and colleagues from France conclude that NH residents with unusual fatigue, behavioral change, anorexia, malaise or falls should be tested by rRT-PCR for an early identification of the first SARS-CoV-2 cases.

 

Gutiérrez-Gutiérrez B, del Toro MD, Borobia AM, et al. Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study. The Lancet Infectious Diseases February 23, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00019-0/fulltext

Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. Using two large cohorts with more than 3500 patients from Spain, the authors developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes, including a total of 16 variables. Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more co-morbidities and even higher inflammatory parameters than phenotype B. These results might help to better classify patients for clinical management. However, whether the model and derived calculator might be helpful in clinical practice is unknown. Moreover, the pathophysiological mechanisms of the phenotypes must be investigated.

 

Severe COVID-19

Yao Y, Ye F, Li K, et al. Genome and epigenome editing identify CCR9 and SLC6A20 as target genes at the 3p21.31 locus associated with severe COVID-19. Sig Transduct Target Ther February 22, 2021, 6, 85. https://www.nature.com/articles/s41392-021-00519-1

Recently, genome-wide association studies (GWASs) have identified chromosome 3p21.31 (sentinel variant: rs11385942) to be associated with severe COVID-19. By utilizing CRISPR/Cas9-mediated genomic deletion, the authors identified CCR9 and SLC6A20 as potential target genes of the 3p21.31 locus.

 

Feldstein LR, Tenforde MW, Friedman KW, et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA Network February 24, 2021. JAMA February 24, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777026

Incredibly large case series of 1116 patients aged less than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Comparing children and adolescents with MIS-C vs those with severe COVID-19, MIS-C was distinguished by certain demographic features and clinical presentations including being aged 6 to 12 years, being of non-Hispanic Black race, having severe cardiovascular or mucocutaneous involvement, and having more extreme inflammation.

 

25 February

Variants

Paper of the Day

Zhou D, Dejnirattisai W, Supasa P, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera. Cell February 23, 2021. Full-text: https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2900226-9

The new variants have multiple changes in the immunodominant spike protein which facilitates viral cell entry via the ACE receptor. Mutations in the receptor recognition site on the spike are of great concern due to their potential for immune escape. Daming Zhou and colleagues from Oxford, UK  describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K although K417N and N501Y act together against some important antibody classes.  The neutralization titer for B.1.351 reduced 8 to 9-fold for both the Pfizer and AstraZeneca vaccinees. E484K, K417N and N501Y caused widespread escape from monoclonal antibodies. However, let‘s keep in mind that even if antibody responses to the new variants are not able to prevent infection, they may moderate severity. Moreover, T cell responses to spike may not be disrupted by the mutational changes described here.

 

Li Q, Nie J, Wu J. No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants. Cell February 23, 2021. https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2900231-2

More experiments on B.1.351 (also known as 501Y.V2). These variants DO NOT confer increased infectivity in multiple cell types except for murine (not human!) ACE2-overexpressing cells, where a substantial increase in infectivity was observed. As seen in the other paper, the susceptibility of the variants to neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of Spike.

 

Vasques Nonaka CK, Franco MM, Gräf T, et al. Genomic evidence of SARS-CoV-2 reinfection involving E484K spike mutation, Brazil. Emerg Infect Dis. February 19, 2021. https://wwwnc.cdc.gov/eid/article/27/5/21-0191_article

A case of reinfection from distinct virus lineages in Brazil harboring the E484K mutation, a variant associated with escape from neutralizing antibodies (see above). Both episodes were considered to be mild.

 

Transmission

Spinelli MA, Gliden DV, Gennatas ED. Importance of non-pharmaceutical interventions in lowering the viral inoculum to reduce susceptibility to infection by SARS-CoV-2 and potentially disease severity. Lancet Inf Dis February 22, 2021. Full-text: https://doi.org/10.1016/S1473-3099(20)30982-8

Matthew Spinelli and colleagues argue that even as safe and effective vaccines are being rolled out, non-pharmaceutical interventions (including social distancing, mask wearing, and improved ventilation) will continue to play an essential role in suppressing SARS-CoV-2 transmission until equitable and widespread vaccine administration has been completed. In this personal viewpoint, they review the influence of the viral inoculum on disease susceptibility for several human pathogens and the preliminary data available for SARS-CoV-2.

 

Diagnostics

Toh ZQ, Higgings RA, Anderson J, et al. The use of dried blood spots for the serological evaluation of SARS-CoV-2 antibodies. Journal of Public Health, fdab011, 22 February 2021. https://doi.org/10.1093/pubmed/fdab011

Zheng Quan Toh and colleagues from Melbourne compared the SARS-CoV-2 IgG antibody response in paired serum and eluates from dried blood spot specimens. The IgG seropositivity rate was similar between serum and DBS specimens (18.9%, 18/95 versus 16.8%, 16/95), respectively. DBS would facilitate serosurveillance efforts particularly in hard-to-reach populations.

 

Clinical

Markewitz R, Torge A, Wandinger KP. et al. Clinical correlates of anti-SARS-CoV-2 antibody profiles in Spanish COVID-19 patients from a high incidence region. Sci Rep 11, 4363 (2021). https://doi.org/10.1038/s41598-021-83969-5

No prognostic value of SARS-CoV-2 antibodies (assessed by the EUROIMMUN assay) in this cohort. Serum samples from 347 Spanish patients from a high-incidence region were collected at one point in time (ranging from 0 to 33 days since onset of symptoms). Neither the presence, nor the levels of antibodies served as prognostic markers. The presence and level of antibodies was not associated with age, sex, duration of hospitalization, treatment in the ICU or death. A subgroup of patients (IgG 4%) did not develop antibodies at the time of sample collection. Compared to the patients that did, no differences were found.

 

Zhao Y, Cunningham MH, Mediavilla JR, et al. Diagnosis, clinical characteristics, and outcomes of COVID-19 patients from a large healthcare system in northern New Jersey. Sci Rep 11, 4389 (2021). https://doi.org/10.1038/s41598-021-83959-7

In this large cohort of 722 patients from New Jersey, viral load, as indicated by the cycle of threshold (Ct) values from the RT-PCR test, was significantly higher in the oldest patient group (≥ 80), and inversely correlated with survival.

 

dos Santos LA, Germano de Góis Filho P, Fantini Silva AM, et al. Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers. J Infection, February 12, 2021. DOI:https://doi.org/10.1016/j.jinf.2021.01.020

In 33 patients with recurrent COVID-19 and a positive PCR, recurrence was associated with working as a healthcare professional, blood-group A, and low IgG response to infection. All had recovered from first episode symptoms, returned to work and later suffered recurrent symptoms. Of note, recurrent episodes tended to be more severe, with one fatal infection.

 

Treatment

Cross RW, Prasad AN, Borisevich V. Use of convalescent serum reduces severity of COVID-19 in nonhuman primates. Cell Rep February 23, 2021. Full-text: https://doi.org/10.1016/j.celrep.2021.108837

Several  human  clinical  trials  on the passive transfer of convalescent plama have yielded mixed results. In this animal experiment on 10 African green monkeys, sera with high SARS-CoV-2 neutralizing antibody titers showed the greatest benefit. Data suggested passive transfer as a therapy in humans in early stages of disease.

 

Xie C, Chen Y, Luo D, et al. Therapeutic potential of C1632 by inhibition of SARS-CoV-2 replication and viral-induced inflammation through upregulating let-7. Sig Transduct Target Ther 6, 84 (2021). https://doi.org/10.1038/s41392-021-00497-4

MicroRNAs (miRNAs) are small, non-coding RNAs that play regulatory roles in gene expression by targeting their mRNA. The authors report that let-7, an miRNA that is ubiquitously expressed in human cells, blocks SARS-CoV-2 replication by targeting S and M protein. In addition, let-7 suppresses the expression of multiple inflammatory factors. C1632, a small molecule serving as a let-7 stimulator, is capable of upregulating the expression of let-7, thus possibly reducing viral replication and secretion of inflammatory cytokines.

 

24 February

Immunology

Paper of the Day

Tang J, Ravichandran S, Lee Y, et al. Antibody affinity maturation and plasma IgA associate with clinical outcome in hospitalized COVID-19 patients. Nat Commun 12, 1221 (February 22, 2021). Full-text: https://www.nature.com/articles/s41467-021-21463-2

A comprehensive longitudinal antibody analysis on 25 SARS-CoV-2 PCR-confirmed hospitalized COVID-19 patients. In more severe COVID-19 patients, even though they could generate high binding and neutralizing antibody titers, there was a block to antibody affinity maturation that may be linked to deficiency in CD4 cells, and especially T follicular helper cell subsets, which are required for entry into the germinal center. Sustained high levels of proinflammatory cytokines (IL-6 and IL-8), high serum IgA, and blunted affinity maturation against the pre-fusion spike protein were predictive of the worst outcome for hospitalized patients. An elevated inflammatory response may be augmented by low-affinity antibodies that are not efficient in controlling SARS-CoV-2 replication.

 

Epidemiology

Zimmerman FJ, Anderson NW. Association of the Timing of School Closings and Behavioral Changes With the Evolution of the Coronavirus Disease 2019 Pandemic in the US. JAMA Pediatr February 22, 2021. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2776608

This cross-sectional study used US COVID-19 data (March to May 2020) and anonymized cell phone as well as internet data. The main findings: voluntary behavioral changes, such as reductions in time spent at work, had an association with COVID-19 incidence and mortality that was 3 times stronger than that of school closures. According to Nathaniel W. Anderson and Frederick J. Zimmerman, their findings suggest that less harmful ways of preventing SARS-CoV-2 transmission are available than mandatory school closures (note: this is based on data prior to the occurrence of more transmittable variants).

 

Gold JA, Gettings JR, Kimball A, et al. Clusters of SARS-CoV-2 Infection Among Elementary School Educators and Students in One School District — Georgia, December 2020–January 2021. MMWR Morb Mortal Wkly Rep. ePub: 22 February 2021. Full-text:  http://dx.doi.org/10.15585/mmwr.mm7008e4

Vaccinate and test the teachers! This investigation in a Georgia school district from December 1, 2020 to January 22, 2021, identified nine clusters of COVID-19 cases involving 13 educators and 32 students at six elementary schools. Consistent with findings from international studies, the report found that initial infections among educators played a substantial role in in-school SARS-CoV-2 transmission and subsequent chains of infection to other educators, students, and households, highlighting the importance of preventing infections among educators in particular.

 

Virology

Bullock HA, Goldsmith CS, Zaki SR, Martines RB, Miller SE. Difficulties in differentiating coronaviruses from subcellular structures in human tissues by electron microscopy. Emerg Infect Dis, February 18, 2021 Apr [date cited]. https://wwwnc.cdc.gov/eid/article/27/4/20-4337_article

In attempts to attribute pathology directly to tissue damage caused by SARS-CoV-2, investigators have inaccurately reported subcellular structures, including coated vesicles, multivesicular bodies, and vesiculating rough endoplasmic reticulum, as coronavirus particles. Hannah A. Bullock from Atlanta and colleagues describe some morphologic features of coronavirus that distinguish it from subcellular structures.

 

Clinical

Dai CL, Kornilov SA, Roper RT, et al. Characteristics and Factors Associated with COVID-19 Infection, Hospitalization, and Mortality Across Race and Ethnicity. Clin Infect Dis. 2021 Feb 20:ciab154. PubMed: https://pubmed.gov/33608710. Full-text: https://doi.org/10.1093/cid/ciab154

This retrospective cohort study examining 629,953 patients tested for SARS-CoV-2 in a large US health system, Hispanics who tested positive at a higher rate required excess hospitalization and mechanical ventilation and had higher odds of in-hospital mortality despite younger age.

 

Long COVID-19

Klein H, Asseo K, Karni N, et al. Onset, duration and unresolved symptoms, including smell and taste changes, in mild COVID-19 infections. A cohort study in Israeli patients. Clin Microbiol Infect. 2021 Feb 16:S1198-743X(21)00083-5. PubMed: https://pubmed.gov/33607252. Full-text: https://doi.org/10.1016/j.cmi.2021.02.008

Of 103 patients with mild COVID-19, 46% had at least one unresolved symptom at six months, most commonly fatigue (22%), smell and taste changes (15% and 8%, respectively), and breathing difficulties (8%).

 

Logue JK, Franko NM, McCulloch D, et al. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw Open, February 19, 2021;4(2):e210830. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0830

A longitudinal prospective cohort of adults with COVID-19 (11 asymptomatic, 150 outpatients with mild disease, 16 with severe illness) was compared with a concurrent cohort of healthy patients. Between 3 and 9 months after onset of illness, the most common persistent symptoms were fatigue (14%) and loss of sense of smell or taste (14%). Notably, 14 participants, including 9 non-hospitalized individuals, reported negative impacts on activity of daily living after infection. With > 60 million cases worldwide, even a small incidence of long-term debility could have enormous health and economic consequences.

 

Zhou M, Wong CK, Un KC, et al. Cardiovascular sequalae in uncomplicated COVID-19 survivors. PLoS One. 2021 Feb 11;16(2):e0246732. PubMed: https://pubmed.gov/33571321. Full-text: https://doi.org/10.1371/journal.pone.0246732

Cardiac abnormality is common (but mostly self-limiting) among COVID survivors with mild disease: a systematic cardiac screening was performed among 97 consecutive COVID-19 survivors (mean age 46 years, all with non-severe disease), including treadmill exercise test and cardiac magnetic resonance imaging (CMR). Median duration from discharge to screening was 11 days. Cardiac abnormalities were detected in 42.3% including sinus bradycardia (29.9%), newly detected T-wave abnormality (8.2%) and elevated troponin level (6.2%). For COVID-19 survivors with persistent elevation of troponin levels after discharge or newly detected T wave abnormalities, echocardiography and CMR did not reveal any evidence of infarct, myocarditis, or left ventricular systolic dysfunction.

 

Collateral damage

Ghafil C, Matsushima K, Henry R, et al. Trends in Trauma Admissions During the COVID-19 Pandemic in Los Angeles County, California. JAMA Netw Open. February 22, 2021;4(2):e211320. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.1320

Less accidents (for a few weeks) but more gunshots? In this retrospective cohort study of 6777 trauma admissions in Los Angeles County from January 1 to June 7, 2020, overall volume transiently decreased but quickly returned to baseline. Mechanisms of injury were significantly different, with a steady increase in admissions for “penetrating” injuries (in other words: mainly gunshots).

 

Treatment

Hunt BJ, De Paula EV, McLintock C, Dumantepe M. Prophylactic anticoagulation for patients in hospital with covid-19. BMJ. 2021 Feb 19;372:n487. PubMed: https://pubmed.gov/33608304. Full-text: https://doi.org/10.1136/bmj.n487

The risk of hospital-associated venous thromboembolism for medical in-patients is greatest in the first 90 days post-discharge, and many units are using unlicensed extended thromboprophylaxis with LMWH or direct acting oral anticoagulants for patients discharged after COVID-19. Recent retrospective data showing low rates of hospital-associated venous thromboembolism post-discharge are reassuring, but according to this editorial, randomized trials formally evaluating the need for extended thromboprophylaxis are now required.

 

23 February

Transmission

Paper of the Day

Wang Z, Galea ER, Grandison A, et al. Inflight Transmission of COVID-19 Based on Experimental Aerosol Dispersion Data. Journal of Travel Medicine, February 19, 2021. taab023, https://doi.org/10.1093/jtm/taab023

No nuts on planes. This elegant analysis demonstrated that while there is a significant reduction in aerosol concentration due to the nature of the cabin ventilation and filtration system, this does not necessarily mean that there is a low probability or risk of in-flight infection. Main results: 1. The economy cabin exhibits the highest probability of infection. 2. Average risk (without masks) for a 2-hour flight in a B777–200 aircraft ranges from 0.1% to 2.5% and for a 12-hour flight from 0.8% to 10.8%, respectively. 3. If all passengers wear face masks throughout the 12-hour flight, the average infection probability can be reduced by approximately 73%/32% for high/low efficiency masks. 4. If face masks are worn by all passengers except during a one-hour meal service, the average infection probability is increased by 59%/8% compared to the situation where the mask is not removed. Bottom line: Don’t remove your KN95 mask. No nuts, no meals. And better forget your frequent flyer status as long as you are unvaccinated (actually, forget it anyway, we’ll get warm here up north and Zoom works fine).

 

Bender JK, Brandl M, Höhle M, Buchholz U, Zeitlmann N. Analysis of asymptomatic and presymptomatic transmission in SARS-CoV-2 outbreak, Germany, 2020. Emerg Infect Dis February 18, 2021 Apr [date cited]. https://wwwnc.cdc.gov/eid/article/27/4/20-4576_article

Jennifer K. Bender and colleagues determined secondary attack rates (SAR) among close contacts of 46 symptomatic and 7 asymptomatic patients from Southern Germany. Little to no transmission occurred from asymptomatic case-patients. Pre-symptomatic transmission was more frequent than symptomatic transmission.

 

Virology

Kim MC, Cui C, Shin KR, et al. Duration of Culturable SARS-CoV-2 in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 18;384(7):671-673. PubMed: https://pubmed.gov/33503337 . Full-text: https://doi.org/10.1056/NEJMc2027040

How long can we find culturable virus? Not beyond day 12. Min-Chul Kim and colleagues from Seoul, Korea, cultured SARS-CoV-2 in serial respiratory samples obtained from 21 hospitalized patients with COVID-19 to assess the duration of shedding of viable virus. The latest positive viral culture was 12 days after symptom onset (in one patient). Viral culture was positive only in samples with a cycle-threshold value of 28.4 or less.

 

Diagnostics

Harritshøj LH, Gybel-Brask M, Afzal S, et al. Comparison of sixteen serological SARS-CoV-2 immunoassays in sixteen clinical laboratories. J Clin Microbiol. 2021 Feb 11:JCM.02596-20. PubMed: https://pubmed.gov/33574119. Full-text: https://doi.org/10.1128/JCM.02596-20

This comparative study of 15 commercial and one in-house laboratory serological SARS-CoV-2 assays pinpoints differences in accuracy; most total-Ab and IgG assays (not all), including assays with potential for high-throughput production in automated laboratories, reached pre-defined criteria for acceptable performance. Diagnostic accuracy was higher in the group of the SARS-CoV-2 total Ab assays compared to the group of the SARS-CoV-2 IgG assays.

 

Al Suwaidi H, Senok A, Varghese R, et al. Saliva for molecular detection of SARS-CoV-2 in school-aged children. Clin Microb Infection, February 19, 2021. https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00084-7/fulltext

Use saliva in children! For this COVID-19 screening study in Dubai, United Arab Emirates, each child provided paired nasopharyngeal (NP) swab and saliva. Main results: detection in NP swab (16.7%; 81/485) and saliva (15.9%; 77/485) did not differ. Cycle threshold values were significantly higher in NP swab/saliva pairs with discordant findings compared to those with both specimens positive.

 

Clinical

Schinkel M, Appelman B, Butler J, et al. Association of clinical sub-phenotypes and clinical deterioration in COVID-19: further cluster analyses. Intensive Care Med (2021). February 18, 2021. https://doi.org/10.1007/s00134-021-06363-9

Among patients admitted to ten teaching hospitals across the Netherlands, three sub-phenotypes were identified.

  • Sub-phenotype 1 (n = 592) mainly included females (75%, median age 63), characterized by a high prevalence of gastro-intestinal complaints (84%) and sputum production (63%). Co-morbidities and medication usage were scarce. The composite outcome of ICU admittance/death rates was relatively low (25%).
  • Sub-phenotype 2 (n = 876) included more males (80%, median age 63 years) with few co-morbidities and the lowest medication usage of all three groups. Patients presented with less symptoms than those in sub-phenotype 1, but ICU admittance/death rates were higher (31%).
  • Sub-phenotype 3 (n = 551) mostly consisted of older males (80%, median age 76) with multiple co-morbidities, mainly diabetes (62%), hypertension (88%) and other cardiovascular diseases (72%), and consequent medication usage. Patients reported less symptoms such as dyspnea (67%), headache (9%) and myalgia (12%). ICU admission and/or 21-day mortality occurred in 43%.

The authors believe the main value of these sub-phenotypes lies not with their ability to discriminate between clinical outcomes, but in their potential to understand disease heterogeneity and find more homogeneous patient subgroups that may respond more similarly to certain treatments.

 

Collateral damage

Fong MW, Leung NHL, Cowling BJ, Wu P. Upper respiratory infections in schools and childcare centers reopening after COVID-19 dismissals, Hong Kong. Emerg Infect Dis, February 17, 2021 (May date cited). https://wwwnc.cdc.gov/eid/article/27/5/21-0277_article

A large number of outbreaks of acute upper respiratory tract infections (URTIs), likely rhinovirus infections, were identified in October–November 2020 in reopened primary schools, secondary schools, kindergartens, childcare centers, and nursery schools in Hong Kong; these outbreaks led to further territory-wide school dismissals for younger children. Increased susceptibility to rhinoviruses during prolonged school closures and dismissals for coronavirus disease and varying effectiveness of nonpharmaceutical interventions may have heightened transmission of cold-causing viruses when school attendance resumed.

 

Co-morbidities

Quartuccio L, Treppo E, Binutti M, Del Frate G, De Vita S. Timing of Rituximab and immunoglobulin level influence the risk of death for COVID-19 in ANCA-associated vasculitis. Rheumatology (Oxford). 2021 Feb 20:keab175. PubMed: https://pubmed.gov/33609106 . Full-text: https://doi.org/10.1093/rheumatology/keab175

SARS-CoV-2 infections in two patients with polyangiitis who had been treated with rituximab. One died, one was asymptomatic. As timing of rituximab and IgG levels were quite different between the two cases, the authors speculate that this conditioned the final outcome greatly.

 

Severe COVID-19

Shah P, Smith H, Olarewaju A, et al. Is Cardiopulmonary Resuscitation Futile in Coronavirus Disease 2019 Patients Experiencing In-Hospital Cardiac Arrest? Critical Care Medicine: February 2021 – Volume 49 – Issue 2 – p 201-208. Full-text: https://doi.org/10.1097/CCM.0000000000004736

Well, probably yes. Out of 1094 COVID-19 patients who were admitted to three hospitals in Georgia, 63 patients suffered from in-hospital cardiac arrest with attempted resuscitation and were included in this study. Although return of spontaneous circulation was achieved in 29% of patients, it was brief in all of them. The in-hospital mortality was 100%.

 

Treatment

Ma S, Xu C, Liu S, et al. Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials. Sig Transduct Target Ther 6, 83 (2021). https://doi.org/10.1038/s41392-021-00521-7

In this meta-analysis including 7 RCTs and 6250 severe COVID-19 patients, corticosteroid treatment was related to a reduction of all-cause mortality and disease progression, but not with an increase in serious adverse events. Of note, survival benefit was absent if RECOVERY trial was excluded. More robust supporting data are required.

 

February

Epidemiology

Paper of the Day

Nelson EJ, McKune SL, Ryan KA, et al. SARS-CoV-2 Positivity on or After 9 Days Among Quarantined Student Contacts of Confirmed Cases. JAMA February 19, 2021. doi:10.1001/jama.2021.2392 https://jamanetwork.com/journals/jama/fullarticle/2776857

Testing at day 9 instead of 14 days of strict quarantine in students: this study found no evidence that an earlier return to school with a negative test result was linked with subsequent symptomatic illness. Among 799 student contacts of confirmed COVID-19 cases with a negative test result on days 9 to 14, only 1 student became symptomatic after returning to school and had a positive SARS-CoV-2 test result on day 14 after an initial negative test result on day 9. The virus from this student was genetically distinct from the virus isolated from the confirmed COVID-19 case to which the student had been exposed.

 

Brecht I, Peckeu L, Laga M, et al. Reducing contacts to stop SARS-CoV-2 transmission during the second pandemic wave in Brussels, Belgium, August to November 2020. Euro Surveill February 17,. 2021;26(7):pii=2100065. https://doi.org/10.2807/1560-7917.ES.2021.26.7.2100065

This study shows how stringent physical distancing measures (a limit to three close contacts per person, a curfew, closure of bars and recommended teleworking) that were introduced 1 month after a persistent increase in Rt, sufficiently controlled transmission in Belgium, even with high case numbers and without closing schools or full lockdown (remember, this was prior to the occurrence of B.1.1.7).

 

Virology

Cao W, Dong C, Kim S, et al. Biomechanical Characterization of SARS-CoV-2 Spike RBD and Human ACE2 Protein-Protein Interaction. Cell February 17, 2021. Full-text: https://www.cell.com/biophysj/fulltext/S0006-3495(21)00141-7

Using spectroscopy, the authors studied the interaction between the receptor-binding domain (RBD) at viral surface spike (S) protein of different coronaviruses and the angiotensin-converting enzyme 2 (ACE2) receptor expressed on many human cell types. The dissociate rate for RBD-CoV2−ACE2 and RBD-CoV1−ACE2 bonds or interactions were significantly different, possibly explaining the greater infectivity of SARS-CoV-2 vs SARS-CoV-1.

 

Vaccine

Gee J, Marquez P, Su J, et al. First Month of COVID-19 Vaccine Safety Monitoring — United States, December 14, 2020–January 13, 2021. MMWR Morb Mortal Wkly Rep. ePub: 19 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7008e3

From December 14, 2020 to January 13, 2021, a total of 13,794,904 COVID-19 vaccine doses were administered in the US. Anaphylaxis rates were comparable with those reported after receipt of other vaccines. No unexpected patterns of reactions or other safety concerns have been identified during early monitoring.

 

Transmission

Kristiansen MF, Heimustovu BH, á Borg S, Mohr TH, Gislason H, Møller LF, et al. Epidemiology and clinical course of first wave coronavirus disease cases, Faroe Islands. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202589

The Faroe Islands are a unique place to investigate the effects of COVID-19. Because of large scale testing in the country, few unrecorded cases are expected. Mapping the transmission chains of COVID-19 on the islands reveals that most cases infected few or no secondary contacts, whereas 3 superspreading cases set off long, aggressive chains that led to most of the identified secondary locally transmitted cases.

 

Clinical

Elezkurtaj S, Greuel S, Ihlow J, et al. Causes of death and comorbidities in hospitalized patients with COVID-19. Sci Rep 11, February 19, 2021. https://www.nature.com/articles/s41598-021-82862-5

They die from COVID-19. In 26 decedents who had clinically presented with severe COVID-19, Sefer Elezkurtaj from the Charité in Berlin, Germany, found that septic shock and multi-organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. The majority of patients died of COVID-19 with only contributory implications of pre-existing health conditions.

 

Bajaj R, Sinclair HC, Patel K. Delayed-onset myocarditis following COVID-19. Lancet Resp Med February 19, 2021. DOI:https://doi.org/10.1016/S2213-2600(21)00085-0. Full text: https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00085-0/fulltext

Nine patients with acute cardiac decompensation, negative RT-PCR for SARS-CoV-2, markedly increased serum troponin, and substantially raised inflammatory markers: Retesh Bajaj and colleagues from London suggest that this series describes cardiogenic shock due to a multisystem inflammatory syndrome in adults (MIS-A) after COVID-19.

 

Co-morbidities

Brix TH, Hegedüs L, Hallas J, et al. Risk and course of SARS-CoV-2 infection in patients treated for hypothyroidism and hyperthyroidism. Lancet Diabetes and Endocrinology February 19, 2021. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00028-0/fulltext

This large case-control study from Denmark indicates that patients treated for hypothyroidism or hyperthyroidism do not have an increased risk of contracting SARS-CoV-2 infection. The results also suggest that treatment for thyroid dysfunction, when controlling for relevant confounding, does not influence the prognosis of SARS-CoV-2 infection.

 

Mitchel KM, Dimitrov D, Silhol R, et al. The potential effect of COVID-19-related disruptions on HIV incidence and HIV-related mortality among men who have sex with men in the USA: a modelling study. Lancet HIV February 19, 2021. https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(21)00022-9/fulltext

What is the impact of COVID-19 on the HIV pandemic? This deterministic, compartmental HIV transmission model for MSM in Baltimore, US, used available data on COVID-19-related disruptions to HIV services to predict effects of reductions in sexual partners, condom use, HIV testing, viral suppression, PrEP and ART use. Results: it depends. A 25% reduction in sexual partnerships is estimated to offset the effect of the combined service disruptions on new HIV infections.

 

Treatment

Mathews KS, Soh H, Shaefi S, et al. Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure. Crit Care Med. 2021 Feb 17. PubMed: https://pubmed.gov/33595960 . Full-text: https://journals.lww.com/ccmjournal/Abstract/9000/Prone_Positioning_and_Survival_in_Mechanically.95335.aspx

Pro-proning: among 2338 eligible patients in this multicenter cohort study, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were “well-balanced” between proned and non-proned patients. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with non-proned patients (HR: 0.84; 95% CI: 0.73–0.97).

 

21 February

Vaccines

Paper of the Day

Voysey M, Costa Clemens SA, Madhi SA. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet February 19, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00432-3/fulltext

In the case of the ChAdOx1 nCoV-19 (AZD1222) vaccine, it may be better to wait with the second shot. This pre-specified pooled analysis of AstraZeneca’s vaccine trials suggests that a 3-month dose interval might have advantages over a program with a shorter dosing interval. In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81% at ≥ 12 weeks) than in those with a short interval (vaccine efficacy 55% at < 6 weeks).

 

Epidemiology

Tian L, Li X, Qi F et al. Harnessing peak transmission around symptom onset for non-pharmaceutical intervention and containment of the COVID-19 pandemic. Nat Commun February 19, 2021. https://www.nature.com/articles/s41467-021-21385-z

Epidemiological modeling study, focusing on transmission around symptom onset by both pre-symptomatic and symptomatic viral carriers.

 

Immunology

Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 2021 Feb 18;184(4):861-880. PubMed: https://pubmed.gov/33497610 . Full-text: https://doi.org/10.1016/j.cell.2021.01.007

CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. In this brilliant review of the adaptive immune response to SARS-CoV-2, Alessandro Sette and Shane Crotty discuss the specific functions and kinetics of these adaptive immune responses, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.

 

Lee HK, Knabl L, Pipperger L, et al. Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community. Sci Rep 11, 4243 (2021). https://www.nature.com/articles/s41598-021-83110-6

The ski resort of Ischgl, Austria experienced a superspreading event in early March 2020. In April, a seroprevalence of approximately 42% was found in the Ischgl population (n = 1867), with approximately 17% of these being asymptomatic. This comparative investigation of immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals 4 – 6 weeks following the superspreading event showed no statistically significant differences. These results demonstrate that development of an antibody response to COVID-19 following viral exposure and seroconversion in asymptomatic cases is not necessarily associated with sustained alterations in the immune system transcriptome.

 

Rha MS, Jeong HW, Ko JH, et al. PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Immunity. 2021 Jan 12;54(1):44-52.e3. PubMed: https://pubmed.gov/33338412. Full-text: https://doi.org/10.1016/j.immuni.2020.12.002

More about SARS-CoV-2-specific CD8+ T cells. The highlights: 1) SARS-CoV-2-specific CD8+ T cells are effector memory cells in convalescent individuals; 2) CCR7+CD45RA+ cells are increased among SARS-CoV-2-specific cells in the late phase; 3) SARS-CoV-2-specific CD8+ T cells have fewer IFN-γ+ cells than flu-specific cells; 4) PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional.

 

Wheatley AK, Juno JA, Wang JJ, et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat Commun 12, 1162 (2021). https://www.nature.com/articles/s41467-021-21444-5

This longitudinal cohort of 64 participants who recovered from COVID-19 suggests that SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long term protection. Both neutralizing and binding antibody responses decay after recovery from COVID-19, assessed by both polyclonal assays and at the level of single antibody clonotypes with a mass spectrometry-based assay.

 

Supasa P, Daming Z, Dejnirattisai W, et al. Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera. Cell 2021, published 18 February. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00222-1

Gavin Screaton, Piyada Supasa and colleagues mapped the impact of the N501Y mutation by structure/function analysis of a large panel of well-characterised monoclonal antibodies. B.1.1.7 was harder to neutralize but widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed (Supasa 2021).

 

Clinical

Jeffery-Smith A, Iyanger N, Williams SV, et al. Antibodies to SARS-CoV-2 protect against re-infection during outbreaks in care homes, September and October 2020. Euro Surveill. 2021 Feb;26(5):2100092. PubMed: https://pubmed.gov/33541486. Full-text: https://doi.org/10.2807/1560-7917.ES.2021.26.5.2100092

Prior infection with SARS-CoV-2 as determined by antibody or RT-PCR positivity was highly protective at 4 months. Only one re-infection occurred in a seropositive staff member, whose antibodies were boosted following re-infection.

 

Rha MS, Jeong HW, Ko JH, et al. PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Immunity. 2021 Jan 12;54(1):44-52.e3. PubMed: https://pubmed.gov/33338412. Full-text: https://doi.org/10.1016/j.immuni.2020.12.002

More about SARS-CoV-2-specific CD8+ T cells. The highlights: 1) SARS-CoV-2-specific CD8+ T cells are effector memory cells in convalescent individuals; 2) CCR7+CD45RA+ cells are increased among SARS-CoV-2-specific cells in the late phase; 3) SARS-CoV-2-specific CD8+ T cells have fewer IFN-γ+ cells than flu-specific cells; 4) PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional.

 

Treatment

Qiao J, Li YS, Zeng R. SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science 18 Feb 2021: eabf1611. https://science.sciencemag.org/content/early/2021/02/17/science.abf1611.full

The authors designed and synthesized 32 new bicycloproline-containing protease inhibitors derived from either boceprevir or telaprevir, two (older) approved drugs for hepatitis C. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays and displayed good pharmacokinetic properties and safety in rats.

 

Raman AS, Barge VB, Darivenula AK, et al. A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in COVID-19 patients with Regular Intravenous Immunoglobulin Therapy. J Infect Dis. 2021 Feb 15:jiab098. PubMed: https://pubmed.gov/33585890 . Full-text: https://doi.org/10.1093/infdis/jiab098

Immunoglobulins for COVID-19? In this open-label, multicenter, randomized study on COVID-19 patients with moderate pneumonia in India, 100 patients were randomized 1:1 either to receive IVIG + standard of care (SOC) or SOC only. Duration of hospital stay was significantly shorter in the IVIG group compared to that of SOC alone (7,7 vs. 17,5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation were not significantly different (24% vs 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 vs 18 days).

 

Beyond Corona

Killock D. Unleashing the immune system against cancer. Nature 2020, published 10 December. Full-text: https://www.nature.com/articles/d42859-020-00076-7

2010 witnessed a second landmark in the development of immune-checkpoint inhibitors (ICIs) when ipilimumab became the first agent shown to prolong overall survival (OS) in patients with advanced-stage melanoma.

 

French

If you read French, read Stromboni C. Sous la pression du variant anglais, Dunkerque voit flamber l’épidémie de Covid-19. Le Monde 2021, published 20 February. Full-text : https://www.lemonde.fr/planete/article/2021/02/20/sous-la-pression-du-variant-anglais-dunkerque-voit-flamber-l-epidemie-de-covid-19_6070631_3244.html

Le taux d’incidence est trois fois plus élevé que la moyenne nationale, et la part du variant « B.1.1.7 » estimée à 72 % des cas. L’hôpital voit affluer de nombreux patients, souvent plus jeunes.

 

Dagorn G. Covid-19 : comment le variant B.1.1.7, apparu en Angleterre, menace de relancer l’épidémie en France. Le Monde 2021, published 19 February. Full-text : https://www.lemonde.fr/les-decodeurs/article/2021/02/19/comment-le-variant-britannique-menace-de-destabiliser-l-epidemie-en-france_6070563_4355770.html

En deux mois, ce variant a précipité l’Angleterre dans une nouvelle phase de l’épidémie, et pourrait provoquer une troisième vague tout aussi brutale en France.

 

20 February

Treatment

Paper of the Day

Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Feb 17. PubMed: https://pubmed.gov/33595634. Full-text: https://doi.org/10.1001/jama.2020.26848

The end of all speculations and hopes on immunomodulatory and anti-inflammatory properties of 25-hydroxyvitamin D? In this multicenter placebo-controlled trial from Brazil including 240 hospitalized patients with COVID-19 who were moderately to severely ill, vitamin D had no effect. A single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay.

 

Leaf DE, Ginde AA. Vitamin D3 to Treat COVID-19: Different Disease, Same Answer. JAMA. 2021 Feb 17. PubMed: https://pubmed.gov/33595641. Full-text: https://doi.org/10.1001/jama.2020.26850

Comment: according to Adit Ginde and David Leaf, several limitations should be considered. The main issue: the study was underpowered. And as always, further studies should determine whether vitamin D3 supplementation could be useful in other settings, dosages and patient populations. It is important to remain open-minded.

 

Epidemiology

Mwananyanda L, Gill CJ, MacLeod W, et al. Covid-19 deaths in Africa: prospective systematic postmortem surveillance study. BMJ. 2021 Feb 17;372:n334. PubMed: https://pubmed.gov/33597166. Full-text: https://doi.org/10.1136/bmj.n334

Do we vastly underestimate the impact of COVID-19 in Africa? Maybe. In this study of all deceased people of all ages at a University Hospital in Lusaka, Zambia, 70/364 (19,2%) were PCR positive. Most deaths in people with COVID-19 (51/70; 73%) occurred in the community; none had been tested for SARS-CoV-2 before death.

 

Variants

Liu Y, Liu J, Xia H, et al. Neutralizing Activity of BNT162b2-Elicited Serum – Preliminary Report. N Engl J Med. 2021 Feb 17. PubMed: https://pubmed.gov/33596352. Full-text: https://doi.org/10.1056/NEJMc2102017

Some more in vitro data on vaccine efficacy in SARS-CoV-2 variants. The authors produced different recombinant viruses, among them one with all the mutations found in the S gene in the B.1.351 lineage. After a single shot of BNT162b2 from Pfizer/BioNTech, neutralization of the B.1.351-spike virus was weaker by approximately two thirds. However, according to Yang Liu and colleagues, it remains unclear what this reduction means in terms of protection.

 

Wu K, Werner AP, Koch M, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine – Preliminary Report. N Engl J Med. 2021 Feb 17. PubMed: https://pubmed.gov/33596346. Full-text: https://doi.org/10.1056/NEJMc2102179

Same with Moderna’s vaccine. In vitro reductions by a factor of 2,7-6,4 in titers of neutralizing antibodies against the partial or full panel of mutations. Again, protection against B.1.351 remains to be determined.

Twitter: Some more in vitro data on vaccine efficacy in SARS-CoV-2 variants (in particular B.1.351), after BNT162b2 from Pfizer/BioNTech https://doi.org/10.1056/NEJMc2102017 and Moderna https://doi.org/10.1056/NEJMc2102179

 

Vaccines

Amit S, Regev-Yochay G, Afek A, et al. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. Lancet February 18, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00448-7/fulltext

Good news from Israel, showing substantial early reductions in SARS-CoV-2 infection and symptomatic COVID-19 rates following first mRNA vaccine dose administration. Using a retrospective cohort of 9109 vaccine-eligible HCWs, Sharon Amit and colleagues estimate adjusted rate reductions of SARS-CoV-2 infections of 30% and 75% for days 1–14 and days 15–28 after the first dose, respectively.

 

Olliaro P. What does 95% COVID-19 vaccine efficacy really mean? Lancet Inf Dis February 17, 2021. Full-text: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00075-X/fulltext

Important note of caution: using simple mathematics, Piero Olliaro explains that 94–95% efficacy does not mean that 95% of people are protected from disease with the vaccine. This distinction is all the more important as we do not know whether and how it could vary if the vaccines were deployed on populations with different exposures, transmission levels, and attack rates.

 

Clinical

Pifarré i Arolas H, Acosta E, López-Casasnovas G. et al. Years of life lost to COVID-19 in 81 countries. Sci Rep February 18, 2021. Full-text: https://www.nature.com/articles/s41598-021-83040-3

Some numbers: The total years life lost (YLL) as of January 06, 2021 is 20.507.518. In heavily affected countries this is between 2 and 9 times the median YLL of seasonal influenza or between a quarter and a half of heart disease. Three quarters of the YLL are borne by people dying before age 75. Men have lost 45% more years of life than women.

 

Lee JT, Hesse EM, Paulin HN, et al. Clinical and Laboratory Findings in Patients with Potential SARS-CoV-2 Reinfection, May-July 2020. Clin Infect Dis. 2021 Feb 18:ciab148. PubMed: https://pubmed.gov/33598716. Full-text: https://doi.org/10.1093/cid/ciab148

Reinfection within 90 days of the initial infection seems to be unlikely. Investigating 73 patients with potential SARS-CoV-2 reinfection in the US in May-July 2020, the authors ruled out reinfection in almost all cases.

 

Reuken PA, Stallmach A, Pletz MW et al. Severe clinical relapse in an immunocompromised host with persistent SARS-CoV-2 infection. Leukemia February 19, 2021. https://www.nature.com/articles/s41375-021-01175-8

Another case of a female patient with a rituximab-treated B cell lymphoma with severe relapse 4 months after moderate COVID-19. These days, hematologic therapies should be selected with caution, particularly those containing anti-CD20 antibodies.

 

19 February

Variants

Paper of the Day

Garcia-Beltran WF, Lam EC, St. Denis K, et al. Circulating SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. medRxiv 2021, posted 18 February. Full-text: https://doi.org/10.1101/2021.02.14.21251704

While many strains, such as B.1.1.7, B.1.1.298, or B.1.429, continue to be potently neutralized despite the presence of individual receptor-binding domain (RBD) mutations, other circulating SARS-CoV-2 variants escape vaccine-induced humoral immunity. The P.2 variant, which contains an E484K mutation within the RBD region, was capable of significantly reducing the neutralization potency of fully vaccinated individuals. Similarly, the P.1 strain, which has three RBD mutations, more effectively escaped neutralization. Finally, B.1.351 variants exhibited remarkable resistance to neutralization, largely due to three mutations in RBD but with a measurable contribution from non-RBD mutations. The magnitude of the effect is such that B.1.351 strains escape neutralizing vaccine responses like SARS-CoV-1 (SARS 2002/2003) and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. Alejandro Balazs, Wilfredo F. Garcia-Beltran and colleagues emphasize the need to develop broadly protective interventions against the evolving pandemic.

 

Resende PC, Delatorre D, Gräf T, et al. Evolutionary Dynamics and Dissemination Pattern of the SARS-CoV-2 Lineage B.1.1.33 During the Early Pandemic Phase in Brazil. Front. Microbiol 2021, 17 February. Full-text: https://www.frontiersin.org/articles/10.3389/fmicb.2020.615280/

Paula Cristina Resende et al. investigated the origin of the major and most widely disseminated SARS-CoV-2 Brazilian lineage B.1.1.33 that evolved from an ancestral clade, here designated B.1.1.33-like. The B.1.1.33-like lineage may have been introduced from Europe or may have arisen in Brazil in early February 2020 and a few weeks later gave origin to the lineage B.1.1.33.

 

Virology

Kistler KE, Bedford T. Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229e. Elife. 2021 Jan 19;10:e64509. PubMed: https://pubmed.gov/33463525. Full-text: https://doi.org/10.7554/eLife.64509

Kathryn Kistler and Trevor Bedford provide evidence that at least two of the seasonal coronaviruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively selected genetic changes in these viruses that enable them to escape recognition by the immune system.

 

Transmission

Kissler S, Fauver JR, Mack C, et al. Densely sampled viral trajectories suggest longer duration of acute infection with B.1.1.7 variant relative to non-B.1.1.7 SARS-CoV-2.  dash.harvard.edu 2021, accessed 17 February. Full-text: https://dash.harvard.edu/handle/1/37366884

B.1.1.7 may cause longer infections with similar peak viral concentration compared to non-B.1.1.7 variants. This extended duration may contribute to B.1.1.7 SARS CoV-2’s increased transmissibility. Yonatan Grad, Stephen Kissler and colleagues assessed longitudinal PCR tests performed in a cohort of 65 individuals infected with SARS-CoV-2 undergoing daily surveillance testing, including seven infected with B.1.1.7.

 

B.1.1.7 non-B.1.1.7
Mean duration of the
proliferation phase
5,3 days

(2,7, 7,8)

(90% credible interval)

2,0 days

(0,7, 3,3)

Mean duration of the
clearance phase
8,0 days

(6,1, 9,9)

6,2 days

(5,1, 7,1)

Mean overall duration of infection
(proliferation + clearance phase)
13,3 days

(10,1, 16,5)

8,2 days

(6,5, 9,7)

Peak viral concentration 19,0 Ct

(15,8, 22,0)

20,2 Ct

(19,0, 21,4)

log10 RNA copies/ml 8,5

(7,6, 9,4)

8,2

(7,8, 8,5)

 

 

Tan ZP, Silwal L, Bhatt SP, et al. Experimental characterization of speech aerosol dispersion dynamics. Sci Rep 11, 3953 (2021). Full-text: https://www.nature.com/articles/s41598-021-83298-7

Relative to sneezing and coughing, non-symptomatic aerosol-producing activities such as speaking are highly understudied. Here, Vrishank Raghav, Zu Puayen Tan and colleagues of Auburn University, US, delve into the details of jet phases and puff phases. One of their conclusions: speaking may represent a higher transmission risk than coughs and sneezes. Sneezing and coughing are singular events with a plume-front that passes by quickly, whereas speaking is a prolonged activity continuously producing plumes of aerosols.

 

Shriner SA, Ellis JW, Root JJ, Roug A, Stopak SR, Wiscomb GW, et al. SARS-CoV-2 exposure in escaped mink, Utah, USA. Emerg Infect Dis. 2021 Mar. Full-text: https://doi.org/10.3201/eid2703.204444

Free-range mink, presumed domestic escapees, exhibited high antibody titers, suggesting a potential SARS-CoV-2 transmission pathway to native wildlife. Interactions or shared resources between escaped mink and wild mink or other wildlife species represent potential transmission pathways for spillover of SARS-CoV-2 into wildlife and could lead to health consequences or establishment of new reservoirs in susceptible wildlife

 

Illingworth C, Hamilton W, Warne B, et al. Superspreaders drive the largest outbreaks of hospital onset COVID-19 infection. OSF Preprints 2021, posted 15 February. Full-text: https://osf.io/wmkn3/

Chris Illingworth et al. provides a detailed retrospective analysis of nosocomial SARS-CoV-2 transmission. Their data were consistent with a pattern of superspreading, where 20% of individuals caused 80% of transmission events.

 

Prevention

Arnold C. Covid-19: How the lessons of HIV can help end the pandemic. BMJ 2021, published 16 February. Full-text: https://doi.org/10.1136/bmj.n216

Harm reduction, which proved its worth in HIV/AIDS, can help stem the COVID-19 pandemic by helping people change their behavior. Carrie Arnold explains how.

 

Immunology

Neeland MR, Bannister S, Clifford V, et al. Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children. Nat Commun 12, 1084 (2021). Full-text: https://www.nature.com/articles/s41467-021-21414-x

Melanie Neeland et al. provide a comprehensive characterization of innate cells responding during the acute and convalescent phase of mild pediatric COVID-19. The authors report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. The authors found that infection in children is characterized by increased activation of neutrophils and low circulating proportions of all monocyte subsets, dendritic cells and natural killer cells, in contrast to SARS-CoV-2-infected adults who showed reductions in the non-classical monocyte fraction only.

 

Vaccine

Kupferschmidt K. Unprotected African health workers die as rich countries buy up COVID-19 vaccines. Science 2021, published 17 February. Full-text: https://www.sciencemag.org/news/2021/02/unprotected-african-health-workers-die-rich-countries-buy-covid-19-vaccines

While we are discussing how soon we can immunize everyone in the EU or the US, health workers continue to die in countries with zero doses administered so far.

 

18 February

Treatment

Paper of the Day

de Vries RD, Schmitz KS, Bovier Full-text:, et al. Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets. Science 2021, published 17 February. Full-text: https://doi.org/10.1126/science.abf4896

Matteo Porotto, Rory de Vries and colleagues propose a highly stable SARS-CoV-2 specific lipopeptide as a candidate antiviral for pre-exposure and early post-exposure prophylaxis for SARS-CoV-2 transmission in humans. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. The intranasal [SARSHRC-PEG4]2-chol peptide presented in this study is the first successful prophylaxis that prevents SARS-CoV-2 transmission in a relevant animal model, providing complete protection during a 24-hour period of intense direct contact.

 

Epidemiology

Emanuel EJ, Bright R, Gounder C. A Dismal Spring Awaits Unless We Slow the Spread of Covid-19. The New York Times 2021, published 17 February. Full-text: https://www.nytimes.com/2021/02/17/opinion/covid-19-precautions.html

How soon life returns to normal depends on what we do now.

 

Variants

Hodcroft EB, Domman DB, Snyder DJ, et al. Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677. medRxiv 2021, posted 14 January. Full-text: https://doi.org/10.1101/2021.02.12.21251658

Emma Hodcroft et al. describe 7 newly identified coronavirus variants in the US with a mutation in spike position 677 (also named after birds, Mockingbird to Yellowhammer). The authors promise to keep an eye on S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.

 

Hoffmann M, Arora P, Groß R, et al. SARS-CoV-2 variants B.1.351 and B.1.1.248: Escape from therapeutic antibodies and antibodies induced by infection and vaccination. medRxiv 2021, posted 11 February. Full-text: https://doi.org/10.1101/2021.02.11.430787

Stefan Pöhlmann, Markus Hoffmann and colleagues show that B1351 (first detected in South Africa) and P1 (alias B11248, first detected in Brazil) were partially (casirivimab, in REGN-COV2, Regeneron) or fully (bamlanivimab, Lilly) resistant to monoclonal antibodies and was less efficiently inhibited by serum/plasma from convalescent individuals or those vaccinated with the Pfizer-BioNTech vaccine.

 

Vaccines

Collier D, Ferreira I, Datir R, et al. Age-related heterogeneity in Neutralising antibody responses to SARS-CoV-2 following BNT162b2 vaccination. MedRxiv 2021, posted 16 February. Full-text: https://doi.org/10.1101/2021.02.03.21251054

Ravindra Gupta, Dami Collier and colleagues present a study of the immune response to the Pfizer/BioNTech vaccine in people aged 80 or older compared to younger people. Three weeks after the first dose a lower proportion of participants over 80 years old achieved an adequate neutralization titer of > 1:20 for 50% neutralization as compared to those under 80 (8/17 versus 19/24, p = 0,03); however, T cell responses were not different in those above or below 80 years. Following the second dose, 50% neutralizing antibody titers were above 1:20 in all individuals and there was no longer a difference by age.

 

Remmel A. COVID vaccines and safety: what the research says. Nature 2021, published 16 February. Full-text: https://www.nature.com/articles/d41586-021-00290-x

It is clear that coronavirus vaccines are safe and effective, but as more are rolled out, researchers are learning about the extent and nature of side effects.

 

Clinical

Purdy A, Ido F, Sterner S, et al. Myocarditis in COVID-19 presenting with cardiogenic shock: a case series. European Heart Journal – Case Reports, Volume 5, Issue 2, 16 February 2021. Full-text: https://academic.oup.com/ehjcr/article/5/2/ytab028/6138217

Adam Purdy and colleagues describe two cases of COVID-19 induced myocarditis presenting with cardiogenic shock. These cases highlight the importance of recognizing late presentation viral myocarditis secondary to COVID-19 infection, even in patients without underlying cardiac disease.

 

Lecler A, Cotton F, Lersy F, Kremer S, Héran F; SFNR’s COVID Study Group. Ocular MRI Findings in Patients with Severe COVID-19: A Retrospective Multicenter Observational Study. Radiology. 2021 Feb 16:204394. PubMed: https://pubmed.gov/33591889. Full-text: https://doi.org/10.1148/radiol.2021204394

Augustin Lecler et al. report a series of patients with severe COVID-19 presenting with abnormal MRI findings of the ocular globe, showing that 7% of patients with severe COVID-19 presented with one or several nodules of the posterior pole of the globe.

 

Severe COVID

Zeberg H, Pääbo S. A genomic region associated with protection against severe COVID-19 is inherited from Neandertals. PNAS 2021, published 2 March. Full-text: https://www.pnas.org/content/118/9/e2026309118

Svante Pääbo and Hugo Zeberg show that a haplotype on chromosome 12, which is associated with a ∼22% reduction in relative risk of becoming severely ill with COVID-19 when infected by SARS-CoV-2, is inherited from the Neanderthals. A great thanks to them!

 

Pediatrics

Blatz AM, Oboite M, Chiotos K, et al. Cutaneous findings in SARS-CoV-2-associated Multisystem Inflammatory Disease in Children (MIS-C). Open Forum Infectious Diseases, published 16 February. Full-text: https://doi.org/10.1093/ofid/ofab074

The differential diagnosis of pediatric rash in times of COVID.

 

German

If you read German, read Hecking C. Adiós Corona-Tristesse. Der Spiegel, 17 February. Full-text: https://www.spiegel.de/reise/europa/la-gomera-deutsche-im-corona-exil-adios-corona-tristesse-a-663cccff-1fcf-4372-a8e6-0b279836d7a4

Badewetter, offene Restaurants, Glasfaser-Internet: Hunderte Deutsche verbringen den Shutdown-Winter auf La Gomera. Hier können sie entspannen. Denn die Kanareninsel ist fast virusfrei – zumindest offiziell.

 


Find earlier Top 10 papers at https://covidreference.com/archive.


By Christian Hoffmann &
Bernd S. Kamps

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