Outstanding Papers

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If you don’t read anything, read at least the following 22 papers.

  1. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. PubMed: https://pubmed.gov/32109013. Full-text: https://doi.org/10.1056/NEJMoa2002032 (Outstanding)


  1. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17. PubMed: https://pubmed.gov/32182409. Fulltext: https://doi.org/10.1056/NEJMc2004973 (Outstanding)


  1. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18. PubMed: https://pubmed.gov/32187464. Fulltext: https://doi.org/10.1056/NEJMoa2001282 (Outstanding)


  1. Yu F, Yan L, Wang N, et al. Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients. Clin Infect Dis. 2020 Mar 28. PubMed: https://pubmed.gov/32221523. Fulltext: https://doi.org/10.1093/cid/ciaa345 (Outstanding) | Is sputum sufficient for diagnosis? In a total of 323 samples from 76 pts, the average viral load in sputum (17429 copies/test) was significantly higher than in throat swabs (2552) and nasal swabs (651). Viral load was also higher in the early and progressive stages than in the recovery stage. If these data are confirmed, collection of specimen would be much easier.


  1. Wölfel R, Corman VM, Guggemos W. et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020, April 1. Full-text: https://doi.org/10.1038/s41586-020-2196-x (Outstanding) | Important work, showing active virus replication in upper respiratory tract tissues (in contrast to SARS). In a detailed virological analysis of nine cases, pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 108 RNA copies per throat swab, day 4), more than 1000 times higher than seen with SARS-CoV. Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples, in spite of high virus RNA concentration. Blood and urine never yielded virus. Shedding of viral RNA from sputum continued after the end of symptoms.


  1. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-1448. PubMed: https://pubmed.gov/32132184. Full-text: https://doi.org/10.1126/science.abb2762 (Outstanding) | Using cryo–electron microscopy, it is shown how SARS-CoV-2 binds to human cells. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Authors present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. The structures provide a basis for the development of therapeutics targeting this crucial interaction.


  1. Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. 2020 May;581(7807):215-220. PubMed: https://pubmed.gov/32225176. Full-text: https://doi.org/10.1038/s41586-020-2180-5 (Outstanding) | To elucidate the SARS-CoV-2 RBD and ACE2 interaction at a higher resolution/atomic level, authors used X-ray crystallography. Binding mode was very similar to SARS-CoV, arguing for convergent evolution of both viruses. The epitopes of two SARS-CoV antibodies targeting the RBD were also analysed with the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.


  1. Leung NHL, Chu DKW, Shiu EYC, et al. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nat Med. 2020 May;26(5):676-680. PubMed: https://pubmed.gov/32371934. Full-text: https://doi.org/10.1038/s41591-020-0843-2 (Outstanding) | Do face masks work? Yes, but it depends. This important study from Hong Kong (performed 2013-16) quantified virus in respiratory droplets and aerosols in exhaled breath. In total, 111 participants (infected with seasonal coronavirus, influenza or rhinovirus) were randomized to wear (or not) a simple surgical face mask. Results suggested that masks could be used by ill people to reduce onward transmission. But note the small numbers: in respiratory droplets, seasonal coronavirus was found in 0/11 droplets (aerosols: 0/11) from participants wearing face masks, compared to 3/10 (aerosols: 4/10) without masks. Influenza viruses were detected in 1/27 (aerosols 6/27!) with face masks, compared to 6/23 (8/23) without. For rhinovirus, there were no significant differences at all. Of note, authors also identified virus in some participants who did not cough at all during the 30-min exhaled breath collection, suggesting droplet and aerosol routes of transmission from individuals with no obvious signs or symptoms.


  1. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020 Apr 15. PubMed: https://pubmed.gov/32296168. Full-text: https://doi.org/10.1038/s41591-020-0869-5 (Outstanding) | Important work on viral shedding: this may begin 2 to 3 days before the appearance of the first symptoms and infectiousness profile may more closely resemble that of influenza than that of SARS. Analyzing a total of 414 throat swabs in 94 patients, the highest viral load was found at the time of symptom onset. Infectiousness started from 2.3 days (95% CI, 0.8–3.0 days) before symptom onset and peaked at 0.7 days (95% CI, −0.2–2.0 days) before symptom onset. The authors estimated that 44% (95%CI 25-69%) of secondary cases were infected during the index cases’ presymptomatic stage. Infectiousness was estimated to decline quickly within 7 days.


  1. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020 Jun;26(6):845-848. PubMed: https://pubmed.gov/32350462. Full-text: https://doi.org/10.1038/s41591-020-0897-1 (Outstanding) | One of the largest studies to date, reporting on acute antibody responses (using magnetic chemiluminescence enzyme immunoassay) in 285 patients (mostly non-severe COVID-19, 39 treated at ICU). Within 19 days after symptom onset, 100% of patients tested positive for antiviral IgG. Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. The median day of seroconversion for both IgG and IgM was 13 days post-symptom onset. No association between plateau IgG levels and clinical characteristics of the patients was found.


  1. Wang C, Li W, Drabek D, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun. 2020 May 4;11(1):2251. PubMed: https://pubmed.gov/32366817. Full-text: https://doi.org/10.1038/s41467-020-16256-y (Outstanding) | The first report of a human monoclonal antibody that neutralizes SARS-CoV-2. 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition. This antibody could be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2.


  1. Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: Current State of the Science. 2020 Jun 16;52(6):910-941. PubMed: https://pubmed.gov/32505227. Full-text: https://doi.org/10.1016/j.immuni.2020.05.002 (Outstanding) | Brilliant review on the current knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death.


  1. Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. 2020 Jun 25;181(7):1489-1501.e15. PubMed: https://pubmed.gov/32473127. Full-text: https://doi.org/10.1016/j.cell.2020.05.015 (Outstanding) | Cellular response is a major knowledge gap. This important study identified circulating SARS-CoV-2−specific CD8 and CD4 T cells in around 70 and 100% of 20 COVID-19 convalescent patients, respectively. CD4 T cell responses to the spike protein were robust and correlated with the magnitude of IgG titers. Of note, the authors detected SARS-CoV-2−reactive CD4 T cells in 40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating seasonal coronaviruses and SARS-CoV-2.


  1. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. 2020 May 28;181(5):1036-1045.e9. PubMed: https://pubmed.gov/32416070. Full-text: https://doi.org/10.1016/j.cell.2020.04.026
    (Outstanding) | Incredible in-depth analysis of host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. Data consistently revealed a unique and inappropriate inflammatory response to SARS-CoV-2 which is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. It is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. The authors propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation.


  1. Zhang X, Tan Y, Ling Y, et al. Viral and host factors related to the clinical outcome of COVID-19. 2020 May 20. PubMed: https://pubmed.gov/32434211. Full-text: https://doi.org/10.1038/s41586-020-2355-0 (Outstanding) | Viral variants do not affect outcome. This important study on 326 cases found at least two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Patients infected with these different clades did not exhibit significant difference in clinical features, mutation rate or transmissibility. Lymphocytopenia, especially a reduced CD4+ and CD8+ T cell counts upon admission, was predictive of disease progression. High levels of IL-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age, lymphocytopenia, and its associated cytokine storm.


  1. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. 2020 May 22;369:m1985. PubMed: https://pubmed.gov/32444460. Full-text: https://doi.org/10.1136/bmj.m1985
    (outstanding) | Clinical data from 20,133 patients, admitted to (or diagnosed in) 208 acute care hospitals in the UK until April 19. Median age was 73 years (interquartile range 58-82) and 60% were men. Comorbidities were common, namely chronic cardiac disease (31%), diabetes (21%), non-asthmatic chronic pulmonary disease (18%). Overall, 41% of patients were discharged alive, 26% died, and 34% continued to receive care. 17% required admission to high dependency or intensive care units; of these, 28% were discharged alive, 32% died, and 41% continued to receive care. Of those receiving mechanical ventilation, 17% were discharged alive, 37% died, and 46% remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital.


  1. Somsen GA, van Rijn C, Kooij S, Bem RA, Bonn D. Small droplet aerosols in poorly ventilated spaces and SARS-CoV-2 transmission. Lancet Respir Med. 2020 May 27. PubMed: https://pubmed.gov/32473123. Full-text: https://doi.org/10.1016/S2213-2600(20)30245-9 (Outstanding) | Doors and windows open! Important study, analyzing droplet production due to coughs and speech by measuring the droplet size distribution, travel distance and velocity, and the airborne time in relation to the level of air ventilation (no ventilation, mechanical ventilation only, and mechanical ventilation supported by the opening of an entrance door and a small window). In the best ventilated room, after 30 s the number of droplets had halved, whereas with no ventilation this took about 5 min!


  1. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Jun 3:NEJMoa2016638. PubMed: https://pubmed.gov/32492293. Full-text: https://doi.org/10.1056/NEJMoa2016638 (Outstanding) | In total, 821 asymptomatic participants were randomized to receive hydroxychloroquine or placebo within 4 days after exposure (88% with a high-risk exposure). Incidence of confirmed SARS-CoV-2 was 11.8% with CQ and 14.3% with placebo. Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported. This is bad news because after high-risk or moderate-risk exposure to Covid-19, HCQ did not prevent infection when used as postexposure prophylaxis within 4 days after exposure.


  1. Day T, Gandon S, Lion S, et al. On the evolutionary epidemiology of SARS-CoV-2. Curr Biol 2020, June 11. Full-text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287426
    (Outstanding) | Outstanding essay about what little is currently known about the evolution of SARS-CoV-2. At present, there is a lack of compelling evidence that any existing variants impact the progression, severity, or transmission of COVID-19 in an adaptive manner. The authors discuss the potential evolutionary routes that SARS-CoV-2 might take and dispel some of the current misinformation that is circulating in the media.


  1. Major J, Crotta S, Llorian M, et al. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. 2020 Jun 11:eabc2061. PubMed: https://pubmed.gov/32527928. Full-text: https://doi.org/10.1126/science.abc2061 (Outstanding) | Key message: Interferon may be helpful during early infection and harmful at later stages. IFN-λ mainly signals in epithelia, inducing localized antiviral immunity, and has a key role in the reduction of epithelial proliferation and differentiation during lung repair. In animal and cell experiments, the authors show that IFN-induced p53 directly reduces epithelial proliferation and differentiation, increasing disease severity and susceptibility to bacterial superinfections. Excessive or prolonged IFN production may aggravate viral infection by impairing lung epithelial regeneration.


  1. Pfeifer M, Ewig S, Voshaar T, et al. Position Paper for the State-of-the-Art Application of Respiratory Support in Patients with COVID-19. Respiration. 2020 Jun 19:1-21. PubMed: https://pubmed.gov/32564028. Full-text: https://doi.org/10.1159/000509104 (Outstanding) | Important statements including observations about the pathophysiology of acute respiratory failure (ARF). Pulmonary damage in advanced COVID-19 often differs from acute respiratory distress syndrome (ARDS). Two types (type L and type H) are differentiated, corresponding to early- and late-stage lung damage. This differentiation should be taken into consideration in respiratory support. Based on current knowledge, inhalation therapy, nasal high-flow therapy (NHF), continuous positive airway pressure (CPAP), or non-invasive ventilation (NIV) can be performed without an increased risk of infection to staff if PPE is provided. In ARF, NIV should be carried out in an intensive care unit or a comparable setting by experienced staff. If the ARF progresses under CPAP/NIV, intubation should be implemented without delay in patients who do not have a “do not intubate”.


  1. Bouhaddou M, Memon D, Meyer B, et al. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. 2020 Jun 28:S0092-8674(20)30811-4. PubMed: https://pubmed.gov/32645325. Full-text: https://doi.org/10.1016/j.cell.2020.06.034 (Outstanding) | Nothing to do next weekend? Then read this incredible work of 66 pages (> 400 references!). In brief: proteomics approaches that globally quantify changes in protein abundance and phosphorylation represent a powerful tool to elucidate mechanisms of viral pathogenesis by providing a snapshot of how cellular pathways and processes are rewired upon infection. Using a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, the 78 (!) authors present the global phosphorylation and protein abundance landscape of SARS-CoV-2 infection, map phosphorylation changes to disrupted kinases and pathways, and use these profiles to find drugs with the potential to treat SARS-CoV-2 infection. In total, 87 compounds (10 FDA-approved drugs) were identified.