Top 10: October 6

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By Christian Hoffmann &
Bernd S. Kamps

 

This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing the text to give it early visibility.

6 October

Epidemiology

Hicks SM, Pohl K, Neeman T, et al. A dual antigen ELISA allows the assessment of SARS-CoV-2 antibody seroprevalence in a low transmission setting. J Infect Dis. 2020 Oct 3:jiaa623. PubMed: https://pubmed.gov/33009908 . Full-text: https://doi.org/10.1093/infdis/jiaa623

Low prevalence in Australia. Using an ELISA-based approach that combines IgG responses to both the Nucleocapsid and Spike-receptor binding domain antigens, the authors have shown that excellent sensitivity and specificity can be achieved in low prevalence areas. Frequency of antibodies in a cohort of 2,991 elective surgery patients providing blood samples at 10 hospital sites across Australia in June-July 2020 was only 0.28% (0 to 1.15%).

 

Immunology

Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell October 05, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.10.001

CD4+ T cells are essential for adaptive anti-viral immunity. However, due to the rarity of SARS-CoV-2-specific cells in the total CD4+ T cell populations, signals from these cells are likely to be masked by the relative abundance of other non-antigen specific CD4+ T cells. Benjamin J. Meckiff from La Jolla (CA, USA) provide important insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells by performing single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. They found remarkable heterogeneity in the nature of CD4+ T cell subsets that are reactive to SARS-CoV-2 and other respiratory viruses, and across individual patients with differing severity of COVID-19. In 18 hospitalized patients (compared to 22 non-hospitalized patients), proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2 were increased, while the proportion of SARS-CoV-2-reactive regulatory T cells (TREG) were reduced. Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T helper (TH)1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells.

 

Transmission

Schwartz NG, Moorman AC, Makaretz A, et al. Adolescent with COVID-19 as the Source of an Outbreak at a 3-Week Family Gathering — Four States, June–July 2020. MMWR Morb Mortal Wkly Rep. ePub: 5 October 2020. Full-text: http://dx.doi.org/10.15585/mmwr.mm6940e2

Children can serve as the source for COVID-19 outbreaks, even when their symptoms are mild. In this outbreak that occurred during a 3-week family gathering of five households, an adolescent aged 13 years was the suspected primary patient. Among the 14 persons who stayed in the same house, 12 experienced symptoms. Of note, none of the additional six family members who maintained outdoor physical distance without face masks during two longer visits (10 and 3 hours) to the family gathering developed symptoms.

 

Diagnostics

Procop GW, Brock JE, Reineks EZ, et al. A Comparison of Five SARS-CoV-2 Molecular Assays With Clinical Correlations. Am J Clin Pathol. 2020 Oct 5:aqaa181. PubMed: https://pubmed.gov/33015712 . Full-text: https://doi.org/10.1093/ajcp/aqaa181

A total of 239 specimens (168 contained SARS-CoV-2) were tested by five nucleic acid amplification test methods. The assays that lacked a nucleic acid extraction step produced more false-negative reactions than assays that included this step. The false-negative rates were 0 % for the CDC 2019 nCoV Real-Time RT-PCR Diagnostic Panel, 3.5% for TIB MOLBIOL/Roche Assay, 2.4% for Xpert Xpress SARS-CoV-2 (Cepheid), 11.9% for Simplexa COVID-19 Direct Kit (DiaSorin), and 16.7% for the ID Now COVID-19 (Abbott). Most false negatives were seen in patients with low viral loads.

 

Yilmaz A, Marklund E, Andersson M, et al. Upper respiratory tract levels of SARS-CoV-2 RNA and duration of viral RNA shedding do not differ between patients with mild and severe/critical COVID-19. J Infect Dis. 2020 Oct 6:jiaa632. PubMed: https://pubmed.gov/33020822 . Full-text: https://doi.org/10.1093/infdis/jiaa632

Aylin Yilmaz and colleagues from Gothenburg/Sweden have analyzed viral RNA loads over time from nasopharynx/throat in 56 patients with mild and severe/critical COVID-19. Neither the viral RNA loads in the upper respiratory tract, nor the time to viral RNA clearance differed between patients with mild or severe/critical disease.

 

Clinical

Grasselli G, Greco M, Zanella A, et al. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. JAMA Intern Med 2020; 180(10):1345-1355. Full-text: https://doi.org/10.1001/jamainternmed.2020.3539

An update from Lombardy/Italy. This large retrospective, observational cohort study included 3,988 consecutive critically ill patients referred for ICU admission until April 22, 2020. Median age was 63 (IQR 56-69) and 79.9% were men. At ICU admission, 87.3% required invasive mechanical ventilation (IMV). The median length of IMV was 10 (IQR, 6-17) days. In the subgroup of the first 1,715 patients, as of May 30, 2020, 836 (48.7%) had died in the ICU. Independent risk factors associated with mortality included older age (hazard ratio 1.75), male sex (1.57), high fraction of inspired oxygen (1.14), high positive end-expiratory pressure (1.04) and history of chronic obstructive pulmonary disease (1.68), hypercholesterolemia (1.25), and type 2 diabetes (1.18).

 

Treatment

RECOVERY Collaborative Group, and others. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet October 5, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)32013-4

After preliminary results were made public on June 29, 2020, this is now the full paper on the lopinavir/r arm in the RECOVERY trial. Between March 19, 2020, and June 29, 2020, 1,616 patients admitted to hospital were randomly allocated to receive lopinavir/r and 3,424 patients to receive usual care. Lopinavir/r had no benefit. Overall, 374 (23%) patients allocated to lopinavir/r and 767 (22%) patients allocated to usual care died within 28 days. Results were consistent across all prespecified subgroups. No significant difference in time until discharge alive from hospital (median 11 days in both groups) or the proportion of patients discharged from hospital alive within 28 days was found. Although the lopinavir/r, dexamethasone, and hydroxychloroquine groups have now been stopped, the RECOVERY trial continues to study the effects of azithromycin, tocilizumab, convalescent plasma, and REGN-CoV2 (see our Trump special yesterday).

 

Wilt TJ, Kaka AS, MacDonald R, Greer N, Obley A, Duan-Porter W. Remdesivir for Adults With COVID-19 : A Living Systematic Review for an American College of Physicians Practice Points. Ann Intern Med Oct 5, 2020. PubMed: https://pubmed.gov/33017170 . Full-text: https://doi.org/10.7326/M20-5752

And what about remdesivir? This review of published studies through 31 August 2020 (4 RCTs) indicates that in hospitalized adults with COVID-19, remdesivir “probably” improves recovery and reduces serious adverse events and may reduce mortality and time to clinical improvement, although with little to no difference in hospital length of stay. Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity.

 

Jose Luis Rodriguez-Garcia, Gines Sanchez-Nievas, Juan Arevalo-Serrano, Cristina Garcia-Gomez, Jose Maria Jimenez-Vizuete, Elisa Martinez-Alfaro. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study. Rheumatology, October 6, 2020. Full-text: https://doi.org/10.1093/rheumatology/keaa587

Janus kinase (JAK) inhibitors such as baricitinib may be beneficial in treating SARS-CoV-2 infection by inhibiting ACE2-mediated endocytosis. This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia who received lopinavir/ritonavir and HCQ plus either corticosteroids (controls, n=50) or corticosteroids and baricitinib (n=62). A higher proportion of patients required supplemental oxygen both at discharge (62% vs 26%) and 1 month later (28% vs 13%) in the control group, providing the first evidence for a possible synergistic effect of baricitinib and corticosteroids in SARS-CoV-2 pneumonia.

 

Pediatrics

Anil R. Maharaj, PhD; Huali Wu, PhD; Christoph P. Hornik, et al. Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019. JAMA Pediatr October 5, 2020; 174(10):e202422. Full-text: https://doi.org/10.1001/jamapediatrics.2020.2422

This pharmacokinetic simulation study estimates appropriate pediatric-specific dosing regimens for remdesivir. The pediatric dosing for Ebola virus disease (EVD), consisting of 5 mg/kg intravenous load (day 1) followed by 2.5 mg/kg daily (≥day 2), may be too high in children younger than 12 years (geometric mean plasma AUC 0 to infinity values were 147% to 256% of the adult value for simulations based on dosing recommendations for EVD).




French

If you read French, read Covid-19 : en Ile-de-France, plus de 40 % des lits en réanimation sont occupés par des patients contaminés. Le Monde 2020, published 6 October. Full-text : https://www.lemonde.fr/planete/article/2020/10/06/en-ile-de-france-plus-de-40-des-lits-en-reanimation-sont-occupes-par-des-malades-du-covid-19_6055013_3244.html

Sur 2 393 patients Covid-19 hospitalisés dans les huit départements d’Ile-de-France, 449 ont été admis en service de réanimation, a annoncé mardi l’ARS.