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By Christian Hoffmann &
Bernd S. Kamps

 

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24 September

Epidemiology

Brett TS, Rohani P. Transmission dynamics reveal the impracticality of COVID-19 herd immunity strategies. Proc Natl Acad Sci U S A. 2020 Sep 22:202008087. PubMed: https://pubmed.gov/32963094. Full-text: https://doi.org/10.1073/pnas.2008087117

Various governments have entertained the idea of achieving herd immunity through natural infection as a means of ending the long-term threat of COVID-19. This has provoked alarm in sections of the public health community. This work confirms that this alarm is well founded: if social distancing is maintained at a fixed level, hospital capacity needs to be much larger than presently available to achieve herd immunity without exceeding capacity; otherwise, the final outbreak size will be insufficient to achieve herd immunity.

 

Virology

Muñoz-Fontela C, Dowling WE, Funnell SGP, et al. Animal models for COVID-19. Nature. 2020 Sep 23. PubMed: https://pubmed.gov/32967005. Full-text: https://doi.org/10.1038/s41586-020-2787-6

Mice, hamsters, ferrets, minks, cats, pigs, fruit bats, monkeys: a variety of murine models for mild and severe COVID-19 have been described, or are under development. All will be useful for vaccine and antiviral evaluation and some share features with the human disease. According to this review (performed by a huge international collaboration), however, no murine model at present recapitulates all aspects of human COVID-19, especially unusual features such as the pulmonary vascular disease and hyperinflammatory syndromes observed in adults and children, respectively.

 

Immunology

Huang J, Hume AJ, Abo KM, et al. SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response. Cell Stem Cell September 18, 2020. Full-text: https://doi.org/10.1016/j.stem.2020.09.013

Jessie Huang and colleagues present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2, using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. Their model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.

 

Diagnostics

The National SARS-CoV-2 Serology Assay Evaluation Group. Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison. Lancet September 23, 2020.  Full-text: https://doi.org/10.1016/S1473-3099(20)30634-4

A benchmark study in immunoassay assessment. This UK group did a head-to-head assessment of five SARS-CoV-2 IgG assays, including four commercial assays (Abbott, LIAISON/DiaSorin, Elecsys/Roche, and Siemens), plus a novel in-house 384-well/Oxford ELISA in 976 (!) pre-pandemic blood samples and 536 (!) blood samples with confirmed SARS-CoV-2 infection. All assays had a high sensitivity (92.7-99.1%) and specificity (98.7-99.9%). The most sensitive test assessed was the in-house ELISA. The Siemens assay and Oxford immunoassay achieved 98% sensitivity/specificity without further optimization. However, a limitation of this work was the small number of pauci-symptomatic and asymptomatic cases analyzed.

 

Yang OO, Ibarrondo FJ. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. Reply. N Engl J Med. 2020 Sep 23;383(16):10.1056/NEJMc2027051#sa4. PubMed: https://pubmed.gov/32966713. Full-text: https://doi.org/10.1056/NEJMc2027051

The controversy about antibody kinetics in patients with mild COVID-19 is ongoing. Some groups have reported a rapid decline, some have observed stability. According to the authors, several factors probably explain these apparent contradictions, including varying methods used and the heterogeneity among the study participants.

 

Clinical

Pereyra D, Heber S, Jilma B, Zoufaly A, Assinger A. Routine haematological parameters in COVID-19 prognosis. The Lancet Hematology, 7, ISSUE 10, e709, October 01, 2020.

A “negative” study is sometimes valuable: After hundreds of studies emphasizing the prognostic values of clinical and laboratory chemical parameters in hospitalized COVID-19 patients, it’s important to hear that it’s not that easy (at least in Austria). David Pereyra and colleagues analyzed data from 210 consecutive hospitalized patients with COVID-19. In this cohort, hematological parameters such as thrombocytes, neutrophil-to-lymphocyte ratio or d-dimers did not allow prediction of patient outcome. These routine parameters, despite giving guidance on the overall health of the patient, might not always accurately indicate COVID-19-related complications.

 

Rubin R. As Their Numbers Grow, COVID-19 “Long Haulers” Stump Experts. JAMA September 23, 2020. Full-text: https://doi.org/10.1001/jama.2020.17709

In this nice perspective Rita Rubin summarizes current knowledge on people who still haven’t fully recovered from COVID-19 weeks or even months after symptoms first arose. Fatigue appears to be the most common symptom, followed by muscle or body aches, shortness of breath or difficulty breathing, and difficulty concentrating.

 

Treatment

Doi Y, Hibino M, Hase R, et al. A prospective, randomized, open-label trial of early versus late favipiravir in hospitalized patients with COVID-19. Antimicrob Agents Chemother. 2020 Sep 21:AAC.01897-20. PubMed: https://pubmed.gov/32958718. Full-text: https://doi.org/10.1128/AAC.01897-20

No effect of viral clearance with favipiravir. In this RCT, 69 patients with asymptomatic to mild COVID-19 were randomly assigned to early or late favipiravir therapy (same regimen starting day 1 or day 6). Viral clearance occurred within 6 days in 67% and 56% (adjusted hazard ratio 1.42; 95% CI 0.76–2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, time to defervescence (no fever) was 2.1 days and 3.2 days (aHR, 1.88; 95%CI 0.81–4.35). During therapy, 84% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by RT-PCR by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred to any of the patients in either treatment group during the 28-day participation.

 

Baicus C, Pinte L, Stoichitoiu LE, Badea C. Hydroxychloroquine for prophylaxis of COVID-19 physicians survey: Despite lack of evidence, many would take or give to dear ones, and despite the perceived necessity of an RCT, few would participate. J Eval Clin Pract. 2020 Sep 21. PubMed: https://pubmed.gov/32955801. Full-text: https://doi.org/10.1111/jep.13484

It does not seem entirely impossible that the authors made themselves rather unpopular with their colleagues, publishing the results of this survey performed in early April. A total of 784 Romanian doctors were interviewed about their thoughts on HCQ. Despite the lack of evidence at that time, 36% considered the evidence as existing, and 22% were ready to take or to give hydroxychloroquine prophylactically to family. Almost all (92%) considered an RCT necessary, but only 42% were willing to participate. There was only a very weak correlation (Kendall’s tau _b = 0.255, P < 0.001) between the belief that an RCT is necessary and the willingness to enroll in such an RCT. In any case, the toughest paper title of the day (the discussion is remarkably short).