Copy-editor: Rob Camp

9 December

Immunology

Galani IE, Rovina N, Lampropoulou V, et al. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat Immunol. 2020 Dec 4. PubMed: https://pubmed.gov/33277638. Full-text: https://doi.org/10.1038/s41590-020-00840-x

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage. This brilliant work suggests that this paradigm might not apply for COVID-19. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients, Ioanna-Evdokia Galani from Athens, Greece and colleagues show here that IFN-λ and type I IFN production are both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. By comparison, in 16 patients with influenza, IFN-λ and type I IFN were induced earlier, robustly, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. These data point to an un-tuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure. Fantastic work (take a look at the beautiful figures) which is among the 10 most important COVID-19 immunology papers of the year.

Poston D, Weisblum Y, Wise H, et al. Absence of SARS-CoV-2 neutralizing activity in pre-pandemic sera from individuals with recent seasonal coronavirus infection. Clin Infect Dis. 2020 Dec 3:ciaa1803. PubMed: https://pubmed.gov/33270134. Full-text: https://doi.org/10.1093/cid/ciaa1803

Daniel Poston and colleagues measured neutralizing activity against SARS-CoV-2 in pre-pandemic sera from 37 Scottish patients with prior PCR-confirmed seasonal coronavirus infection. While neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable. This data argues against a broad role for pre-existing protective humoral immunity against SARS-CoV-2.

Zheng J, Wang Y, Li K, Meyerholz DK, Allamargot C, Perlman S. SARS-CoV-2-induced immune activation and death of monocyte-derived human macrophages and dendritic cells. J Infect Dis. 2020 Dec 5:jiaa753. PubMed: https://pubmed.gov/33277988. Full-text: https://doi.org/10.1093/infdis/jiaa753

Infection of macrophages and dendritic cells potentially plays a major role in COVID-19 pathogenesis, even in the absence of productive infection. Jian Zheng and colleagues from Iowa demonstrate that SARS-CoV-2 infection of human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) was abortive but induced the production of multiple antiviral and pro-inflammatory cytokines. Despite the lack of efficient replication in MDMs, SARS-CoV-2 induced profound IFN-mediated cell death of host cells. Macrophage activation and death was not enhanced by exposure to low levels of convalescent plasma, suggesting that antibody-dependent enhancement of infection does not contribute to cell death.

Diagnostics

Yang S, Stanzione N, Uslan DZ, Garner OB, de St Maurice A. Clinical and Epidemiologic Evaluation of Inconclusive COVID-19 PCR Results Using a Quantitative Algorithm. Am J Clin Pathol. 2020 Dec 4:aqaa251. PubMed: https://pubmed.gov/33274731. Full-text: https://doi.org/10.1093/ajcp/aqaa251

Most PCR assays are designed to detect two or more specific target gene regions. An inconclusive result can rarely occur when only one of the targets is detected (< 1%). Shangxin Yang developed a quantitative algorithm to assess and interpret inconclusive PCR results, by combining laboratory, clinical, and epidemiologic data. They determined 5 (28%) of 18 (CDC assay) and 20 (39%) of 51 (TaqPath assay) cases to be false positive. Lowering the cycle threshold cut-off from 40 to 37 in the TaqPath assay resulted in a dramatic reduction of the false-positive rate to 14%. Testing of asymptomatic individuals was associated with a significantly higher probability of having a false-positive result.

Hodges G, Pallisgaard J, Schjerning Olsen AM, et al. Association between biomarkers and COVID-19 severity and mortality: a nationwide Danish cohort study. BMJ Open. 2020 Dec 2;10(12):e041295. PubMed: https://pubmed.gov/33268425. Full-text: https://doi.org/10.1136/bmjopen-2020-041295

In a large study from Denmark, analyzing all patients aged ≥ 18 years admitted to hospital with COVID-19 from 27th of February to 1st of May 2020, with available biochemistry data, of the 1310 patients admitted to hospital (54,6% men; median age 73,6 years), 352 (26,9%) experienced the composite endpoint and 263 (20,1%) died. Elevated levels of CRP, leucocytes, procalcitonin, urea, troponins and D-dimer, and low levels of eGFR were associated with higher standardized absolute risk of death/ICU admission within 30 days.

Clinical

Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Persistent symptoms 1.5-6 months after COVID-19 in non-hospitalised subjects: a population-based cohort study. Thorax. 2020 Dec 3:thoraxjnl-2020-216377. PubMed: https://pubmed.gov/33273028. Full-text: https://doi.org/10.1136/thoraxjnl-2020-216377

The authors from Norway conducted a postal survey at the end of June 2020 among non-hospitalized patients, about 1–4 months after the positive PCR test. Of the 451 subjects (48%) who responded to the survey, > 50% (women 53%, men 67%) had no symptoms 1.5–6 months after symptom onset while 16% reported dyspnea, 12% loss/disturbance of smell, and 10% loss/disturbance of taste. Co-morbidities and a high symptom load during the acute phase were associated with persistent symptoms. At 1.5–6 months, however, there was no difference in symptoms according to length of time since COVID-19 onset. Note that these patients were non-hospitalized.

Arnold DT, Hamilton FW, Milne A, et al. Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort. Thorax. 2020 Dec 3:thoraxjnl-2020-216086. PubMed: https://pubmed.gov/33273026. Full-text: https://doi.org/10.1136/thoraxjnl-2020-21608633271595

Hospitalized patients may differ. In this observational study from the UK, at 8–12 weeks post-admission, 163 survivors were invited to a systematic clinical follow-up. Of 131 participants, 110 attended the follow-up clinic. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) and limitations in reported physical ability. However, clinically significant abnormalities in chest radiograph, exercise tests, blood tests and spirometry were less frequent (35%), especially in patients not requiring supplementary oxygen during their acute infection (7%).

Treatment

Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020 Dec 2:S1201-9712(20)32506-6. PubMed: https://pubmed.gov/33278625. Full-text: https://doi.org/10.1016/j.ijid.2020.11.191

Ivermectin, an inexpensive, over-the-counter medicine, is widely used as a preventative against COVID-19 in many South/Latin American countries. However, the evidence that ivermectin protects from COVID-19 is scant. This group from Bangladesh conducted a randomized, double-blind, placebo-controlled trial of oral ivermectin alone or in combination with doxycycline compared with placebo among 72 hospitalized patients. Virological clearance was earlier in the 5-day ivermectin treatment arm versus the placebo group (9,7 days vs. 12,7 days; p = 0.02); but not in the ivermectin + doxycycline arm (11,5 days; p = 0.27). There were no severe adverse drug events recorded in the study. According to the authors, “larger trials will be needed to confirm these preliminary findings”.

Honjo K, Russel RM, Li R, et al. Convalescent Plasma-Mediated Resolution of COVID-19 in a Patient with Humoral Immunodeficiency. Cell Rep Med December 05, 2020. Full-text: https://doi.org/10.1016/j.xcrm.2020.100164

Interesting case report. Convalescent plasma (CP) is widely used to treat COVID-19, but without formal evidence of efficacy. Here, Kazuhito Honjo and colleagues report the beneficial effects of CP in a severely ill COVID-19 patient with prolonged pneumonia and CLL, who was unable to generate an antiviral antibody response of her own. On day 33 after becoming symptomatic, the patient received CP containing high-titer neutralizing antibodies, defervesced and improved clinically within 48 hours, and was discharged on day 37. Hence, when present in sufficient quantities, NAbs to SARS-CoV-2 may have clinical benefit even if administered relatively late in the disease course.

Pediatrics

Stowe J, Smith H, Thurland T, et al. Stillbirths During the COVID-19 Pandemic in England, April-June 2020. JAMA. Published online December 7, 2020. Full-text: https://doi.org/10.1001/jama.2020.21369

Julia Stowe and colleagues used national and regional hospitalization data in England to assess the risk of stillbirths during the COVID-19 pandemic. Contrasting previous reports from single hospitals, there was no evidence of any increase in stillbirths regionally or nationally when compared with the same months in the previous year and despite variable community SARS-CoV-2 incidence rates in different regions. This data is reassuring given the concerns about patients, including pregnant women, receiving fewer services or being hesitant to access health care during the pandemic.

French

If you read French, read Lemarié A, Cazi E. Covid-19 : à l’hôpital, l’épineuse question du « tri » des patients. Le Monde 2020, published 8 December. Full-text : https://www.lemonde.fr/planete/article/2020/12/07/covid-19-a-l-hopital-l-epineuse-question-du-tri-des-patients_6062435_3244.html

Avec l’épidémie due au coronavirus, les situations où les soignants ont dû prioriser les malades à prendre en charge se sont multipliées, au-delà des services de réanimation.

Thibault H. Covid-19 : comment une traque méthodique et intrusive a permis à la Corée du Sud de maîtriser le virus. Le Monde 2020, published 8 December. Full-text : https://www.lemonde.fr/planete/article/2020/12/08/covid-19-comment-une-traque-methodique-et-intrusive-a-permis-a-la-coree-du-sud-de-maitriser-le-virus_6062564_3244.html

Ce pays de 52 millions d’habitants est parvenu à limiter le bilan à 549 morts depuis le début de la pandémie, tout en maintenant la liberté de circulation.

Audureau W. Covid-19 : comparer les restrictions en France à celles d’autres pays donne une image déformée de la réalité. Le Monde 2020, published 8 December. Full-text : https://www.lemonde.fr/les-decodeurs/article/2020/11/30/covid-19-gare-aux-comparaisons-hatives-entre-les-restrictions-en-france-et-dans-d-autres-pays_6061696_4355770.html

La stratégie sanitaire de la France est souvent opposée à celle d’autres pays, comme l’Argentine, l’Espagne et la Suède. Des parallèles périlleux.

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