Severe COVID-19 is associated with an overactive inflammatory response mediated by macrophages. Here, we analyzed the phenotype and function of neutrophils in COVID-19 patients. We found that neutrophils from severe COVID-19 patients express high levels of CD11b and CD66b, spontaneously produce CXCL8 and CCL2 and show a strong association with platelets. Production of CXCL8 correlated with plasmatic concentrations of LDH and D-dimer. Whole blood assays revealed that neutrophils from severe COVID-19 patients show a clear association with IgG immune complexes. Moreover, we found that sera from severe patients contain high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Interestingly, when integrated in immune complexes, anti-SARS-CoV-2 IgG antibodies from severe patients displayed a higher pro-inflammatory profile compared with antibodies from mild patients. Our study suggests that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils worsening the course of COVID-19.

Summary Severe COVID‐19 is associated with a systemic inflammatory response and progressive CD4+ T‐cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4+ T‐cell dysfunction in COVID‐19. We observed a high frequency of CD4+ T cell–platelet aggregates in COVID‐19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID‐19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)‐α production by CD4+ T cells. In addition, interferon (IFN)‐γ production was increased by platelets from HD but not from COVID‐19 inpatients. A high expression of PD‐L1 was found in platelets from COVID‐19 patients to be inversely correlated with IFN‐γ production by activated CD4+ T cells cocultured with platelets. We also found that a PD‐L1‐blocking antibody significantly restored platelets’ ability to stimulate IFN‐γ production by CD4+ T cells. Our study suggests that platelets might contribute to disease progression in COVID‐19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+ T cells functionality.

Objectives This research aims to study the efficacy of tannins co-supplementation on disease duration, severity and clinical symptoms, microbiota composition and inflammatory mediators in SARS-CoV2 patients. Trial design This is a prospective, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the efficacy of the administration of the dietary supplement ARBOX, a molecular blend of quebracho and chestnut tannins extract and Vit B12, in patients affected by COVID-19. Participants 18 years of age or older, admitted to Hospital de Clinicas Jose de San Martin, Buenos Aires University (Argentina), meeting the definition of "COVID-19 confirmed case" (https://www.argentina.gob.ar/salud/coronavirus-COVID-19/definicion-de-caso). Inclusion Criteria Participants are eligible to be included in the study if the following criteria apply: Any gender ≥18 years old Informed consent for participation in the study Virological diagnosis of SARS-CoV-2 infection (real-time PCR) Exclusion Criteria Participants are excluded from the study if any of the following criteria apply: Pregnant and lactating patients Patients who cannot take oral therapy (with severe cognitive decline, assisted ventilation, or impaired consciousness) Hypersensitivity to polyphenols Patients already in ICU or requiring mechanical ventilation Patients already enrolled in other clinical trials Decline of consent Intervention and comparator Experimental: TREATED ARM Participants will receive a supply of 28 -- 390 mg ARBOX capsules for 14 days. Patients will be supplemented with 2 capsules of ARBOX per day. Placebo Comparator: CONTROL ARM Participants will receive placebo supply for 14 days. The placebo will be administered with the identical dose as described for the test product. All trial participants will receive standard therapy, which includes: Antipyretics or Lopinavir / Ritonavir, Azithromycin and Hydroxychloroquine, as appropriate (treatment currently recommended by the department of Infectious Diseases of the Hospital de Clínicas that could undergo to modifications). In addition, if necessary: supplemental O2, non-invasive ventilation, antibiotic therapy. Main outcomes Primary Outcome Measures: Time to hospital discharge, defined as the time from first dose of ARBOX to hospital discharge [ Time Frame: Throughout the Study (Day 0 to Day 28) ] Secondary Outcome Measures: 28-day all-cause mortality [ Time Frame: Throughout the Study (Day 0 to Day 28) ]-proportion Invasive ventilation on day 28 [ Time Frame: Throughout the Study (Day 0 to Day 28) ]-proportion Level of inflammation parameters and cytokines [ Time Frame: day 1-14 ] -mean difference Difference in fecal intestinal microbiota composition and intestinal permeability [ Time Frame: day 1-14 ] Negativization of COVID-PCR at day 14 [ Time Frame: day 14 ]-proportion Randomization Potential study participants were screened for eligibility 24 hours prior to study randomization. Patients were randomly assigned via computer-generated random numbering (1:1) to receive standard treatment coupled with tannin or standard treatment plus placebo (control group). Blinding (masking) Study personnel and participants are blinded to the treatment allocation, as both ARBOX and placebo were packed in identical containers. Thus, all the used capsules had identical appearance. Numbers to be randomized (sample size) Considering an alpha error of 5%, a power of 80% a sample size of 70 patients per branch was estimated. 140 patients in total. Trial Status The protocol version is number V2, dated May 23, 2020. The first patient, first visit was on June 12, 2020; the recruitment end date was October 6, 2020. The protocol was not submitted earlier because the enrollment of some patients took place after the closure of the recruitment on the clinicaltrials platform. In fact, due to the epidemiological conditions, due to the decrease of the cases in Argentina during the summer period, the recruitment stopped t before reaching the number of 140 patients (as indicated in the webpage). However, since there was a new increase in cases, the enrolment was resumed in order to reach the number of patients initially planned in the protocol. The final participant was recruited on February 14, 2021. Trial registration ClinicalTrials.gov, number: NCT04403646, registered on May 27th, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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