Oral corticoid, aspirin, anticoagulant, colchicine, and furosemide to improve the outcome of hospitalized COVID-19 patients-the COCAA-COLA cohort study Dear Editor, Corticosteroids mitigate 28-day all-cause mortality in coronavirus disease-2019 (COVID-19) patients requiring oxygen or mechanical ventilation (meta-analysis summary odds ratio (OR), 0.66; 95%-confidence interval (95%IC), [0.53-0.82]; P < 0.001); however, mortality remains high (32.7%). 1 In a previous observational cohort study, we established that an early 4-day treatment combining corticosteroid (prednisolone dose equivalent, 1.25 mg/kg/24 h) and furosemide (80 mg/day) was effective in reducing the need for mechanical ventilation and overall mortality (OR, 0.35 [0.11-1.01]; P = 0.04) in non-critically ill COVID-19 patients. 2 The GRECCO-19 randomized trial suggested a benefit of colchicine in preventing clinical deterioration in hospitalized noncritically ill COVID-19 patients. 3 Similarly, an observational cohort study reported that salicylate treatment was associated with reduction in intensive care unit (ICU) and mechanical ventilation requirements in hospitalized COVID-19 patients, although in-hospital death was not significantly modified. 4 Moreover, prophylactic or intermediate-dose anticoagulation was highly recommended in hospitalized COVID-19 patients who are at high-risk of venous thromboembolic events (VTE). 5 Specifically, direct oral anticoagulant use was shown to be associated with improved outcome. 6 Based on the data discussed above and the pathophysiology of COVID-19 and its complications, i.e. thrombosis, inflammation and congestion, we hypothesized that a five-drug regimen consisting in a 5-day course of 1 mg/kg/day prednisone, 80 mg/day furosemide, 75 mg/day salicylate, colchicine (1 mg loading dose followed by 0.5 mg one hour later then 0.5 mg every 8 h as recommended to treat acute gout) 7 and direct anti-Xa inhibitor such as rivaroxaban or apixaban would optimally mitigate COVID-19-attributed mortality. To address the effectiveness of this five-drug regimen, we designed an observational cohort study (COrtiCoid-Aspirin-Anticoagulant-Colchicine-LAsix R , the COCAA-COLA study) including all successive non-critically ill COVID-19 patients requiring > 1 L/min-oxygen and admitted to our ward between 2020/01/09 and 2020/11/30 (during the second wave in France). Patients who did not receive this regimen were treated with dexamethasone (6 mg once daily for up to 10 days) 8 and low-molecular weight heparin (control group). All patients received standard of care, i.e. oxygen with flow adapted to oximetry, proton pump inhibitor, antibiotics, insulin, potassium supplementation and loperamide if needed. No antiviral or additional immunomodulatory therapy was used due to the absence of clearly demonstrated benefit. Systematic chest computed tomography angiography was performed on admission if not contra-indicated. Anticoagulants (direct anti

ObjectiveThe worldwide COVID-19 vaccination campaign triggered several autoimmune diseases. We hereby aimed to describe IgA vasculitis (IgAV) following COVID- 19 vaccination.MethodsWe conducted a French national multi-centre, retrospective study of new onset adult IgAV diagnosis following COVID-19 vaccination.ResultsTwelve patients with a new onset IgAV were included. Five were women (41.6%), and the median age was 52,5 years IQR [30.75-60.5]. Ten received an mRNA vaccine. Two patients received a viral vector vaccine. The median time from vaccination to onset of symptoms was 11.5 days with an IQR of [4.25-21.25]. The vasculitis occurred after the first vaccine dose in most patients (n=8). All patients had skin involvement, with skin necrosis in four patients. Seven patients had joint involvement and 2 had arthritis. Four had non-severe gastrointestinal involvement. Two had non-severe renal involvement. Median C-reactive protein was 26 mg/l [10-66.75], median creatininaemia was 72 μmol/l [65-81], one patient had eGFR < 60 ml/min at management. All patients received a treatment, including glucocorticosteroids in 9 patients (75%). Five patients received a vaccine dose after developing IgAV, one of them experienced a minor cutaneous relapse.ConclusionBaseline presentation of IgAV following COVID-19 vaccination was mild to moderate and outcomes were favourable. Thus, a complete COVID-19 vaccination regimen should be completed in this population. Of note, a fortuitous link cannot be ruled out requiring a worldwide pharmacovigilance search now to confirm these findings.

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.