Search

Abstract Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

An amendment to this paper has been published and can be accessed via the original article.

Background: Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight dependence remain unclear., Objectives: To evaluate PEGylated lipid nanoparticle (LNP) vaccine (BNT162b2) tolerance and explore the mechanism of reactivity in PEG and/or PS80 allergic patients., Methods: PEG/PS80 dual- (n = 3), PEG mono- (n = 7), and PS80 mono-allergic patients (n = 2) were included. Tolerability of graded vaccine challenges was assessed. Basophil activation testing on whole blood (wb-BAT) or passively sensitized donor basophils (allo-BAT) was performed using PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). Serum PEG-specific IgE was measured in patients (n = 10) and controls (n = 15)., Results: Graded BNT162b2 challenge in dual- and PEG mono-allergic patients (n = 3/group) was well tolerated and induced anti-spike IgG seroconversion. PS80 mono-allergic patients (n = 2/2) tolerated single-dose BNT162b2 vaccination. Wb-BAT reactivity to PEG-containing antigens was observed in dual- (n = 3/3) and PEG mono- (n = 2/3), but absent in PS80 mono-allergic patients (n = 0/2). BNT162b2 elicited the highest in vitro reactivity. BNT162b2 reactivity was IgE mediated, complement independent, and inhibited in allo-BAT by preincubation with short PEG motifs, or detergent-induced LNP degradation. PEG-specific IgE was only detectable in dual-allergic (n = 3/3) and PEG mono-allergic (n = 1/6) serum., Conclusion: PEG and PS80 cross-reactivity is determined by IgE recognizing short PEG motifs, whereas PS80 mono-allergy is PEG-independent. PS80 skin test positivity in PEG allergics was associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels, and enhanced BAT reactivity. Spherical PEG exposure via LNP enhances BAT sensitivity through increased avidity. All PEG and/or PS80 excipient allergic patients can safely receive SARS-CoV-2 vaccines., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Detection dogs were trained to detect SARS-CoV-2 infection based on armpit sweat odor. Sweat samples were collected using cotton pads under the armpits of negative and positive human patients, confirmed by qPCR, for periods of 15-30 min. Multiple hospitals and organizations throughout Belgium participated in this study. The sweat samples were stored at -20°C prior to being used for training purposes. Six dogs were trained under controlled atmosphere conditions for 2-3 months. After training, a 7-day validation period was conducted to assess the dogs' performances. The detection dogs exhibited an overall sensitivity of 81%, specificity of 98%, and an accuracy of 95%. After validation, training continued for 3 months, during which the dogs' performances remained the same. Gas chromatography/mass spectrometry (GC/MS) analysis revealed a unique sweat scent associated with SARS-CoV-2 positive sweat samples. This scent consisted of a wide variety of volatiles, including breakdown compounds of antiviral fatty acids, skin proteins and neurotransmitters/hormones. An acceptability survey conducted in Belgium demonstrated an overall high acceptability and enthusiasm toward the use of detection dogs for SARS-CoV-2 detection. Compared to qPCR and previous canine studies, the detection dogs have good performances in detecting SARS-CoV-2 infection in humans, using frozen sweat samples from the armpits. As a result, they can be used as an accurate pre-screening tool in various field settings alongside the PCR test., Competing Interests: CC is the founder of DrArmpit BV. AA and AM are founders of Arome Science Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer A-LC is currently co-organizing a Research Topic with one of the authors DG., (Copyright © 2023 Callewaert, Pezavant, Vandaele, Meeus, Vankrunkelsven, Van Goethem, Plumacker, Misset, Darcis, Piret, De Vleeschouwer, Staelens, Van Varenbergh, Tombeur, Ottevaere, Montag, Vandecandelaere, Jonckheere, Vandekerckhove, Tobback, Wieers, Marot, Anseeuw, D’Hoore, Tuyls, De Tavernier, Catteeuw, Lotfi, Melnik, Aksenov, Grandjean, Stevens, Gasthuys and Guyot.)

Background: Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients., Methods: In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge., Findings: Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N  = 67 vs. SOC N  = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p  = 0.24) or mortality (intervention n  = 3 [4.6%] vs. SOC n  = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p  = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding., Conclusions: In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Vaccination against COVID-19 constitutes a huge hope and a major challenge. For the first time in modern history, a global vaccination campaign has started worldwide in a short period of time and with products that were recently developed. Consequently, legitimate concerns regarding the safety and tolerability of COVID-19 vaccines arise.In line with international allergy societies, the Belgian Society for Allergy and Clinical Immunology (BelSACI) provides this statement to guide health care providers (general practitioners, specialists including allergists) and stakeholders.In this statement, we first review current evidence on allergic reactions to vaccines and the potential risk factors that have been identified.Second, we provide a risk stratification method that may be used as a worksheet during the vaccination campaign.Finally, we discuss the management of suspected or confirmed allergic reactions following vaccination.

Background: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19., Methods: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement., Discussion: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome., Trial Registration: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Survival after lung transplantation (LTx) for idiopathic pulmonary fibrosis (IPF) is worse compared to other indications for LTx. We investigated the effect of several pretransplant variables including the use of pretransplant corticosteroids (CS) on post-transplant graft and chronic lung allograft dysfunction (CLAD)-free survival and functional testing (maximum inspiratory and expiratory pressure, six-minute walk test, quadriceps and hand pinch force) in a small cohort of IPF patients. We retrospectively compared two groups of IPF patients (n = 36 on CS vs. n = 18 not on CS) who underwent LTx between 2000 and 2016. Analysis of 54 IPF-LTx patients showed no significant effect on graft survival or functional tests except for maximum inspiratory pressure (P = 0.033) between these two groups (all LTx patients, CS vs. no CS). Regression analysis showed significant impact of procedure with a hazard ratio of 0.423 (CI 95% 0.194, 0.924) favoring sequential single LTx (SSLTx) compared to single lung transplantation (SLTx). When analyzing only the 40 SSLTx patients, corticosteroid-free patients showed significantly better graft survival compared to patients on CS (P = 0.045) and CLAD-free survival (P = 0.019). The possible detrimental effect of corticosteroid therapy before LTx was demonstrated in this cohort of SSLTx patients, which questions the use of corticosteroids in a pretransplantation setting., (© 2018 Steunstichting ESOT.)