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1.
ERJ open research ; 8(2), 2022.
Article in English | EuropePMC | ID: covidwho-1782050

ABSTRACT

Background Long-term outcome data of coronavirus disease 2019 (COVID-19) survivors are needed to understand their recovery trajectory and additional care needs. Methods A prospective observational multicentre cohort study was carried out of adults hospitalised with COVID-19 from March through May 2020. Workup at 3 and 12 months following admission consisted of clinical review, pulmonary function testing, 6-min walk distance (6MWD), muscle strength, chest computed tomography (CT) and quality of life questionnaires. We evaluated factors correlating with recovery by linear mixed effects modelling. Results Of 695 patients admitted, 299 and 226 returned at 3 and 12 months, respectively (median age 59 years, 69% male, 31% severe disease). About half and a third of the patients reported fatigue, dyspnoea and/or cognitive impairment at 3 and 12 months, respectively. Reduced 6MWD and quadriceps strength were present in 20% and 60% at 3 months versus 7% and 30% at 12 months. A high anxiety score and body mass index correlated with poor functional recovery. At 3 months, diffusing capacity for carbon monoxide (DLCO) and total lung capacity were below the lower limit of normal in 35% and 18%, decreasing to 21% and 16% at 12 months;predictors of poor DLCO recovery were female sex, pre-existing lung disease, smoking and disease severity. Chest CT improved over time;10% presented non-progressive fibrotic changes at 1 year. Conclusion Many COVID-19 survivors, especially those with severe disease, experienced limitations at 3 months. At 1 year, the majority showed improvement to almost complete recovery. To identify additional care or rehabilitation needs, we recommend a timely multidisciplinary follow-up visit following COVID-19 admission. Most hospitalised #COVID19 survivors show promising recovery 1 year after discharge, although mild symptoms may linger. Severe impairments are rare, but this study suggests an evaluation of the individual care needs after discharge.https://bit.ly/3sZK45x

2.
Lancet Respir Med ; 9(12): 1427-1438, 2021 12.
Article in English | MEDLINE | ID: covidwho-1621131

ABSTRACT

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , COVID-19 , Cytokine Release Syndrome , Respiratory Insufficiency , Aged , Belgium , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Female , Ferritins , Humans , Hypoxia , Interleukin-1/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Male , Middle Aged , Oxygen , Prospective Studies , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , SARS-CoV-2 , Treatment Outcome
3.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1594167

ABSTRACT

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Subject(s)
COVID-19/complications , Hepatitis A Virus Cellular Receptor 2/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Monocytes/metabolism , Receptors, IgG/metabolism , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Alveolar Epithelial Cells/pathology , B-Lymphocytes/immunology , Blood Vessels/pathology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Child , Cohort Studies , Complement Activation , Cytokines/metabolism , Enterocytes/pathology , Female , Humans , Immunity, Humoral , Inflammation/pathology , Interferon Type I/metabolism , Interleukin-15/metabolism , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/immunology , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/pathology
4.
Nat Rev Immunol ; 22(2): 77-84, 2022 02.
Article in English | MEDLINE | ID: covidwho-1585843

ABSTRACT

Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.


Subject(s)
COVID-19 , Complement System Proteins , Blood Coagulation , COVID-19/immunology , Complement Activation , Humans , Inflammation , Thrombosis
5.
JAMA ; 326(6): 499-518, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1413703

ABSTRACT

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Interleukin-6/antagonists & inhibitors , Aged , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Cause of Death , Coinfection , Disease Progression , Drug Therapy, Combination , Female , Glucocorticoids/therapeutic use , Hospitalization , Humans , Male , Middle Aged , Prospective Studies , Randomized Controlled Trials as Topic , Respiration, Artificial
8.
Angew Chem Int Ed Engl ; 60(17): 9467-9473, 2021 04 19.
Article in English | MEDLINE | ID: covidwho-1037522

ABSTRACT

The search for vaccines that protect from severe morbidity and mortality because of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) is a race against the clock and the virus. Here we describe an amphiphilic imidazoquinoline (IMDQ-PEG-CHOL) TLR7/8 adjuvant, consisting of an imidazoquinoline conjugated to the chain end of a cholesterol-poly(ethylene glycol) macromolecular amphiphile. It is water-soluble and exhibits massive translocation to lymph nodes upon local administration through binding to albumin, affording localized innate immune activation and reduction in systemic inflammation. The adjuvanticity of IMDQ-PEG-CHOL was validated in a licensed vaccine setting (quadrivalent influenza vaccine) and an experimental trimeric recombinant SARS-CoV-2 spike protein vaccine, showing robust IgG2a and IgG1 antibody titers in mice that could neutralize viral infection in vitro and in vivo in a mouse model.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Imidazoles/therapeutic use , Immunity, Innate/drug effects , Quinolines/therapeutic use , Animals , COVID-19 Vaccines/immunology , Cholesterol/analogs & derivatives , Cholesterol/immunology , Cholesterol/therapeutic use , Female , Humans , Imidazoles/immunology , Influenza A Virus, H1N1 Subtype/drug effects , Influenza Vaccines/immunology , Influenza Vaccines/therapeutic use , Influenza, Human/prevention & control , Membrane Glycoproteins/agonists , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Polyethylene Glycols/therapeutic use , Quinolines/immunology , Recombinant Proteins/immunology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , Surface-Active Agents/therapeutic use , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists
9.
Respir Res ; 22(1): 12, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-1015870

ABSTRACT

In their letter-to-the-editor entitled "Misconceptions of pathophysiology of happy hypoxemia and implications for management of COVID-19", Tobin et al. (Respir Res 21:249, 2020) debated our views on happy hypoxemia in COVID-19 (Respir Res 21:198, 2020). We thank the authors for their interesting comments and alternative viewpoints, and we would like to clarify several important aspects raised.


Subject(s)
COVID-19 , Hypoxia , COVID-19/complications , Humans , SARS-CoV-2
11.
Front Immunol ; 11: 596761, 2020.
Article in English | MEDLINE | ID: covidwho-972668

ABSTRACT

The disease course of COVID-19 in patients with immunodeficiencies is unclear, as well as the optimal therapeutic strategy. We report a case of a 37-year old male with common variable immunodeficiency disorder and a severe SARS-CoV-2 infection. After administration of convalescent plasma, the patient's condition improved rapidly. Despite clinical recovery, viral RNA remained detectable up to 60 days after onset of symptoms. We propose that convalescent plasma might be considered as a treatment option in patients with CVID and severe COVID-19. In addition, in patients with immunodeficiencies, a different clinical course is possible, with prolonged viral shedding.


Subject(s)
Antibodies, Viral/administration & dosage , COVID-19/therapy , Common Variable Immunodeficiency , RNA, Viral , SARS-CoV-2 , Virus Shedding , Adult , COVID-19/blood , COVID-19/immunology , Common Variable Immunodeficiency/blood , Common Variable Immunodeficiency/immunology , Common Variable Immunodeficiency/therapy , Humans , Immunization, Passive , Male , RNA, Viral/blood , RNA, Viral/immunology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Virus Shedding/drug effects , Virus Shedding/immunology
12.
Trials ; 21(1): 981, 2020 Nov 27.
Article in English | MEDLINE | ID: covidwho-947944

ABSTRACT

BACKGROUND: The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of patients having recovered from SARS and severe influenza to patients actively having the disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. METHODS: DAWn-Plasma is a multicentre nation-wide, randomized, open-label, phase II proof-of-concept clinical trial, evaluating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19 in Belgium. Patients hospitalized with a confirmed diagnosis of COVID-19 are eligible when they are symptomatic (i.e. clinical or radiological signs) and have been diagnosed with COVID-19 in the 72 h before study inclusion through a PCR (nasal/nasopharyngeal swab or bronchoalveolar lavage) or a chest-CT scan showing features compatible with COVID-19 in the absence of an alternative diagnosis. Patients are randomized in a 2:1 ratio to either standard of care and convalescent plasma (active treatment group) or standard of care only. The active treatment group receives 2 units of 200 to 250 mL of convalescent plasma within 12 h after randomization, with a second administration of 2 units 24 to 36 h after ending the first administration. The trial aims to include 483 patients and will recruit from 25 centres across Belgium. The primary endpoint is the proportion of patients that require mechanical ventilation or have died at day 15. The main secondary endpoints are clinical status on day 15 and day 30 after randomization, as defined by the WHO Progression 10-point ordinal scale, and safety of the administration of convalescent plasma. DISCUSSION: This trial will either provide support or discourage the use of convalescent plasma as an early intervention for the treatment of hospitalized patients with COVID-19 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04429854 . Registered on 12 June 2020 - Retrospectively registered.


Subject(s)
Antibodies, Viral/immunology , COVID-19/therapy , SARS-CoV-2/genetics , Adult , Antibodies, Viral/blood , Belgium/epidemiology , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Combined Modality Therapy/methods , Female , Global Burden of Disease , Hospitalization/trends , Humans , Immunization, Passive/methods , Male , Mortality , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/immunology , Safety , Standard of Care/statistics & numerical data , Treatment Outcome
13.
Trials ; 21(1): 934, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-934298

ABSTRACT

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). 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.


Subject(s)
Complement C5/antagonists & inhibitors , Coronavirus Infections/complications , Hypoxia/drug therapy , Pneumonia, Viral/complications , Respiratory Insufficiency/drug therapy , Acute Disease , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Belgium/epidemiology , Betacoronavirus/isolation & purification , COVID-19 , Case-Control Studies , Ceftriaxone/administration & dosage , Ceftriaxone/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Drug Therapy, Combination , Humans , Infusions, Intravenous , Injections, Subcutaneous , Oxygen/blood , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Prospective Studies , SARS-CoV-2 , Safety , Treatment Outcome
14.
bioRxiv ; 2020 Oct 23.
Article in English | MEDLINE | ID: covidwho-900770

ABSTRACT

The search for vaccines that protect from severe morbidity and mortality as a result of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) is a race against the clock and the virus. Several vaccine candidates are currently being tested in the clinic. Inactivated virus and recombinant protein vaccines can be safe options but may require adjuvants to induce robust immune responses efficiently. In this work we describe the use of a novel amphiphilic imidazoquinoline (IMDQ-PEG-CHOL) TLR7/8 adjuvant, consisting of an imidazoquinoline conjugated to the chain end of a cholesterol-poly(ethylene glycol) macromolecular amphiphile). This amphiphile is water soluble and exhibits massive translocation to lymph nodes upon local administration, likely through binding to albumin. IMDQ-PEG-CHOL is used to induce a protective immune response against SARS-CoV-2 after single vaccination with trimeric recombinant SARS-CoV-2 spike protein in the BALB/c mouse model. Inclusion of amphiphilic IMDQ-PEG-CHOL in the SARS-CoV-2 spike vaccine formulation resulted in enhanced immune cell recruitment and activation in the draining lymph node. IMDQ-PEG-CHOL has a better safety profile compared to native soluble IMDQ as the former induces a more localized immune response upon local injection, preventing systemic inflammation. Moreover, IMDQ-PEG-CHOL adjuvanted vaccine induced enhanced ELISA and in vitro microneutralization titers, and a more balanced IgG2a/IgG1 response. To correlate vaccine responses with control of virus replication in vivo, vaccinated mice were challenged with SARS-CoV-2 virus after being sensitized by intranasal adenovirus-mediated expression of the human angiotensin converting enzyme 2 (ACE2) gene. Animals vaccinated with trimeric recombinant spike protein vaccine without adjuvant had lung virus titers comparable to non-vaccinated control mice, whereas animals vaccinated with IMDQ-PEG-CHOL-adjuvanted vaccine controlled viral replication and infectious viruses could not be recovered from their lungs at day 4 post infection. In order to test whether IMDQ-PEG-CHOL could also be used to adjuvant vaccines currently licensed for use in humans, proof of concept was also provided by using the same IMDQ-PEG-CHOL to adjuvant human quadrivalent inactivated influenza virus split vaccine, which resulted in enhanced hemagglutination inhibition titers and a more balanced IgG2a/IgG1 antibody response. Enhanced influenza vaccine responses correlated with better virus control when mice were given a lethal influenza virus challenge. Our results underscore the potential use of IMDQ-PEG-CHOL as an adjuvant to achieve protection after single immunization with recombinant protein and inactivated virus vaccines against respiratory viruses, such as SARS-CoV-2 and influenza viruses.

15.
J Allergy Clin Immunol ; 147(2): 520-531, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-792893

ABSTRACT

BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.


Subject(s)
COVID-19/epidemiology , Genetic Diseases, Inborn/epidemiology , Immunologic Deficiency Syndromes/epidemiology , SARS-CoV-2 , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Retrospective Studies , Risk Factors , Severity of Illness Index , Young Adult
17.
Nat Rev Immunol ; 20(10): 594-602, 2020 10.
Article in English | MEDLINE | ID: covidwho-759596
18.
Respir Res ; 21(1): 198, 2020 Jul 28.
Article in English | MEDLINE | ID: covidwho-680693

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) pandemic is a global crisis, challenging healthcare systems worldwide. Many patients present with a remarkable disconnect in rest between profound hypoxemia yet without proportional signs of respiratory distress (i.e. happy hypoxemia) and rapid deterioration can occur. This particular clinical presentation in COVID-19 patients contrasts with the experience of physicians usually treating critically ill patients in respiratory failure and ensuring timely referral to the intensive care unit can, therefore, be challenging. A thorough understanding of the pathophysiological determinants of respiratory drive and hypoxemia may promote a more complete comprehension of a patient's clinical presentation and management. Preserved oxygen saturation despite low partial pressure of oxygen in arterial blood samples occur, due to leftward shift of the oxyhemoglobin dissociation curve induced by hypoxemia-driven hyperventilation as well as possible direct viral interactions with hemoglobin. Ventilation-perfusion mismatch, ranging from shunts to alveolar dead space ventilation, is the central hallmark and offers various therapeutic targets.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Hypoxia/etiology , Lung/physiopathology , Oxygen Consumption/physiology , Pandemics , Pneumonia, Viral/complications , Respiratory Insufficiency/complications , COVID-19 , Coronavirus Infections/epidemiology , Critical Illness , Humans , Hypoxia/metabolism , Hypoxia/physiopathology , Pneumonia, Viral/epidemiology , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/physiopathology , SARS-CoV-2
20.
Immunity ; 52(6): 1039-1056.e9, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-209829

ABSTRACT

The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.


Subject(s)
Cell Plasticity/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Immunity , Macrophages/immunology , Macrophages/metabolism , Respirovirus Infections/etiology , Antigen Presentation , Biomarkers , Disease Susceptibility , Gene Expression Profiling , Gene Expression Regulation , Gene Regulatory Networks , Immunophenotyping , Interferon Type I/metabolism , Monocytes/immunology , Monocytes/metabolism , Organ Specificity/immunology , Receptors, Fc/metabolism , Respirovirus Infections/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Transcription Factors , Virus Diseases/genetics , Virus Diseases/immunology , Virus Diseases/metabolism , Virus Diseases/virology
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