Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Clin Infect Dis ; 2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1852986

ABSTRACT

Binding levels and neutralization activity of anti-type 1 interferon (T1IFN) autoantibodies peaked during acute COVID-19 and markedly decreased thereafter. Most patients maintained some ability to neutralize T1IFN into convalescence despite lower levels of binding IgG. Identifying these autoantibodies in healthy individuals before they develop critical viral disease may be challenging.

2.
Nat Med ; 28(5): 1050-1062, 2022 05.
Article in English | MEDLINE | ID: covidwho-1701612

ABSTRACT

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.


Subject(s)
COVID-19 , COVID-19/complications , COVID-19/genetics , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/genetics , T-Lymphocytes
3.
Open forum infectious diseases ; 8(Suppl 1):S325-S326, 2021.
Article in English | EuropePMC | ID: covidwho-1602651

ABSTRACT

Background Approximately 10-20% of patients with critical COVID-19 harbor neutralizing autoantibodies (auto-Abs) that target type I interferons (IFN), a family of cytokines that induce critical innate immune defense mechanisms upon viral infection. Studies to date indicate that these auto-Abs are mostly detected in men over age 65. Methods We screened for type I IFN serum auto-Abs in sera collected < 21 days post-symptom onset in a subset of 103 COVID-19 inpatients and 24 outpatients drawn from a large prospective cohort study of SARS-CoV-2 infected patients enrolled across U.S. Military Treatment Facilities. The mean age of this n = 127 subset of study participants was 55.2 years (SD = 15.2 years, range 7.7 – 86.2 years), and 86/127 (67.7%) were male. Results Among those hospitalized 49/103 (47.6%) had severe COVID-19 (required at least high flow oxygen), and nine subjects died. We detected neutralizing auto-Abs against IFN-α, IFN-ω, or both, in four inpatients (3.9%, 8.2% of severe cases), with no auto-Abs detected in outpatients. Three of these patients were white males over the age of 62, all with multiple comorbidities;two of whom died and the third requiring high flow oxygen therapy. The fourth patient was a 36-year-old Hispanic female with a history of obesity who required mechanical ventilation during her admission for COVID-19. Conclusion These findings support the association between type I IFN auto-antibody production and life-threatening COVID-19. With further validation, reliable high-throughput screening for type I IFN auto-Abs may inform diagnosis, pathogenesis and treatment strategies for COVID-19, particularly in older males. Our finding of type I IFN auto-Ab production in a younger female prompts further study of this autoimmune phenotype in a broader population. Disclosures David A. Lindholm, MD, American Board of Internal Medicine (Individual(s) Involved: Self): Member of Auxiliary R&D Infectious Disease Item-Writer Task Force. No financial support received. No exam questions will be disclosed ., Other Financial or Material Support David Tribble, M.D., DrPH, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work)) Simon Pollett, MBBS, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work))

4.
Clin Infect Dis ; 2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1556902

ABSTRACT

Binding levels and neutralization activity of anti-type 1 interferon (T1IFN) autoantibodies peaked during acute COVID-19 and markedly decreased thereafter. Most patients maintained some ability to neutralize T1IFN into convalescence despite lower levels of binding IgG. Identifying these autoantibodies in healthy individuals before they develop critical viral disease may be challenging.

5.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1434875

ABSTRACT

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Interferon Type I/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Autoantibodies/blood , COVID-19/mortality , Case-Control Studies , Child , Child, Preschool , Critical Illness , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Infant , Infant, Newborn , Interferon-alpha/immunology , Middle Aged , Young Adult
6.
Front Immunol ; 12: 720205, 2021.
Article in English | MEDLINE | ID: covidwho-1403477

ABSTRACT

Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Polyendocrinopathies, Autoimmune/drug therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , COVID-19/complications , COVID-19/genetics , COVID-19/immunology , Female , Humans , Interferons/genetics , Interferons/immunology , Male , Mutation , Polyendocrinopathies, Autoimmune/complications , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Transcription Factors/genetics , Transcription Factors/immunology
7.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367379

ABSTRACT

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Interferon Type I/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Autoantibodies/blood , COVID-19/mortality , Case-Control Studies , Child , Child, Preschool , Critical Illness , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Infant , Infant, Newborn , Interferon-alpha/immunology , Middle Aged , Young Adult
8.
Immunol Cell Biol ; 99(9): 917-921, 2021 10.
Article in English | MEDLINE | ID: covidwho-1325006

ABSTRACT

Type-I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID-19). Several lines of evidence suggest that impaired type-I IFN signaling may predispose to severe COVID-19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type-I IFNs influence outcomes in patients with COVID-19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type-I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID-19 at three Italian hospitals. The presence of circulating AAbs to type-I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type-I IFN AAbs. Our findings provide further support for the role of type-I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID-19 pneumonia in severe acute respiratory syndrome coronavirus 2-infected individuals.


Subject(s)
Autoantibodies/immunology , COVID-19 , Interferon Type I/immunology , Antibodies, Neutralizing/immunology , COVID-19/immunology , Humans , Intensive Care Units , Italy
9.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1066211

ABSTRACT

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Subject(s)
Antibodies, Neutralizing/immunology , Autoantibodies/immunology , Autoimmune Diseases , COVID-19 , Genetic Diseases, Inborn , Interferon-alpha , Receptor, Interferon alpha-beta , SARS-CoV-2 , Yellow Fever Vaccine , Yellow fever virus , Adolescent , Adult , Aged , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , COVID-19/genetics , COVID-19/immunology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , HEK293 Cells , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Male , Middle Aged , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Yellow Fever Vaccine/adverse effects , Yellow Fever Vaccine/genetics , Yellow Fever Vaccine/immunology , Yellow fever virus/genetics , Yellow fever virus/immunology
10.
Science ; 370(6515)2020 10 23.
Article in English | MEDLINE | ID: covidwho-889832

ABSTRACT

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.


Subject(s)
Autoantibodies/blood , Coronavirus Infections/immunology , Interferon Type I/immunology , Interferon alpha-2/immunology , Pneumonia, Viral/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Asymptomatic Infections , Betacoronavirus , COVID-19 , Case-Control Studies , Critical Illness , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Pandemics , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL