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1.
Sci Transl Med ; 13(612): eabh2624, 2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1371845

ABSTRACT

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN­specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non­COVID-19 controls revealed a lack of type I IFN­stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN­specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN­specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.


Subject(s)
Autoantibodies , COVID-19 , Interferon Type I , Autoantibodies/immunology , COVID-19/immunology , Humans , Interferon Type I/immunology
2.
Nature ; 591(7848): 124-130, 2021 03.
Article in English | MEDLINE | ID: covidwho-1368933

ABSTRACT

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/physiopathology , Interferons/antagonists & inhibitors , Interferons/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Antibodies, Viral/blood , Antibody Formation , Base Sequence , COVID-19/blood , COVID-19/virology , Female , Humans , Immunoglobulin G/immunology , Interferons/metabolism , Male , Neutrophils/immunology , Neutrophils/pathology , Protein Domains , Receptor, Interferon alpha-beta/antagonists & inhibitors , Receptor, Interferon alpha-beta/immunology , Receptor, Interferon alpha-beta/metabolism , Receptors, IgG/immunology , Single-Cell Analysis , Viral Load/immunology
4.
JAMA Dermatol ; 157(8): 947-953, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1279331

ABSTRACT

Importance: Beginning in March 2020, case reports and case series linked the COVID-19 pandemic with an increased occurrence of chilblains, but this association has not been evaluated in an epidemiologic study. Objective: To assess whether a correlation exists between COVID-19 incidence and chilblains incidence. Design, Setting, and Participants: A retrospective cohort study was conducted within the Kaiser Permanente Northern California system from January 1, 2016, to December 31, 2020; health plan members of all ages were included. Exposure: COVID-19 incidence in 207 location-months, representing 23 geographic locations in northern California across 9 months. Main Outcome and Measures: Chilblains incidence was the main outcome. The association of chilblains incidence with COVID-19 incidence across the 207 location-months was measured using the Spearman rank correlation coefficient. Results: Of 780 patients with chilblains reported during the pandemic, 464 were female (59.5%); mean (SD) age was 36.8 (21.8) years. COVID-19 incidence was correlated with chilblains incidence at 207 location-months (Spearman coefficient 0.18; P = .01). However, only 17 of 456 (3.7%) patients with chilblains tested during the pandemic were positive for SARS-CoV-2, and only 9 of 456 (2.0%) were positive for SARS-CoV-2 within 6 weeks of the chilblains diagnosis. Test results of 1 of 97 (1.0%) patients were positive for SARS-CoV-2 IgG antibodies. Latinx patients were disproportionately affected by COVID-19 but not by chilblains. Conclusions and Relevance: This cohort study found that in northern California, the incidence of chilblains increased during the pandemic but was correlated weakly with the incidence of COVID-19 across 207 location-months. These findings may have resulted from a causal role of COVID-19, increased care-seeking by patients with chilblains during the pandemic, or changes in behavior during shelter in place.


Subject(s)
COVID-19/epidemiology , Chilblains/epidemiology , Adolescent , Adult , COVID-19/complications , COVID-19/diagnosis , California/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Humans , Incidence , Infant , Male , Middle Aged , Retrospective Studies , Young Adult
5.
Front Public Health ; 9: 627654, 2021.
Article in English | MEDLINE | ID: covidwho-1241212

ABSTRACT

The COVID-19 pandemic has re-focused attention on mechanisms that lead to zoonotic disease spillover and spread. Commercial wildlife trade, and associated markets, are recognized mechanisms for zoonotic disease emergence, resulting in a growing global conversation around reducing human disease risks from spillover associated with hunting, trade, and consumption of wild animals. These discussions are especially relevant to people who rely on harvesting wildlife to meet nutritional, and cultural needs, including those in Arctic and boreal regions. Global policies around wildlife use and trade can impact food sovereignty and security, especially of Indigenous Peoples. We reviewed known zoonotic pathogens and current risks of transmission from wildlife (including fish) to humans in North American Arctic and boreal biomes, and evaluated the epidemic and pandemic potential of these zoonoses. We discuss future concerns, and consider monitoring and mitigation measures in these changing socio-ecological systems. While multiple zoonotic pathogens circulate in these systems, risks to humans are mostly limited to individual illness or local community outbreaks. These regions are relatively remote, subject to very cold temperatures, have relatively low wildlife, domestic animal, and pathogen diversity, and in many cases low density, including of humans. Hence, favorable conditions for emergence of novel diseases or major amplification of a spillover event are currently not present. The greatest risk to northern communities from pathogens of pandemic potential is via introduction with humans visiting from other areas. However, Arctic and boreal ecosystems are undergoing rapid changes through climate warming, habitat encroachment, and development; all of which can change host and pathogen relationships, thereby affecting the probability of the emergence of new (and re-emergence of old) zoonoses. Indigenous leadership and engagement in disease monitoring, prevention and response, is vital from the outset, and would increase the success of such efforts, as well as ensure the protection of Indigenous rights as outlined in the United Nations Declaration on the Rights of Indigenous Peoples. Partnering with northern communities and including Indigenous Knowledge Systems would improve the timeliness, and likelihood, of detecting emerging zoonotic risks, and contextualize risk assessments to the unique human-wildlife relationships present in northern biomes.


Subject(s)
Animals, Wild , COVID-19 , Animals , Arctic Regions , Ecosystem , Humans , Pandemics/prevention & control , SARS-CoV-2 , United States , Zoonoses/epidemiology
6.
Dermatol Online J ; 26(12)2020 Dec 15.
Article in English | MEDLINE | ID: covidwho-1017482

ABSTRACT

Distinctive patterns in the cutaneous manifestations of COVID-19 have been recently reported. We conducted a systematic review to identify case reports and case series characterizing cutaneous manifestations of confirmed COVID-19. Key demographic and clinical data from each case were extracted and analyzed. The primary outcome measure was risk factor analysis of skin related outcomes for severe COVID-19 disease. Seventy-one case reports and series comprising 144 cases of cutaneous involvement in COVID-19 were included. The most frequently occurring morphologies were: morbilliform (30.6%), varicelliform (18.8%), urticarial (13.2%), chilblains-like (12.5%), and acro-ischemic (9%). The median age of patients was 51 years (mean: 45.9, range: 0 to 91). Patients with chilblains-like eruptions had lower frequencies of extracutaneous COVID-19 symptoms (5/18, 27.8%, P<0.05) and were less likely to have severe COVID-19 disease (2/18, 11%, 95% CI 1.4% to 34.7%, P=0.02). Patients with livedoid and acro-ischemic morphologies had severe COVID-19 more frequently than those with other morphologies (17/21, 81%, 95% CI 58.0% to 94.5%, P<0.0001). The most frequently observed cutaneous manifestations of COVID-19 (morbilliform, varicelliform, and urticarial) are well-described patterns of viral exanthems. However, chilblains-like, livedoid, and acro-ischemic morphologies are not traditionally associated with viral infections and were significantly associated with severity of COVID-19 disease.


Subject(s)
COVID-19/complications , SARS-CoV-2 , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Risk Factors , Skin Diseases, Viral/epidemiology , Skin Diseases, Viral/etiology , Young Adult
7.
Res Sq ; 2020 Oct 28.
Article in English | MEDLINE | ID: covidwho-903184

ABSTRACT

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

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