Lack of association between pandemic chilblains and SARS-CoV-2 infection

An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 9; pp. 1 - 9
Main Authors Gehlhausen, Jeff R., Little, Alicia J., Ko, Christine J., Emmenegger, Marc, Lucas, Carolina, Wong, Patrick, Klein, Jon, Lu, Peiwen, Mao, Tianyang, Jaycox, Jillian, Wang, Eric, Ugwu, Nelson, Muenker, Cate, Mekael, Dilgash, Klein, Rhonda Q., Patrignelli, Robert, Antaya, Richard, McNiff, Jennifer, Damsky, William, Kamath, Kathy, Shon, John, Ring, Aaron M., Yildirim, Inci, Omer, Saad, Ko, Albert I., Aguzzi, Adriano, Iwasaki, Akiko
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 01.03.2022
Subjects
Adult
Antibodies
Antigens
Biological Sciences
Biopsy
Chilblains - epidemiology
Chilblains - immunology
Chilblains - virology
Connecticut - epidemiology
Coronaviruses
COVID-19
COVID-19 - complications
COVID-19 - epidemiology
Enzyme-linked immunosorbent assay
Epitopes
Female
Humans
Immunohistochemistry
Infections
Lymphocytes
Lymphocytes T
Male
Middle Aged
Pandemics
Respiratory diseases
Retrospective Studies
SARS-CoV-2 - immunology
Serology
Severe acute respiratory syndrome coronavirus 2
T cell receptors
Titration
Viral diseases
Young Adult
Connecticut
covid toe
SARS-CoV-2
pernio
interferon
chilblain
Online AccessGet full text

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Abstract An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2–associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as “covid toes” during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.
AbstractList Chilblain diagnoses have increased during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and have been attributed to viral infection and a subsequent robust antiviral immune response. As a result, providers have managed these cases differently than idiopathic chilblains, which are associated with cold exposure. The relationship between pandemic chilblains and SARS-CoV-2 infection, however, remains unclear as most patients do not test positive for SARS-CoV-2–specific PCR or antibodies. To better understand this disconnect, we enrolled cases of pandemic chilblains in a study and performed detailed immune profiling of antibody and T cell responses. Additionally, we compared immunohistochemical staining of pandemic chilblains with prepandemic tissues. Our results do not support SARS-CoV-2 as the cause of the increased chilblain incidence. An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2–associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as “covid toes” during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.
An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.
An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2–associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as “covid toes” during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.
An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.
Author Ugwu, Nelson
Wang, Eric
Kamath, Kathy
Yildirim, Inci
Lucas, Carolina
Wong, Patrick
Aguzzi, Adriano
Gehlhausen, Jeff R.
Patrignelli, Robert
Ko, Christine J.
Klein, Rhonda Q.
Omer, Saad
Lu, Peiwen
Shon, John
Mao, Tianyang
Iwasaki, Akiko
Ko, Albert I.
Little, Alicia J.
Mekael, Dilgash
Emmenegger, Marc
McNiff, Jennifer
Jaycox, Jillian
Damsky, William
Klein, Jon
Antaya, Richard
Muenker, Cate
Ring, Aaron M.
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/35217624$$D View this record in MEDLINE/PubMed
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Linehan, Melissa
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Copyright Copyright © 2022 the Author(s). Published by PNAS.
Copyright National Academy of Sciences Mar 1, 2022
Copyright © 2022 the Author(s). Published by PNAS. 2022
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Keywords covid toe
SARS-CoV-2
pernio
interferon
chilblain
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License Copyright © 2022 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
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1A complete list of the Yale IMPACT Team can be found in SI Appendix.
Contributed by Akiko Iwasaki; received December 6, 2021; accepted January 5, 2022; reviewed by Shawn Demerhi and Elizabeth Grice
Author contributions: J.R.G., S.O., A.I.K., A.A., and A.I. designed research; J.R.G., A.J.L., C.J.K., M.E., C.L., P.W., J.K., P.L., T.M., J.J., E.W., Y.I.T., N.U., C.M., D.M., R.A., J.M., K.K., A.M.R., and I.Y. performed research; A.J.L., C.J.K., M.E., R.Q.K., R.P., R.A., J.M., W.D., J.S., A.M.R., I.Y., and A.A. contributed new reagents/analytic tools; J.R.G., M.E., C.L., P.W., J.K., P.L., T.M., J.J., E.W., K.K., J.S., A.M.R., S.O., A.I.K., A.A., and A.I. analyzed data; Y.I.T. processed, stored, and distributed biospecimens; A.I. supervised the project and established collaborations; and J.R.G. and A.I. wrote the paper.
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Snippet An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral...
Chilblain diagnoses have increased during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and have been attributed to viral infection...
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SubjectTerms Adult
Antibodies
Antigens
Biological Sciences
Biopsy
Chilblains - epidemiology
Chilblains - immunology
Chilblains - virology
Connecticut - epidemiology
Coronaviruses
COVID-19
COVID-19 - complications
COVID-19 - epidemiology
Enzyme-linked immunosorbent assay
Epitopes
Female
Humans
Immunohistochemistry
Infections
Lymphocytes
Lymphocytes T
Male
Middle Aged
Pandemics
Respiratory diseases
Retrospective Studies
SARS-CoV-2 - immunology
Serology
Severe acute respiratory syndrome coronavirus 2
T cell receptors
Titration
Viral diseases
Young Adult
Title Lack of association between pandemic chilblains and SARS-CoV-2 infection
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