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Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis
Purpose Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care fo...
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| Published in: | Journal of clinical immunology 2022-02, Vol.42 (2), p.350-364 |
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| container_end_page | 364 |
| container_issue | 2 |
| container_start_page | 350 |
| container_title | Journal of clinical immunology |
| container_volume | 42 |
| creator | Kernan, Kate F. Ghaloul-Gonzalez, Lina Vockley, Jerry Lamb, Janette Hollingshead, Deborah Chandran, Uma Sethi, Rahil Park, Hyun-Jung Berg, Robert A. Wessel, David Pollack, Murray M. Meert, Kathleen L. Hall, Mark W. Newth, Christopher J. L. Lin, John C. Doctor, Allan Shanley, Tom Cornell, Tim Harrison, Rick E. Zuppa, Athena F. Banks, Russel Reeder, Ron W. Holubkov, Richard Notterman, Daniel A. Dean, J. Michael Carcillo, Joseph A. |
| description |
Purpose
Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown.
Methods
We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype.
Results
More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10,
p
= 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11,
p
= 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin
≥
500
ng/mL, OR: 2.16, 95% CI: 1.28–3.66,
p
= 0.004), lymphopenia (lymphocyte count |
| doi_str_mv | 10.1007/s10875-021-01183-4 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8720168</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2626114763</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-cf8df38a0943795007a721eab261b99d29d672e15946b419cd78aa93e7596e6a3</originalsourceid><addsrcrecordid>eNp9kU1vEzEQhi0EoqHwBzggS1y4LPhr1-sLUhWVEqkSkfi4Wl7vbOJq1w62Nygn_nodUkrhwGkkzzOv550XoZeUvKWEyHeJklbWFWG0IpS2vBKP0ILWklesVuwxWhAmaaWoYGfoWUo3hBDesPopOuNCSV7eF-jnOsLejOAt4DDgtcnbsAHvLDa-x-uQwWdnxvHwsLXyXYgeX8YY4nFqNU2zd_mAL1IK1pkMPf5mojM-J-w8Xm7d2Efw-IfLW_wZ9hChlF1y6Tl6MpgxwYu7eo6-frj8svxYXX-6Wi0vrisrpMiVHdp-4K0hSnCp6uLeSEbBdKyhnVI9U30jGdBaiaYTVNletsYoDrJWDTSGn6P3J93d3E3Q22IrmlHvoptMPOhgnP67491Wb8Jet5IR2rRF4M2dQAzfZ0hZTy5ZGEfjIcxJl0XK0akgR_T1P-hNmKMv9gpVOCpkwwvFTpSNIaUIw_0ylOhjvvqUry756l_5alGGXj20cT_yO9AC8BOQSstvIP75-z-yt9iEslI</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2626114763</pqid></control><display><type>article</type><title>Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis</title><source>Springer Nature</source><creator>Kernan, Kate F. ; Ghaloul-Gonzalez, Lina ; Vockley, Jerry ; Lamb, Janette ; Hollingshead, Deborah ; Chandran, Uma ; Sethi, Rahil ; Park, Hyun-Jung ; Berg, Robert A. ; Wessel, David ; Pollack, Murray M. ; Meert, Kathleen L. ; Hall, Mark W. ; Newth, Christopher J. L. ; Lin, John C. ; Doctor, Allan ; Shanley, Tom ; Cornell, Tim ; Harrison, Rick E. ; Zuppa, Athena F. ; Banks, Russel ; Reeder, Ron W. ; Holubkov, Richard ; Notterman, Daniel A. ; Dean, J. Michael ; Carcillo, Joseph A.</creator><creatorcontrib>Kernan, Kate F. ; Ghaloul-Gonzalez, Lina ; Vockley, Jerry ; Lamb, Janette ; Hollingshead, Deborah ; Chandran, Uma ; Sethi, Rahil ; Park, Hyun-Jung ; Berg, Robert A. ; Wessel, David ; Pollack, Murray M. ; Meert, Kathleen L. ; Hall, Mark W. ; Newth, Christopher J. L. ; Lin, John C. ; Doctor, Allan ; Shanley, Tom ; Cornell, Tim ; Harrison, Rick E. ; Zuppa, Athena F. ; Banks, Russel ; Reeder, Ron W. ; Holubkov, Richard ; Notterman, Daniel A. ; Dean, J. Michael ; Carcillo, Joseph A.</creatorcontrib><description>
Purpose
Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown.
Methods
We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype.
Results
More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10,
p
= 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11,
p
= 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin
≥
500
ng/mL, OR: 2.16, 95% CI: 1.28–3.66,
p
= 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60,
p
= 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76,
p
= 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68,
p
= 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5,
p
= 0.019).
Conclusion
Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.</description><identifier>ISSN: 0271-9142</identifier><identifier>EISSN: 1573-2592</identifier><identifier>DOI: 10.1007/s10875-021-01183-4</identifier><identifier>PMID: 34973142</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Biomedical and Life Sciences ; Biomedicine ; Cell number ; Child ; Children ; Exome Sequencing ; Ferritin ; Heredity ; Humans ; Immunity ; Immunodeficiency ; Immunologic Deficiency Syndromes - genetics ; Immunological diseases ; Immunology ; Infectious Diseases ; Inflammation ; Internal Medicine ; Lymphocytes ; Lymphopenia ; Medical Microbiology ; Original ; Original Article ; Oxygenation ; Pediatrics ; Phenotype ; Phenotypes ; Point mutation ; Prevalence ; Sepsis ; Sepsis - epidemiology ; Sepsis - genetics ; Thrombocytopenia</subject><ispartof>Journal of clinical immunology, 2022-02, Vol.42 (2), p.350-364</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-cf8df38a0943795007a721eab261b99d29d672e15946b419cd78aa93e7596e6a3</citedby><cites>FETCH-LOGICAL-c474t-cf8df38a0943795007a721eab261b99d29d672e15946b419cd78aa93e7596e6a3</cites><orcidid>0000-0002-6337-841X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34973142$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kernan, Kate F.</creatorcontrib><creatorcontrib>Ghaloul-Gonzalez, Lina</creatorcontrib><creatorcontrib>Vockley, Jerry</creatorcontrib><creatorcontrib>Lamb, Janette</creatorcontrib><creatorcontrib>Hollingshead, Deborah</creatorcontrib><creatorcontrib>Chandran, Uma</creatorcontrib><creatorcontrib>Sethi, Rahil</creatorcontrib><creatorcontrib>Park, Hyun-Jung</creatorcontrib><creatorcontrib>Berg, Robert A.</creatorcontrib><creatorcontrib>Wessel, David</creatorcontrib><creatorcontrib>Pollack, Murray M.</creatorcontrib><creatorcontrib>Meert, Kathleen L.</creatorcontrib><creatorcontrib>Hall, Mark W.</creatorcontrib><creatorcontrib>Newth, Christopher J. L.</creatorcontrib><creatorcontrib>Lin, John C.</creatorcontrib><creatorcontrib>Doctor, Allan</creatorcontrib><creatorcontrib>Shanley, Tom</creatorcontrib><creatorcontrib>Cornell, Tim</creatorcontrib><creatorcontrib>Harrison, Rick E.</creatorcontrib><creatorcontrib>Zuppa, Athena F.</creatorcontrib><creatorcontrib>Banks, Russel</creatorcontrib><creatorcontrib>Reeder, Ron W.</creatorcontrib><creatorcontrib>Holubkov, Richard</creatorcontrib><creatorcontrib>Notterman, Daniel A.</creatorcontrib><creatorcontrib>Dean, J. Michael</creatorcontrib><creatorcontrib>Carcillo, Joseph A.</creatorcontrib><title>Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis</title><title>Journal of clinical immunology</title><addtitle>J Clin Immunol</addtitle><addtitle>J Clin Immunol</addtitle><description>
Purpose
Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown.
Methods
We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype.
Results
More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10,
p
= 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11,
p
= 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin
≥
500
ng/mL, OR: 2.16, 95% CI: 1.28–3.66,
p
= 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60,
p
= 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76,
p
= 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68,
p
= 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5,
p
= 0.019).
Conclusion
Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.</description><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell number</subject><subject>Child</subject><subject>Children</subject><subject>Exome Sequencing</subject><subject>Ferritin</subject><subject>Heredity</subject><subject>Humans</subject><subject>Immunity</subject><subject>Immunodeficiency</subject><subject>Immunologic Deficiency Syndromes - genetics</subject><subject>Immunological diseases</subject><subject>Immunology</subject><subject>Infectious Diseases</subject><subject>Inflammation</subject><subject>Internal Medicine</subject><subject>Lymphocytes</subject><subject>Lymphopenia</subject><subject>Medical Microbiology</subject><subject>Original</subject><subject>Original Article</subject><subject>Oxygenation</subject><subject>Pediatrics</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Point mutation</subject><subject>Prevalence</subject><subject>Sepsis</subject><subject>Sepsis - epidemiology</subject><subject>Sepsis - genetics</subject><subject>Thrombocytopenia</subject><issn>0271-9142</issn><issn>1573-2592</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kU1vEzEQhi0EoqHwBzggS1y4LPhr1-sLUhWVEqkSkfi4Wl7vbOJq1w62Nygn_nodUkrhwGkkzzOv550XoZeUvKWEyHeJklbWFWG0IpS2vBKP0ILWklesVuwxWhAmaaWoYGfoWUo3hBDesPopOuNCSV7eF-jnOsLejOAt4DDgtcnbsAHvLDa-x-uQwWdnxvHwsLXyXYgeX8YY4nFqNU2zd_mAL1IK1pkMPf5mojM-J-w8Xm7d2Efw-IfLW_wZ9hChlF1y6Tl6MpgxwYu7eo6-frj8svxYXX-6Wi0vrisrpMiVHdp-4K0hSnCp6uLeSEbBdKyhnVI9U30jGdBaiaYTVNletsYoDrJWDTSGn6P3J93d3E3Q22IrmlHvoptMPOhgnP67491Wb8Jet5IR2rRF4M2dQAzfZ0hZTy5ZGEfjIcxJl0XK0akgR_T1P-hNmKMv9gpVOCpkwwvFTpSNIaUIw_0ylOhjvvqUry756l_5alGGXj20cT_yO9AC8BOQSstvIP75-z-yt9iEslI</recordid><startdate>20220201</startdate><enddate>20220201</enddate><creator>Kernan, Kate F.</creator><creator>Ghaloul-Gonzalez, Lina</creator><creator>Vockley, Jerry</creator><creator>Lamb, Janette</creator><creator>Hollingshead, Deborah</creator><creator>Chandran, Uma</creator><creator>Sethi, Rahil</creator><creator>Park, Hyun-Jung</creator><creator>Berg, Robert A.</creator><creator>Wessel, David</creator><creator>Pollack, Murray M.</creator><creator>Meert, Kathleen L.</creator><creator>Hall, Mark W.</creator><creator>Newth, Christopher J. L.</creator><creator>Lin, John C.</creator><creator>Doctor, Allan</creator><creator>Shanley, Tom</creator><creator>Cornell, Tim</creator><creator>Harrison, Rick E.</creator><creator>Zuppa, Athena F.</creator><creator>Banks, Russel</creator><creator>Reeder, Ron W.</creator><creator>Holubkov, Richard</creator><creator>Notterman, Daniel A.</creator><creator>Dean, J. Michael</creator><creator>Carcillo, Joseph A.</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6337-841X</orcidid></search><sort><creationdate>20220201</creationdate><title>Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis</title><author>Kernan, Kate F. ; Ghaloul-Gonzalez, Lina ; Vockley, Jerry ; Lamb, Janette ; Hollingshead, Deborah ; Chandran, Uma ; Sethi, Rahil ; Park, Hyun-Jung ; Berg, Robert A. ; Wessel, David ; Pollack, Murray M. ; Meert, Kathleen L. ; Hall, Mark W. ; Newth, Christopher J. L. ; Lin, John C. ; Doctor, Allan ; Shanley, Tom ; Cornell, Tim ; Harrison, Rick E. ; Zuppa, Athena F. ; Banks, Russel ; Reeder, Ron W. ; Holubkov, Richard ; Notterman, Daniel A. ; Dean, J. Michael ; Carcillo, Joseph A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-cf8df38a0943795007a721eab261b99d29d672e15946b419cd78aa93e7596e6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cell number</topic><topic>Child</topic><topic>Children</topic><topic>Exome Sequencing</topic><topic>Ferritin</topic><topic>Heredity</topic><topic>Humans</topic><topic>Immunity</topic><topic>Immunodeficiency</topic><topic>Immunologic Deficiency Syndromes - genetics</topic><topic>Immunological diseases</topic><topic>Immunology</topic><topic>Infectious Diseases</topic><topic>Inflammation</topic><topic>Internal Medicine</topic><topic>Lymphocytes</topic><topic>Lymphopenia</topic><topic>Medical Microbiology</topic><topic>Original</topic><topic>Original Article</topic><topic>Oxygenation</topic><topic>Pediatrics</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Point mutation</topic><topic>Prevalence</topic><topic>Sepsis</topic><topic>Sepsis - epidemiology</topic><topic>Sepsis - genetics</topic><topic>Thrombocytopenia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kernan, Kate F.</creatorcontrib><creatorcontrib>Ghaloul-Gonzalez, Lina</creatorcontrib><creatorcontrib>Vockley, Jerry</creatorcontrib><creatorcontrib>Lamb, Janette</creatorcontrib><creatorcontrib>Hollingshead, Deborah</creatorcontrib><creatorcontrib>Chandran, Uma</creatorcontrib><creatorcontrib>Sethi, Rahil</creatorcontrib><creatorcontrib>Park, Hyun-Jung</creatorcontrib><creatorcontrib>Berg, Robert A.</creatorcontrib><creatorcontrib>Wessel, David</creatorcontrib><creatorcontrib>Pollack, Murray M.</creatorcontrib><creatorcontrib>Meert, Kathleen L.</creatorcontrib><creatorcontrib>Hall, Mark W.</creatorcontrib><creatorcontrib>Newth, Christopher J. L.</creatorcontrib><creatorcontrib>Lin, John C.</creatorcontrib><creatorcontrib>Doctor, Allan</creatorcontrib><creatorcontrib>Shanley, Tom</creatorcontrib><creatorcontrib>Cornell, Tim</creatorcontrib><creatorcontrib>Harrison, Rick E.</creatorcontrib><creatorcontrib>Zuppa, Athena F.</creatorcontrib><creatorcontrib>Banks, Russel</creatorcontrib><creatorcontrib>Reeder, Ron W.</creatorcontrib><creatorcontrib>Holubkov, Richard</creatorcontrib><creatorcontrib>Notterman, Daniel A.</creatorcontrib><creatorcontrib>Dean, J. Michael</creatorcontrib><creatorcontrib>Carcillo, Joseph A.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kernan, Kate F.</au><au>Ghaloul-Gonzalez, Lina</au><au>Vockley, Jerry</au><au>Lamb, Janette</au><au>Hollingshead, Deborah</au><au>Chandran, Uma</au><au>Sethi, Rahil</au><au>Park, Hyun-Jung</au><au>Berg, Robert A.</au><au>Wessel, David</au><au>Pollack, Murray M.</au><au>Meert, Kathleen L.</au><au>Hall, Mark W.</au><au>Newth, Christopher J. L.</au><au>Lin, John C.</au><au>Doctor, Allan</au><au>Shanley, Tom</au><au>Cornell, Tim</au><au>Harrison, Rick E.</au><au>Zuppa, Athena F.</au><au>Banks, Russel</au><au>Reeder, Ron W.</au><au>Holubkov, Richard</au><au>Notterman, Daniel A.</au><au>Dean, J. Michael</au><au>Carcillo, Joseph A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis</atitle><jtitle>Journal of clinical immunology</jtitle><stitle>J Clin Immunol</stitle><addtitle>J Clin Immunol</addtitle><date>2022-02-01</date><risdate>2022</risdate><volume>42</volume><issue>2</issue><spage>350</spage><epage>364</epage><pages>350-364</pages><issn>0271-9142</issn><eissn>1573-2592</eissn><abstract>
Purpose
Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown.
Methods
We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype.
Results
More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10,
p
= 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11,
p
= 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin
≥
500
ng/mL, OR: 2.16, 95% CI: 1.28–3.66,
p
= 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60,
p
= 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76,
p
= 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68,
p
= 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5,
p
= 0.019).
Conclusion
Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34973142</pmid><doi>10.1007/s10875-021-01183-4</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-6337-841X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0271-9142 |
| ispartof | Journal of clinical immunology, 2022-02, Vol.42 (2), p.350-364 |
| issn | 0271-9142 1573-2592 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8720168 |
| source | Springer Nature |
| subjects | Biomedical and Life Sciences Biomedicine Cell number Child Children Exome Sequencing Ferritin Heredity Humans Immunity Immunodeficiency Immunologic Deficiency Syndromes - genetics Immunological diseases Immunology Infectious Diseases Inflammation Internal Medicine Lymphocytes Lymphopenia Medical Microbiology Original Original Article Oxygenation Pediatrics Phenotype Phenotypes Point mutation Prevalence Sepsis Sepsis - epidemiology Sepsis - genetics Thrombocytopenia |
| title | Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T15%3A24%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Prevalence%20of%20Pathogenic%20and%20Potentially%20Pathogenic%20Inborn%20Error%20of%20Immunity%20Associated%20Variants%20in%20Children%20with%20Severe%20Sepsis&rft.jtitle=Journal%20of%20clinical%20immunology&rft.au=Kernan,%20Kate%20F.&rft.date=2022-02-01&rft.volume=42&rft.issue=2&rft.spage=350&rft.epage=364&rft.pages=350-364&rft.issn=0271-9142&rft.eissn=1573-2592&rft_id=info:doi/10.1007/s10875-021-01183-4&rft_dat=%3Cproquest_pubme%3E2626114763%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c474t-cf8df38a0943795007a721eab261b99d29d672e15946b419cd78aa93e7596e6a3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2626114763&rft_id=info:pmid/34973142&rfr_iscdi=true |