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Journal article
Type 2 immune responses are associated with less severe COVID-19 in a hospitalized cohort
The journal of allergy and clinical immunology. Global, v 4(4), 100515
01 Nov 2025
PMID: 40709330
Abstract
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly after its identification in December 2019 to cause a global pandemic. The respiratory tract is the primary site of infection, and there is a large range in the severity of respiratory illnesses caused by the virus. Defining molecular and cellular factors for protection from severe disease and death has been a goal to better understand and to predict and mitigate the effects of SARS-CoV-2 and future coronaviruses.
Despite well-known susceptibilities to respiratory viral infections, respiratory allergy and allergic asthma have not been identified as risk factors for severe coronavirus disease 2019 (COVID-19) in most epidemiologic studies and may be protective. We sought to investigate associations between markers of type 2 (T2) immune responses with SARS-CoV-2 clinical outcomes and virus loads in a cohort of 1164 individuals hospitalized for COVID-19 from May 2020 to March 2021 as part of the IMPACC study.
We characterized the clinical outcomes, as defined by severity trajectory groups reflecting the degree of respiratory support required, virus loads, and antibody titers of COVID-19 infections in IMPACC participants in relation to molecular and cellular markers of T2 immune responses through multiple assays, including, (1) IL-4, IL-5, and IL-13 levels in serum Olink data, (2) T2 cellular signatures in blood cytometry by time of flight data, (3) relative quantification of T2 signaling gene pathways in airway RNA sequencing data, and/or (4) T2 pathways in peripheral blood mononuclear cell RNA sequencing data. We also investigated the outcomes of individuals with self-reported asthma and evidence of T2 immune responses.
The diagnosis of asthma (odd ratio = 1.27), elevated serum T2 cytokine levels (median fold change = 1.06), and a higher frequency of TH2 cells (difference = +2%) were associated with less severe clinical disease during hospitalization. Distinct T2-related transcriptomic changes in nasal and blood samples were associated with reduced virus loads. This included the expression of T2-regulated genes implicated in T-/B-cell activation and apoptosis in nasal samples and the expression of T2-regulated genes implicated in myeloid differentiation and reactive oxygen species signaling in blood. Among these, several canonical T2-regulated genes that were increased in less severe disease were identified to have antiviral properties in large high-throughput screens.
T2 immune responses were associated with lower virus loads and more favorable clinical outcomes, suggesting that T2 inflammation related to asthma and allergic diseases may have a direct protective effect against SARS-CoV-2.
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- Title
- Type 2 immune responses are associated with less severe COVID-19 in a hospitalized cohort
- Creators
- IMPACC Network (Collaboration)Carolyn S. Calfee - University of California, San FranciscoNaresh Doni Jayavelu - Behavioral Tech Research, Inc.Jingjing Qi - Icahn School of Medicine at Mount SinaiCarly E. Milliren - Boston Children's HospitalAl Ozonoff - Boston Children's HospitalShanshan Liu - Boston Children's HospitalOfer Levy - Boston Children's HospitalLindsey R. Baden - National Institute of Allergy and Infectious DiseasesEsther Melamed - The University of Texas at AustinGrace A. McComsey - University Hospitals of ClevelandCharles B. Cairns - Drexel UniversityJoanna Schaenman - University of California, Los AngelesAlbert C. Shaw - Yale UniversityDavid A. Hafler - Yale UniversityDavid B. Corry - Baylor College of MedicineFarrah Kheradmand - Baylor College of MedicineMark A. Atkinson - University of FloridaScott C. Brakenridge - University of FloridaNelson I. Agudelo Higuita - OU HealthJordan P. Metcalf - University of Oklahoma Health Sciences CenterCatherine L. Hough - Oregon Health & Science UniversityWilliam B. Messer - Oregon Health & Science UniversityBali Pulendran - Palo Alto UniversityKari C. Nadeau - Stanford UniversityMark M. Davis - Stanford UniversityLinda N. Geng - Stanford UniversityAna Fernandez Sesma - Icahn School of Medicine at Mount SinaiViviana Simon - Icahn School of Medicine at Mount SinaiFlorian Krammer - Icahn School of Medicine at Mount SinaiChris Bime - University of ArizonaSteven E. Bosinger - Emory UniversityWalter Eckalbar - University of California, San FranciscoHanno Steen - Boston Children's HospitalHolden T. Maecker - Stanford UniversityPatrice M. Becker - National Institute of Allergy and Infectious DiseasesAlison D. Augustine - National Institute of Allergy and Infectious DiseasesSteven M. Holland - National Institute of Allergy and Infectious DiseasesLindsey B. Rosen - National Institute of Allergy and Infectious DiseasesSerena Lee - National Institute of Allergy and Infectious DiseasesTatyana Vaysman - National Institute of Allergy and Infectious DiseasesJoann Diray-Arce - National Institute of Allergy and Infectious DiseasesJing Chen - Boston Children's HospitalAlvin Kho - Boston Children's HospitalAnnmarie Hoch - Boston Children's HospitalAna C. Chang - Boston Children's HospitalKerry McEnaney - Boston Children's HospitalBrenda Barton - Boston Children's HospitalClaudia Lentucci - Boston Children's HospitalMaimouna D. Murphy - Boston Children's HospitalMehmet Saluvan - Boston Children's HospitalTanzia Shaheen - Boston Children's HospitalCaitlin Syphurs - Boston Children's HospitalMarisa Albert - Boston Children's HospitalArash Nemati Hayati - Boston Children's HospitalRobert Bryant - Boston Children's HospitalJames Abraham - Boston Children's HospitalSanya Thomas - Boston Children's HospitalMitchell Cooney - Boston Children's HospitalMeagan Karoly - Boston Children's HospitalMatthew C. Altman - Behavioral Tech Research, Inc.Scott Presnell - University of WashingtonBernard Kohr - University of WashingtonTomasz Jancsyk - University of WashingtonAzlann Arnett - University of WashingtonBjoern Peters - La Jolla Institute for ImmunologyJames A. Overton - La Jolla Institute for ImmunologyRandi Vita - La Jolla Institute for ImmunologyKerstin Westendorf - La Jolla Institute for ImmunologyPatrick van Zalm - Boston Children's HospitalBenoit Fatou - Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MassKinga K. Smolen - Boston Children's HospitalArthur Viode - Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MassSimon van Haren - Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MassMeenakshi Jha - Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MassDavid Stevenson - Boston Children's HospitalOludare Odumade - Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MassLindsey R. Baden - National Institute of Allergy and Infectious DiseasesKevin Mendez - Brigham and Women's HospitalJessica Lasky-Su - Brigham and Women's HospitalAlexandra Tong - Brigham and Women's HospitalRebecca Rooks - Brigham and Women's HospitalMichael Desjardins - Brigham and Women's HospitalAmy C. Sherman - Brigham and Women's HospitalStephen R. Walsh - Brigham and Women's HospitalXhoi Mitre - Brigham and Women's HospitalJessica Cauley - Brigham and Women's HospitalXiofang Li - Brigham and Women's HospitalBethany Evans - Brigham and Women's HospitalChristina Montesano - Brigham and Women's HospitalJose Humberto Licona - Brigham and Women's HospitalJonathan Krauss - Brigham and Women's HospitalNicholas C. Issa - Brigham and Women's HospitalJun Bai Park Chang - Brigham and Women's HospitalNatalie Izaguirre - Brigham and Women's HospitalScott R. Hutton - Metabolon Inc, Morrisville, NCGreg Michelotti - Metabolon Inc, Morrisville, NCKari Wong - Metabolon Inc, Morrisville, NCScott J. Tebbutt - University of British ColumbiaCasey P. Shannon - University of British ColumbiaRafick-Pierre Sekaly - Case Western Reserve UniversitySlim Fourati - University Hospitals of ClevelandPaul Harris - Case Western Reserve UniversityScott Sieg - Case Western Reserve UniversitySusan Pereira Ribeiro - Case Western Reserve UniversityElias K. Haddad - Drexel UniversityMichele A. Kutzler - Drexel UniversityMariana Bernui - Drexel UniversityGina Cusimano - Drexel UniversityJennifer Connors - Drexel UniversityKyra Woloszczuk - Drexel UniversityDavid Joyner - Drexel UniversityCarolyn Edwards - Drexel UniversityEdward Lee - Drexel University, Tower Health Hospital, Philadelphia, PaEdward Lin - Drexel UniversityNataliya Melnyk - Drexel UniversityDebra L. Powell - Drexel UniversityJames N. Kim - Drexel UniversityI. Michael Goonewardene - Drexel UniversityBrent Simmons - Drexel University, Tower Health Hospital, Philadelphia, PaCecilia M. Smith - Drexel UniversityMark Martens - Drexel University, Tower Health Hospital, Philadelphia, PaBrett Croen - Drexel University, Tower Health Hospital, Philadelphia, PaNicholas C. Semenza - Drexel UniversityMathew R. Bell - Drexel University, Tower Health Hospital, Philadelphia, PaSara Furukawa - Drexel UniversityRenee McLin - Drexel University, Tower Health Hospital, Philadelphia, PaGeorge P. Tegos - Drexel University, Tower Health Hospital, Philadelphia, PaBrandon Rogowski - Drexel University, Tower Health Hospital, Philadelphia, PaNathan Mege - Drexel UniversityKristen Ulring - Drexel University, Tower Health Hospital, Philadelphia, PaPam Schearer - Drexel University, Tower Health Hospital, Philadelphia, PaJudie Sheidy - Drexel University, Tower Health Hospital, Philadelphia, PaCrystal Nagle - Drexel University, Tower Health Hospital, Philadelphia, PaVicki Seyfert-Margolis - MyOwnMed Inc, Bethesda, MdNadine Rouphael - Emory and Henry CollegeSteven E. Bosinger - Emory UniversityArun K. Boddapati - Emory and Henry CollegeGreg K. Tharp - Emory and Henry CollegeKathryn L. Pellegrini - Emory and Henry CollegeBrandi Johnson - Emory and Henry CollegeBernadine Panganiban - Emory and Henry CollegeChristopher Huerta - Emory and Henry CollegeEvan J. Anderson - Emory and Henry CollegeHady Samaha - Emory and Henry CollegeJonathan E. Sevransky - Emory and Henry CollegeLaurel Bristow - Emory and Henry CollegeElizabeth Beagle - Emory and Henry CollegeDavid Cowan - Emory and Henry CollegeSydney Hamilton - Emory and Henry CollegeThomas Hodder - Emory and Henry CollegeAmer Bechnak - Emory and Henry CollegeAndrew Cheng - Emory and Henry CollegeAneesh Mehta - Emory and Henry CollegeCaroline R. Ciric - Emory and Henry CollegeChristine Spainhour - Emory and Henry CollegeErin Carter - Emory and Henry CollegeErin M. Scherer - Emory and Henry CollegeJacob Usher - Emory and Henry CollegeKieffer Hellmeister - Emory and Henry CollegeLaila Hussaini - Emory and Henry CollegeLauren Hewitt - Emory and Henry CollegeNina Mcnair - Emory and Henry CollegeSonia Wimalasena - Emory and Henry CollegeAna Fernandez-Sesma - Icahn School of Medicine at Mount SinaiHarm Van Bakel - Icahn School of Medicine at Mount SinaiSeunghee Kim-Schulze - Icahn School of Medicine at Mount SinaiAna Silvia Gonzalez Reiche - Icahn School of Medicine at Mount SinaiBrian Lee - Icahn School of Medicine at Mount SinaiJuan Manuel Carreño - Icahn School of Medicine at Mount SinaiGagandeep Singh - Icahn School of Medicine at Mount SinaiAriel Raskin - Icahn School of Medicine at Mount SinaiJohnstone Tcheou - Icahn School of Medicine at Mount SinaiZain Khalil - Icahn School of Medicine at Mount SinaiAdriana van de Guchte - Icahn School of Medicine at Mount SinaiKeith Farrugia - Icahn School of Medicine at Mount SinaiZenab Khan - Icahn School of Medicine at Mount SinaiGeoffrey Kelly - Icahn School of Medicine at Mount SinaiKomal Srivastava - Icahn School of Medicine at Mount SinaiLily Q. Eaker - Icahn School of Medicine at Mount SinaiMaria C. Bermúdez-González - Icahn School of Medicine at Mount SinaiLubbertus C.F. Mulder - Icahn School of Medicine at Mount SinaiKatherine F. Beach - Icahn School of Medicine at Mount SinaiMiti Saksena - Icahn School of Medicine at Mount SinaiDeena Altman - Icahn School of Medicine at Mount SinaiErna Kojic - Icahn School of Medicine at Mount SinaiLevy A. Sominsky - Icahn School of Medicine at Mount SinaiArman Azad - Icahn School of Medicine at Mount SinaiDominika Bielak - Icahn School of Medicine at Mount SinaiHisaaki Kawabata - Icahn School of Medicine at Mount SinaiTemima Yellin - Icahn School of Medicine at Mount SinaiMiriam Fried - Icahn School of Medicine at Mount SinaiLeeba Sullivan - Icahn School of Medicine at Mount SinaiSara Morris - Icahn School of Medicine at Mount SinaiGiulio Kleiner - Icahn School of Medicine at Mount SinaiDaniel Stadlbauer - Icahn School of Medicine at Mount SinaiJayeeta Dutta - Icahn School of Medicine at Mount SinaiHui Xie - Icahn School of Medicine at Mount SinaiManishkumar Patel - Icahn School of Medicine at Mount SinaiKai Nie - Icahn School of Medicine at Mount SinaiAdeeb Rahman - Immunai Inc, New York, NYSarah A.R. Siegel - Oregon Health & Science UniversityPeter E. Sullivan - Oregon Health & Science UniversityZhengchun Lu - Oregon Health & Science UniversityAmanda E. Brunton - Oregon Health & Science UniversityMatthew Strand - Oregon Health & Science UniversityZoe L. Lyski - Oregon Health & Science UniversityFelicity J. Coulter - Oregon Health & Science UniversityCourtney Micheleti - Oregon Health & Science UniversityYael Rosenberg-Hasson - Stanford University School of MedicineMichael Leipold - Stanford University School of MedicineNatalia Sigal - Stanford University School of MedicineAngela Rogers - Stanford University School of MedicineAndrea Fernandes - Stanford University School of MedicineMonali Manohar - Stanford University School of MedicineEvan Do - Stanford University School of MedicineIris Chang - Stanford University School of MedicineAlexandra S. Lee - Stanford University School of MedicineCatherine Blish - Stanford University School of MedicineHenna Naz Din - Stanford University School of MedicineJonasel Roque - Stanford University School of MedicineMaja Artandi - Stanford University School of MedicineNeera Ahuja - Stanford University School of MedicineSamuel S. Yang - Stanford University School of MedicineSharon Chinthrajah - Stanford University School of MedicineThomas Hagan - Stanford University School of MedicineElaine F. Reed - University of California, Los AngelesRamin Salehi-Rad - University of California, Los AngelesAdreanne M. Rivera - University of California, Los AngelesHarry C. Pickering - University of California, Los AngelesSubha Sen - University of California, Los AngelesDavid Elashoff - University of California, Los AngelesDawn C. Ward - University of California, Los AngelesJenny Brook - University of California, Los AngelesEstefania Ramires Sanchez - University of California, Los AngelesMegan Llamas - University of California, Los AngelesClaudia Perdomo - University of California, Los AngelesClara E. Magyar - University of California, Los AngelesJennifer Fulcher - University of California, Los AngelesDavid J. Erle - University of California, San FranciscoCarolyn M. Hendrickson - University of California, San FranciscoKirsten N. Kangelaris - University of California, San FranciscoViet Nguyen - University of California, San FranciscoDeanna Lee - University of California, San FranciscoSuzanna Chak - University of California, San FranciscoRajani Ghale - University of California, San FranciscoAna Gonzalez - University of California, San FranciscoAlejandra Jauregui - University of California, San FranciscoCarolyn Leroux - University of California, San FranciscoLuz Torres Altamirano - University of California, San FranciscoAhmad Sadeed Rashid - University of California, San FranciscoAndrew Willmore - University of California, San FranciscoPrescott G. Woodruff - University of California, San FranciscoMatthew F. Krummel - University of California, San FranciscoSidney Carrillo - University of California, San FranciscoAlyssa Ward - University of California, San FranciscoCharles R. Langelier - University of California, San FranciscoRavi Patel - University of California, San FranciscoMichael Wilson - University of California, San FranciscoRavi Dandekar - University of California, San FranciscoBonny Alvarenga - University of California, San FranciscoJayant Rajan - University of California, San FranciscoAndrew W. Schroeder - University of California, San FranciscoGabriela K. Fragiadakis - University of California, San FranciscoAlexandra Tsitsiklis - University of California, San FranciscoEran Mick - University of California, San FranciscoYanedth Sanchez Guerrero - University of California, San FranciscoChristina Love - University of California, San FranciscoLenka Maliskova - University of California, San FranciscoMichael Adkisson - University of California, San FranciscoAleksandra Leligdowicz - University of California, San FranciscoAlexander Beagle - University of California, San FranciscoArjun Rao - University of California, San FranciscoAustin Sigman - University of California, San FranciscoBushra Samad - University of California, San FranciscoCindy Curiel - University of California, San FranciscoCole Shaw - University of California, San FranciscoGayelan Tietje-Ulrich - University of California, San FranciscoJeff Milush - University of California, San FranciscoJonathan Singer - University of California, San FranciscoJoshua J. Vasquez - University of California, San FranciscoKevin Tang - University of California, San FranciscoLegna Betancourt - University of California, San FranciscoLekshmi Santhosh - University of California, San FranciscoLogan Pierce - University of California, San FranciscoMaria Tecero Paz - University of California, San FranciscoMichael Matthay - University of California, San FranciscoNeeta Thakur - University of California, San FranciscoNicklaus Rodriguez - University of California, San FranciscoNicole Sutter - University of California, San FranciscoNorman Jones - University of California, San FranciscoPratik Sinha - University of California, San FranciscoPriya Prasad - University of California, San FranciscoRaphael Lota - University of California, San FranciscoSadeed Rashid - University of California, San FranciscoSaurabh Asthana - University of California, San FranciscoSharvari Bhide - University of California, San FranciscoTasha Lea - University of California, San FranciscoYumiko Abe-Jones - University of California, San FranciscoRuth R. Montgomery - Yale UniversitySteven H. Kleinstein - Yale School of MedicineJeremy P. Gygi - Yale School of MedicineShrikant Pawar - Yale School of MedicineAnna Konstorum - Yale School of MedicineErnie Chen - Yale School of MedicineChris Cotsapas - Yale School of MedicineXiaomei Wang - Yale School of MedicineLeqi Xu - Yale School of MedicineCharles Dela Cruz - Yale School of MedicineAkiko Iwasaki - Yale School of MedicineSubhasis Mohanty - Yale School of MedicineAllison Nelson - Yale School of MedicineYujiao Zhao - Yale School of MedicineShelli Farhadian - Yale School of MedicineHiromitsu Asashima - Yale School of MedicineOmkar Chaudhary - Yale School of MedicineAndreas Coppi - Yale School of MedicineJohn Fournier - Yale School of MedicineM. Catherine Muenker - Yale School of MedicineKhadir Raddassi - Yale School of MedicineMichael Rainone - Yale School of MedicineWilliam Ruff - Yale School of MedicineSyim Salahuddin - Yale School of MedicineWade L. Shulz - Yale School of MedicinePavithra Vijayakumar - Yale School of MedicineHaowei Wang - Yale School of MedicineEsio Wunder - Yale School of MedicineH. Patrick Young - Yale School of MedicineAlbert I. Ko - Yale School of MedicineXiomei Wang - Yale School of MedicineDylan Duchen - Yale School of MedicineDenise Esserman - Yale School of Public Health, New Haven, ConnLeying Guan - Yale School of Public Health, New Haven, ConnAnderson Brito - Yale School of Public Health, New Haven, ConnJessica Rothman - Yale School of Public Health, New Haven, ConnNathan D. Grubaugh - Yale School of Public Health, New Haven, ConnFarrah Kheradmand - Baylor College of MedicineLi-Zhen Song - Baylor College of MedicineEbony Nelson - Baylor College of MedicineLauren A. Sinko - OU HealthJ. Leland Booth - OU HealthDouglas A. Drevets - OU HealthBrent R. Brown - OU HealthMonica Kraft - University of ArizonaJarrod Mosier - University of ArizonaHeidi Erickson - University of ArizonaRon Schunk - University of ArizonaHiroki Kimura - University of ArizonaMichelle Conway - University of ArizonaDave Francisco - University of ArizonaAllyson Molzahn - University of ArizonaConnie Cathleen Wilson - University of ArizonaTrina Hughes - University of ArizonaBianca Sierra - University of ArizonaMark A. Atkinson - University of FloridaRicardo F. Ungaro - University of FloridaBrittany Roth Manning - University of FloridaLyle Moldawer - University of FloridaJordan Oberhaus - University of FloridaFaheem W. Guirgis - University of FloridaBrittney Borresen - University of South FloridaMatthew L. Anderson - University of South FloridaCole Maguire - University of Texas, Austin, TexDennis Wylie - University of Texas, Austin, TexJustin F. Rousseau - University of Texas, Austin, TexKerin C. Hurley - University of Texas, Austin, TexJanelle N. Geltman - University of Texas, Austin, TexNadia Siles - University of Texas, Austin, TexJacob E. Rogers - University of Texas, Austin, TexElias K. Haddad - Drexel UniversityPrescott G. Woodruff - University of California, San FranciscoRuth R. Montgomery - Yale UniversitySlim Fourati - University Hospitals of Cleveland
- Publication Details
- The journal of allergy and clinical immunology. Global, v 4(4), 100515
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- National Institutes of Health (NIH): 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U1 9AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U1 9AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI 128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104 870-07, 3U19AI089992-09, 3U19AI128913-03, 5T32DA0 18926-18 National Institute of Allergy and Infectious Diseases, NIH: 3U19AI1289130, U19AI128913-04S1, R01AI 122220 National Science Foundation: DMS2310836
Funded by the National Institutes of Health (NIH; 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U1 9AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U1 9AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI 128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104 870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA0 18926-18); the National Institute of Allergy and Infectious Diseases, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI 122220); and the National Science Foundation (DMS2310836).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Psychiatry; Medicine (Graduate); College of Medicine; Infectious Diseases (and HIV Medicine); Emergency Medicine; General Internal Medicine
- Web of Science ID
- WOS:001541395600001
- Scopus ID
- 2-s2.0-105010683903
- Other Identifier
- 991022161841804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Allergy
- Immunology