Delayed Mucosal Antiviral Responses Despite Robust Peripheral Inflammation in Fatal COVID-19
Authors: Sidhu Jasmin K , Siggins Matthew K , Liew Felicity , Russell Clark D , Uruchurtu Ashley S S , Davis Christopher , Turtle Lance , Moore Shona C , Hardwick Hayley E , Oosthuyzen Wilna , Thomson Emma C , Semple Malcolm G , Baillie J Kenneth , Openshaw Peter J M , Thwaites Ryan S ,   ISARIC4C investigators, Baillie J Kenneth , Openshaw Peter J M , Semple Malcolm G , Alex Beatrice , Andrikopoulos Petros , Bach Benjamin , Barclay Wendy S , Bogaert Debby , Chand Meera , Chechi Kanta , Cooke Graham S , Filipe Ana da Silva , de Silva Thushan , Docherty Annemarie B , Correia Gonçalo dos Santos , Dumas Marc-Emmanuel , Dunning Jake , Fletcher Tom , Green Christoper A , Greenhalf William , Griffin Julian L , Gupta Rishi K , Harrison Ewen M , Ho Antonia Ying Wai , Holden Karl , Horby Peter W , Ijaz Samreen , Khoo Saye , Klenerman Paul , Law Andrew , Lewis Matthew R , Liggi Sonia , Lim Wei Shen , Maslen Lynn , Mentzer Alexander J , Merson Laura , Meynert Alison M , Moore Shona C , Noursadeghi Mahdad , Olanipekun Michael , Osagie Anthonia , Palmarini Massimo , Palmieri Carlo , Paxton William A , Pollakis Georgios , Price Nicholas , Rambaut Andrew , Robertson David L , Russell Clark D , Sancho-Shimizu Vanessa , Sands Caroline J , Scott Janet T , Sigfrid Louise , Solomon Tom , Sriskandan Shiranee , Stuart David , Summers Charlotte , Swann Olivia V , Takats Zoltan , Takis Panteleimon , Tedder Richard S , Thompson A A Roger , Thomson Emma C , Thwaites Ryan S , Turtle Lance C W , Zambon Maria , Drake Thomas M , Fairfield Cameron J , Knight Stephen R , Mclean Kenneth A , Murphy Derek , Norman Lisa , Pius Riinu , Shaw Catherine A , Connor Marie , Dalton Jo , Gamble Carrol , Girvan Michelle , Halpin Sophie , Harrison Janet , Jackson Clare , Lee James , Marsh Laura , Plotkin Daniel , Roberts Stephanie , Saviciute Egle , Clohisey Sara , Hendry Ross , Knight Susan , Lahnsteiner Eva , Law Andrew , Leeming Gary , Norris Lucy , Scott-Brown James , Tait Sarah , Wham Murray , Carson Gail , Clark Richard , Coutts Audrey , Donnelly Lorna , Fawkes Angie , Gilchrist Tammy , Hafezi Katarzyna , MacGillivray Louise , Maclean Alan , McCafferty Sarah , Morrice Kirstie , Murphy Lee , Wrobel Nicola , Adeniji Kayode , Agranoff Daniel , Agwuh Ken , Ail Dhiraj , Aldera Erin L , Alegria Ana , Allen Sam , Angus Brian , Ashish Abdul , Atkinson Dougal , Bari Shahedal , Barlow Gavin , Barnass Stella , Barrett Nicholas , Bassford Christopher , Basude Sneha , Baxter David , Beadsworth Michael , Bernatoniene Jolanta , Berridge John , Berry Colin , Best Nicola , Bothma Pieter , Brittain-Long Robin , Bulteel Naomi , Burden Tom , Burtenshaw Andrew , Caruth Vikki , Chadwick David , Chadwick David , Chambler Duncan , Chee Nigel , Child Jenny , Chukkambotla Srikanth , Clark Tom , Collini Paul , Cosgrove Catherine , Cupitt Jason , Cutino-Moguel Maria-Teresa , Dark Paul , Dawson Chris , Dervisevic Samir , Donnison Phil , Douthwaite Sam , Drummond Andrew , DuRand Ingrid , Dushianthan Ahilanadan , Dyer Tristan , Evans Cariad , Eziefula Chi , Fegan Chrisopher , Finn Adam , Fullerton Duncan , Garg Sanjeev , Garg Atul , Gkrania-Klotsas Effrossyni , Godden Jo , Goldsmith Arthur , Graham Clive , Grammatikopoulos Tassos , Hardy Elaine , Hartshorn Stuart , Harvey Daniel , Havalda Peter , Hawcutt Daniel B , Hobrok Maria , Hodgson Luke , Hormis Anil , Howard Joanne , Jacobs Michael , Jain Susan , Jennings Paul , Kaliappan Agilan , Kasipandian Vidya , Kegg Stephen , Kelsey Michael , Kendall Jason , Kerrison Caroline , Kerslake Ian , Koch Oliver , Koduri Gouri , Koshy George , Laha Shondipon , Laird Steven , Larkin Susan , Leiner Tamas , Lillie Patrick , Limb James , Linnett Vanessa , Little Jeff , Lyttle Mark , MacMahon Michael , MacNaughton Emily , Mankregod Ravish , Masson Huw , Matovu Elijah , McCullough Katherine , McEwen Ruth , Meda Manjula , Mills Gary , Minton Jane , Mohandas Kavya , Mok Quen , Moon James , Moore Elinoor , Morgan Patrick , Morris Craig , Mortimore Katherine , Moses Samuel , Mpenge Mbiye , Mulla Rohinton , Murphy Michael , Nagarajan Thapas , Nagel Megan , Nelson Mark , Norris Lillian , O'Shea Matthew K , Ostermann Marlies , Otahal Igor , Pais Mark , Palmieri Carlo , Panchatsharam Selva , Papakonstantinou Danai , Papineni Padmasayee , Paraiso Hassan , Patel Brij , Pattison Natalie , Pepperell Justin , Peters Mark , Phull Mandeep , Pintus Stefania , Planche Tim , Post Frank , Price David , Prout Rachel , Rae Nikolas , Reschreiter Henrik , Reynolds Tim , Richardson Neil , Roberts Mark , Roberts Devender , Rose Alistair , Rousseau Guy , Ruge Bobby , Ryan Brendan , Saluja Taranprit , Cole Sarah , Schmid Matthias L , Shah Aarti , Shankar-Hari Manu , Shanmuga Prad , Sharma Anil , Shawcross Anna , Pooni Jagtur Singh , Sizer Jeremy , Smith Richard , Snelson Catherine , Spittle Nick , Staines Nikki , Stambach Tom , Stewart Richard , Subudhi Pradeep , Szakmany Tamas , Tatham Kate , Thomas Jo , Thompson Chris , Thompson Robert , Tridente Ascanio , Tupper-Carey Darell , Twagira Mary , Vallotton Nick , Vancheeswaran Rama , Vincent Rachel , Vincent-Smith Lisa , Visuvanathan Shico , Vuylsteke Alan , Waddy Sam , Wake Rachel , Walden Andrew , Welters Ingeborg , Whitehouse Tony , Whittaker Paul , Whittington Ashley , Wijesinghe Meme , Williams Martin , Wilson Lawrence , Winchester Stephen , Wiselka Martin , Wolverson Adam , Wootton Daniel G , Workman Andrew , Yates Bryan , Young Peter , McDonald Sarah E , Shaw Victoria , Ahmed Katie A , Armstrong Jane A , Ashworth Milton , Asiimwe Innocent G , Bakshi Siddharth , Barlow Samantha L , Booth Laura , Brennan Benjamin , Bullock Katie , Carlucci Nicola , Cass Emily , Catterall Benjamin WA , Clark Jordan J , Clarke Emily A , Cole Sarah , Cooper Louise , Cox Helen , Davis Christopher , Dincarslan Oslem , Carracedo Alejandra Doce , Dunn Chris , Dyer Philip , Elliott Angela , Evans Anthony , Finch Lorna , Fisher Lewis W S , Flaherty Lisa , Foster Terry , Garcia-Dorival Isabel , Gunning Philip , Hartley Catherine , Holmes Anthony , Jensen Rebecca L , Jones Christopher B , Jones Trevor R , Khandaker Shadia , King Katharine , Kiy Robyn T , Koukorava Chrysa , Lake Annette , Lant Suzannah , Latawiec Diane , Lavelle-Langham Lara , Lefteri Daniella , Lett Lauren , Livoti Lucia A , Mancini Maria , Massey Hannah , Maziere Nicole , McDonald Sarah , McEvoy Laurence , McLauchlan John , Metelmann Soeren , Miah Nahida S , Middleton Joanna , Mitchell Joyce , Moore Shona C , Murphy Ellen G , Penrice-Randal Rebekah , Pilgrim Jack , Prince Tessa , Reynolds Will , Ridley P Matthew , Sales Debby , Shaw Victoria E , Shears Rebecca K , Small Benjamin , Subramaniam Krishanthi S , Szemiel Agnieska , Taggart Aislynn , Tanianis-Hughes Jolanta , Thomas Jordan , Trochu Erwan , van Tonder Libby , Wilcock Eve , Zhang J Eunice , Keating Seán , Donegan Cara , Spencer Rebecca G , Chikowore Primrose , Donohue Chloe , Griffiths Fiona , Hardwick Hayley , Oosthuyzen Wilna 
Published: December 2023

Abstract

Background
While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation.

Methods
We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0–5 days after symptom onset) or late (6–20 days after symptom onset) phase.

Results
Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease.

Conclusions
Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.