Accelarated immune ageing is associated with COVID-19 disease severity

ISARIC4C Investigators; D Adeloye; JK Baillie; A Bularga; L Daines; NI Lone; NL Mills; DE Newby; R Pius; M Shankar-Hari; A Sheikh; CL Sudlow; S Walmsley; B Zheng

doi:10.1186/s12979-023-00406-z

Accelarated immune ageing is associated with COVID-19 disease severity

ISARIC4C Investigators, D Adeloye, JK Baillie, A Bularga, L Daines, NI Lone, NL Mills, DE Newby, R Pius, M Shankar-Hari, A Sheikh, CL Sudlow, S Walmsley, B Zheng

Research output: Contribution to journal › Article › peer-review

Abstract

Background
The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.

Results
We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity (
= 0.174, p = 0.043), with a major influence being disease severity (
= 0.188, p = 0.01).

Conclusions
Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Original language	English
Article number	6
Number of pages	18
Journal	Immunity and Ageing
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12979-023-00406-z
Publication status	Published - 11 Jan 2024

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s12979-023-00406-zFinal published version, 3.21 MBLicence: Creative Commons: Attribution (CC-BY)

https://immunityageing.biomedcentral.com/articles/10.1186/s12979-023-00406-zLicence: Creative Commons: Attribution (CC-BY)

Cite this

@article{df97fcda77854988b0c0be4ba19c5057,

title = "Accelarated immune ageing is associated with COVID-19 disease severity",

abstract = "BackgroundThe striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.ResultsWe performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of na{\"i}ve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01).ConclusionsOur analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.",

author = "{ISARIC4C Investigators} and JM Lord and T Veenith and J Sullivan and A Sharma-Oates and AG Richter and NJ Greening and HJC Mcauley and RA Evans and P Moss and SC Moore and L Turtle and N Gautam and A Gilani and M Bajaj and LV Wain and C Brightling and B Raman and M Marks and A Singapuri and O Elneima and PJM Openshaw and NA Duggal and K Abel and H Adamali and D Adeloye and O Adeyemi and R Adrego and LA Aguilarjimenez and S Ahmad and NA Haider and R Ahmed and N Ahwireng and M Ainsworth and B Al-Sheklly and A Alamoudi and M Ali and M Aljaroof and AM All and L Allan and RJ Allen and L Allerton and L Allsop and P Almeida and D Altmann and MA Corral and S Amoils and D Anderson and C Antoniades and G Arbane and A Arias and C Armour and L Armstrong and N Armstrong and D Arnold and H Arnold and A Ashish and A Ashworth and M Ashworth and S Aslani and H Assefa-Kebede and C Atkin and P Atkin and R Aul and H Aung and L Austin and C Avram and A Ayoub and M Babores and R Baggott and J Bagshaw and D Baguley and L Bailey and JK Baillie and S Bain and M Bakali and M Bakau and E Baldry and D Baldwin and M Baldwin and C Ballard and A Banerjee and B Bang and RE Barker and L Barman and S Barratt and F Barrett and D Basire and N Basu and M Bates and A Bates and R Batterham and H Baxendale and H Bayes and M Beadsworth and P Beckett and M Beggs and M Begum and P Beirne and D Bell and R Bell and K Bennett and E Beranova and A Bermperi and A Berridge and C Berry and S Betts and E Bevan and K Bhui and M Bingham and K Birchall and L Bishop and K Bisnauthsing and J Blaikely and A Bloss and A Bolger and CE Bolton and J Bonnington and A Botkai and C Bourne and M Bourne and K Bramham and L Brear and G Breen and J Breeze and A Briggs and E Bright and S Brill and K Brindle and L Broad and A Broadley and C Brookes and M Broome and A Brown and A Brown and J Brown and J Brown and J Brown and M Brown and M Brown and V Brown and T Brugha and N Brunskill and M Buch and P Buckley and A 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and P Cullinan and D Cuthbertson and L Daines and M Dalton and P Daly and A Daniels and P Dark and J Dasgin and A David and C David and E Davies and F Davies and G Davies and G Davies and K Davies and MJ Davies and J Dawson and E Daynes and {De Soyza}, A and B Deakin and A Deans and C Deas and J Deery and S Defres and A Dell and K Dempsey and E Denneny and J Dennis and A Dewar and R Dharmagunawardena and N Diar-Bakerly and C Dickens and A Dipper and S Diver and SN Diwanji and M Dixon and R Djukanovic and H Dobson and SL Dobson and AB Docherty and A Donaldson and T Dong and N Dormand and A Dougherty and R Dowling and S Drain and K Draxlbauer and K Drury and P Dulawan and A Dunleavy and S Dunn and C Dupont and J Earley and N Easom and C Echevarria and S Edwards and C Edwardson and H El-Taweel and A Elliott and K Elliott and Y Ellis and A Elmer and D Evans and H Evans and J Evans and RA Evans and RA Evans and T Evans and C Evenden and L Evison and L Fabbri and S Fairbairn and A Fairman 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Yousuf and A Zawia and L Zeidan and B Zhao and B Zheng and O Zongo",

year = "2024",

month = jan,

day = "11",

doi = "10.1186/s12979-023-00406-z",

language = "English",

volume = "21",

journal = "Immunity and Ageing",

issn = "1742-4933",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Accelarated immune ageing is associated with COVID-19 disease severity

AU - ISARIC4C Investigators

AU - Lord, JM

AU - Veenith, T

AU - Sullivan, J

AU - Sharma-Oates, A

AU - Richter, AG

AU - Greening, NJ

AU - Mcauley, HJC

AU - Evans, RA

AU - Moss, P

AU - Moore, SC

AU - Turtle, L

AU - Gautam, N

AU - Gilani, A

AU - Bajaj, M

AU - Wain, LV

AU - Brightling, C

AU - Raman, B

AU - Marks, M

AU - Singapuri, A

AU - Elneima, O

AU - Openshaw, PJM

AU - Duggal, NA

AU - Abel, K

AU - Adamali, H

AU - Adeloye, D

AU - Adeyemi, O

AU - Adrego, R

AU - Aguilarjimenez, LA

AU - Ahmad, S

AU - Haider, NA

AU - Ahmed, R

AU - Ahwireng, N

AU - Ainsworth, M

AU - Al-Sheklly, B

AU - Alamoudi, A

AU - Ali, M

AU - Aljaroof, M

AU - All, AM

AU - Allan, L

AU - Allen, RJ

AU - Allerton, L

AU - Allsop, L

AU - Almeida, P

AU - Altmann, D

AU - Corral, MA

AU - Amoils, S

AU - Anderson, D

AU - Antoniades, C

AU - Arbane, G

AU - Arias, A

AU - Armour, C

AU - Armstrong, L

AU - Armstrong, N

AU - Arnold, D

AU - Arnold, H

AU - Ashish, A

AU - Ashworth, A

AU - Ashworth, M

AU - Aslani, S

AU - Assefa-Kebede, H

AU - Atkin, C

AU - Atkin, P

AU - Aul, R

AU - Aung, H

AU - Austin, L

AU - Avram, C

AU - Ayoub, A

AU - Babores, M

AU - Baggott, R

AU - Bagshaw, J

AU - Baguley, D

AU - Bailey, L

AU - Baillie, JK

AU - Bain, S

AU - Bakali, M

AU - Bakau, M

AU - Baldry, E

AU - Baldwin, D

AU - Baldwin, M

AU - Ballard, C

AU - Banerjee, A

AU - Bang, B

AU - Barker, RE

AU - Barman, L

AU - Barratt, S

AU - Barrett, F

AU - Basire, D

AU - Basu, N

AU - Bates, M

AU - Bates, A

AU - Batterham, R

AU - Baxendale, H

AU - Bayes, H

AU - Beadsworth, M

AU - Beckett, P

AU - Beggs, M

AU - Begum, M

AU - Beirne, P

AU - Bell, D

AU - Bell, R

AU - Bennett, K

AU - Beranova, E

AU - Bermperi, A

AU - Berridge, A

AU - Berry, C

AU - Betts, S

AU - Bevan, E

AU - Bhui, K

AU - Bingham, M

AU - Birchall, K

AU - Bishop, L

AU - Bisnauthsing, K

AU - Blaikely, J

AU - Bloss, A

AU - Bolger, A

AU - Bolton, CE

AU - Bonnington, J

AU - Botkai, A

AU - Bourne, C

AU - Bourne, M

AU - Bramham, K

AU - Brear, L

AU - Breen, G

AU - Breeze, J

AU - Briggs, A

AU - Bright, E

AU - Brill, S

AU - Brindle, K

AU - Broad, L

AU - Broadley, A

AU - Brookes, C

AU - Broome, M

AU - Brown, A

AU - Brown, J

AU - Brown, M

AU - Brown, V

AU - Brugha, T

AU - Brunskill, N

AU - Buch, M

AU - Buckley, P

AU - Bularga, A

AU - Bullmore, E

AU - Burden, L

AU - Burdett, T

AU - Burn, D

AU - Burns, G

AU - Burns, A

AU - Busby, J

AU - Butcher, R

AU - Butt, A

AU - Byrne, S

AU - Cairns, P

AU - Calder, PC

AU - Calvelo, E

AU - Carborn, H

AU - Card, B

AU - Carr, C

AU - Carr, L

AU - Carson, G

AU - Carter, P

AU - Casey, A

AU - Cassar, M

AU - Cavanagh, J

AU - Chablani, M

AU - Chalder, T

AU - Chalmers, JD

AU - Chambers, RC

AU - Chan, F

AU - Channon, KM

AU - Chapman, K

AU - Charalambou, A

AU - Chaudhuri, N

AU - Checkley, A

AU - Chen, J

AU - Cheng, Y

AU - Chetham, L

AU - Childs, C

AU - Chilvers, ER

AU - Chinoy, H

AU - Chiribiri, A

AU - Chong-James, K

AU - Choudhury, G

AU - Choudhury, N

AU - Chowienczyk, P

AU - Christie, C

AU - Chrystal, M

AU - Clark, D

AU - Clark, C

AU - Clarke, J

AU - Clohisey, S

AU - Coakley, G

AU - Coburn, Z

AU - Coetzee, S

AU - Cole, J

AU - Coleman, C

AU - Conneh, F

AU - Connell, D

AU - Connolly, B

AU - Connor, L

AU - Cook, A

AU - Cooper, B

AU - Cooper, J

AU - Cooper, S

AU - Copeland, D

AU - Cosier, T

AU - Coulding, M

AU - Coupland, C

AU - Cox, E

AU - Craig, T

AU - Crisp, P

AU - Cristiano, D

AU - Crooks, MG

AU - Cross, A

AU - Cruz, I

AU - Cullinan, P

AU - Cuthbertson, D

AU - Daines, L

AU - Dalton, M

AU - Daly, P

AU - Daniels, A

AU - Dark, P

AU - Dasgin, J

AU - David, A

AU - David, C

AU - Davies, E

AU - Davies, F

AU - Davies, G

AU - Davies, K

AU - Davies, MJ

AU - Dawson, J

AU - Daynes, E

AU - De Soyza, A

AU - Deakin, B

AU - Deans, A

AU - Deas, C

AU - Deery, J

AU - Defres, S

AU - Dell, A

AU - Dempsey, K

AU - Denneny, E

AU - Dennis, J

AU - Dewar, A

AU - Dharmagunawardena, R

AU - Diar-Bakerly, N

AU - Dickens, C

AU - Dipper, A

AU - Diver, S

AU - Diwanji, SN

AU - Dixon, M

AU - Djukanovic, R

AU - Dobson, H

AU - Dobson, SL

AU - Docherty, AB

AU - Donaldson, A

AU - Dong, T

AU - Dormand, N

AU - Dougherty, A

AU - Dowling, R

AU - Drain, S

AU - Draxlbauer, K

AU - Drury, K

AU - Dulawan, P

AU - Dunleavy, A

AU - Dunn, S

AU - Dupont, C

AU - Earley, J

AU - Easom, N

AU - Echevarria, C

AU - Edwards, S

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AU - Zhao, B

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PY - 2024/1/11

Y1 - 2024/1/11

N2 - BackgroundThe striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.ResultsWe performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01).ConclusionsOur analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

AB - BackgroundThe striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.ResultsWe performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01).ConclusionsOur analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_uoe&SrcAuth=WosAPI&KeyUT=WOS:001141793000001&DestLinkType=FullRecord&DestApp=WOS_CPL

U2 - 10.1186/s12979-023-00406-z

DO - 10.1186/s12979-023-00406-z

M3 - Article

C2 - 38212801

SN - 1742-4933

VL - 21

JO - Immunity and Ageing

JF - Immunity and Ageing

IS - 1

M1 - 6

ER -

Accelarated immune ageing is associated with COVID-19 disease severity

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