Longitudinal Analysis of COVID-19 Patients Shows Age-Associated T Cell Changes Independent of Ongoing Ill-Health

Abstract

ObjectivesThe immunological and inflammatory changes following acute COVID-19 are hugely variable. Persistent clinical symptoms following resolution of initial infection, termed long COVID, are also hugely variable, but association with immunological changes has not been described. We investigate changing immunological parameters in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms.MethodsWe performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed as cardinal features of long COVID using the Chalder Fatigue Scale and 6-minute-walk test. The relationships between these clinical outcomes and convalescent immunological results were investigated.ResultsWe identify persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common in this cohort. These symptoms were not associated with immune cell populations or circulating inflammatory cytokines.ConclusionWe demonstrate myeloid recovery but persistent T cell abnormalities in convalescent COVID-19 patients more than three months after initial infection. These changes are more marked with age and are independent of ongoing subjective ill-health, fatigue and reduced exercise tolerance.

Duration of post-COVID-19 symptoms are associated with sustained SARS-CoV-2 specific immune responses

“…Our group and others have observed T cell activation that persists into the early convalescent phase following SARS-CoV-2 infection ( 1 , 8 ), but few studies have investigated phenotypic differences into the intermediate and late phases of convalescence, particularly in individuals with prolonged symptom syndromes. One recent study observed longitudinal changes in T cell activation independent of ongoing symptoms ( 9 ). To investigate T cell changes in our cohort, we first characterized T cell activation as determined by dual expression of HLA-DR and CD38, previously shown to be upregulated in severely infected COVID-19 patients ( 2 ), and found that the CD4 + T cell population had increased HLA-DR + CD38 + expression when comparing early and intermediate time points, as well as when comparing the early time point with CoV – controls ( Figure 2A ; P = 0.024 and P = 0.021, respectively).…”

“…Our group and others have characterized the acute immune response to COVID-19, finding dramatic immune dysregulation in peripheral blood samples from infected individuals ( 1 – 7 ), especially in those with severe infection. Evidence suggests some of these immune perturbations persist into the convalescent phase of infection ( 1 , 8 , 9 ). Antigen-specific immune responses during the acute and early convalescent stages of infection have been found to play an important role in overall patient outcomes ( 10 – 15 ).…”

Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection

“…A previous study examined vitamin D levels during initial infection in hospitalised patients and persistent symptoms at eight weeks post illness and also found no relationship [ 61 ]. The lack of associations seen emphasise that long COVID remains a symptom-driven disease, with no reliable or reproducible biomarker [ 62 , 63 ]. This is also reflected in the levels of CRP and IL-6 recorded, with the majority being within normal range.…”

A Short Corticosteroid Course Reduces Symptoms and Immunological Alterations Underlying Long-COVID

“…We did not find any differences in natural killer (NK) cell subpopulations, except for decreased terminal NK cells in PSP compared with NSP ( p < 0.05) that recovered after treatment ( p < 0.01, Figure S1 ). Within the monocyte compartment, there was a trend towards overrepresentation of intermediate monocytes (CD14+CD16+) in PSP, as observed during acute COVID-19 [ 18 , 19 , 20 ], while classical (CD14+CD16−) and non-classical (CD14−CD16+) monocytes showed similar levels to NSP ( Figure S2a ). The surface expression of CCR2, CCR5, HLA-DR, and CD86 in the non-inflammatory, classical monocytes was similar between NSP and PSP ( Figure S2b ).…”

“…All NSP and PSP included in the study had a current negative antigen test and RT-PCR for SARS-CoV-2 from nasopharyngeal samples; however, this does not exclude the possibility of viral persistence in other locations such as central nervous or digestive systems [ 24 , 25 , 26 ]. Alterations in the T cell compartment have been described in convalescent COVID-19 patients, particularly the persistence of activated CD8+ T cells for up to 6 months post-infection [ 19 , 27 ]. Despite the aforementioned disturbances in the distribution of T cell populations, the secretion of interleukin (IL)-2, interferon gamma (IFNg), and tumor necrosis factor alpha (TNFa) by CD4+ or CD8+ T cells after polyclonal in vitro stimulation was similar between PSP and NSP, and corticosteroid treatment did not have a clear effect on cytokine synthesis ( Figure S4 ).…”