Divergent adaptive immune responses define two types of Long COVID, 2023, Chakrabarti et al

[John Mac]

The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage.

To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination.

Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months.

They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29).The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01).

The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups.

Multiplexed antibody analyses to 30 different viral antigens showed that LC-patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses.

A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC-patients, while response frequencies were high in the LC+ and RE groups.

Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC-group.

These findings provide evidence for two major types of antiviral immune responses in long COVID.Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients.

In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%).

These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221961/abstract

 

[Hutan]

These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

Instead, I think it's reasonable to argue that the fact that the two LC groups showed very similar persistent symptoms suggests that seropositivity to SARS-CoV-2 doesn't have much to do with the etiology of Long Covid.

 

[EndME]

Quite interesting work from a group looking at slighty different things than all other groups. Good to see.

 

[SNT Gatchaman]

See related threads —

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2 (2023 preprint)
Distinct T cell functional profiles in SARS-CoV-2 seropositive and seronegative children associated with endemic human coronavirus cross-reactivity (2023 preprint)

 

[SNT Gatchaman]

Early studies had shown that one third of the long COVID patients in the PERSICOR cohort were seronegative by spike ELISA assay, while their spectrum of symptoms was as severe as that of seropositive patients. This contrasted with the lower rate of seronegative infection seen in the general population of COVID-19 patients, which ranged from 2 to 24%

As seronegative patients represented a substantial part of the cohort and had rarely been included in previous long COVID reports, we chose to study this group in parallel to that of seropositive patients. Using highly sensitive antibody and T cell assays, we could document immunological signs of a previous SARS-CoV-2 infection in half of ELISA-seronegative long COVID patients, suggesting the presence of an insufficient antiviral adaptive response in this group. In contrast, seropositive long COVID patients showed persistently high antibody and CD4+ T cell responses, that did not differ in magnitude and breadth from those of individuals who had recovered from COVID-19.

A limited subset of LC patients (17.4%) had an infection documented by PCR. In addition, 39.1% of LC- patients fulfilled the definition of having a clinically probable SARS-CoV-2 infection, based on the occurrence of at least 3 listed symptoms including anosmia/ageusia during the acute COVID-19 stage. Combining all 5 criteria (CD4, IgG, IgA, PCR, and clinical) showed that 82.6% of patients in the LC group had signs of a probable SARS-CoV-2 infection. Taken together, this analysis showed that a majority of seronegative long COVID patients were likely to have been infected by SARS-CoV-2, highlighting the relevance of studying virally induced pathogenic mechanisms in this group.

Meanwhile, elsewhere in Paris and reported in Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic (2022, JAMA Internal Medicine)

Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks.

The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection.