Background There is currently limited information on clinical severity phenotypes of symptoms and functional disability in Post-COVID Syndrome (PCS) METHODS: A purposive sample of 370 PCS patients from a dedicated community COVID-19 rehabilitation service were assessed using the C19-YRS (COVID-19 Yorkshire Rehabilitation Scale) where each symptom or functional difficulty was scored on a 0-10 Likert scale and also compared with before infection. Phenotypes based on symptom severity were extracted to identify any noticeable patterns. Correlation between symptom severity, functional disability and overall health was explored. Results Mean age was 47 years, with 237 (64%) female. Median duration of symptoms was 211 days (interquartile range 143 to 353). Symptoms and functional difficulties increased substantially when compared to before infection. Three distinct severity phenotypes of mild (n=90), moderate (n=186) and severe (n=94) were identified where severity of individual symptoms was of similar severity within each phenotype. Symptom scores were strongly positively correlated with functional difficulty scores (0.7, 0.6 to 0.7) and moderately negatively correlated with overall health (-0.4, -0.3 to -0.5). Conclusions This is the first study reporting on severity phenotypes in a largely non-hospitalised PCS cohort. Severity phenotypes might help stratify patients for targeted interventions and planning of care pathways. Word count: 199 This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.27456

Post-COVID Syndrome symptoms, functional disability and clinical severity phenotypes in hospitalised and non-hospitalised individuals: a cross-sectional evaluation from a community COVID rehabilitation service.

In the COVID-19 pandemic, a male bias in hospitalization and mortality has become apparent. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that gene-dose of Toll-Like Receptor (TLR) 7, one of the crucial pattern recognition receptors for SARS-CoV-2 RNA, could contribute to the sex-skewed severity. This gene is localized on the X chromosome and female immune cells with X-chromosome inactivation (XCI) escape of this gene have biallelic TLR7 expression. As a consequence, these immune cells may produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 is the PPR that causes IFN production. A delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect. Other X-linked immune genes are discussed in the context of the COVID-19 sex bias.

Why Females Do Better: The X Chromosomal TLR7 Gene-Dose Effect in COVID-19.

The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

/pdf/impact-of-pre-existing-chronic-viral-infection-and-37kmy1mf.pdf

Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

Epstein-Barr virus (EBV) reactivation has been proposed as a driver of Long COVID (LC), but studies in well-characterized post-acute COVID-19 cohorts of individuals with and without Long COVID symptoms over a time course consistent with current case definitions of LC are limited. In a cohort of 294 hundred adults with a history of SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were associated with serological evidence of recent EBV reactivation (early antigen-D IgG positivity or nuclear antigen IgG levels >600 U/mL), but not with ongoing EBV viremia.. Importantly, Long COVID was also observed in the small proportion without evidence of prior or recent EBV infection, suggesting that EBV reactivation is not a prerequisite for this condition. Overall, these findings expand our knowledge of the relationships between EBV reactivation and LC and suggest that further assessment during the acute phase of COVID-19 is warranted.

/pdf/evidence-of-recent-epstein-barr-virus-reactivation-in-2x2qr5fv.pdf

Evidence of recent Epstein-Barr virus reactivation in individuals experiencing Long COVID

Background
The immunopathological pathways enabling post-COVID syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition.
Methods
Thirty-three patients were included for longitudinal clinical and autoantibody analyses of whom 12 patients were assessed for cytokines and lymphocyte populations. Patients were followed during 7-11 months after acute COVID-19. Autoimmune profile and immunological status were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry. 
Results
Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by upregulated IFN-α, TNF-α, G-CSF, IL-17A, IL-6, IL-1β, and IL-13, whereas IP-10 was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of IgG S1-SARS-CoV-2 antibodies remained elevated over time.
Discussion
The clinical manifestations of PCS are associated with the persistence of a proinflammatory, and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

https://medrxiv.org/content/10.1101/2021.11.17.21266457v1.full.pdf

Persistent Autoimmune Activation and Proinflammatory State in Post-COVID Syndrome

A proportion of patients surviving acute COVID-19 infection develop post-COVID syndrome (long COVID) encompassing physical and neuropsychiatric symptoms lasting longer than 12 weeks. Here we studied a prospective cohort of individuals with long COVID (the ADAPT study) compared to age/gender matched subjects without long COVID, healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found an elevated diffuse serum inflammatory cytokine profile in symptomatic long COVID subjects that was maintained at 8 months post-infection and was not observed in asymptomatic COVID-19 survivors. This inflammatory profile consisted of 15 cytokines that positively correlated; revealing an apparent diffuse, potentially coordinated, low level up regulation of a spectrum of immune and inflammatory mediators. In addition, we found an absence of subsets of un-activated naive T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. In contrast, individual serum cytokines from the interferon I and III classes, T cell activation markers and plasma ACE2, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.

/pdf/immunological-dysfunction-persists-for-8-months-following-4ixnqcxit6.pdf

Anette Howe

Papers

Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection