Health Status, Persistent Symptoms, and Effort Intolerance One Year After Acute COVID-19 Infection.

BACKGROUND: The long-term prevalence and risk factors for post-acute COVID-19 sequelae (PASC) are not well described and may have important implications for unvaccinated populations and policy makers. OBJECTIVE: To assess health status, persistent symptoms, and effort tolerance approximately 1 year after COVID-19 infection DESIGN: Retrospective observational cohort study using surveys and clinical data PARTICIPANTS: Survey respondents who were survivors of acute COVID-19 infection requiring Emergency Department presentation or hospitalization between March 3 and May 15, 2020. MAIN MEASURE(S): Self-reported health status, persistent symptoms, and effort tolerance KEY RESULTS: The 530 respondents (median time between hospital presentation and survey 332 days [IQR 325-344]) had mean age 59.2±16.3 years, 44.5% were female and 70.8% were non-White. Of these, 41.5% reported worse health compared to a year prior, 44.2% reported persistent symptoms, 36.2% reported limitations in lifting/carrying groceries, 35.5% reported limitations climbing one flight of stairs, 38.1% reported limitations bending/kneeling/stooping, and 22.1% reported limitations walking one block. Even those without high-risk comorbid conditions and those seen only in the Emergency Department (but not hospitalized) experienced significant deterioration in health, persistent symptoms, and limitations in effort tolerance. Women (adjusted relative risk ratio [aRRR] 1.26, 95% CI 1.01-1.56), those requiring mechanical ventilation (aRRR 1.48, 1.02-2.14), and people with HIV (aRRR 1.75, 1.14-2.69) were significantly more likely to report persistent symptoms. Age and other risk factors for more severe COVID-19 illness were not associated with increased risk of PASC. CONCLUSIONS: PASC may be extraordinarily common 1 year after COVID-19, and these symptoms are sufficiently severe to impact the daily exercise tolerance of patients. PASC symptoms are broadly distributed, are not limited to one specific patient group, and appear to be unrelated to age. These data have implications for vaccine hesitant individuals, policy makers, and physicians managing the emerging longer-term yet unknown impact of the COVID-19 pandemic.

Paradoxical Effects of Endoplasmic Reticulum Aminopeptidase 1 Deficiency on HLA-B27 and Its Role as an Epistatic Modifier in Experimental Spondyloarthritis.

OBJECTIVE: We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA). METHODS: ERAP1-knockout rats were created using genome editing and bred with HLA-B27/human ß2 -microglobulin-transgenic (HLA-B27-Tg) rats and HLA-B7-Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses. Animals were examined for clinical features of disease, and tissue was assessed by histology. RESULTS: ERAP1 deficiency increased the ratio of folded to unfolded (ß2 m-free) HLA-B27 heavy chains, while having the opposite effect on HLA-B7. Furthermore, in rats with ERAP1 deficiency, HLA-B27 misfolding was reduced, while free HLA-B27 heavy chain dimers on the cell surface and monomers were increased. The effects of ERAP1 deficiency persisted during up-regulation of HLA-B27 and led to a reduction in endoplasmic reticulum stress. ERAP1 deficiency reduced the prevalence of arthritis in HLA-B27-Tg rats by two-thirds without reducing gastrointestinal inflammation. Dendritic cell abnormalities attributed to the presence of HLA-B27, including reduced allogeneic T cell stimulation and loss of CD103-positive/major histocompatibility complex class II-positive cells, were not rescued by ERAP1 deficiency, while excess Il23a up-regulation was mitigated. CONCLUSION: ERAP1 deficiency reduced HLA-B27 misfolding and improved folding while having opposing effects on HLA-B7. The finding that HLA-B27-Tg rats had partial protection against SpA in this study is consistent with genetic evidence that loss-of-function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis. Functional studies support the concept that the effects of ERAP1 on HLA-B27 and SpA may be a consequence of how peptides affect the biology of this allotype rather than their role as antigenic determinants.