Post-acute sequelae of SARS-CoV-2 infection: relationship of central nervous system manifestations with physical disability and systemic inflammation

Abstract

Background Despite the multitude of clinical manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC), studies applying statistical methods to directly investigate patterns of symptom co-occurrence and their biological correlates are scarce. Methods We assessed 30 symptoms pertaining to different organ systems in 749 adults (age = 55 ± 14 years; 47% female) during in-person visits conducted at 6–11 months after hospitalization due to coronavirus disease 2019 (COVID-19), including six psychiatric and cognitive manifestations. Symptom co-occurrence was initially investigated using exploratory factor analysis (EFA), and latent variable modeling was then conducted using Item Response Theory (IRT). We investigated associations of latent variable severity with objective indices of persistent physical disability, pulmonary and kidney dysfunction, and C-reactive protein and D-dimer blood levels, measured at the same follow-up assessment. Results The EFA extracted one factor, explaining 64.8% of variance; loadings were positive for all symptoms, and above 0.35 for 16 of them. The latent trait generated using IRT placed fatigue, psychiatric, and cognitive manifestations as the most discriminative symptoms (coefficients > 1.5, p < 0.001). Latent trait severity was associated with decreased body weight and poorer physical performance (coefficients > 0.240; p ⩽ 0.003), and elevated blood levels of C-reactive protein (coefficient = 0.378; 95% CI 0.215–0.541; p < 0.001) and D-dimer (coefficient = 0.412; 95% CI 0.123–0.702; p = 0.005). Results were similar after excluding subjects with pro-inflammatory comorbidities. Conclusions Different symptoms that persist for several months after moderate or severe COVID-19 may unite within one latent trait of PASC. This trait is dominated by fatigue and psychiatric symptoms, and is associated with objective signs of physical disability and persistent systemic inflammation.

Fatigue and cognitive impairment after COVID-19: A prospective multicentre study

“… 34 Furthermore, measures of inflammation have been found to be associated with overall post-COVID syndrome severity, independent of confounding inflammatory comorbidities, and COVID-related mortality, and have thus been suggested as diagnostic and prognostic biomarkers. 35 , 36 Indeed, C-reactive protein (CRP) levels were significantly correlated with concomitant fatigue severity in our univariate linear regression analysis (standardised beta=-0.08, p = 0.013), but showed no association in multivariable models. Future studies should investigate a wider spectrum of pro-inflammatory cytokines as potential biomarkers of post-COVID fatigue.…”

Fatigue after COVID‐19 in non‐hospitalized patients according to sex

“…Similarly, in a cohort of 2000 patients from five public hospitals in Spain, female sex was not only associated with fatigue 8 months after discharge, but also with at least three post‐COVID symptoms (Fernández‐de‐las‐Peñas et al., 2022 ). In a recent Brazilian study, the authors investigated the co‐occurrence of 30 symptoms of different body organs, and showed that fatigue, psychiatric, and cognitive manifestations were the most discriminatory for the so‐called post‐acute sequelae of the SARS‐CoV‐2 infection (Busatto et al., 2022 ). Similar to the results of our research, a previous large Spanish cohort study confirmed the tendency for fatigue to decrease over months since the infection onset (Fernández‐de‐las‐Peñas et al., 2022 ).…”

Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with long-COVID in Japan

“…Furthermore, administration of iTBS, which has a facilitatory effect on the DLPFC, may strengthen neural rhythms, including theta-phase and gamma-amplitude coupling, which is also related to cognitive function, and may even lead to enhanced neuroplasticity ( Jannati et al, 2022 ) in the same region, thereby improving cognitive function ( Buzsaki and Draguhn, 2004 , Luber and Lisanby, 2014 , Noda et al, 2018 , Noda et al, 2017 , Thut et al, 2011 ). Regarding chronic fatigue of long-COVID, we observed a significant improvement on PS score; however, subjective improvement on chronic fatigue was limited, suggesting that TMS neuromodulation by itself might not be effective enough to address the systemic pathophysiology ( Busatto et al, 2022 , Montes-Ibarra et al, 2022 , Nunes et al, 2022 , Tate et al, 2022 ) other than the brain that may cause chronic fatigue. Thus, it would be necessary to consider the combination therapy with bottom-up neuromodulation approach, such as acupuncture, in addition to TMS in the future ( Lee and Chae, 2022 , Noda et al, 2015 ).…”