Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Multiple early factors anticipate post-acute COVID-19 sequelae.

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Challenges and opportunities in long COVID research.

Long COVID (LC) is a condition in which patients do not fully recover from the initial SARS-CoV-2 infection but rather have persistent or new symptoms for months to years following the infection. Ongoing research efforts are investigating the pathophysiologic mechanisms of LC and exploring preventative and therapeutic treatment approaches for patients. As a burgeoning area of investigation, LC research can be structured to be more inclusive, innovative, and effective. In this perspective, we highlight opportunities for patient engagement and diverse research expertise, as well as the challenges of developing definitions and reproducible studies. Our intention is to provide a foundation for collaboration and progress in understanding the biomarkers and mechanisms driving LC.

Early clues regarding the pathogenesis of long-COVID.

Intense investigation into the predictors and determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), including 'long COVID', is underway. Recent studies provide clues to the mechanisms that might drive this condition, with the goal of identifying host or virus factors that can be intervened upon to prevent or reverse PASC.

SARS-CoV-2, periodontal pathogens, and host factors: The trinity of oral post-acute sequelae of COVID-19.

COVID-19 as a pan-epidemic is waning but there it is imperative to understand virus interaction with oral tissues and oral inflammatory diseases. We review periodontal disease (PD), a common inflammatory oral disease, as a driver of COVID-19 and oral post-acute-sequelae conditions (PASC). Oral PASC identifies with PD, loss of teeth, dysgeusia, xerostomia, sialolitis-sialolith, and mucositis. We contend that PD-associated oral microbial dysbiosis involving higher burden of periodontopathic bacteria provide an optimal microenvironment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These pathogens interact with oral epithelial cells activate molecular or biochemical pathways that promote viral adherence, entry, and persistence in the oral cavity. A repertoire of diverse molecules identifies this relationship including lipids, carbohydrates and enzymes. The S protein of SARS-CoV-2 binds to the ACE2 receptor and is activated by protease activity of host furin or TRMPSS2 that cleave S protein subunits to promote viral entry. However, PD pathogens provide additional enzymatic assistance mimicking furin and augment SARS-CoV-2 adherence by inducing viral entry receptors ACE2/TRMPSS, which are poorly expressed on oral epithelial cells. We discuss the mechanisms involving periodontopathogens and host factors that facilitate SARS-CoV-2 infection and immune resistance resulting in incomplete clearance and risk for 'long-haul' oral health issues characterising PASC. Finally, we suggest potential diagnostic markers and treatment avenues to mitigate oral PASC.

Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Randomized Phase 2 Trial of RSLV-132.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). METHODS: This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). RESULTS: A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. CONCLUSION: While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.

Estimates of Incidence and Predictors of Fatiguing Illness after SARS-CoV-2 Infection.

This study aimed to estimate the incidence rates of post-COVID-19 fatigue and chronic fatigue and to quantify the additional incident fatigue caused by COVID-19. We analyzed electronic health records data of 4,589 patients with confirmed COVID-19 during February 2020-February 2021 who were followed for a median of 11.4 (interquartile range 7.8-15.5) months and compared them to data from 9,022 propensity score-matched non-COVID-19 controls. Among COVID-19 patients (15% hospitalized for acute COVID-19), the incidence rate of fatigue was 10.2/100 person-years and the rate of chronic fatigue was 1.8/100 person-years. Compared with non-COVID-19 controls, the hazard ratios were 1.68 (95% CI 1.48-1.92) for fatigue and 4.32 (95% CI 2.90-6.43) for chronic fatigue. The observed association between COVID-19 and the significant increase in the incidence of fatigue and chronic fatigue reinforces the need for public health actions to prevent SARS-CoV-2 infections.

Substantial health and economic burden of COVID-19 during the year after acute illness among US adults at high risk of severe COVID-19.

BACKGROUND: Post-COVID conditions encompass a range of long-term symptoms after SARS-CoV-2 infection. The potential clinical and economic burden in the United States is unclear. We evaluated diagnoses, medications, healthcare use, and medical costs before and after acute COVID-19 illness in US patients at high risk of severe COVID-19. METHODS: Eligible adults were diagnosed with COVID-19 from April 1 to May 31, 2020, had ≥ 1 condition placing them at risk of severe COVID-19, and were enrolled in Optum's de-identified Clinformatics® Data Mart Database for ≥ 12 months before and ≥ 13 months after COVID-19 diagnosis. Percentages of diagnoses, medications, resource use, and costs were calculated during baseline (12 months preceding diagnosis) and the post-acute phase (12 months after the 30-day acute phase of COVID-19). Data were stratified by age and COVID-19 severity. RESULTS: The cohort included 19,558 patients (aged 18-64 y, n = 9381; aged ≥ 65 y, n = 10,177). Compared with baseline, patients during the post-acute phase had increased percentages of blood disorders (16.3%), nervous system disorders (11.1%), and mental and behavioral disorders (7.7%), along with increases in related prescriptions. Overall, there were substantial increases in inpatient and outpatient healthcare utilization, along with a 23.0% increase in medical costs. Changes were greatest among older patients and those admitted to the intensive care unit for acute COVID-19 but were also observed in younger patients and those who did not require COVID-19 hospitalization. CONCLUSIONS: There is a significant clinical and economic burden of post-COVID conditions among US individuals at high risk for severe COVID-19.

Substantial health and economic burden of COVID-19 during the year after acute illness among US adults not at high risk of severe COVID-19.

BACKGROUND: Patients recovering from SARS-CoV-2 infection and acute COVID-19 illness can experience a range of long-term post-acute effects. The potential clinical and economic burden of these outcomes in the USA is unclear. We evaluated diagnoses, medications, healthcare utilization, and medical costs before and after acute COVID-19 illness in US patients who were not at high risk of severe COVID-19. METHODS: This study included eligible adults who were diagnosed with COVID-19 from April 1 to May 31, 2020, who were 18 - 64 years of age, and enrolled within Optum's de-identified Clinformatics® Data Mart Database for 12 months before and 13 months after COVID-19 diagnosis. Patients with any condition or risk factor placing them at high risk of progression to severe COVID-19 were excluded. Percentages of diagnoses, medications, healthcare utilization, and costs were calculated during baseline (12 months preceding diagnosis) and the post-acute phase (12 months after the 30-day acute phase of COVID-19). Data were stratified into 3 cohorts according to disposition during acute COVID-19 illness (i.e., not hospitalized, hospitalized without intensive care unit [ICU] admission, or admitted to the ICU). RESULTS: The study included 3792 patients; 56.5% of patients were men, 44% were White, and 94% did not require hospitalization. Compared with baseline, patients during the post-acute phase had percentage increases in the diagnosis of the following disorders: blood (166%), endocrine and metabolic (123%), nervous system (115%), digestive system (76%), and mental and behavioral (75%), along with increases in related prescriptions. Substantial increases in all measures of healthcare utilization were observed among all 3 cohorts. Total medical costs increased by 178% during the post-acute phase. Those who were hospitalized with or without ICU admission during the acute phase had the greatest increases in comorbidities and healthcare resource utilization. However, the burden was apparent across all cohorts. CONCLUSIONS: As evidenced by resource use in the post-acute phase, COVID-19 places a significant long-term clinical and economic burden among US individuals, even among patients whose acute infection did not merit hospitalization.

Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID).

BACKGROUND: Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections. METHODS: A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC. RESULTS: Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts. CONCLUSIONS: Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

Meta-analysis of Cognitive Function Following Non-severe SARS-CoV-2 Infection.

To effectively diagnose and treat subjective cognitive symptoms in post-acute sequalae of COVID-19 (PASC), it is important to understand objective cognitive impairment across the range of acute COVID-19 severity. Despite the importance of this area of research, to our knowledge, there are no current meta-analyses of objective cognitive functioning following non-severe initial SARS-CoV-2 infection. The aim of this meta-analysis is to describe objective cognitive impairment in individuals with non-severe (mild or moderate) SARS-CoV-2 cases in the post-acute stage of infection. This meta-analysis was pre-registered with Prospero (CRD42021293124) and utilized the PRISMA checklist for reporting guidelines, with screening conducted by at least two independent reviewers for all aspects of the screening and data extraction process. Fifty-nine articles (total participants = 22,060) with three types of study designs met our full criteria. Individuals with non-severe (mild/moderate) initial SARS-CoV-2 infection demonstrated worse objective cognitive performance compared to healthy comparison participants. However, those with mild (nonhospitalized) initial SARS-CoV-2 infections had better objective cognitive performance than those with moderate (hospitalized but not requiring ICU care) or severe (hospitalized with ICU care) initial SARS-CoV-2 infections. For studies that used normative data comparisons instead of healthy comparison participants, there was a small and nearly significant effect when compared to normative data. There were high levels of heterogeneity (88.6 to 97.3%), likely reflecting small sample sizes and variations in primary study methodology. Individuals who have recovered from non-severe cases of SARS-CoV-2 infections may be at risk for cognitive decline or impairment and may benefit from cognitive health interventions.

Persistent brain metabolic impairment in long COVID patients with persistent clinical symptoms: a nine-month follow-up [18F]FDG-PET study.

PURPOSE: A hypometabolic profile involving the limbic areas, brainstem and cerebellum has been identified in long COVID patients using [18F]fluorodeoxyglucose (FDG)-PET. This study was conducted to evaluate possible recovery of brain metabolism during the follow-up of patients with prolonged symptoms. METHODS: Fifty-six adults with long COVID who underwent two brain [18F]FDG-PET scans in our department between May 2020 and October 2022 were retrospectively analysed, and compared to 51 healthy subjects. On average, PET1 was performed 7 months (range 3-17) after acute COVID-19 infection, and PET2 was performed 16 months (range 8-32) after acute infection, because of persistent severe or disabling symptoms, without significant clinical recovery. Whole-brain voxel-based analysis compared PET1 and PET2 from long COVID patients to scans from healthy subjects (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected) and PET1 to PET2 (with the same threshold, and secondarily with a less constrained threshold of p-voxel < 0.005 uncorrected, p-cluster < 0.05 uncorrected). Additionally, a region-of-interest (ROI) semiquantitative anatomical approach was performed for the same comparisons (p < 0.05, corrected). RESULTS: PET1 and PET2 revealed voxel-based hypometabolisms consistent with the previously reported profile in the literature. This between-group analysis comparing PET1 and PET2 showed minor improvements in the pons and cerebellum (8.4 and 5.2%, respectively, only significant under the less constrained uncorrected p-threshold); for the pons, this improvement was correlated with the PET1-PET2 interval (r = 0.21, p < 0.05). Of the 14,068 hypometabolic voxels identified on PET1, 6,503 were also hypometabolic on PET2 (46%). Of the 7,732 hypometabolic voxels identified on PET2, 6,094 were also hypometabolic on PET1 (78%). The anatomical ROI analysis confirmed the brain hypometabolism involving limbic region, the pons and cerebellum at PET1 and PET2, without significant changes between PET1 and PET2. CONCLUSION: Subjects with persistent symptoms of long COVID exhibit durable deficits in brain metabolism, without progressive worsening.

Cerebrospinal fluid metabolomic and proteomic characterization of neurologic post-acute sequelae of SARS-CoV-2 infection.

The mechanism by which SARS-CoV-2 causes neurological post-acute sequelae of SARS-CoV-2 (neuro-PASC) remains unclear. Herein, we conducted proteomic and metabolomic analyses of cerebrospinal fluid (CSF) samples from 21 neuro-PASC patients, 45 healthy volunteers, and 26 inflammatory neurological diseases patients. Our data showed 69 differentially expressed metabolites and six differentially expressed proteins between neuro-PASC patients and healthy individuals. Elevated sphinganine and ST1A1, sphingolipid metabolism disorder, and attenuated inflammatory responses may contribute to the occurrence of neuro-PASC, whereas decreased levels of 7,8-dihydropterin and activation of steroid hormone biosynthesis may play a role in the repair process. Additionally, a biomarker cohort consisting of sphinganine, 7,8-dihydroneopterin, and ST1A1 was preliminarily demonstrated to have high value in diagnosing neuro-PASC. In summary, our study represents the first attempt to integrate the diagnostic benefits of CSF with the methodological advantages of multi-omics, thereby offering valuable insights into the pathogenesis of neuro-PASC and facilitating the work of neuroscientists in disclosing different neurological dimensions associated with COVID-19.

Lactate dehydrogenase contribution to symptom persistence in long COVID: A pooled analysis.

There's critical need for risk predictors in long COVID. This meta-analysis evaluates the evidence for an association between plasma lactate dehydrogenase (LDH) and long COVID and explores the contribution of LDH to symptoms persistent across the distinct post-acute sequelae of COVID-19 (PASC) domains. PubMed, EMBASE, Web of Science, and Google Scholar were searched for articles published up to 20 March 2023 for studies that reported data on LDH levels in COVID-19 survivors with and without PASC. Random-effect meta-analysis was employed to estimate the standardized mean difference (SMD) with corresponding 95% confidence interval of each outcome. There were a total of 8289 study participants (3338 PASC vs. 4951 controls) from 46 studies. Our meta-analysis compared to the controls showed a significant association between LDH elevation and Resp-PASC [SMD = 1.07, 95%CI = 0.72, 1.41, p = 0.01] but not Cardio-PASC [SMD = 1.79, 95%CI = -0.02, 3.61, p = 0.05], Neuro-PASC [SMD = 0.19, 95%CI = -0.24, 0.61, p = 0.40], and Gastrointestinal-PASC [SMD = 0.45, 95%CI = -1.08, 1.98, p = 0.56]. This meta-analysis suggests elevated LDH can be used for predicting Resp-PASC, but not Cardio-PASC, Neuro-PASC or gastrointestinal-PASC. Thus, elevated plasma LDH following COVID infection may be considered as a disease biomarker.

COVID-19 and long-term impact on symptoms and Health-Related Quality of Life in Costa Rica: the RESPIRA cohort study.

BACKGROUND: Evidence continues to accumulate regarding the potential long-term health consequences of COVID-19 in the population. To distinguish between COVID-19-related symptoms and health limitations from those caused by other conditions, it is essential to compare cases with community controls using prospective data ensuring case-control status. The RESPIRA study addresses this need by investigating the lasting impact of COVID-19 on Health-related Quality of Life (HRQoL) and symptomatology in a population-based cohort in Costa Rica, thereby providing a robust framework for controlling HRQoL and symptoms. METHODS: The study comprised 641 PCR-confirmed, unvaccinated cases of COVID-19 and 947 matched population-based controls. Infection was confirmed using antibody tests on enrollment serum samples and symptoms were monitored monthly for 6 months post-enrolment. Administered at the 6-month visit (occurring between 6- and 2-months post-diagnosis for cases and 6 months after enrollment for controls), HRQoL and Self-Perceived Health Change were assessed using the SF-36, while brain fog, using three items from the Mental Health Inventory (MHI). Regression models were utilized to analyze SF-36, MHI scores, and Self-Perceived Health Change, adjusted for case/control status, severity (mild case, moderate case, hospitalized) and additional independent variables. Sensitivity analyses confirmed the robustness of the findings. RESULTS: Cases showed significantly higher prevalences of joint pain, chest tightness, and skin manifestations, that stabilized at higher frequencies from the fourth month post-diagnosis onwards (2.0%, 1.2%, and 0.8% respectively) compared to controls (0.9%, 0.4%, 0.2% respectively). Cases also exhibited significantly lower HRQoL than controls across all dimensions in the fully adjusted model, with a 12.4 percentage-point difference [95%CI: 9.4-14.6], in self-reported health compared to one year prior. Cases reported 8.0% [95%CI: 4.2, 11.5] more physical limitations, 7.3% [95%CI: 3.5, 10.5] increased lack of vitality, and 6.0% [95%CI: 2.4, 9.0] more brain fog compared to controls with similar characteristics. Undiagnosed cases detected with antibody tests among controls had HRQoL comparable to antibody negative controls. Differences were more pronounced in individuals with moderate or severe disease and among women. CONCLUSIONS: PCR-confirmed unvaccinated cases experienced prolonged HRQoL reductions 6 months to 2 years after diagnosis, this was particularly the case in severe cases and among women. Mildly symptomatic cases showed no significant long-term sequelae.

Designing and analyzing studies of coronavirus disease 2019 and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 among immunocompromised individuals.

Observational studies of coronavirus disease 2019 (COVID-19) among transplant candidates and recipients remain important as immunocompromised patients formed a very small proportion of patients included in COVID-19 trials and large database analyses. We discuss methods that have been used in such analyses to evaluate the impact of vaccination on the risk of symptomatic COVID-19 in such patients and on the probability of developing post-acute sequelae of severe acute respiratory syndrome coronavirus 2 after the onset of infection. We also propose future directions for research and discuss the methods that will be useful to conduct such investigations. The study design and analytical issues that we consider have the potential to be helpful not only for COVID-19 research but also for other infections as well.

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses.

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs. In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an 'original antigenic sin' (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

Anxiety and depression symptoms among patients with long COVID: a retrospective cohort study.

Patients suffering from post-acute sequelae of COVID-19 (PASC) have a higher prevalence of anxiety and depression than the general population. The long-term trajectory of these sequelae is still unfolding. To assess the burden of anxiety and depression among patients presenting to the University of Iowa Hospitals and Clinics (UIHC) post-COVID-19 clinic, we analyzed how patient factors influenced Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) scores. In this retrospective cohort study, the GAD-7 and PHQ-9 questionnaire scores of patients presenting to the UIHC post-COVID clinic between March 2021-February 2022 (N = 455) were compared to the scores of a sample of patients presenting to the general internal medicine (GIM) clinic during the same period (N = 94). Our analysis showed that patients with an absent history of depression on their electronic medical record (EMR) problem list scored significantly higher on the GAD-7 (mean difference -1.62, 95% CI -3.12 to -0.12, p = 0.034) and PHQ-9 (mean difference -4.45, 95% CI -5.53 to -3.37, p < 0.001) questionnaires compared to their similar counterparts in the GIM clinic. On the other hand, patients with an absent history of anxiety on their EMR problem list scored significantly higher on the GAD-7 (mean difference -2.90, 95% CI -4.0 to -1.80, p < 0.001) but not on the PHQ-9 questionnaire (p = 0.196). Overall, patients with PASC may have experienced a heavier burden of newly manifest anxiety and depression symptoms compared to patients seen in the GIM clinic. This suggests that the mental health impacts of PASC may be more pronounced in patients with no prior history of anxiety or depression.

Gastrointestinal Manifestations and Their Association with Neurologic and Sleep Problems in Long COVID-19 Minority Patients: A Prospective Follow-Up Study.

BACKGROUND: Long-COVID is a condition post SARS-CoV-2 infection with persistent or recurring symptoms affecting multiple organs, and may involve viral persistence, changes to the microbiome, coagulopathies, and alterations to neuro-immune interactions. These factors can disrupt the Gut-Brain Axis, which is a complex system involving bidirectional communication between the central nervous system and the gastrointestinal (GI) system. As a result of these disruptions, individuals with long-COVID may develop post-infectious functional GI disorders, which can cause a range of symptoms affecting the digestive system. AIM: To understand frequency of GI manifestations of Long-COVID and to determine association with sleep or neurological symptoms in a predominantly minority population. METHODS: We included patients with positive SARS-CoV-2 PCR (n = 747) who were hospitalized from Feb. 2020 to May 2021 at Howard University Hospital and followed between 6 and 12 months from discharge. GI, sleep, and neurological symptoms (via the Montreal Cognitive Assessment (MoCA) scoring system) were assessed using a standardized questionnaire. Linear regression analysis, χ2 and Fisher's exact test were utilized to determine the statistical significance of correlations of GI/Neuro/COVID. RESULTS: The mean age of patients was 58, with 51.6% females and a predominant African American ethnicity (73.6%, n = 550). A total of 108 patients died during their initial hospital stay, with the remaining 639 patients followed-up. Three hundred fifty (350) patients responded to the questionnaire (57 patients died during the follow-up period). Overall, 39 (13.3%) patients reported GI-related symptoms, out of which 19 (6.4%) had persistent symptoms and 20 (6.8%) developed new onset GI symptoms. Nausea and vomiting were the most common 24/39 (61.5%), followed by abdominal pain 7/39 (18%), diarrhea 5/39 (12.8%), and others 3/39 (7.6%). Patients who presented with vomiting during acute SARS-CoV-2 infection were more likely to have Long-COVID GI manifestations (P = 0.023). Use of ACE inhibitors, abnormal lymphocyte count and elevated ferritin are other variables that showed significant associations with Long-COVID GI manifestations (P = 0.03, 0.006 and 0.03, respectively). During follow-up, a total of 28 (9.5%) patients reported difficulty with sleep and 79 (27%) patients had abnormal MoCA assessment. With further analysis, there was a trend between presentation of GI symptoms on admission with abnormal MoCA assessment, and an association between abnormal LFTs and history of liver disease during hospitalization with subsequent sleep problems. Baseline characteristics, clinical comorbidities, other laboratory values, hospital length of stay, mechanical ventilation, medications during hospitalization, re-admission and Flu or COVID-19 vaccination have not shown any association with Long-COVID GI symptoms in our cohort. CONCLUSION: Dyspeptic symptoms were common GI manifestations in the acute and post COVID periods. GI symptoms, abnormal LFTs and a history of liver disease during the acute infectious phase associates with abnormal MoCA and sleep problems during follow-up. Further large population studies are needed to determine if COVID-19 leads to a GI symptoms-associated Long-COVID phenotypes and other symptoms through the Gut-Brain-Axis.