Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection (preprint)

To understand the roles of acute phase viral dynamics and host immune responses in PASC, we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR. Participants self-collected nasal specimens up to 21 times within the first 28 days after symptom onset; Interviewer-administered clinical questionnaires and blood samples were collected at enrollment and days 9, 14, 21, 28, and month 4 and 8 post-symptom. Defining PASC as the presence of any symptom new or worse since infection reported at their 4-month visit, we compared viral markers (quantity and duration of viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-a, IFN-a, IFN-g, MCP, IP-10, and Spike IgG) over the acute period. In comparison to those who fully recovered, those who developed PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA, infectious virus, and N-antigen, longer duration of viral shedding, and lower Spike-specific IgG levels within the first 10 days of the acute phase of illness. No significant differences were identified among a panel of host immune markers, though there was a trend toward higher initial levels of certain markers (e.g., MCP-1, IFN-a, and IFN-g) in those who went on to develop PASC. Early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC. These findings highlight the importance of understanding the early biological markers from acute SARS-CoV-2 infection in the natural history of PASC.

Risk-based prediction for optimal timing of booster vaccination for COVID-19 to prevent severe disease (preprint)

While waning protection from vaccination and natural infection against SARS-CoV-2 infection is well-documented, recent analyses have also found waning of protection against severe COVID-19. This highlights a broader need to understand the optimal timing of COVID-19 booster vaccines specific to an individual to mitigate the risk of severe COVID-19, while accounting for waning of protection and differential risk by age group and immune status. Here we show that more frequent COVID-19 booster vaccination (every 6-12 months) in older age groups and the immunocompromised population would effectively mitigate the burden of severe COVID-19, while frequent boosters in the younger population may only provide modest benefit. Analyzing United States COVID-19 surveillance and seroprevalence data in a microsimulation model, we estimated that in persons 75+ years, annual and semiannual bivalent boosters would reduce annual absolute risk of severe COVID-19 by 311 (277-369) and 578 (494-671) cases, respectively, compared to a one-time bivalent booster dose. In contrast, for persons 18-49 years, the model estimated that annual and semiannual bivalent boosters would reduce annual absolute risk of severe COVID-19 by 20 (13-26) and 37 (24-50) cases per 100,000 persons, respectively, compared to a one-time bivalent booster dose. Persons with prior infection had a much lower benefit of more frequent boosting, while immunocompromised persons had larger benefit. This study underscores the benefit of customizing timing of COVID-19 booster vaccines based on individual risk.

Researching COVID to enhance recovery (RECOVER) adult study protocol: Rationale, objectives and design (preprint)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged [≥]18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms (preprint)

Background: The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. Methods: We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to wide-spread rollout of SARS-CoV-2 vaccines. Cross sectional regression models adjusted for various clinical covariates and longitudinal mixed effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms in general, as well as LC phenotypes. Results: We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of LC symptoms. Specifically, we show that, although neutralizing antibody responses to the original, infecting strain of SARS-CoV-2 were not associated with LC in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Conclusions: Our findings suggest that relationships between various immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses.

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2 (preprint)

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple omics assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients (preprint)

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as Long COVID. The underlying pathophysiology of Long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of COVID infection and certain other post-COVID sequelae, their potential role in Long COVID is important to investigate. Here we apply a well-established, unbiased, proteome-wide autoantibody detection technology (PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with Long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected which separates individuals with prior COVID infection from those never exposed to COVID, we did not detect patterns of autoreactivity that separate individuals with Long COVID relative to individuals fully recovered from SARS-CoV-2 infection. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and Long COVID was apparent by this assay.

Longitudinal and Quantitative Fecal Shedding Dynamics of SARS-CoV-2, Pepper Mild Mottle Virus and CrAssphage (preprint)

Wastewater-based epidemiology (WBE) emerged during the COVID-19 pandemic as a scalable and broadly applicable method for community-level monitoring of infectious disease burden, though the lack of high-quality, longitudinal fecal shedding data of SARS-CoV-2 and other viruses limits the interpretation and applicability of wastewater measurements. In this study, we present longitudinal, quantitative fecal shedding data for SARS-CoV-2 RNA, as well as the commonly used fecal indicators Pepper Mild Mottle Virus (PMMoV) RNA and crAss-like phage (crAssphage) DNA. The shedding trajectories from 48 SARS-CoV-2 infected individuals suggest a highly individualized, dynamic course of SARS-CoV-2 RNA fecal shedding, with individual measurements varying from below limit of detection to 2.79x10^6 gene copies/mg - dry mass of stool (gc/mg-dw). Of individuals that contributed at least 3 samples covering a range of at least 15 of the first 30 days after initial acute symptom onset, 77.4% had at least one positive SARS-CoV-2 RNA stool sample measurement. We detected PMMoV RNA in at least one sample from all individuals and in 96% (352/367) of samples overall; and measured crAssphage DNA above detection limits in 80% (38/48) of individuals and 48% (179/371) of samples. Median shedding values for PMMoV and crAssphage nucleic acids were 1x10^5 gc/mg-dw and 1.86x10^3 gc/mg-dw, respectively. These results can be used to inform and build mechanistic models to significantly broaden the potential of WBE modeling and to provide more accurate insight into SARS-CoV-2 prevalence estimates.

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

ABSTRACT 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. SUMMARY The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.

A high-resolution melt curve toolkit to identify lineage-defining SARS-CoV-2 mutations (preprint)

The emergence of severe acute respiratory syndrome 2 (SARS-CoV-2) variants of concern (VOCs), with mutations linked to increased transmissibility, vaccine escape and virulence, has necessitated the widespread genomic surveillance of SARS-CoV-2. This has placed a strain on global sequencing capacity, especially in areas lacking the resources for large scale sequencing activities. Here we have developed three separate multiplex high resolution melting (HRM) assays to enable the identification of Alpha, Beta, Delta and Omicron VOCs, assay based on HRM analysis, an endpoint RT-qPCR detection method. The assays were evaluated against whole genome sequencing on upper-respiratory swab samples collected at varying points of the UK pandemic. The sensitivities of the eight individual primer sets were all 100%, and specificity ranged from 94.6 to 100%. The multiplex HRM assays have potential as a tool for high throughput surveillance of SARS-CoV-2 VOCs, particularly in areas with limited genomics facilities.

Reduced Exercise Capacity, Chronotropic Incompetence, Inflammation and Symptoms in Post-Acute COVID-19 (preprint)

BACKGROUND Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring. METHODS In the Long-Term Impact of Infection with Novel Coronavirus (LIINC) Cohort, we performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection. We used logistic and linear regression to compare those with and without cardiopulmonary symptoms (dyspnea, chest pain, palpitations) adjusting for confounders. RESULTS One hundred twenty individuals were studied, among whom 46 participants (unselected for symptom status) had at least one advanced test performed at median 17 months (IQR 15-18). Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), smaller RV volume and stroke volume and higher extracellular volume were present among those with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/15 (87%) participants with reduced exercise capacity (<85% predicted) reported cardiopulmonary symptoms or fatigue (p=0.008). Adjusted peak VO2 was 2.7 ml/kg/min lower among those with cardiopulmonary symptoms (95%CI -6.9 to 1.5; p=0.20) or -11% predicted (95%CI -27 to 5, p=0.17). Including fatigue along with cardiopulmonary symptoms, the adjusted difference in peak VO2 was -5.9 ml/kg/min (-9.6 to -2.3; p=0.002) or -21% predicted (-35 to -7; p=0.006). Chronotropic incompetence was the primary abnormality among 9/15 with reduced peak VO2. Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187; p=0.03). Those with chronotropic incompetence had higher hsCRP, lower heart rate recovery, and lower heart rate variability suggestive of autonomic dysfunction. CONCLUSIONS Reduced exercise capacity and reduced heart rate response to exercise, and hsCRP are associated with persistent cardiopulmonary symptoms more than 1 year following COVID-19. Chronic inflammation and autonomic dysfunction may underlie cardiopulmonary PASC.

Infectious viral shedding of SARS-CoV-2 Delta following vaccination: a longitudinal cohort study (preprint)

The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P=0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset.

Effect of oral nirmatrelvir on Long COVID symptoms: a case series (preprint)

As the SARS-CoV-2 pandemic continues to evolve, efforts to understand variability in COVID-19 recovery, as well as the impact of factors including viral variants, vaccine status, and COVID-19 treatment on the development and persistence of Long COVID symptoms have intensified. We report three cases that demonstrate that variability in the timing of nirmatrelvir therapy may be associated with different outcomes and underscores the need for systematic study of antiviral therapy for this disease condition.

Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation. (preprint)

Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation - measured as beta-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher beta-glucan correlated with higher levels of markers of inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, beta-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-kB signaling. Using an in vitro Dectin-1/NF-kB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-kB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-kB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

POST-ACUTE SEQUELAE AND ADAPTIVE IMMUNE RESPONSES IN PEOPLE LIVING WITH HIV RECOVERING FROM SARS-COV-2 INFECTION (preprint)

Background: Limited data are available on the long-term clinical and immunologic consequences of SARS-CoV-2 infection in people with HIV (PWH). Methods: We measured SARS-CoV-2 specific humoral and cellular immune responses in people with and without HIV recovering from COVID-19 (n=39 and n=43, respectively) using binding antibody, surrogate virus neutralization, intracellular cytokine staining, and inflammatory marker assays. We identified individuals experiencing symptomatic post-acute sequelae of SARS-CoV-2 infection (PASC) and evaluated immunologic parameters. We used linear regression and generalized linear models to examine differences by HIV status in the magnitude of inflammatory and virus-specific antibody and T cell responses, as well as differences in the prevalence of PASC. Results: Among PWH, we found broadly similar SARS-CoV-2-specific antibody and T cell immune responses as compared with a well-matched group of HIV-negative individuals. PWH had 70% lower relative levels of SARS-CoV-2 specific memory CD8+ T cells (p=0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2 specific CD4+ T cells (p=0.007). Higher CD4/CD8 ratio was associated with lower PD-1 expression on SARS-CoV-2 specific CD8+ T cells (0.34-fold effect, p=0.02). HIV status was strongly associated with PASC (odds ratio 4.01, p=0.008), and the proportion of PD-1+ CD4+ T cells and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms. Conclusions: We identified potentially important differences in SARS-CoV-2-specific CD4+ and CD8+ T cells that might have implications for long-term immunity conferred by natural infection. HIV status strongly predicted the presence of PASC. Larger and more detailed studies of PASC in PWH are urgently needed.

Taking care of the caregivers: The moderating role of reflective supervision in the relationship between COVID-19 stress and the mental and professional well-being of the IECMH workforce.

The present study examined the relationships between COVID-related stress, mental health and professional burnout in the infant and early child mental health (IECMH) workforce and examined reflective supervision and consultation (RSC) as a potential protective factor in the context of COVID-related stress. Participants included 123 adults (n = 121 female, modal age range 30-39 years) in the TN IECMH workforce (mean years of experience = 13.6 years) surveyed in June/July 2020. Sector representation was quite varied (home visiting, childcare, child welfare, early intervention). Results indicated the majority (63%) of the sample was caring for someone else (e.g., child or elderly person) while working at home, 46% of the sample had depression symptoms (18% in the moderate-severe range), and 75% of the sample had anxiety symptoms (33% in the moderate-severe range). Higher COVID stress was associated with higher internalizing symptoms and burnout levels and this relationship was mediated by self-care behaviors such that the more COVID stress one reported, the fewer self-care behaviors they engaged in, and the higher the risk for internalizing and burnout. Finally, the pathway from COVID stress to self-care behaviors was moderated by RSC. IECMH professionals who received less than 1 year (or no experience) of RSC showed a significant decrease in self-care behaviors during times of low, average and high levels of COVID stress compared to those who received 1 year or more of RSC. Implications for both policy and practice will be discussed.

El presente estudio examinó las relaciones entre el estrés causado por el COVID, la salud mental y el cansancio profesional en la fuerza laboral de IECMH y examinó la supervisión y consulta con reflexión (RSC) como un potencial factor de protección en el contexto del estrés relacionado con COVID. Los participantes fueron 123 adultos (edad modal entre 30-39 años) de la fuerza laboral de IECMH en TN (años promedio de experiencia = 13.6 años). La representación de sector fue muy variada (visitas a casa, bienestar infantil, intervención temprana). Los resultados indicaron que el 63% del grupo muestra tenía bajo su cuidado a alguien más mientras trabajaba en casa, el 46% del grupo muestra presentaba síntomas de depresión y el 75% del grupo muestra tenía síntomas de ansiedad. El más alta estrés por COVID se asoció con más altos síntomas de internalización y niveles de cansancio y esta relación fue mediada por conductas de autocuidado de manera que mientras más estrés por COVID se reportaba, ellos participaban en menos conductas de autocuidado y era más alto el riesgo de internalización y cansancio. Finalmente, el paso del estrés por COVID a las conductas de autocuidado fue moderado por RSC. Los profesionales de IECMH que recibieron menos de 1 año (o ninguna experiencia) de RSC mostraron una significativa baja en conductas de autocuidado durante momentos de bajos, promedio y altos niveles de estrés por COVID, comparados con aquellos que recibieron 1 año o más de RSC. Se discuten las implicaciones tanto para políticas como para la práctica.

Cette étude a examiné les relations entre le stress lié au COVID, la santé mentale et le burnout professionnel chez les effectifs de IECMH et examiné la supervision et la consultation de réflexion (RSC en anglais) en tant que facteur de protection potentiel dans le contexte du stress lié au COVID. Les participants ont inclus 123 adultes (tranche d'âge modale 30-39 ans) dans les effectifs TN IECHM (moyenne d'années d'expérience - 13,6 années). La représentation par secteur était assez variée (visites à domicile, bien-être de l'enfant, intervention précoce). Les résultats indiquent que 63% de l'échantillon prenait soin de quelqu'un d'autre tout en travaillant à la maison, 46% de l'échantillon présentaient des symptômes de dépression et 75% de l'échantillon avaient des symptômes d'anxiété. Un stress COVID plus élevé était lié avec des symptômes d'internalisation plus élevés et des niveaux de burnout plus élevés et cette relation était mitigée par des comportements d'auto-soin, à tel point que plus quelqu'un faisait état de stress de COVID, le moins cette même personne s'engageait en comportement d'auto-soin, et les plus élevé s'avérait le risque d'internalisation et de burnout. Enfin, la trajectoire du stress COVID aux comportements d'auto-soin était modérée par la RSC. Les professionnels IECMH ayant reçu moins d'une année (ou pas d'expérience) de la RSC ont présenté une baisse importante dans les comportements d'auto-soin durant les moments de niveaux de stress COVID bas, moyens et élevés, comparés à ceux ayant reçu une année ou plus de RSC. Les implications pour les politiques et les pratiques seront discutées.

Role of antibodies, inflammatory markers, and echocardiographic findings in post-acute cardiopulmonary symptoms after SARS-CoV-2 infection (preprint)

ABSTRACT BACKGROUND Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. METHODS In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after PCR-confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. RESULTS We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex (OR 2.55, 95%CI 1.13-5.74) and hospitalization during acute infection (OR 3.25, 95%CI 1.08-9.82) were associated with symptoms. IgG antibody to SARS-CoV-2 receptor binding domain (OR 1.38 per doubling, 95%CI 1.38-1.84) and high-sensitivity C-reactive protein (OR 1.31 per doubling, 95%CI 1.00-1.71) were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with pericardial effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters (including left ventricular ejection fraction and strain, right ventricular strain, pulmonary artery pressure) or high-sensitivity troponin, NT-pro-BNP, interleukin-10, interferon-gamma, or tumor necrosis factor-alpha. CONCLUSIONS Among adults in the post-acute phase of SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted. FUNDING This work was supported by the UCSF Division of Cardiology at Zuckerberg San Francisco General, and the National Institutes of Health/National Heart Lung Blood Institute and National Institute of Allergy and Infectious Diseases. MSD is supported by NIH 5K12HL143961. MJP is supported on NIH T32 AI60530-12. JDK is supported by NIH K23AI135037. TJH is supported by NIH/NIAID 3R01A1141003-03S1. PYH is supported by NIH/NAID 2K24AI112393-06. This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1TR001872. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. GRAPHICAL ABSTRACT

Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC) (preprint)

Background: The biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood. Methods: We measured markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported central nervous system (CNS) PASC symptoms during the late recovery timepoint. We compared fold-changes in marker values between those with and without CNS PASC symptoms using linear mixed effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. Results: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p=0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p=0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison to those who did not report CNS PASC symptoms (p=0.041). Those who went on to report CNS PASC also exhibited elevations in IL-6 (48% higher during early recovery and 38% higher during late recovery), MCP-1 (19% higher during early recovery), and TNF-alpha (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery. Conclusions: Self-reported neurologic symptoms present >90 days following SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at early recovery timepoints, suggesting that early injury can result in long-term disease. The correlation of GFAP and NfL with markers of systemic immune activation suggests one possible mechanism that might contribute to these symptoms. Additional work is needed to better characterize these processes and to identify interventions to prevent or treat this condition.

Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown. METHODS: We measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)-attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods. RESULTS: During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor-α (1.14-fold higher mean ratio [95% confidence interval {CI}, 1.01-1.28]; P = .028) and interferon-γ-induced protein 10 (1.28-fold higher mean ratio [95% CI, 1.01-1.62]; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio [95% CI, .98-1.70]; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio [95% CI, 1.11-1.86]; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms. CONCLUSIONS: Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

SARS-CoV-2 serology across scales: a framework for unbiased seroprevalence estimation incorporating antibody kinetics and epidemic recency (preprint)

Serosurveys are a key resource for measuring SARS-CoV-2 cumulative incidence. A growing body of evidence suggests that asymptomatic and mild infections (together making up over 95% of all infections) are associated with lower antibody titers than severe infections. Antibody levels also peak a few weeks after infection and decay gradually. We developed a statistical approach to produce adjusted estimates of seroprevalence from raw serosurvey results that account for these sources of spectrum bias. We incorporate data on antibody responses on multiple assays from a post-infection longitudinal cohort, along with epidemic time series to account for the timing of a serosurvey relative to how recently individuals may have been infected. We applied this method to produce adjusted seroprevalence estimates from five large-scale SARS-CoV-2 serosurveys across different settings and study designs. We identify substantial differences between reported and adjusted estimates of over two-fold in the results of some surveys, and provide a tool for practitioners to generate adjusted estimates with pre-set or custom parameter values. While unprecedented efforts have been launched to generate SARS-CoV-2 seroprevalence estimates over this past year, interpretation of results from these studies requires properly accounting for both population-level epidemiologic context and individual-level immune dynamics.