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1.
Topics in Antiviral Medicine ; 30(1 SUPPL):247-248, 2022.
Article in English | EMBASE | ID: covidwho-1880706

ABSTRACT

Background: The biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood. We measured plasma markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as < and > 90 days since COVID-19 onset, respectively). We hypothesized that those experiencing persistent neurologic symptoms would have elevations in these markers. Methods: 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 markers during early recovery (MCP-1, IL-6, TNF-a, IFN-g);these correlations were attenuated during late recovery. Conclusion: Self-reported neurologic symptoms present approximately four months 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 will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.

2.
Topics in Antiviral Medicine ; 30(1 SUPPL):38-39, 2022.
Article in English | EMBASE | ID: covidwho-1880187

ABSTRACT

Background: Cardiopulmonary symptoms and reduced exercise capacity can persist after SARS-CoV-2 infection. Mechanisms of post-acute sequelae of COVID-19 ("PASC" or "Long COVID") remain poorly understood. We hypothesized that systemic inflammation would be associated with reduced exercise capacity and pericardial/myocardial inflammation. Methods: As part of a COVID recovery cohort (NCT04362150) we assessed symptoms, biomarkers, and echocardiograms in adults >2 months after PCR-confirmed SARS-CoV-2 infection. In a subset, we performed cardiac magnetic resonance imaging (CMR), ambulatory rhythm monitoring (RM), and cardiopulmonary exercise testing (CPET) >12 months after acute infection. Associations between symptoms and oxygen consumption (VO2), cardiopulmonary parameters and biomarkers were evaluated using linear and logistic regression with adjustment for age, sex, BMI, and time since infection. Results: We studied 120 participants (median age 51, 42% female, and 47% had cardiopulmonary symptoms at median 7 months after acute infection). Elevated hsCRP was associated with symptoms (OR 1.32 per doubling, 95%CI 1.01-1.73, p=0.04). No differences in echocardiographic indices were found except for presence of pericardial effusions among those with symptoms (p=0.04). Of the subset (n=33) who underwent CMR at a median 17 months, all had normal cardiac function (LVEF 53-76%), 9 (27%) had pericardial effusions and none had findings suggestive of prior myocarditis. There were no differences on RM by symptoms. On CPET, 33% had reduced exercise capacity (peak VO2 <85% predicted). Individuals with symptoms had lower peak VO2 compared to those reporting recovery (28.4 vs 21.4 ml/kg/min, p=0.04, Figure). Elevated hsCRP was independently associated with lower peak VO2 after adjustment (-9.8 ml/kg/min per doubling, 95%CI-17.0 to-2.5;p=0.01, Figure). The predominant mechanism of reduced peak VO2 was chronotropic incompetence (HR 19% lower than predicted, 95%CI 11-26%;p<0.0001, Figure). Chronotropic incompetence on CPET correlated with lower peak HR during ambulatory RM (p<0.001). Conclusion: Persistent systemic inflammation (hsCRP) is associated with pericardial effusions and reduced exercise capacity > 1 year after acute SARS-CoV-2 infection. This finding appears to be driven mainly by chronotropic incompetence rather than respiratory compromise, cardiac pump dysfunction, or deconditioning. Evaluation of therapeutic strategies to target inflammation and/or chronotropy to alleviate PASC is urgently needed.

3.
Topics in Antiviral Medicine ; 30(1 SUPPL):121, 2022.
Article in English | EMBASE | ID: covidwho-1880045

ABSTRACT

Background: SARS-CoV-2 produces variable immune responses leading to different levels of immune protection. The relationship between neutralizing antibody level (NAb) and protective immunity has been well characterized after infection and vaccination. While comparatively specific T cell responses tend to be more variable, the impacts of these responses have broad implications on long-term immunity and their role in protective immunity has not been as clearly defined. Using data from our prospective cohort study and studies of clinical protective immunity/efficacy (from vaccines), we predicted protective immunity over time in relation to SARS-CoV-2-specific T cell dynamics. Methods: With linear mixed-effects models from our published immune data from people recovering from COVID-19, we simulated the Spike (S)-specific interferon-γ (IFNγ)+ CD4+, S-specific IFNγ+ CD8+, and nucleocapsid (N)-specific IFNγ+ CD8+ T cells over time (n=500 individuals). We then predicted NAbs from linear regression models developed from the same cohort. Finally, protective immunity from NAb titers was simulated from a published model. We similarly simulated 25, 50, and 75% lower T cell responses than those observed post-COVID-19 to understand how immune response variation may impact protective immunity. Results: Virus-specific T cell responses resulted in similar protective immunity across T cell subsets, but with differences in variability over time. Protective immunity for IFNγ+ S CD8 T cells spanned from 86-95%, while for IFNγ+ S CD4 T cells and IFNγ+ N CD4 T cells it ranged from 81-96% and 84-95% respectively. Further, based on simulated dampened T cell responses, protective immunity overall did not drop below 81% less than nine months after infection even with a 75% reduction in specific T cell immunity. Conclusion: NAbs are often the singular focus to predict protective immunity and the role of virus-specific T cell immunity has often been discussed as a secondary immune response. Our analysis demonstrates that for SARS-CoV-2, certain T cells responses can reliably predict protective immunity and may be intrinsically linked. Simulating dampened T cell response to mimic a more virulent strain or inadequate immune response, demonstrated that dampened T cell response may not be responsible for inadequate protective immunity in these scenarios. In the absence of prospective clinical data, similar models may be utilized to explore the impact of potential therapeutics on immune responses and resulting protective immunity.

4.
PubMed; 2022.
Preprint in English | PubMed | ID: ppcovidwho-338328

ABSTRACT

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: We performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection in the UCSF Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC;NCT04362150 ) and correlated findings with previously measured biomarkers. We used logistic regression to estimate associations with PASC symptoms (dyspnea, chest pain, palpitations, and fatigue) adjusted for confounders and linear regression to estimate differences between those with and without symptoms adjusted for confounders. RESULTS: Out of 120 participants in the cohort, 46 participants (unselected for symptom status) had at least one advanced cardiac test performed at median 17 months following initial SARS-CoV-2 infection. Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), higher extracellular volume was associated 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), 13/23 (57%) with cardiopulmonary symptoms or fatigue had reduced exercise capacity (peak VO 2 <85% predicted) compared to 2/16 (13%) without symptoms (p=0.008). The adjusted difference in peak VO 2 was 5.9 ml/kg/min lower (-9.6 to -2.3;p=0.002) or -21% predicted (-35 to -7;p=0.006) among those with symptoms. Chronotropic incompetence was the primary abnormality among 9/15 (60%) with reduced peak VO 2 . Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187;p=0.03). Inflammatory markers (hsCRP, IL-6, TNF-alpha) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO 2 more than 1 year later. CONCLUSIONS: Cardiopulmonary symptoms and elevated inflammatory markers present early in PASC are associated with objectively reduced exercise capacity measured on cardiopulmonary exercise testing more than 1 year following COVID-19. Chronotropic incompetence may explain reduced exercise capacity among some individuals with PASC. Clinical Perspective: What is New?Elevated inflammatory markers in early post-acute COVID-19 are associated with reduced exercise capacity more than 1 year later.Impaired chronotropic response to exercise is associated with reduced exercise capacity and cardiopulmonary symptoms more than 1 year after SARS-CoV-2 infection.Findings on ambulatory rhythm monitoring point to perturbed autonomic function, while cardiac MRI findings argue against myocardial dysfunction and myocarditis. Clinical Implications: Cardiopulmonary testing to identify etiologies of persistent symptoms in post-acute sequalae of COVID-19 or "Long COVID" should be performed in a manner that allows for assessment of heart rate response to exercise. Therapeutic trials of anti-inflammatory and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing.

5.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-333553

ABSTRACT

BACKGROUND: The absence of systematic surveillance for SARS-CoV-2 has curtailed accurate appraisal of transmission intensity. Our objective was to perform case detection of an entire rural community to quantify SARS-CoV-2 transmission using PCR and antibody testing. METHODS: We conducted a cross-sectional survey of the prevalence and cumulative incidence of SARS-CoV-2 infection in the rural town of Bolinas, California (population 1,620), four weeks following shelter-in-place orders. Residents and county essential workers were tested between April 20th-24th, 2020. Prevalence by PCR and seroprevalence combining data from two forms of antibody testing were performed in parallel (Abbott ARCHITECT IgG to nucleocapsid protein and in-house IgG ELISA to the receptor binding domain). RESULTS: Of 1,891 participants, 1,312 were confirmed Bolinas residents (>80% community ascertainment). Zero participants were PCR positive. Assuming 80% sensitivity, it would have been unlikely to observe these results (p<0.05) if there were >3 active infections in the community. Based on antibody results, estimated prevalence of prior infection was 0.16% (95% CrI: 0.02%, 0.46%). Seroprevalence estimates using only one of the two tests would have been higher, with greater uncertainty. The positive predictive value (PPV) of a positive result on both tests was 99.11% (95% CrI: 95.75%, 99.94%), compared to PPV 44.19%-63.32% (95% CrI range 3.25%-98.64%) if only one test was utilized. CONCLUSIONS: Four weeks following shelter-in-place, active and prior SARS-CoV-2 infection in a rural Northern California community was extremely rare. In this low prevalence setting, use of two antibody tests increased the PPV and precision of seroprevalence estimates.

6.
Open Forum Infectious Diseases ; 8(SUPPL 1):S805, 2021.
Article in English | EMBASE | ID: covidwho-1746280

ABSTRACT

Background. Limited data are available on whether there are differences in the immune response to SARS-CoV-2 vaccination by HIV status or by mRNA vaccine type. Methods. We saved residual outpatient laboratory samples of all previously mRNA-vaccinated individuals in the adult medicine clinics of a public hospital with a large outpatient HIV clinic during May 2021, and then excluded individuals with prior SARS-CoV-2 infection. We next 1:1 matched 100 PLWH to 100 outpatient HIVnegative adult medicine patients receiving care for chronic medical conditions on days since completion of second vaccination (minimum 10), sex, age +/-5 years, and the type of mRNA vaccine received. We defined a non-response as reciprocal pseudovirus neutralizing titer< 10 and anti-RBD IgG< 10 relative fluorescent units, and compared non-response by HIV status using mixed models. Results. In each matched group there were 13 women;25 received the mRNA-1273 vaccine and 75 received the BNT162b2 vaccine;the median age was 59. The median time from second vaccination was 35 days (IQR: 20-63). Among PLWH, the median CD4+ T-cell count was 511 (IQR: 351-796) and 5 individuals had HIV RNA > 200. We found 2.4-fold greater odds of pseudovirus neutralizing antibody non-response among PLWH compared to people without HIV (95% CI=1.1-5.4). Although few individuals in each group did not mount an IgG response (12 among PLWH vs. 5;p=0.08), continuous anti-RBD IgG concentrations were 43% lower among PLWH (95% CI=0.36-0.88). Among PLWH, when adjusting for age, sex, and days post-vaccination, each 100-cell increase in CD4+T-cell count was associated with 22% higher neutralizing antibody titers (GMR 1.22;95% CI=1.09-1.37). Unsuppressed HIV RNA >200 was associated with 89% lower neutralizing antibody titers (GMR 0.11;95% CI=0.01-0.84). Receipt of the BNT162b2 vs. mRNA-1273 vaccine was associated with 77% lower neutralizing titers (GMR 0.23;95% CI=0.08-0.65) among PLWH. Post-mRNA Vaccination SARS-CoV-2 IgG Concentrations and Pseudovirus Neutralizing Titers by HIV Status and Vaccine Conclusion. PLWH had lower than expected response to mRNA SARS-CoV-2 vaccines, with the highest non-response among those with low CD4+ counts, unsuppressed HIV RNA, and those who received the BNT162b2 vaccine. Immunization strategies to improve immune responses among PLWH should be studied, and may include booster vaccination or preference of the mRNA-1273 vaccine in this group.

8.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-293448

ABSTRACT

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.

9.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-293236

ABSTRACT

Serology has provided valuable diagnostic and epidemiological data on antibody responses to SARS-CoV-2 in diverse patient cohorts. Deployment of high content, multiplex serology platforms across the world, including in low and medium income countries, can accelerate longitudinal epidemiological surveys. Here we report multiSero, an open platform to enable multiplex serology with up to 48 antigens in a 96-well format. The platform consists of three components: ELISA-array of printed proteins, a commercial or home-built plate reader, and modular python software for automated analysis (pysero). We validate the platform by comparing antibody titers against the SARS-CoV-2 Spike, receptor binding domain (RBD), and nucleocapsid (N) in 114 sera from COVID-19 positive individuals and 87 pre-pandemic COVID-19 negative sera. We report data with both a commercial plate reader and an inexpensive, open plate reader (nautilus). Receiver operating characteristic (ROC) analysis of classification with single antigens shows that Spike and RBD classify positive and negative sera with the highest sensitivity at a given specificity. The platform distinguished positive sera from negative sera when the reactivity of the sera was equivalent to the binding of 1 ng mL a

10.
J Virus Erad ; 7(1): 100025, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-957267

ABSTRACT

This discussion paper addresses the safety of HIV cure studies, particularly those involving stopping antiretroviral therapy, known as an analytic treatment interruption (ATI) in the context of the SARS-CoV-2 pandemic. More than 30 studies listed on ClinicalTrials.gov include an ATI and many others were planned to begin over the next 12 months but most were halted due to the COVID-19 pandemic. We consider the ethics, risks and practical considerations to be taken into account before re-opening HIV cure clinical trials, noting the specific risks of ATI in the context of circulating SARS-CoV-2.

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