ABSTRACT
Background: There is mounting evidence regarding the frequency and spectrum of post-acute sequelae of SARS-CoV-2 infection (PASC), but a search for causes has been elusive. Recently, a plasma-based assay for SARS-CoV-2 antigen has been developed, which in initial use revealed that a high fraction of severely affected patients with PASC had circulating antigen. It is unknown whether detectable SARS-CoV-2 antigen is specific for PASC or how the assay performs in a broader clinical spectrum of patients with PASC. Method(s): We evaluated a cohort of patients with RNA-confirmed SARS-CoV-2 infection enrolled >=3 weeks following initial symptoms. Participants, both with and without PASC at enrollment, were identified via facility- and communitybased advertising and examined every 4 months. An interviewer-administered questionnaire ascertained presence of 30 different symptoms (new or worse compared to pre-COVID) in the prior 2 days at each exam. Using the single molecule array (Simoa) assay, we measured spike, S1, and nucleocapsid SARSCoV- 2 antigens in plasma collected at time of symptom assessment. Result(s): We examined 172 participants (50% men, 46% non-white, median age 46 years) who contributed 667 timepoints from 0.7 to 15.4 months following infection, at which 66% featured report of >=1 symptom. Sixty-one of 667 timepoints (9.1%) representing 24% of persons had >=1 detectable SARSCoV- 2 antigen. Among the 437 timepoints at which >=1 symptom was present, 9.8% had >=1 detectable antigen;this compares to 7.8% of timepoints at which symptoms were absent. In comparison to those without symptoms, individuals with several specific symptom complexes (gastrointestinal, musculoskeletal, and central neurologic) more commonly had detectable antigen (Figure). Hospitalization during acute COVID-19 was strongly related to antigen detection. Conclusion(s): Among a diverse group of SARS-CoV-2-infected persons in the post-acute phase of infection, SARS-CoV-2 antigen is detectable in plasma in both those with and without symptoms but more commonly in those with gastrointestinal, musculoskeletal, and central neurologic complaints. The findings indicate that antigen persists in at least some persons and suggest (but do not prove) that antigen is causally related to symptoms. That antigen is found in only a fraction of those with PASC indicates either that not all symptoms are driven by antigen, current plasma antigen detection is insensitive relative to tissue, or nominal PASC symptoms are sometimes unrelated to SARS-CoV-2. (Figure Presented).
ABSTRACT
Background: Reduced exercise capacity occurs as a post-acute sequela of COVID-19 ("PASC" or "Long COVID"). Cardiopulmonary exercise testing (CPET) is the gold standard for measuring exercise capacity and identifying reasons for exercise limitations. Only one prior study used CPET to examine exercise limitations among people living with HIV (PLWH). Extending our prior findings in PASC, we hypothesized that PLWH would have a greater reduction in exercise capacity after SARS-CoV-2 co-infection due to chronotropic incompetence (inability to increase heart rate). Method(s): We performed CPET within a COVID recovery cohort that included PLWH (NCT04362150). We evaluated associations of HIV and prior SARS-CoV- 2 infection with or without PASC with: (1) exercise capacity (peak oxygen consumption, VO2) and (2) adjusted heart rate reserve (AHRR, marker of chronotropic incompetence) using linear regression with adjustment for age, sex, and body mass index. Result(s): We included 83 participants (median age 54, 35% female, 10% hospitalized, 37 (45%) PLWH) who underwent CPET at 16 months (IQR 14-17) after SARS-CoV-2 infection. Among PLWH (median duration living with diagnosed HIV 21 years (IQR 15-28), all virally suppressed on antiretroviral therapy), 14 (39%) had not had SARS-CoV-2 infection, 12 (32%) had prior SARSCoV- 2 infection without PASC, and 11 (30%) had PASC (Long COVID symptoms at CPET). Median CD4 count was 608 (370-736) and CD4/CD8 ratio 0.92 (0.56-1.27). Peak VO2 was reduced among PLWH compared to individuals without HIV with an achieved exercise capacity only 80% vs 99% (p=0.005, Fig.), a difference in peak VO2 of 5.5 ml/kg/min (95%CI 2.7-8.2, p< 0.001). Exercise capacity did not vary by SARS-CoV-2 infection among PLWH (p=0.48 for uninfected vs infected;p=0.25 for uninfected vs no PASC;p=0.32 no PASC vs PASC). Chronotropic incompetence was present in 38% of PLWH vs 11% without HIV (p=0.002), and AHRR (normal >80%) was significantly reduced among PLWH vs individuals without HIV (60% vs 83%, p< 0.0001, Fig.). Heart rate response varied by SARSCoV- 2 status among those with HIV: namely, 3/14 (21%) without SARS-CoV-2, 4/12 (25%) with SARS-CoV-2 without PASC, and 7/11 (64%) with PASC (p=0.04 PASC vs no PASC). Among PLWH, CD4 count, CD4/CD8 ratio, and hsCRP were not associated with peak VO2 or AHRR. Conclusion(s): Exercise capacity is reduced among PLWH, with no differences by SARS-CoV-2 infection or PASC. Chronotropic incompetence may be a mechanism of reduced exercise capacity among PLWH. (Figure Presented).
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.