Post-Acute Sequelae and Adaptive Immune Responses in People Living With Hiv Recovering From Sars-Cov-2 Infection

Peluso, Michael J.; Spinelli, Matthew A; Deveau, Tyler-Marie; Forman, Carrie A; Munter, Sadie E.; Mathur, Sujata; Tang, Alexander; Lu, Scott; Goldberg, Sarah A; Arreguin, Mireya; Hoh, Rebecca; Chen, Jessica Y.; Martínez, Enrique Ortega; Chenna, Ahmed; Winslow, John; Petropoulos, Christos J.; Sette, Alessandro; Weiskopf, Daniella; Kumar, Nitasha; Lynch, Kara L.; Hunt, Peter W.; Durstenfeld, Matthew S; Hsue, Priscilla Y.; Kelly, John D.; Martin, Jeffrey N.; Glidden, David V.; Gandhi, Monica; Deeks, Steven G.; Rutishauser, Rachel L.; Henrich, Timothy J.

doi:10.1101/2022.02.10.22270471

Cited by 12 publications

(21 citation statements)

References 74 publications

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“…This suggests that HIV may predispose to more severe disease and higher rates of EBV reactivation. Although not statistically significant, a higher proportion of participants with HIV experienced LC (20.2% versus 16.7%), and we have previously reported differences in the post-acute immune responses between people with and without HIV infection (Peluso et al, 2022b). Further study of autoreactive and other post-EBV infectious processes in this specific participant cohort is warranted.…”

Section: Discussionmentioning

confidence: 62%

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

Peluso

Deveau

Munter

et al. 2022

Preprint

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Epstein-Barr virus (EBV) reactivation has been proposed as a driver of Long COVID (LC), but studies in well-characterized post-acute COVID-19 cohorts of individuals with and without Long COVID symptoms over a time course consistent with current case definitions of LC are limited. In a cohort of 294 hundred adults with a history of 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 associated with serological evidence of recent EBV reactivation (early antigen-D IgG positivity or nuclear antigen IgG levels >600 U/mL), but not with ongoing EBV viremia.. Importantly, Long COVID was also observed in the small proportion without evidence of prior or recent EBV infection, suggesting that EBV reactivation is not a prerequisite for this condition. Overall, these findings expand our knowledge of the relationships between EBV reactivation and LC and suggest that further assessment during the acute phase of COVID-19 is warranted.

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Section: Discussionmentioning

confidence: 62%

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

Peluso

Deveau

Munter

et al. 2022

Preprint

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“…In this analysis, we included a only small number of HIV-infected individuals (we only analyzed a subset of UCSF LIINC cohort); however, a recent study focused on LIINC participants with HIV suggested that HIV infection is indeed a risk factor for developing PASC (127). Whether the preexisting microbial translocation and chronic inflammation during HIV infection (115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126), post surviving Ebola disease (128), and/or during other aging-related conditions (104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114) contribute to PASC warrants further investigation using longitudinal samples before and after acute COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Giron¹,

Peluso²,

Ding³

et al. 2022

JCI Insight

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Long COVID, a type of Post-Acute Sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 could be exacerbated by microbial translocation (from gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation -measured as β-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 β-glucan correlated with higher 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, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling.Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from negative controls. This higher NF-κB signaling was abrogated by Piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

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“…As previously reported, the LIINC study is a San Francisco-based post-COVID cohort that includes longitudinal symptom assessment. 27 In a subset, we measured biomarkers and performed echocardiograms. 9 Here we report findings from the subset who have undergone additional cross-sectional cardiopulmonary testing including CPET, CMR, and ambulatory rhythm monitoring.…”

Section: Methodsmentioning

confidence: 99%

“…25,26 We designed the Long-Term Impact of Infection with Novel Coronavirus (LIINC) study (NCT 04362150) to evaluate physical and mental health following SARS-COV-2 infection by including individuals representing the full spectrum of acute illness (asymptomatic to severe) and post-acute-recovery (full recovery, symptomatic PASC). 27 The purpose of this sub-study was to elucidate mechanisms underlying cardiopulmonary symptoms present more than 1 year following SARS-CoV-2 infection by comparing symptomatic and recovered individuals using blood-based markers, echocardiography, CMR, CPET, and ambulatory rhythm monitoring.…”

Section: Introductionmentioning

confidence: 99%

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

Durstenfeld

Peluso

Kaveti

et al. 2022

Preprint

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BACKGROUNDMechanisms 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.METHODSIn 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.RESULTSOne 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.CONCLUSIONSReduced 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.Clinical PerspectiveWhat is New?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 MRIfindings argue against myocardial dysfunction and myocarditis.Clinical ImplicationsCardiopulmonary 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 antiviral, anti-inflammatory, and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing.

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Post-Acute Sequelae and Adaptive Immune Responses in People Living With Hiv Recovering From Sars-Cov-2 Infection

Cited by 12 publications

References 74 publications

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

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

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

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