Early clues regarding the pathogenesis of long-COVID

Peluso, Michael J.; Deeks, Steven G.

doi:10.1016/j.it.2022.02.008

Cited by 103 publications

(100 citation statements)

References 12 publications

(17 reference statements)

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“…6 Characterizing phenotypes of cardiopulmonary PASC with multi-modality cardiac testing may yield insights into mechanisms which remain incompletely understood but may include inflammation, aberrant immune activation, and endothelial dysfunction. 7,8 We previously demonstrated that inflammatory markers and possibly pericardial effusions were associated with symptoms 6 months after SARS-CoV-2 infection. 9 We and others have demonstrated normal cardiac function on echocardiography 3-6 months after COVID-19, suggesting that other techniques are needed to identify physiologic correlates of symptoms.…”

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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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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“…However, the pathophysiological mechanisms that drive this inflammation remain unknown. Among the hypothesized drivers are pre-existing medical comorbidities, such as diabetes or obesity, the degree of SARS-CoV-2 viremia during acute infection, latent Epstein-Barr virus reactivation, and the production of autoantibodies (25–27). We have been investigating a known driver of systemic inflammation and severity during other respiratory-related diseases, microbial translocation resulting from disruption in the gut-lung axis.…”

Section: Introductionmentioning

confidence: 99%

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

Giron

Peluso

Ding

et al. 2022

Preprint

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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.

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“…This is an area which merits careful consideration, since eradication of latent infection would provide a cure for at least 200,000 cancers each year [69] and perhaps protect part of the patients diagnosed with devastating and crippling autoimmune diseases. Now that some clues on the possible pathogenesis of long-COVID are beginning to surface [20,70], the major culprits seem to be identified, with hyperactivation of coagulation leading to diffuse microvascular thrombosis with organ damage, viral persistence due to neutralization of the host defenses, with inflammatory damages, or prolonged virus-induced immunologic alterations, including autoimmunity and aberrant responses [4,9,17,[23][24][25]30,34,36]. To these factors, largely agreed upon, one may add resurrection of EBV from dormancy [1], with the amplification of the most recognized pathogenic mechanisms [39,65].…”

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confidence: 99%

“…However, it is thought that more than psychiatric and relation problems are present in COVID-19 sequelae, and in fact, long-COVID can be observed in non-hospitalized and even asymptomatic patients, as well as children [ 15 , 16 , 17 , 18 , 19 ]. Therefore, several studies have started to unveil the possible pathogenetic mechanisms of this heterogeneous clinical picture [ 20 ]. Epidemiological and clinical studies indicated various co-factors for the development of post-acute symptoms, such as sex, age, obesity, chronic lung disease (including asthma), diabetes, hospitalization, and prolonged viral shedding [ 2 , 4 , 16 , 17 , 21 , 22 ].…”

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confidence: 99%

“…Epidemiological and clinical studies indicated various co-factors for the development of post-acute symptoms, such as sex, age, obesity, chronic lung disease (including asthma), diabetes, hospitalization, and prolonged viral shedding [ 2 , 4 , 16 , 17 , 21 , 22 ]. However, mechanistic insights have only recently surfaced, and among them high-level SARS-CoV-2 viremia, EBV reactivation during acute infection, individual gut microbiome profile, and the presence of autoantibodies, in particular those directed against type I interferons (IFNs), have been associated with increased risk of PASC [ 20 , 23 , 24 , 25 , 26 , 27 ].…”

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