Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases

Zollner, A; Koch, Robert; Jukic, A; Pfister, A; Meyer, M.; Rössler, Annika; Kimpel, Janine; Adolph, Timon E.; Tilg, Herbert

doi:10.1053/j.gastro.2022.04.037

Cited by 219 publications

(246 citation statements)

References 34 publications

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“…Elevated inflammatory markers, especially hsCRP, IL-6, and TNF-α could be due to higher severity of acute illness, 37 persistent immune activation, 38 and/or ongoing antigen stimulation from viral persistence. 39–43…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Moreover, while SARS-CoV-2 is typically viewed as an acute respiratory infection, it is increasingly recognized that SARS-CoV-2 infection can persist for months in certain anatomical sites (e.g. the gut) or in individuals with sub-optimal immune responses (28)(29)(30). Moreover, the natural history of sarbecovirus infection in non-human species such as bats, and the degree to which it is a persistent infection is poorly documented.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins

Zhang

Zang

Stevenson

et al. 2022

Preprint

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Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T-cells. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

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“…Taken together, the reported findings by Zollner et al 4 do not directly prove the functional role of persisting viral antigens as causative for persistent symptoms or the specificity of the gut as a reservoir of viral antigens. However, this report makes an important contribution to the field by showing that persistent viral antigens in the intestine are present in patients with long-COVID and may play a key role the pathogenesis of post-COVID symptoms.…”

mentioning

confidence: 64%

“… 2 In this issue of Gastroenterology , 2 articles focus on the intestine and pressing issues in dealing with the COVID-19 pandemic. 3 , 4 The first article, by Miyakawa et al, 3 addresses the direct infection of intestinal cells by SARS-CoV2. Gastrointestinal symptoms, including diarrhea, abdominal cramping, and pain, are frequently observed in patients with COVID-19, 5 , 6 , 7 , 8 possibly due to direct infection of the intestinal cells.…”

mentioning

confidence: 99%

“…Fecal shedding of viral RNA has been observed to persist longer than oropharyngeal shedding of SARS-CoV2, 18 , 19 putting the gastrointestinal tract into the focus of the study of postacute sequelae of COVID-19. In this issue, Zollner et al 4 describe substantial novel scientific arguments to this debate by demonstrating persistence of viral antigens in the colon as long as 257 days after initial virus detection, even in the absence of persistent fecal shedding. They made use of various detection methods, including detection of viral RNA by quantitative polymerase chain reaction ( RNA-dependent RNA polymerase, nucleocapsid, spike, and envelope proteins) as well as immunofluorescence of colonic biopsy specimens (nucleocapsid protein).…”

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confidence: 99%

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Rear Window—What Can the Gut Tell Us About Long-COVID?

Leppkes

Neurath

2022

Gastroenterology

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Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases

Cited by 219 publications

References 34 publications

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

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

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins

Rear Window—What Can the Gut Tell Us About Long-COVID?

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