Long COVID and SARS-CoV-2 persistence: new answers, more questions

In their study in The Lancet Infectious Diseases, Wenting Zuo and colleagues collected tissue samples from 225 patients who had recovered from mild COVID-19 and found that SARS-CoV-2 viral RNA was distributed across ten distinct solid tissues, plasma, and blood cells up to 4 months after infection. Importantly, detection of viral RNA, and higher virus copy numbers, were significantly associated with post-COVID-19 condition (also known as long COVID; odds ratio for association of persistent viral RNA with long COVID symptoms=5·17, 95% CI 2·64–10·13, p<0·0001).1Zuo W He D Liang C et al.The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China.Lancet Infect Dis. 2024; (published online April 22.)https://doi.org/10.1016/S1473-3099(24)00171-3PubMed Google Scholar These findings further reinforce, and expand, a growing body of literature from different independent researchers showing that long COVID is associated with persistence of SARS-CoV-2 RNA and proteins in different body tissues and cells.2Proal AD VanElzakker MB Aleman S et al.SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC).Nat Immunol. 2023; 24: 1616-1627Crossref PubMed Scopus (26) Google Scholar In turn, SARS-CoV-2 persistence might result in long COVID symptoms through direct host-cell changes, immune activation, latent virus reactivation, or combinations of the three.3Sherif ZA Gomez CR Connors TJ Henrich TJ Reeves WB Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC).eLife. 2023; 12e86002Crossref Google Scholar From an immune activation perspective, recent studies have found that patients with long COVID have complement dysregulation with signs of thromboinflammation,4Cervia-Hasler C Brüningk SC Hoch T et al.Persistent complement dysregulation with signs of thromboinflammation in active long Covid.Science. 2024; 383eadg7942Crossref PubMed Scopus (10) Google Scholar higher concentrations of circulating non-conventional monocytes associated with various chronic inflammatory conditions, and a T-cell phenotype consistent with T-helper-2-cell-skewed CD4+ T-cell activation.5Klein J Wood J Jaycox JR et al.Distinguishing features of long COVID identified through immune profiling.Nature. 2023; 623: 139-148Crossref PubMed Scopus (49) Google Scholar The persistence of SARS-CoV-2 RNA or particles in multiple tissues for prolonged periods in patients following SARS-CoV-2 infection, particularly in patients with long COVID, is now well documented. However, is the long COVID pro-inflammatory signature the consequence of viral persistence? Some evidence might suggest so. Iwasaki and colleagues found that the concentrations of IgG against SARS-CoV-2 spike and S1 in participants with long COVID were higher compared with vaccination-matched controls, suggesting persistent viral antigens.5Klein J Wood J Jaycox JR et al.Distinguishing features of long COVID identified through immune profiling.Nature. 2023; 623: 139-148Crossref PubMed Scopus (49) Google Scholar Even more strikingly, Peluso and colleagues6Peluso MJ Ryder D Flavell R et al.Multimodal molecular imaging reveals tissue-based T cell activation and viral RNA persistence for up to 2 years following COVID-19.medRxiv. 2023; (published online July 3.) (preprint).https://doi.org/10.1101/2023.07.27.23293177Google Scholar observed T-cell activation up to 2·5 years after SARS-CoV-2 infection, especially in areas of the body such as the gut where SARS-CoV-2 RNA was identified, suggesting that tissue viral persistence could be associated with long-term immunological perturbations. Another study showed that SARS-CoV-2 fragments might drive inflammation by mimicking the action of specific immune molecules in the body.7Zhang Y Bharathi V Dokoshi T et al.Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes.Proc Natl Acad Sci USA. 2024; 121e2300644120Google Scholar Although these findings seem to suggest that viral persistence is linked with immunological activation and long COVID, our understanding of the condition is far from complete. In fact, the persistence of viruses after viral infections is not a new phenomenon exclusively linked with SARS-CoV-2 but, on the contrary, might be a very common scenario. An elegant and visionary study from Pyöriä and colleagues revealed that DNA molecules of 17 species, primarily herpesvirus, parvovirus, papillomavirus, and anellovirus, persist in low amounts in humans.8Pyöriä L Pratas D Toppinen M Hedman K Sajantila A Perdomo MF Unmasking the tissue-resident eukaryotic DNA virome in humans.Nucleic Acids Res. 2023; 51: 3223-3239Crossref PubMed Scopus (4) Google Scholar Similarly, SARS-CoV-2 persistence and increased T-cell activation were also observed in many healthy individuals without long COVID.6Peluso MJ Ryder D Flavell R et al.Multimodal molecular imaging reveals tissue-based T cell activation and viral RNA persistence for up to 2 years following COVID-19.medRxiv. 2023; (published online July 3.) (preprint).https://doi.org/10.1101/2023.07.27.23293177Google Scholar These data suggest that there is a still poorly understood crosstalk between viruses, the host, and other microbes, which can have a significant effect on our health; exactly how SARS-CoV-2 might lead to reactivation of other viruses remains unknown, as does the reason why only some individuals develop long-lasting symptoms or new immune-mediated conditions following COVID-19. Despite these questions remaining unanswered, we should not be surprised at the narrative linking viral infections with chronic persistence and poor outcomes. We have decades of experience with other viral infections leading to chronic inflammation, autoimmune diseases, and cancer, such as Epstein–Barr virus and papillomavirus, but also measles and enteroviruses, in paediatric patients. Let us also not forget that long COVID has been described in children since early in the pandemic.9Buonsenso D Munblit D De Rose C et al.Preliminary evidence on long COVID in children.Acta Paediatr. 2021; 110: 2208-2211Crossref PubMed Scopus (317) Google Scholar Multisystem inflammatory syndrome in children (MIS-C) is a severe condition that has been clearly linked with previous exposure to SARS-CoV-2. Interestingly, persistent SARS-CoV-2 reservoirs have also been shown in both populations (children with long COVID and MIS-C),10Buonsenso D Martino L Morello R Mariani F Fearnley K Valentini P Viral persistence in children infected with SARS-CoV-2: current evidence and future research strategies.Lancet Microbe. 2023; 4: e745-e756Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar and a gut reservoir of SARS-CoV-2 has been linked with the post-acute uncontrolled immune activation that happens in MIS-C.11Yonker LM Gilboa T Ogata AF et al.Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.J Clin Invest. 2021; 131e149633Crossref Scopus (152) Google Scholar We should aspire to have similar in-depth microbiological–immunological studies as in the study by Zuo and colleagues in children. A better understanding of MIS-C will give us the opportunity to further understand similar common conditions such as Kawasaki disease, and understanding long COVID will allow us to better understand myalgic encephalomyelitis–chronic fatigue syndrome, also in young people. All the mentioned findings point toward the same unifying message. Objective biological events begin in some patients who, following viral infections, develop chronic fatigue and several other debilitating symptoms. These patients have been historically neglected and refused care, with rare exceptions. Now, the story is changing. Although the study by Zuo and colleagues did not specifically link viral persistence to organ-specific long COVID symptoms or delineate a specific mechanism for the observations, major studies such as this one are opening a new era in medicine, in which post-acute outcomes of infectious diseases will be prioritised and mechanisms delineated. Although we are only at the beginning, this will benefit all of society. DB has received funding from Pfizer and Roche to study long COVID in children. KGT is funded via NIH OT2 HL161847. The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in ChinaOur findings suggest that residual SARS-CoV-2 can persist in patients who have recovered from mild COVID-19 and that there is a significant association between viral persistence and long COVID symptoms. Further research is needed to verify a mechanistic link and identify potential targets to improve long COVID symptoms. Full-Text PDF