Long-Term Dysfunction of Taste Papillae in SARS-CoV-2 BACKGROUND We sought to determine whether ongoing taste disturbance in the postacute sequelae of coronavirus disease 2019 period is associated with persistent virus in primary taste tissue. METHODS We performed fungiform papillae biopsies on 16 patients who reported taste disturbance lasting more than 6 weeks after molecularly determined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Then, on multiple occasions, we rebiopsied 10 of those patients who still had taste complaints for at least 6 months postinfection. Fungiform papillae obtained from other patients before March 2020 served as negative controls. We performed hematoxylin and eosin staining to examine fungiform papillae morphology and immunofluorescence and fluorescence in situ hybridization to look for evidence of persistent viral infection and immune response. RESULTS In all patients, we found evidence of SARS-CoV-2, accompanying immune response and misshapen or absent taste buds with loss of intergemmal neurite fibers. Six patients reported normal taste perception by 6 months postinfection and were not further biopsied. In the remaining 10, the virus was eliminated in a seemingly random fashion from their fungiform papillae, but four patients still, by history, reported incomplete return to preinfection taste perception by the time we wrote this report. CONCLUSIONS Our data show a temporal association in patients between functional taste, taste papillae morphology, and the presence of SARS-CoV-2 and its associated immunological changes. (Funded by Intramural Research Program/National Institute on Aging/National Institute of Allergy and Infectious Diseases/National Institutes of Health; ClinicalTrials.gov numbers NCT03366168 and NCT04565067.) https://evidence.nejm.org/doi/full/10.1056/EVIDoa2300046
Interesting. My father still hasn't recovered his sense of smell and his taste is affected, though one might follow from the other. That is since his first infection 3 years ago.
Editorial on the paper The Persistence of SARS-CoV-2 and Its Role in Long Covid Postacute sequelae of coronavirus disease 2019 (PASC), more commonly known as long Covid, manifests as ongoing symptoms in various organs of the body more than 4 weeks after the resolution of acute Covid-19.1 A prevalent symptom of PASC is an ongoing loss of taste, but additional persisting symptoms can include neurologic, gastrointestinal, kidney, lung, or heart dysfunction.1,2 There are two broad mechanisms that are thought to underpin the ongoing complications associated with PASC: dysregulated production of inflammatory cytokines and the persistence of virus.3 These two mechanisms are not mutually exclusive, and it is possible that an ongoing inflammatory milieu in patients with PASC is associated with low-level persistent viral replication or the presence of viral ribonucleic acid and/or protein. However, limited direct evidence exists on the role of viral persistence in PASC.4 Understanding whether viral persistence is driving ongoing symptoms will provide an opportunity to develop novel antiviral approaches to eradicate persistent virus and potentially alleviate some of these ongoing symptoms that are often debilitating in their extreme forms. The study by Yao et al.5 that appears in this issue of NEJM Evidence provides elegant evidence that persistent SARS-CoV-2 is associated with at least some ongoing symptoms of PASC. This group previously reported that taste-bud cells contain the angiotensin-converting enzyme 2 receptor that is required for SARS-CoV-2 cell entry and also demonstrated that SARS-CoV-2 is present in taste buds during acute Covid-19.6 Here, using immunofluorescence, they demonstrate the persistence of both viral spike and nucleocapsid proteins in the fungiform papillae, which contain taste buds, for up to 63 weeks following initial Covid-19 diagnosis. Using a very sensitive fluorescence in situ hybridization assay, they demonstrate the ongoing presence of replicating virus and strong evidence that SARS-CoV-2 persists in fungiform papillae. Furthermore, Yao et al.5 demonstrate that SARS-CoV-2 infection is associated with both an increased proportion of effector CD8+ T cells and the presence of the inflammatory cytokine interleukin (IL)-1β. This type of inflammatory milieu has been associated with PASC in other settings,7,8 suggesting that some of the damage to the taste buds may be immune mediated. Effector CD8+ T cells are known to contribute to other viral-inflammatory complications, particularly Epstein–Barr virus–associated infectious mononucleosis, which can be associated with the later development of myalgic encephalomyelitis/chronic fatigue syndrome. Myalgic encephalomyelitis/chronic fatigue syndrome has disease characteristics similar to those of PASC.9 However, effector CD8+ T cells also play a critical role in the clearance of persistent viral infections, and their presence may be indicative of immune control and subsequent viral clearance. More evidence is needed to demonstrate whether these effector populations are mediators of PASC symptoms or whether they could be exploited to promote viral eradication. The most intriguing observation of this study was the demonstration that resolution of infection in the taste buds was associated with a recovery in taste. Whereas a high proportion of the patients with PASC displayed no detectable taste buds at their first-visit biopsy, others had significantly altered morphology, consistent with the notion that a loss of taste is associated with taste-bud destruction. Recovery in taste was consistent with morphologic improvements in taste buds, including the restoration of normal numbers of type II taste receptor cells. This study demonstrates that viral clearance during PASC is closely associated with recovery from symptoms. This discovery may present an opportunity to develop targeted antiviral approaches to eradicate persistent virus. Yao et al.5 have demonstrated the persistent presence of SARS-CoV-2 in human papillae together with the symptomatic deterioration of taste buds and the ablation of taste commonly associated with PASC. Concomitantly, they demonstrate that clearance of SARS-CoV-2 occurs in conjunction with inflation of the effector CD8+ T cell compartment and increased detection of the proinflammatory cytokine IL-1β. Most important, however, is the demonstration that these morphologic changes are reversible and that viral clearance can lead to restored tissue structures and resolution of symptoms. This study identifies a potential therapeutic opportunity for the targeted treatment of viral disease in PASC and, most importantly, suggests that successful eradication of persisting SARS-CoV-2 provides a strategy to overcome the long-term complications associated with PASC. https://evidence.nejm.org/doi/full/10.1056/EVIDe2300165
