Could Viral Persistence Explain Long Covid? 

Author: Dr. Reitz
June 30, 2022 

Introduction 

One serious aspect of Covid is what has been called ‘long Covid”, in which various symptoms can persist for as long as a year or more. These can include fatigue, brain fog, loss of taste and/or smell, and cardiovascular problems. There are two schools of thought on the cause, although these are not mutually exclusive. One attributes long Covid to a dysregulated immune response, including chronic inflammation and/or autoimmunity. The other suggests that the undetected presence and persistent replication of virus at sites in the body other than the upper respiratory tract are causative. 

Paxlovid

The antiviral Paxlovid, a protease inhibitor, has recently proven quite effective in preventing disease progression in patients infected with omicron BA.2[1]. However, there have been recent reports of people treated with Paxlovid who, after testing negative for the presence of SARS-CoV2, become positive again after cessation of treatment, although this is rare. Pfizer’s clinical trials showed a ~2% incidence of rebound in both the Paxlovid and placebo arms, although this occurred in a setting of delta variant dominance and omicron could behave differently. This naturally raises questions. Should Paxlovid treatment be of longer duration? Does this mean that the virus might evolve drug resistance? Data so far have shown this to not be the case. Would it be better to treat simultaneously with more than one antiviral? For example, targeting both the viral protease and the viral replicase? Importantly, considered within the context of long Covid, where is the virus when upper respiratory tract samples are negative? Could it have a latent phase in which virus is not expressed? Or is it present elsewhere and then reseeding the upper respiratory tract upon cessation of treatment? Could this be a feature of long Covid? Could Paxlovid be reducing the viral load to the point where the immune response is weaker? Could viral persistence in long Covid explain why vaccination after infection resolves or improves symptoms in up to 20% of cases[2]? Or why treatment with Paxlovid resolves long Covid in some cases? There also may be an association with viral load; vaccination within 6 months before infection is associated with a somewhat reduced risk of long Covid[3]. 

The antiviral Paxlovid, a protease inhibitor, has recently proven quite effective in preventing disease progression in patients infected with omicron BA.2[1]. However, there have been recent reports of people treated with Paxlovid who, after testing negative for the presence of SARS-CoV2, become positive again after cessation of treatment, although this is rare.

There have been many reports of PCR positivity for viral RNA in stool samples, but except in rare instances, this does not appear to represent live virus[4, 5].

Interestingly, 70% of patients with evidence of persistent virus expression had conditions typical of long Covid, including brain fog, fatigue, and loss of smell, whereas none of the patients who were virus negative had any signs of long Covid.

Long Term Viral Persistence

What, then, is the evidence for long term viral persistence? One should discriminate between evidence for viral RNA and antigens, which may simply represent viral debris, and evidence for active viral replication (negative strand and subgenomic [sgRNA] viral RNA or recovery of live virus). There have been many reports of PCR positivity for viral RNA in stool samples, but except in rare instances, this does not appear to represent live virus[4, 5]. Persistent expression of viral RNA in nasal samples or stool, lasting up to 6 months or longer, has often been reported, but does not necessarily indicate live virus. However, some studies do provide indirect indications for continued viral replication. This includes the presence of sgRNA in oropharyngeal samples from Covid patients who had recovered and previously tested negative[6], strongly suggesting active viral replication. Consistent with this are the increase in breadth and magnitude of CD8 T cell responses in people persistently positive for viral RNA compared to those who remain negative[7], suggestive of continued immune stimulation. Consistent with this is the evolution of the memory B cell population in Covid patients for up to 6 months along with the detection of viral antigen and RNA in intestinal biopsies by immunohistochemistry, in situ hybridization[8] and in brain biopsies, where sgRNA and replicative virus could be demonstrated for up to 7 months post-infection.  

The data thus seem reasonably persuasive for the persistent presence and replication of SARS-CoV2 even after clearance of symptoms, but is this associated with long Covid? As described above, clearance of long Covid symptoms following Paxlovid treatment or post-infection vaccination suggest that this may be the case, but more systematic data of this sort would make a better case for a direct cause. 

A case report of two patients with long Covid showed the presence of viral antigen in breast and appendix tissue at 6 to 15 months after infection. More convincingly, the report demonstrated negative strand viral RNA, indicative of ongoing replication. Perhaps more relevant to an association with long Covid, persistent expression of sgRNA was detectable in gut mucosal tissue from patients with inflammatory bowel disease who had been infected with SARS-CoV2[9]. Although sgRNA is indicative of viral replication, live virus could not be cultured. Interestingly, 70% of patients with evidence of persistent virus expression had conditions typical of long Covid, including brain fog, fatigue, and loss of smell, whereas none of the patients who were virus negative had any signs of long Covid. It should be cautioned, however, that the test population is not typical of the general population. 

Conclusion

To summarize, it is reasonably established that SARS-CoV2 can establish persistent infections in different tissues. It is less certain that this is cause of long Covid, although it seems quite plausible. Association is not necessarily causation. Perhaps long Covid represents a combination of persistent viral expression and an inadequate immune response, but the situation is currently unclear. What is now needed are clinical trials treating long Covid with antivirals and/or vaccines.

References

  1. Wong, C.K.H., et al., Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 inpatients during Hong Kong’s Omicron BA.2 wave: an observational study. medRxiv, 2022: p. 2022.05.19.22275291.
  2. Ayoubkhani, D., et al., Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. BMJ, 2022. 377: p. e069676.
  3. Al-Aly, Z., B. Bowe, and Y. Xie, Long COVID after breakthrough SARS-CoV-2 infection. Nat Med, 2022.
  4. Chen, Y., et al., The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients. J Med Virol, 2020. 92(7): p. 833-840.
  5. Wolfel, R., et al., Virological assessment of hospitalized patients with COVID-2019. Nature, 2020.
  6. Liotti, F.M., et al., Assessment of SARS-CoV-2 RNA Test Results Among Patients Who Recovered From COVID-19 With Prior Negative Results. JAMA internal medicine, 2021. 181(5): p. 702-704.
  7. Vibholm, L.K., et al., SARS-CoV-2 persistence is associated with antigen-specific CD8 T-cell responses. EBioMedicine, 2021. 64: p. 103230.
  8. Gaebler, C., et al., Evolution of antibody immunity to SARS-CoV-2. Nature, 2021. 591(7851): p. 639-644.
  9. Zollner, A., et al., Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases. Gastroenterology, 2022.