An overlap between HHV Reactivation and SARS-COV2 Infections

Again, there's likely to be a deeper connection than is being reported.

Before reading this post please refer to the prior one which looked a bit into human herpesviruses (HHV) in particular.

This post will look at some of the literature on COVID infections and HHV reactivation in order to emphasize the fact that there’s likely something more than a SARS-COV2 modality of myocarditis and other adverse events we are seeing.

One obvious overlap is the similarities between Long COVID and chronic fatigue syndrome- a syndrome which seems to be closely tied to HHV infection or reactivation.

This is why remarks that Long COVID doesn’t exist are rather dangerous, and in some ways come from a place of ignorance or denial in order to create a false presentation of what’s going on. Because post-viral syndromes has always been around one cannot immediately infer that Long COVID doesn’t exist for the sake of creating false narratives.

However, given a lot of the information that has come out it’s likely that symptoms of Long COVID may not be due directly to the virus or the vaccine, but possibly due in part to reactivation of latent HHV which may be brought on by an infection or vaccination. Again, remember that the literature is growing in evidence of HHV and other lifelong, debilitating illnesses.

And as many people discuss the possible neurotropic nature of SARS-COV2 consider that many HHVs are neurotropic themselves and are related to various cases of encephalitis and cognitive decline, with the area being most investigated being a possible link between Alzheimer’s and HHV, as mentioned in the previous article.

The studies included here are ones that I came across and serve as a literature review this available evidence.

COVID and HHV Reactivation

Remember that many factors can lead to HHV reactivation. Even stress can induce the reactivation of herpes simplex viruses, and there’s been an association between sepsis patients and HHV reactivation.¹ It seems that hospitalization of any sort is associated with HHV reactivation, although the link between the two is complex given that it could be the disease in question that may cause reactivation of HHV, or that hospital protocols such as the use of steroids or other treatments may provide for a window of reactivation. There’s even some evidence to suggest that astronauts experience HHV reactivation during travel, which may be due to various stressors as well.²

All this to say that it wouldn’t be out of the ordinary for widespread HHV reactivation to occur amidst a pandemic brought on my SARS-COV2 infections and maybe even some of the stress caused by the lockdowns.

There’s a lot to cover here, so the following sections may lack some organization in order to provide a broad look.

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HHV Reactivation and SARS-COV2 infection

• Gold, et al.³: In small investigation Gold, et al. noted that 20/30 people with long COVID had evidence of EBV reactivation compared to 2/20 control subjects (people infected with SARS-COV2 but did not show long COVID symptoms), suggesting that EBV reactivation may be a possible causative agent in long COVID.

  • Gold, et al. also includes findings from other studies noting high prevalence of EBV in COVID patients:

Chen et al. (2021) of Remnin Hospital at Wuhan University in Wuhan, Hubei province, China were the first to document finding EBV reactivation in COVID-19 patients during the acute phase. They found that 55.2% of hospitalized COVID-19 patients between 9 January 2020 and 29 February 2020 with serological confirmation of past EBV infection also tested positive for EBV VCA IgM, indicating EBV reactivation within two weeks of testing positive for SARS-CoV-2 [19].

Paolucci et al. (2020) tested 104 COVID-19 patients, 42 in an intensive care unit (ICU) and 62 in a sub-intensive care unit (SICU) in Italy and observed EBV reactivation in 95.2% (40/42) of the ICU patients and in 83.6% (51/61) of the SICU patients. They further determined that the median EBV DNA level in ICU patients was significantly higher than that of SICU patients [20]. A similar study in France found evidence of EBV reactivation in 82% (28/34) of COVID-19 ICU patients. Further, they found EBV reactivation to be associated with longer median ICU stays (15 days versus 8 days, p < 0.05) [21].

Lehner et al. (2020) ran EBV and cytomegalovirus (CMV) DNA tests on COVID-19 patients in the Medical ICU at the Medical University Innsbruck, Austria and found that 78% of the COVID-19 patients they tested with respiratory failure requiring invasive ventilation had evidence of EBV viremia [22]. However, CMV viremia was not found to be any more common in COVID-19 patients than in non-COVID-19 patients.

• Banko, et al.⁴: A systematic review of 36 publications examining HHV reactivation during COVID noted evidence of various HHV viral reactivations, with EBV showing the highest prominence, followed by HSV and CMV. Among those with severe COVID EBV reactivation was 6 times greater than non-COVID-19 controls.

  

  From Banko, et al.

Some pieces of literature noted a neurological component of HHV reactivation, possibly suggesting that some of the cognitive impairments and neurological issues seen in some patients may be due to HHV rather than SARS-COV2, although a possible synergistic effect should not be overlooked.

• Haddad, et al.⁵: A case report of 4 people with neurological complications following COVID infection, leading to two having encephalitis and the other two having encephalomyelitis, were found to have evidence of EBV/HSV-1 reactivation when CSF samples were analyzed. Only one patient showed evidence of SARS-COV2 RNA within the CSF, and only one showed severe pulmonary involvement with SARS-COV2. Overall, the presentation didn’t show neurological alterations due to hypoxia, and therefore it’s suggested that the neurological complications in these individuals were caused by HHV reactivation rather than SARS-COV2.

• Carneiro, et al.⁶: Among a small group of 53 COVID positive, hospitalized patients over 80% of patients were found to have had at least one HHV infection/reactivation, with HHV-6, CMV, and HHV-7 showing the highest detection rates. In particular, around 14 of the 53 patients (26.4%) showed neurological complications, with a significance being suggested in those who were HHV-6 positive. This study differed relative to other studies which noted EBV-prevalence as being a main driver of neurological complications, although the larger body of evidence seems to implicate all HHVs as being associated with neurological complications.

  • The authors provide some food for thought, again suggesting that the diagnosis of SARS-COV2-related neurological complications tend to overlap with HHV infections, and therefore may be mistaken.

In 26.4% of the patients, we observed CNS-associated neurological symptoms, such as impaired consciousness, headache, dizziness, acute cerebrovascular disease, and seizure. Similarly, a recent study confirmed SARS-CoV-2/HSV-1 coinfection in a patient with loss of consciousness, disorientation, and dizziness [9], which are symptoms suggestive of herpetic infection. EBV reactivation has also been associated with persistent symptoms observed in patients with COVID or long COVID,including some neurological manifestations, such as confusion and headache, which were observed in our patient group as well [42]. The most commonly detected herpesviruses in patients with neurological changes were HHV-6, CMV, and HHV-7. Although a statistically significant association between neurological changes and herpesvirus detection was only observed for HHV-6, CMV was also detected in several patients, and the reactivation of this virus is also associated with neurological changes in immunocompromised patients [20]. The immunosuppressive condition triggered by SARS-CoV-2 infection may play a role in reactivation herpesvirus, which may cause diffuse encephalitisand myelitis [20]. In addition, some patients were treated with corticosteroids, and we know that use of corticosteroids can trigger herpesvirus reactivation, studies have demonstrated the association between the use of corticosteroids and reactivation of CMV and HHV-6, which coincidentally also were the most detected herpesviruses in our study population [43]. Furthermore, our findings also suggested an association between neurological changes and HSV-1 detection in patients with a high SARS-CoV-2 load. In this group of patients, 33.3% (3/9) showed changes in the CNS and 22.2% (2/9) in the PNS. Given the strong association between HSV-1 reactivation and neurological changes, further investigation of this association is necessary.

• Lino, et al.: From a group of 173 patients suspected of having SARS-COV2 60 ended up testing positive while 13/60 SARS-COV2 positive patients were also positive for HHV-6B. However, the presence of HHV-6B did not correlate with increased mortality, although this may be due to the small sample size or to the strain of HHV-6 found. Nonetheless, the relatively high presence of HHV-6 was worth noting.

These are only a few of the articles I came across, and there are likely to be other articles that may refute or substantiate this association between HHV and SARs-COV2. Nonetheless, it’s important to notice that there’s an overlap in symptoms between these two viruses, especially given that Long COVID symptoms appear to overlap with chronic fatigue syndrome, suggesting that HHV reactivation may be overlooked as a possible culprit and may not be considered in many diagnoses and evaluations for Long COVID.

Note that in many of the cases above the proportion of HHV reactivation was heterogeneous and may come down to various factors such as age, comorbidities and other things of that nature. Thus, there’s likely to be a bit of unpredictability in determining which HHV, or if multiple, may reactivate. Unless otherwise prompted by dermatological signs narrow screening tests may be conducted which also may miss out on certain HHV species.

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Why the overlap?

Given that HHV reactivation is rather common, the question remains as to whether reactivation is uniquely distinct with SARS-COV2 infection or whether this is coincidental. That is, is the course of the pandemic typical of other viral outbreaks, in which case with reported upticks in HHV reactivation and infection?

Unfortunately, I haven’t been able to find anything in the literature in regards to HHV reactivation during flu outbreaks. On the surface, this may suggest that the link is more complex than just any viral infection leading to reactivation, although it’s important to remember that this may, in part, be due to a lack of interest in finding a link between the two viruses.

HHV reactivation is also rather common in many different diseases, and strikingly in all sorts of organ failures of unknown etiology. We’ve seen that some cases of cardiovascular disease have been recognized, usually through biopsy, to correlate with the presence of HHV and other viruses, especially in cases in which the cause of the disease is unknown. This may occur with other organs as well, as indicated by a study from 2019 where it was found that around 22% (6 of the 27 samples taken) of liver samples taken from people who suffered acute liver failure with unknown etiology had detectable HHV-6.⁷

Evidence also seems to suggest that those with ARDS who are put on mechanical ventilation may show elevated rates of HSV and CMV reactivation, with HSV detection appearing to correlate with longer duration on ventilation in this one study.⁸

With all this being said, the presence and detection of HHV may not be associated with the disease being examined. It’s quite possible that all of these reactivations are a consequence of severe illness influencing viral reactivation, but resulting in the virus as acting nothing more than a bystander to the cellular havoc already occurring. Thus, HHV reactivation may just be one of many indicators that the body is not in a proper state.

However, to provide a caveat, I came across a case report in which it was determined that two hospital fatalities may have been associated with otherwise treatable HHV reactivation which was not caught in time.⁹

One patient was a 77-year old woman who complained of severe abdominal pain, with imaging noting gastritis and evidence of abdominal lymphadenopathy. Seven days after admission and worsening symptoms she developed a skin rash, which was noted to be positive for VZV (shingles) and was placed on an antiviral treatment, but unfortunately passed. The other case notes of a woman with T1 diabetes and Stage IV kidney disease who presented with toxic epidermal necrolysis syndrome, developed antibiotic-resistant Pseudomonas pneumonia, and later succumbed to her illness. Post-mortem examination found strange cytopathologies within the lungs, liver, trachea, and skin more akin to HSV cytopathology.

The authors note that the first case was not recognized until too late with the presence of a skin rash whereas the second case was not even considered until autopsy.

This may suggest that a causal factor for HHV reactivation may rely on differential diagnoses aside from PCR and other viral detection methods to infer a distinct pathology related to HHV. Clinicians and pathologists may overlook overlaps as being related to other etiologies aside from HHV reactivation, and so it’s quite possible that many of the signs and symptoms of SARS-COV2 may be due to misattribution, as is quite possible with Long COVID symptoms.

Much of this is a more broad discussion of HHV’s presence in other diseases. Again, the question is why SARS-COV2 may be more closely associated with HHV reactivation.

Unfortunately, there doesn’t appear to be any clear explanation. Some suggestions are that SARS-COV2’s induction of lymphocyte exhaustion or lymphocytopenia may allow room for viral reactivation.

I’m partially critical of COVAIDS narratives, although this dip in immune response with a SARS-COV2 infection does parallel the fact that HHV infections are commonly found in HIV patients and those with immunodeficiencies, so it’s quite possible that reduced adaptive immune function may provide a window for latent virus reactivation.

This also appears to be the case with interferon (IFN) production as well. Evidence suggests that SARS-COV2 may alter interferon responses, with evidence suggesting that autoantibody may be produced against interferon 1 in some patients with severe COVID.¹⁰

This parallels with evidence that some COVID critically ill patients who produce IFN autoantibodies show evidence of HHV infections¹¹, providing additional evidence for immune dysfunction from SARS-COV2 allowing a window for HHV reactivation.

Keep in mind that hospital protocols may also contribute to HHV reactivation, as ventilation and even the use of corticosteroids may increase the risk of viral reactivation, although the latter is considered rather controversial.

So there still appears to be a lot of unknowns between SARS-COV2 and HHV reactivation, although evidence seems to suggest that this is an avenue worth considering when it comes to worse outcomes and Long COVID risk.

More importantly, it suggests that HHV may be overlooked as a possible contributor to SARS-COV2 outcomes, and quite possibly outcomes related to other diseases. Given the presentation of herpesviruses people may wait and check for dermatological signs of viral reactivation, but as noted in the case report above waiting for such a presentation may prove deadly, and in reality many autopsy reports may overlook other viral agents when it comes to myocarditis or sudden cardiac death in lieu of focusing on SARS-COV2 in particular.

With clear signs of people still suffering from Long COVID it also raises a question of whether clinicians are checking for possible HHV reactivation as one factor among many possible factors.

Like with everything, there are parallels that must be drawn between SARS-COV2 infections and vaccinations in order to figure out what commonality exists between the two that would explain HHV reactivation in both scenarios.

The next post will look more closely at some of the evidence of HHV reactivation post-COVID vaccination.

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1. Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, et al. (2014) Reactivation of Multiple Viruses in Patients with Sepsis. PLoS ONE 9(6): e98819. https://doi.org/10.1371/journal.pone.0098819

2. Rooney BV, Crucian BE, Pierson DL, Laudenslager ML and Mehta SK (2019) Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth. Front. Microbiol. 10:16. doi: 10.3389/fmicb.2019.00016

3. Gold, J. E., Okyay, R. A., Licht, W. E., & Hurley, D. J. (2021). Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens (Basel, Switzerland), 10(6), 763. https://doi.org/10.3390/pathogens10060763

4. Banko, A., Miljanovic, D., & Cirkovic, A. (2023). Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 130, 108–125. https://doi.org/10.1016/j.ijid.2023.01.036

5. Haddad, M., Sheybani, F., Olfati, N., Nahayati, M. A., Boostani, R., Layegh, P., & Rashid-Nejad, A. (2023). Central nervous system reactivation of herpesviridae family in patients with COVID-19. Journal of neurovirology, 29(2), 211–217. https://doi.org/10.1007/s13365-023-01132-4

6. Carneiro, V. C. S., Alves-Leon, S. V., Sarmento, D. J. S., Coelho, W. L. D. C. N. P., Moreira, O. D. C., Salvio, A. L., Ramos, C. H. F., Ramos Filho, C. H. F., Marques, C. A. B., da Costa Gonçalves, J. P., Leon, L. A. A., & de Paula, V. S. (2022). Herpesvirus and neurological manifestations in patients with severe coronavirus disease. Virology journal, 19(1), 101. https://doi.org/10.1186/s12985-022-01828-9

7. Raposo, J.V., Alves, A.D.R., dos Santos da Silva, A. et al. Multiplex qPCR facilitates identification of betaherpesviruses in patients with acute liver failure of unknown etiology. BMC Infect Dis 19, 773 (2019). https://doi.org/10.1186/s12879-019-4309-4

8. Hraiech, S., Bonnardel, E., Guervilly, C., Fabre, C., Loundou, A., Forel, J. M., Adda, M., Parzy, G., Cavaille, G., Coiffard, B., Roch, A., & Papazian, L. (2019). Herpes simplex virus and Cytomegalovirus reactivation among severe ARDS patients under veno-venous ECMO. Annals of intensive care, 9(1), 142. https://doi.org/10.1186/s13613-019-0616-6

9. Bookhout, C., Moylan, V., & Thorne, L. B. (2016). Two fatal herpesvirus cases: Treatable but easily missed diagnoses. IDCases, 6, 65–67. https://doi.org/10.1016/j.idcr.2016.09.013

10. Znaidia, M., Demeret, C., van der Werf, S., & Komarova, A. V. (2022). Characterization of SARS-CoV-2 Evasion: Interferon Pathway and Therapeutic Options. Viruses, 14(6), 1247. https://doi.org/10.3390/v14061247

11. Busnadiego, I., Abela, I. A., Frey, P. M., Hofmaenner, D. A., Scheier, T. C., Schuepbach, R. A., Buehler, P. K., Brugger, S. D., & Hale, B. G. (2022). Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease. PLoS biology, 20(7), e3001709. https://doi.org/10.1371/journal.pbio.3001709