INTRODUCTION: The association of Alzheimer’s disease (AD) with herpesvirus infections has been suggested, but the relationship has not been experimentally proven. The study in this report used a two-sample Mendelian randomization analysis to investigate the association of four active herpesvirus infections with AD using summary statistics from genome-wide association studies (GWAS)). The four herpesvirus infections (i.e., chickenpox, shingles, cold sores, mononucleosis) are caused by varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and Epstein-Barr virus (EBV), respectively (Huang et al1 ).

 

DISCUSSION: Recently, an article showed the presence of EBV-specific T cell receptors in the cerebrospinal fluid of patients with AD (Gate et al2). However, their data is not a direct evidence causation. Haung et al., used an analytic approach (Mendelian randomization-MR) using genetic variants as instrumental variables for an exposure. MR analyses are increasingly being used to determine causal effects between potentially modifiable risk factors and outcomes. Three herpes viruses (VZV, EBV, HSV-1) have been previously associated with AD. The authors used GWAS summary statistics data from 23andMe cohorts (Tian et al3). Huang found that mononucleosis (caused by EBV), was associated with a higher risk of AD. Although the specific mechanism underlying the association between infection and AD has not been fully understood, studies have proposed several possible mechanisms. Some have suggested that herpesvirus infections could promote the accumulation of amyloid-β plaques in the brain. Carbone et al4, have suggested that persistent cycles of latency of EBV might contribute to stress the systemic immune response and induce altered inflammatory processes, resulting in cognitive decline during aging. The MR analysis showed that there was no clear evidence to suggest an effect of VZV caused diseases, chickenpox or shingles, on AD. Although, since previous reports showed the use of antiviral agents in herpes zoster patients was associated with lower risks of dementia, further investigation is warranted concerning whether VZV reactivation is involved in AD onset or progression. MR analysis did not show a significant association between cold sores (HSV-1) and AD risk.

 

CONCLUSION: Huang et al found a positive association between mononucleosis and the risk of AD, as well as an association between mononucleosis and family history of AD from MR analysis. Further elucidation of this association could provide insights into the potential biological roles of mononucleosis in AD pathogenesis.

REFERENCES:

  • Huang Shu-Yi, Yu-Xiang Yang, K. Kuo, Hong-Qi Li, Xue-Ning Shen, Shi-Dong Chen, M. Cui, L. Tan, Q. Dong, and Jin-Tai Yu. (2021). Herpesvirus infections and Alzheimer’s disease: a Mendelian randomization study. Alz. Res. Therapy 13:158, 1-8. https://doi.org/10.1186/s13195-021-00905-5
  • Gate, D., G.D. Saligrama, O. Leventhal, A.C. Yang, M.S. Unger, J. Middeldorp, K. Chen, B. Lehallier, D. Channappa, and M.B. De Los Santos, et al. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399-404. https://doi.org/10.1038/s41586-019-1895-7
  • Tian, C., B.S. Hromatka, A.K Kiefer, N. Eriksson, S.M. Noble, J.Y. Tung, and D.A. Hinds. (2017). Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat. Commun. 8,599. https://doi.org/10.1038/s41467-017-00257-5
  • Carbone, I, T. Lazzarotto, M. Ianni, E. Porcellini, P. Forti, E. Masliah, L. Gabrielli, and F. Licastro. (2013). Herpes virus in Alzheimer’s disease:relation to progression of the disease. Neurobiol Aging. 35:122-129. https://doi.org/10.1016/j.neurobiolaging.2013.06.024
MKTG 1069 - Rev A 030722

INTRODUCTION: This is Part IV in a series presenting reports dealing with the reaction of Herpes viruses during the ongoing SARS-CoV-2 pandemic. Numerous articles came out during 2020 linking Herpes virus reactivations during the pandemic. One of these Herpes viruses, Epstein-Barr Virus (EBV) has also been shown to reactivate during the pandemic. It has been reported that 30% of COVID-19 patients have been shown to experience long-term symptoms following the resolution of the disease, which has led to fatigue, brain fog, and rashes. This has become known as long COVID. An analysis of 185 randomly selected COVID-19 patients was initiated to determine if there was an association between the occurrence of long COVID symptoms and reactivation of EBV (Gold et al.1).

 

DISCUSSION: Epstein-Barr virus is a human gamma Herpesvirus. Previous studies have shown that 90% of the global population have been infected with EBV, which become dormant after infection. Primary EBV infection is usually asymptomatic when contracted in childhood. A primary infection in adolescence commonly results in infectious mononucleosis. EBV can also switch between lytic and latent phases of its life cycle in many patients.  EBV reactivation is identified using serological testing for the presence of EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. A variety of clinical manifestations are associated with EBV reactivation. These include fatigue, psychoneurosis/brain fog, sleep disturbance, arthralgia, pharyngitis, myalgia, headache, fever, gastrointestinal complaints and skin rashes. These are many of the same symptoms attributed to long COVID. Of the 185 randomly selected COVID-19 patients, these researchers (Gold et al) found the 30.3% (56/185) reported long COVID symptoms at least 30 days after testing positive for COVID-19. This group included 13 subjects who were initially asymptomatic for COVID-19. They found 66.7% (20/30) of the long-term long COVID subjects, and only 10% (2/20) of long-term control subjects, were positive for EBV reactivation based on positive titers for EBV EA-D IgG or EBV VCA IgM. They also examined a secondary group of patients who were between 21-90 days (short-term) post-diagnosis of COVID-19. They found a similar level of EBV reactivation among these patients. They found 6/9 (66.7%) of short-term long COVID subjects showed evidence of EBV reactivation based on positive titers for EBV EA-D IgG or EBV VCA IgM. The most frequently reported symptoms among those who were positive for EBV reactivation from both the long-term and short-term long COVID groups were fatigue, insomnia, headaches, myalgia, and confusion.  Seven of the long-term subjects of the long COVID group also experienced tinnitus and/or hearing loss. In addition, seven of the subjects in the long-term and 2 in the short-term long COVID with EBV reactivation also experienced frequent skin rashes.

 

CONCLUSION: Chen et al.2, were the first to document finding EBV reactivation in COVID-19 patients during the acute phase. They found 55.2% of hospitalized COVID-19 patients between January 9, and February 29, in 2020, with serological confirmation of past EBV infection, had serological data indicating EBV reactivation within two weeks of testing positive of SAR-CoV-2. Paolucci et al.3 also observed EBV reactivation in 95.2% (40/42) of ICU patients and in 83.6% (52/62) of sub-intensive care units. Together, these studies suggest COVID-19 infection can lead to long COVID symptoms, possibly due to inflammation induced EBV reactivation.

 

REFERENCES:

  • Gold, Jeffrey, R. A. Okyay, W.E. Licht and D.J. Hurley. (2021). Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens 10, 763. https://doi.org/10.3390/pathogens10060763
  • Chen, Ting, J. Song, H. Liu, H. Zheng and C. Chen. (2021). Positive Epstein-Barr virus detection in coronavirus disease 2019 (COVID-19) patients. Sci Rep 11, 10902. https://doi.org/10.1038/s41598-021-90351-y
  • Paolucci, S., L. Cassaniti, F. Novazzi, L. Fiorina, A. Piralla, G. Comolli, R. Bruno, R. Maserati, R. Gulminetti, S. Novati. F. Mojoli, F. Baldanti and San Matteo Pavia COVID-19 Task Force. (2020). EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count. Int J Infect Dis. 104;315-319. https://doi.org/10.1016/j.ijid.2020.12.051
MKTG 1064 - Rev A 020322

INTRODUCTION: This is Part III in a series presenting reports dealing with the reaction of Herpes viruses during the ongoing SARS-CoV-2 pandemic. Numerous articles came out during 2020 linking Varicella-zoster virus (VZV) reactivation which causes Herpes Zoster (HZ) with the pandemic. VZV reactivates in about 1/3 of individuals later in life, after having been infected as a child. During this childhood infection, VZV replication occurs in T-cells which reconfigures the T-cells to become activated memory T-cells with enhanced skin-homing capacity and reduced immune functions1. These VZV-infected T-cells transport the virus to skin and possibly ganglia during the childhood primary infection.

 

DISCUSSION: Case reports around the world have reported reactivation of HZ in patients infected with COVID-19 (SARS-CoV-2). In a case series from Italy, 4 critically ill elderly patient developed HZ. All 4 patients had lymphopenia, especially decreased CD8+ and CD3+ cells which might have contributed to the cessation of latency2. It is known that CD8+ T-cells maintain Herpes virus latency3. There is an altered immune response during a COVID-19 infection which facilitates the replication of COVID-19 and increases the viral load by causing the natural killer (NK) cells and CD8+ T-cells to become exhausted and hence the coronavirus cannot be eliminated. In particular, Zheng et al4, showed that the number of T-cells and CD8+ T-cells was lower in patients with severe disease than in cases with mild disease. The NK-cell counts were reduced markedly in severe cases. The exhausted NK-cells and CD8+ cells showed an increased expression of the CF94/NK group 2 member A (NKG2A) receptor. Of interest, in patients convalescing after therapy, the number of NK and CD8+ T-cells was restored and concomitantly their NKG2A expression was markedly reduced. They hypothesized that the functional exhaustion of cytotoxic lymphocytes associated with COVID-19 infection breaks down the antiviral immunity, and that the enhanced expression of NKG2A, as specifically observed in CD8+ and NK cells, could contribute to the maintenance of this blunted antiviral surveillance. The secondary effect of eliminating or reducing these cytotoxic T lymphocytes, is that many viruses are no longer suppressed by the host immune system. This has resulted in thousands of cases of HZ, in addition to many other virus reactivation (such as human papilloma virus as well as several other Herpes viruses).

 

CONCLUSION: Research data shows that both the infection with SARS-CoV-2 and the vaccination against this virus has led to a large increase in Herpes virus reactivations. Perhaps vaccination against HZ (ShingrixTM) could reduce the appearance of HZ from either of these causes.

REFERENCES:

 

  • Laing, K. J., Werner J.D. Ouwendijk, David M. Koelle, and Georges M.G.M. Verjans. (2018). Immunobiology of Varicella-Zoster Virus Infection. Journal of Infect Dis. 218(S2);S68-74. Https://doi.org/10.1093/infdis/jiy403
  • Tartari, F., A. Spadotto, C.Zengarini, R. Zanoni, A. Guglielmo, A. Adorno, C. Valanzia, and A. Pileri (2020). Herpes zoster in COVID-19 positive patients. Int. J. Dermatology, 59:1028-1029. https://doi.org/10.1111/jid.15001
  • Wei, L., J. Zhao, W. Wu, Y. Zhang, X. Fu, L. Chen, and X. Wang. (2017). Decreased absolute numbers of CD3+ T cells and CD8+ T cells during aging in herpes zoster patients. Scientific Reports, 7:15039. https://doi.org/10.1038/s41598.017.15390.w

Zheng, M., Y. Gao, G. Wang, G. Song, S. Liu, D. Sun, Y. Xu, and Z. Tian. (2020). Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cellular & Mol. Immunol. 17:533-535. https://doi.org/10.1038/s41423.020.0402.2

MKTG 1063 - Rev A 020322

INTRODUCTION: In this 2nd Part, we will present reports dealing with the reaction of another group of Herpes viruses, human herpes virus 6 & 7 (HHV 6-7). Over the last 18 months the SARS-CoV-2 virus has led to an increase in Herpes virus reactivations. This virus (SARS-CoV-2) has a series of evasion mechanisms that allow it to circumvent our immune system, thereby leaving the host vulnerable and thus facilitating replication of the virus and the increase in viral load. Two of these evasion mechanisms include 1) the alteration of the synthesis and functionality of interferons type I (INF-alpha & beta) and type 2 (INF-gamma). This allows SARS-CoV-2 to replicate in host cells without opposition or without an effective antiviral state. And 2) a cytokine storm or excessive activation of M1 macrophages with an inordinate amount of pro-inflammatory cytokines released into the serum1. It is the down-regulation INF-gamma which is thought to lead to the reactivation of many Herpes viruses.

 

DISCUSSION: Pityriasis rosea (PR) is caused by the reactivation of HHV-6-7 and we have seen a rapid rise in cases during the SARS-CoV-2 pandemic. Dursun and Temiz2 found a 5-fold increase in the rate of Pityriasis rosea patients who applied to a dermatology outpatient clinic during the last year (April 1 & May 1 2019 through April 1 & May 1 2020). Collecting data from 2 different months, 1 year apart was to reduce any seasonal development of the disease. There are many other reports of PR in the literature. Birlutiu et al3, reported that the PR cases associated with SARS-CoV-2 infection are in young patients (12-39 years old), with a mean age of 24.12 years, with equal distribution by gender (50/50). The time periods between the onset of the rash and the presentation of the patient to the doctor varied between 3 days and 2 weeks. Healing of the skin lesions required 2-4 weeks ((using antihistamines, antipyretics and topical corticosteroids). Their report adds to other findings regarding the association of PR with SARS-CoV-2 infection, in context of the pandemic, suggesting the need to test patients with PR skin lesions for SARS-CoV-2 infection.  Another type of Herpes virus related disease is Kawasaki disease which is a systemic vasculitis of childhood that can affect the coronary arteries. The exact etiology of Kawasaki disease is still unknown; however, many believe HHV-6 is a primary cause. In a study conducted during the COVID-19 pandemic, Kawasaki disease was found to increase 30-fold compared to previous years4. The study by Dursun & Temiz found a 10-fold increase in patients with Kawasaki disease who applied to the dermatology outpatient clinic, compared to the previous year. They believe this increase of Kawasaki disease during the pandemic may be due to the Coronavirus triggering (i.e., reactivation) of HHV-6.

 

CONCLUSION: In Part I we showed the reports of a large increase of Bell’s Palsy associated with the SARS-CoV-2 infections which is thought to be due to the reactivation of either HSV1/2 or Varicella zoster virus. In Part II we showed the reactivation of other Herpes viruses, HHV-6-7, during the SARS-CoV-2 pandemic. Data is accumulating that the suppression of the immune response during the Coronavirus infection is resulting in the reactivation of a wide range of Herpes viruses.

 

REFERENCES:

 

  • Maldonado, M.D., J. Rmoero-Aibar, and M.A. Perez-San-Gregorio. (2021) COVID-19 pandemic as a risk factor for the reaction of herpes viruses. Epidemiology and Infection 149, e145,1-5. Https://doi.org/10.1017/S09502688s1001333
  • Dursun, R., and A. Temiz. (2020). The clinics of HHV-6 infection in COVID-19 pandemic: Pityriasis rosea and Kawasaki disease. Dermatol Ther 33(4), e13730. Https://doi.org/10.1111/dth.13730.
  • Birlutiu, V., R.M. Birlutiu, and G.M. Lancu. (2021) Pityriasis rosea Gibert triggered by SARS-CoV-2 infection. Medicine 100, 14, 1-5. http://dx.doi.org/10.1097/MD.0000000000025352.
  • Verdoni, L., A. Mazza, A. Gervasoni, L. Martelli, M. Ruggeri, M. Cuiffreda, E. Bonanomi, and L. D’Antiga. (2020) An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet 395, 1771-78. https://doi.org/10.1016/S0140-6736(20)31103-X

 

By David Kilpatrick, PhD and Abbas Vafai, PhD

 

MKTG 1062  – Rev A 091021

INTRODUCTION: One of the consequences of the SAR-CoV-2 infections over the last year has been a large increase in reactivation of herpes viruses. There are numerous reports of COVID-19 patients with suspected reactivation of several different herpes viruses, including human herpes virus 1 and 2 (HSV 1/2), varicella zoster virus (VZV), human herpes virus-6 and 7 (HHV 6/7), as well as Cytomegalovirus (CMV). It is known that cell-mediated immunity plays an important role in herpes virus latency. COVID-19 infection decreases cell-mediated immunity by decreasing lymphocytes, such as CD3+, CD4+, and CD8+ T cells. These cells produce gamma interferon (IFN-γ) which is known to suppress reactivation of herpes viruses. So, if the IFN-γ levels are lowered, viral reactivation occurs. This report will discuss the reactivation of herpes viruses which leads to Bell’s palsy.

DISCUSSION: There are numerous reports (thousands) of COVID-19 patients who subsequently have been diagnosed with Bell’s palsy, such as the report by Neo et al1.  Bell’s palsy is a common cause of lower motor neuron neuropathy and is known to occur upon the reactivation of either HSV1/2, or from VZV. Serological studies have shown that the prevalence of antibodies to HSV among patients with Bell’s palsy is higher than that among healthy control subjects, which suggests that HSV may be involved in the pathogenesis of Bell’s palsy (Adour et al2). In addition to HSV, VZV is known to play a role in Bell’s palsy. A portion of Bell’s palsy patients have what is called, Ramsay Hunt syndrome, but these patients have more severe paralysis at the onset and are less likely to recover completely (Sweeney & Gilden3). Patients with Ramsay Hunt syndrome are characterized by peripheral facial paralysis without ear or mouth rash, and the presence of either fourfold rise in antibody to VZV or the detection of VZV DNA in skin, blood mononuclear cells, or middle ear fluid. It is clear that the suppression of IFN-γ during a COVID-19 infection plays a role in reactivating herpes viruses. The ability of IFN-γ to control chronic herpes virus infection and reactivation from latency is known for many herpes viruses (Presti et al4).

CONCLUSION: Over the last 18 months, there have been thousands of cases of Bell’s palsy associated with either being infected with SAR-CoV-2. It would be prudent to test for Herpes viruses (HSV 1/2, VZV) if COVID-19 patients show Bell’s palsy symptoms.

 

REFERENCES:

  1. Neo, W. L., Jeremy Chung Fai Ng and N. Gopalakrishna Iyer. (2020). The great pretender-Bell’s palsy secondary to SARS-CoV-2? Clinical Case Report, 9:1175-77. https://doi.10.1002/ccr3.3716
  2. Adour, K.K., Bell, D. N., and Hilsinger, R.L.J (1975). Herpes simplex virus in idiopathic facial paralysis (Bell palsy). JAMA 233:527-30. https://doi.10.1001/jama.1975.03260060037015
  3. Sweeney, C.J., and D. H. Gilden. (2001). Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 71:149-154. https://doi.10.1136/jnnp.71.2.149
  4. Presti, R. M., J.L. Pollock, A.J. Dal Canto, A.K. O’Guin, and H.W. Virgin. (1998). Interferon-gamma regulates acute and latent murine cytomegalovirus infection and chronic disease of the great vessels. J. Exp. Med. 188:577-88. https://doi.10.1084/jem.188.3.577

 

By David Kilpatrick, PhD and Abbas Vafai, PhD

MKTG 1061  – Rev A 072621