Increased Risk of Alzheimer’s Disease from Herpesvirus Infection

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
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Recent Issues in Varicella-Zoster Virus Latency, Part III

INTRODUCTION: Reactivation of varicella-zoster virus (VZV) after a primary infection (chickenpox) leads to herpes zoster (HZ-shingles). This short report is the conclusion of  three part series, based on the article by Kennedy et al.1 The possible role which autophagy plays in viral latency will be discussed.

DISCUSSION: Autophagy is a mechanism which host cells use to defend against viral infection. This is achieved using double-membrane vesicles, termed autophagosomes, which deliver trapped viruses to the lysosome for degradation. Specifically, autophagy initiates an innate immune response by cooperating with pattern recognition receptor signaling to induce interferon production. It also selectively degrades immune components associated with viral particles. Following degradation, autophagy coordinates adaptive immunity by delivering virus-derived antigens for presentation to T lymphocytes. The majority of VZV disease manifestations involve increased susceptibility to both primary disseminated infection and reactivation, with the latter case causing herpes zoster or CNS involvement in the form of meningitis, encephalitis and vasculitis. In vitro studies have demonstrated both pro- and antiviral evidence of interactions between VZV replication and autophagy pathways during lytic infection and shown that these virus-host interactions take place in a highly cell-type dependent manner. Whereas autophagy seems to exert antiviral roles in some contexts, the virus may also directly utilize autophagy molecules for its own benefit to enhance replication and viral egress (related to the endoplasmic reticulum and other cells organelles) and thus evade autophagy and subvert this process (Carpenter et al.2; Buckingham et al3). The finding that VZV directly inhibits autophagosome-lysosome fusion may suggest that autophagy does indeed play an important antiviral role in VZV infection, thus explaining/justifying the evolutionary adaptation of the virus to subvert autophagy processes (Graybill et al.4).

CONCLUSION: Specific knowledge concerning a possible role of autophagy in maintaining VZV latency in sensory ganglia in humans is lacking. Additional studies are needed to resolve the specific role of autophagy in VZV infection and to define to what extent altered homeostasis and autophagy processes may influence VZV reactivation and disease. It is unlikely that viral latency can be completely prevented, but current research is more likely to lead to therapies that may treat or prevent viral reactivation in both immunocompetent and immunocompromised individuals.

 

REFERENCES:

  • Kennedy, P.G.E., T.H. Mogensen, and R.J. Cohrs. (2021). Recent Issues in Varicella-Zoster Virus Latency. Viruses 13, 2018. https://doi.org/10.3390/v13102018.
  • Carpenter, J.E., W. Jackson, L. Benetti, and C. Grose. (2011). Autophagosome formation during varicella-zoster virus infection following endoplasmic reticulum stress and the unfolded protein response. J. Virol 85, 9414-9424. https://doi.org/10.1128/JVI.00281-11.
  • Buckingham, E.M., J.E. Caprenter, W. Jackson, L. Zerboni, A.M. Arvin, and C. Grose. (2015). Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection. Proc. Natl. Acad. Sci. 112, 256-261. https://doi.org/10.1073/pnas.1417878112.
  • Graybill, C., M.J. Morgan, M.J. Levin, and K.S. Lee. (2018). Varicella-zoster virus inhibits autophagosome-lysosome fusion and the degradation stage of mTOR-mediated autophagic flux. Virology 522, 220-227. https://doi.org/10.1016/j.virol.2018.07.018.
MKTG 1068 - Rev A 021522
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Recent Issues in Varicella-Zoster Virus Latency, Part II

INTRODUCTION: Reactivation of varicella-zoster virus (VZV) after a primary infection (chickenpox) leads to herpes zoster (HZ-shingles). In Part I, we discussed a review by Kennedy et al1., which looked at some recent issues in Alphaherpesvirus latency, particularly in regards to VZV ganglionic latency. In Part II, we will look at the immunological aspects of Alphaherpesviruses in regards to VZV latency.

 

DISCUSSION: The use of “humanized” mouse models along with the study of human inborn errors of immunity, which results in increased susceptibility to VZV, has been of great value. The authors stated that a clear prominent role is played by cellular immunity conferred by T cells and natural killer (NK) cells. The role of humoral immunity remains less clear as a VZV infection and reactivation does not seem to be a major problem in individuals with antibody deficiencies. Previous clinical studies from the VZV pre-vaccine era did show a significant role on VZV immunoglobulins (VZIG) when given to children at risk of severe VZV infection. VZIG was prepared from donors with recent zoster and high levels of VZV specific immunoglobulins, and a small clinical study demonstrated that VZIG administration in immunosuppressed children modified rather than prevented VZV infection. This resulted in decreased morbidity of chickenpox children with leukemia. As a consequence of those findings, VZIG was widely used to protect children with cancer after exposure to varicella in the United States and Europe, from 1975-1995. Of importance, it was shown that all types of interferons (IFNs) show antiviral activity against VZV and serve essential functions in restricting VZV replication and spread, especially during the viremic phase and in the skin during varicella. IFNs were also thought to be involved in maintaining latency in sensory neuronal ganglia. Some studies suggested a greater antiviral role of Type II IFNs (IFNγ) over Type I IFNs (IFNα/β) against VZV in-vitro, while observations from patients with VZV CNS infection, pneumonitis or disseminated skin eruption/zoster in context of defective Type I or Type II IFN pathways, provided more indirect evidence of important non-redundant roles of both Type I and Type II IFNs in protecting against VZV reactivation. Despite several studies addressing these issues, the precise immune cells and immune mediators required for protective immunity in primary infection versus reactivation have not been clarified. In particular, the individual contribution from different cells types, including lymphocytes, macrophages, plasmacytoid dendritic cells and epithelial/endothelial cells, which are all present in human ganglia remains insufficiently understood and explored. In terms of the immune histological examination of ganglia from paraffin-embedded sections of ganglia obtained post-mortem from a patient with post-herpetic neuralgia years after the herpes zoster rash, revealed the presence of VZV DNA, as well as an immunological cell infiltrate composed of CD4 T cells, CD8 T cells and CD20 B cells, which provides evidence of an ongoing immunological reaction and inflammation years after the reactivation of VZV from latency, Sutherland et al2.

 

CONCLUSION: These studies, and others, lend support to the notion that some degree of chronic low-grade reactivation of Alphaherpesviruses from latency, as well as immune reactions to this event does take place over time in ganglia latently infected with VZV.

 

REFERENCES:

  • Kennedy, P.G.E., T.H. Mogensen, and R.J. Cohrs. (2021). Recent Issues in Varicella-Zoster Virus Latency. Viruses 13, 2018. https://doi.org/10.3390/v13102018
  • Sutherland, J.P., M. Steain, M.E. Buckland, M. Rodriguez, A.L. Cunningham, B. Slobedman, and A. Abendroth. (2019) Persistence of a T Cell Infiltrate in Human Ganglia Years After Herpes Zoster and During Post-herpetic Neuralgia. Front. Microbiol. Volume 10, Article 2017. https://doi.org/10.3389/fmicb.2019.02117
MKTG 1067 - Rev A 021522
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Recent Issues in Varicella-Zoster Virus Latency, Part I

INTRODUCTION: Reactivation of varicella-zoster virus (VZV) after a primary infection (chickenpox) leads to herpes zoster (HZ-shingles). In this review by Kennedy et al1., look at some recent issues in alphaherpesvirus latency, particularly in regards to VZV ganglionic latency. The key question they ask is the nature and extent of viral gene transcription during viral latency. They look at specific viral gene transcripts and the underlying mechanisms which may be involved.

 

DISCUSSION: VZV latency is established in ganglia throughout the entire neuroaxis including the  dorsal root ganglia (DRG), trigeminal ganglia (TG) and also autonomic ganglia including the enteric ganglia. While viral reactivation may occur spontaneously, it can also follow one or more triggering factors such as diminished cell-mediated immunity to the virus as occurs with older age or immunosuppression due to drug treatment or disease, X-ray irradiation, infection, trauma or malignancy. Post-herpetic neuralgia (PHN) is the most well-known complication of HZ, causing severe and constant pain lasting longer than 3 months after the zoster rash. An early study (Cohrs et al2) used a cDNA library from the mRNA of latently infected human ganglia to show that VZV gene transcription in these ganglia was limited to VZV genes 21, 29, 62, and 63. Overall, these results identified the presence of gene 63-encoded transcripts as being the hallmark of VZV latency. However, Depledge et al3 obtained post-mortem ganglia within 6 hours of death and detected just two viral transcripts. In addition to detecting VZV ORF 63, they detected a spliced latency associated VZV transcript (VLT) that mapped antisense to the viral transactivator gene 61. This was a major finding in the VZV ganglion latency field.  These authors followed up this study by clarifying the relation of VZV ORF 63 expression to the expression of the VLT. They reported (Ouwendijk et al4) that during VZV reactivation from the latent state, broad viral gene expression was induced by the VLT-ORF 63 fusion transcript. Kennedy et al further discussed the phenotypic change in chromosomes without altering it’s DNA sequence (called epigenetic modification), particularly by the binding of histone proteins involved in postranslational modification at the 3′ C-terminal domain which forms the basis of the “histone code” that has emerged as a fundamental mechanism regulating transcription. They also discuss the immunological aspects of latency involving T cells and natural killer cells which we will cover in Part II of this report.

 

CONCLUSION: New molecular virological technologies are driving an increased interest in VZV latency. The emergence of epigenetic mechanisms and recent interest in immunological aspects of VZV latency will no doubt lead to further understanding the mechanisms of VZV latency.

REFERENCES:

  • Kennedy, P.G.E., T.H. Mogensen, and R.J. Cohrs. (2021). Recent Issues in Varicella-Zoster Virus Latency. Viruses 13, 2018. https://doi.org/10.3390/v13102018
  • Cohrs, R.J., M. Barbour, and D.H. Gilden. (1996). Varicella-zoster virus (VZV) transcription during latency in human ganglia: Detection of transcripts to genes 21, 29, 62, and 63 in a cDNA library enriched for VZV RNA. J. Virol. 70, 2789-2796. https://doi.org/10.1128/jvi.70.5.2789-2796.1996
  • Depledge, D.P., W.J.D. Ouwendijk, T. Sadaoka, S.E. Braspenning, Y. Mori, R.J. Cohrs, G.M.G.M. Verjans and J. Breuer. (2018). A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61. Nat. Communincations 9,1167. https://doi.org/10.1038/s41467-018-03569-2
  • Ouwendijk, W.J.D., D.P. Depledge, L. Rajbhandari, R. R., Lenac, S. Jonjic, J. Breuer, A. Venkatesan, G.M.G.M. Verjans, and T. Sadaoka. (2020). Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency. Nat. Communications 11,6324. https://doi.org/10.1038/s41467-020-20031-4
MKTG 1066 - Rev A 020322
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Can Varicella Zoster Virus be Transmitted Before Onset of Rash

INTRODUCTION: Varicella-zoster virus (VZV) is a highly contagious Herpesvirus which causes chickenpox (primary infection) or shingles (upon reactivation). VZV poses a nosocomial infection for healthcare workers and patients. The incubation period for the virus is between 10-21 days. It is generally thought that patients are infectious 1-2 days prior to rash onset and between 4-7 days post rash onset. However, there is a lack of data showing the route of transmission, other than from direct contact.

 

DISCUSSION: To better understand the route and timing of VZV transmission, Marin et al1., reviewed the medical literature to assess the routes of transmission prior to rash onset. They searched Medline, Embase, Cochrane Library and CINAHL databases for articles published (any language) through October 31 of 2019. The search terms were ‘Varicella’, ‘chickenpox’, or ‘herpes zoster’, along with ‘transmission’ or ‘spread’ or ‘epidemic’ or ‘isolation’ as well as ‘respiratory’ or ‘airborne’ or ‘nasal/pharyngeal/throat swab’ or ‘before rash’. They screened 693 articles and identified 59 for full-text review. The articles were from around the world, including Europe, Asia, and the United States. Seven articles discussed VZV transmission before varicella rash onset using epidemiological data and 10 with laboratory data. Three of these articles included data from reports of varicella cases during outbreaks in hospitals, three included institutional outbreaks (schools or one in a jail). Each report indicated transmission from an index patient who exposed contacts before being diagnosed with varicella. The reports showed that patients with varicella were infectious at various intervals before the rash appeared; <1 day before in one report, at least 1 day before in two papers, at least 2 days prior in two papers, and at least 4 days prior in one paper. Of the 10 articles that addressed VZV transmission before rash onset with laboratory evidence, five were published during 1966-1989 using the virus culture to identify virus in the oropharynx. Five articles from 1991-1999 examined evidence of VZV DNA presence in the oropharynx using polymerase chain reaction (PCR). Four studies included exposed siblings and three included exposed patients, one study included exposed daycare contacts and one included children and  adult participants in a clinical trial for acyclovir after the appearance of skin lesions. This review of literature confirms the scarcity of evidence in the medical literature on transmission of VZV before varicella rash onset. Several outbreak investigations in healthcare facilities reported potential exposure prior to rash onset in a patient with varicella but no transmission among exposed staff and patients. Laboratory evidence supporting transmission of VZV before rash onset is also very limited. VZV DNA was identified by PCR during the incubation period in only one study. However, methods for specimen collection and storage varied among the studies and may have been suboptimal. In addition, the presence of VZV DNA does not necessarily indicate infectivity or transmissible virus. Isolation of VZV in the respiratory tract of varicella patients is rarely reported. Coughing/sneezing leading to VZV transmission is not characteristic of varicella.

 

CONCLUSION: Based on the available medical literature, VZV transmission seems unlikely prior to rash onset. The authors suggest that providers should continue to implement appropriate infection control measures since the possibility of pre-rash, respiratory transmission of VZV cannot be entirely ruled out. Additional evidence using current or newly developed laboratory VZV assays would be beneficial.

 

REFERENCES:

  1. Marin, M., J. Leung, A.S. Lopez, L. Shepersky, D.S. Schmid, and A. A. Gerson. (2021). Communicability of varicella before rash onset” a literature review. Epidemiology and Infection 149, e131, 1-7. https://doi.org/10.1017/S0950268821001102
MKTG 1065 - Rev A 020322
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Herpes Virus Reactivation: Causes and Consequences Part IV

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
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Herpes Virus Reactivation: Causes and Consequences Part III

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
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Herpes Virus Reactivation, Causes and Consequences, Part II

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

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Herpes Virus Reactivation, Causes and Consequences, Part I

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

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Increase in Herpes Zoster Over the Last 60 Years

INTRODUCTION: Over the last six decades, there has been a steady increase in the number of herpes zoster (HZ, shingles) cases in the United States, including among younger adults.

A 2013 study (Hales et al1) found that rates of shingles have been climbing since the mid-1940s in all age groups. From 1945 to 1949, 0.76 out of every 1,000 people got the disease. Between 2000 and 2007, that number rose to 3.15 people per 1,000. The virus has hit older adults particularly hard. Shingles rates rose 39% from 1992 to 2010 in people over 65. It is now estimated that one in three (1 in 3) people will get HZ during their lifetime.

DISCUSSION: The rise in HZ cases is a complicated issue. Several factors are involved in these cases. As we discussed in a previous Viro Perspective, waning immunity in younger adults or the possible emergence of wild type alleles may be involved with cases seen in those under 50 years of age.

Immunosuppression is a key reason for HZ. Harpaz et al2 discussed the prevalence in immunosuppression in the U.S. They said that the number of immunosuppressed adults in the United States is unknown but thought to be increasing because of both greater life expectancy among immunosuppressed adults due to improvements in medical management, as well as new indications for immunosuppressive treatments.

Immunosuppression increases the risks and severity of primary or reactivation infections. There are many examples of this, such as in the case of a 67-year-old woman with non-Hodgkin’s lymphoma who was undergoing chemotherapy and who presented with an acute alteration of consciousness due to multiple brain lesions3. MRI of the brain revealed multiple and nonspecific lesions of hyperintensity with mild edema in the cortex and subcortex. She was treated with intravenous acyclovir. However, two days after admission, the patient died and was diagnosed with varicella-zoster virus (VZV) encephalitis. This case highlights the risk of VZV reactivation with severe neurological complications in patients undergoing immunosuppressive therapy.

In another example, there was HZ of the trigeminal nerve with multi-dermatomal involvement4. This was an unusual example of HZ with involvement of both the ophthalmic and maxillary divisions of the trigeminal nerve in an immunocompetent patient. Immunocompetence status and age-specific screening should be warranted in case of atypical involvement and according to the patient’s history, while treatment with antiviral drugs should be rapidly initiated in patients at risk. The 2020 pandemic with SARS-CoV-2 is also showing a correlation of COVID-19 infection with the reactivation of VZV, leading to HZ.

CONCLUSION: There is no single cause for the rise in the reactivation of VZV, however it is apparent that the increase in immunosuppression is key. The use of immunosuppressive drugs to prevent other diseases is common, such as in battling cancer. Many other infections also lower the immunocompetence of an individual. It is known that an active immune response producing interferons helps to keep VZV reactivation in check. It is also known that SARS-CoV-2 infections reduce lymphocytes, monocytes, and eosinophils, along with noted reductions of CD4/CD8 T cells, B cells, and natural killer cells. This results in lymphopenia due to the direct infection of lymphocytes with SARS-CoV-2, activation-induced cell death, and impairment to antiviral responses (such as with specific interferons). At some point, it should be investigated if these HZ cases can be reduced using the SHINGRIX vaccine in those under 50.

REFERENCES:

  • Pelloni, L.S., Pelloni, R., and Borradori, L. (2020). Herpes zoster of the trigeminal nerve with multi-dermatomal involvement: a case report of an unusual presentation. BMC Dermatology 20:12 https://doi.org/10.1186/s12895-020-00110-1

By David Kilpatrick, PhD and Abbas Vafai, PhD

MKTG 1060 – Rev A 060321

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