Human Herpesvirus 6 Infection Research Articles

Prevalence of Anti-Human Herpes Virus Type 7 IgG Positivity Rate among Children with Fever and Skin Rash in Diyala Province, Iraq.

Human herpesvirus 7 (HHV-7) is a T-lymphotropic virus isolated from peripheral blood mononuclear cells as beta herpes viruses. It is a highly prevalent virus since over 90% of adults are seropositive. The majority of primary infection occurs in early childhood, and its prevalence peaks at 60 % in 11-13-year-old. This study was designed to investigate the seroprevalence of HHV- 7 infections among apparently healthy children as well as child patients with fever and skin rash in the Diyala community and its association with certain socio-demographic variables. The current study is a cross-sectional study conducted in Diyala province-Iraq, extending from July 2020 to March 2021. A total of 180 child patients with fever and skin rash were included. Their age range was 1-14years. Additionally, 60 healthy age-matched children were enrolled as a control group. A special questionnaire was prepared for this study, including socio-demographic information, clinical notes and the results of a complete blood count. Human privacy was esteemed by obtaining parents' verbal approval. Blood specimen was aspirated from all study groups. Sera were separated and kept at -20 °C until tested. Enzyme-linked immunosorbent assay (ELISA) kits for the detection of anti-HHV-7 IgG were used (Mybiosource-China). Statistical analysis was done using Statistical Package of Social Science (SPSS) version 27, and the P value was considered significant wherever it was less than 0.05. The anti-HHV-7 IgG positivity rate in patients was 19.4%, and that in healthy individuals was 31.7%, with an insignificant difference (P=0.051). The highest HHV-7 IgG positivity rate was found among patients 1-4 years old, matching that in the healthy group with a statistically insignificant difference (P=0.675). The gender, residence and number of children/ family insignificantly affect the distribution of HHV-7 IgG in the control group. The mean±SD of hemoglobulin (Hb) concentration among participants with negative anti-HHV-7 IgG was insignificant compared to their positive counterparts (P=0.987). The mean±SD of total WBC count among those positive for anti-HHV-7 IgG was insignificantly higher than their negative counterpart (P=0.945). The mean±SD lymphocyte count in patients and healthy control positive for anti-HHV-7 IgG were insignificantly higher (P=0.241) and (P=0.344), respectively. Lastly, healthy control positive for anti-HHV-7 IgG had insignificantly higher lymphocyte count (P=0.710). About one-third of healthy children in our community were seropositive for anti-HHV 7 IgG antibodies that are most prevalent at 1-4 years old and are insignificantly associated with gender, residence, and the number of children per family. Furthermore, the HHV-7 infection is insignificantly associated with alterations of complete blood count parameters.

Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field

Herpesviruses are ubiquitous and after primary infection they establish lifelong latency. The impairment of maintaining latency with short-term or long-term consequences could be triggered by other infection. Therefore, reactivation of herpesviruses in COVID-19 patients represents an emerging issue. This study provided the first systematic review with meta-analysis of studies that evaluated active human herpesvirus (HHV) infection (defined as the presence of IgM antibodies or HHV-DNA) in COVID-19 patients and included 36 publications collected by searching through PubMed, SCOPUS, and Web of science until November 2022. The prevalence of active EBV, HHV6, HSV, CMV, HSV1, and VZV infection in COVID-19 population was 41% (95% CI =27%-57%), 3% (95% CI=17%-54%), 28% (95% CI=1%-85%), 25% (95% CI=1%-63%), 22% (95% CI=10%-35%), and 18% (95% CI=4%-34%), respectively. There was a 6 times higher chance for active EBV infection in patients with severe COVID-19 than in non-COVID-19 controls (OR=6.45, 95% CI=1.09-38.13, p=0.040), although there was no difference in the prevalence of all evaluated active herpesvirus infections between COVID-19 patients and non-COVID-19 controls. Future research of herpesvirus and SARS-CoV-2 coinfections must be prioritized to define: who, when and how to be tested, as well as how to effectively treat HHVs reactivations in acute and long COVID-19 patients.

COVID-19, SARS-CoV-2 Vaccination, and Human Herpesviruses Infections.

There are several human herpesviruses. A common characteristic of infection by these viruses is latency, by which the virus assumes a non-replicative state, subverting the attentions of the host's immune response. In immunocompetent hosts, herpesviruses are immunologically controlled, although periodic virus shedding can occur. In situations where immunological control is lost, herpesviruses can reactivate and produce clinically apparent disease. It is now becoming apparent that COVID-19 or exposure to COVID-19 vaccines can exert several effects on the immune system. The pandemic of COVID-19 shows no sign of abating, with new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants continuing to evolve. Several COVID-19 vaccines have been developed, and much of the world's population has either experienced COVID-19 or been vaccinated against it. There are an increasing number of reports of associations between herpesvirus infections or reactivations and COVID-19 or COVID-19 vaccination. For instance, a positive cytomegalovirus serostatus may indicate a greater likelihood of severe COVID-19, and herpes simplex virus reactivation may be linked to increased mortality. Epstein-Barr virus reactivation appears to be associated with post-acute sequelae of COVID-19. Finally, herpes zoster has been reported to be associated with COVID-19 vaccination. This brief narrative review will provide several insights into associations between herpesvirus infections or reactivations and COVID-19 or SARS-CoV-2 vaccination.

Adherence to treatment as a prognostic factor for histoplasmosis in a patient with AIDS

Diseases caused by human herpesvirus 8 (HHV-8) can affect immunosuppressed patients, particularly those co-infected with the human immunodeficiency virus (HIV). Castleman disease is one such condition that is rare and challenging to diagnose, given its numerous nonspecific symptoms and multiple differential diagnoses. This study reports a case of a patient living with HIV who was diagnosed with multicentric Castleman disease, wherein the diagnosis was facilitated by the concomitant presence of Kaposi sarcoma in the gastrointestinal tract, both of which are directly related to HHV-8 infection.

Razvoj produženog COVID-a kao posledice kompleksnog odnosa između Epštajn-Bar virusa i našeg imunskog sistema

Introduction: The pathophysiological development of long COVID (LC) is still insufficiently known. However, post infection fatigue syndromes were seen before, among other pathogens including Epstein-Barr virus (EBV). Considering EBV reservoir in COVID-19 patients, this review aims to present current knowledge related to EBV role in development of LC and with the potential diagnostic utility. EBV infection: Following the primary lytic infection of epithelial oropharyngeal and nasopharyngeal cells EBV establishes a very complex mechanism of lifelong survival in B cells. Latent infection with occasional viral reactivations constantly challenges the host's immune response. In individuals with immune imbalance including COVID-19, it could drive long-term consequences. EBV and COVID-19: The activity of EBV has been shown as the most prevalent human herpesvirus infection in COVID-19 population (41%). Correlation between lymphocytopenia-induced disability to remove the EBV, increases in EBV DNA viremia and COVID-19 complications have also been reported. EBV and long COVID: The positivity of EBV DNA during acute SARS-CoV-2 infection predicted the presence of symptoms up to 60 days after COVID-19. Association between EBV infection and symptoms such as brain fog, fatigue, arthralgia and skin rashes have been also described in post infection sequelae ME/CFS. Anti-EBV early antigen-diffuse (EA-D) IgG antibodies were detectable among two-thirds of respondents experiencing LC. Increases in anti-EBNA1 IgG levels analyzed months following COVID-19 onset in convalescent LC population could serve as a potential marker of EBV reactivation at the time of acute SARS-CoV-2 infection. Some authors also managed to show anti-EBV viral capsid antigen (VCA) IgM seropositivity in half of COVID-19 patients indicating of either coinfection or EBV reactivation. Conclusion: As a multisystemic illness, LC is without a defined spectrum of diagnostic and treatment options. Whereas EBV reactivation alone or together with other risk factors drives LC symptoms, further prospective studies involving different cohorts and tissue reservoirs are necessary to understand underlying biological mechanisms.

Clinical features of Behcet’s uveitis in patients with herpesvirus reactivation

Purpose. To study the possible impact of human herpes viruses (HHV) reactivation: herpes simplex virus type 1 (HSV 1), type 2 (HSV 2), cytomegalovirus (CMV) and Epstein — Barr virus (EBV) on the clinical course of uveitis in Behcet's disease (BD). Material and methods. Serum samples of 106 BD patients (ave. age 39) with uveitis were examined for the presence of antibodies — serological markers of chronic HHV infection and reactivation. Results. In 65 patients (25 with active uveitis (UA), 40 with uveitis remission (UR)), HHV reactivation was detected (mainly HSV 1, less often HSV 2, CMV and EBV — in individual cases), 41 patients had chronic HHV (17 with UA, 24 with UR). Certain clinical symptoms of uveitis were found to depend on HHV activity. Clinical signs of active uveitis (cells in the vitreous body), as well as severe irreversible changes (social blindness and low vision) were significantly more frequently detected in cases of HHV reactivation (p < 0.05) than in chronic HHV. The data obtained allow us to suggest, with some caution, that a subclinical HHV reactivation which stays after the onset of clinical uveitis remission, is an important factor of postuveal complications that are mainly manifested during remission. These complications include epiretinal fibrosis, pronounced optic nerve atrophy, and vasculitis (arterial and venous occlusion). Conclusion. The remission period in patients with subclinical herpesvirus activity is less favorable than in patients without serological markers of HHV reactivation. HHV reactivation that persists after uveitis activity is stopped can contribute to sudden exacerbations of uveitis.

Increased Comorbidities and Hospitalizations Associated with Idiopathic Multicentric Castleman Disease

Background: Castleman disease (CD) describes a group of disorders that share characteristic lymph node histopathology with heterogeneous symptoms. Unicentric Castleman disease (UCD) involves a single region of enlarged lymph nodes, localized symptoms, and is typically curable with excision. In contrast, multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. MCD can be associated with human herpesvirus-8 infection or is idiopathic (iMCD). Presentation is heterogeneous, and multiple clinical phenotypes exist, including iMCD patients who meet criteria for the most severe form of the disease, the TAFRO subtype (thrombocytopenia, anasarca, fevers, reticulin fibrosis, organomegaly). Furthermore, iMCD is difficult to diagnose. Though there is an FDA-approved therapy (siltuximab) for iMCD, major unmet need exists as many patients do not receive this treatment and a subset of patients do not respond to siltuximab. To elucidate the burden of iMCD, we interrogated hospitalization and comorbidity data from patients with iMCD and UCD, as well as from a comparator group of patients who demonstrated iMCD-like features determined to result from a reactive process ('Other'). Methods: The ACCELERATE Natural History registry was leveraged to identify a cohort of 193 patients with a pathology report suggestive of CD. All patients were reviewed by a panel of expert CD physicians to confirm or reject a CD diagnosis. Following review, 85 patients were categorized as having iMCD - including 49 (58%) iMCD-TAFRO, 65 were UCD, and 43 patients were consistent with an inflammatory or reactive processes not reflective of iMCD (Other). Results: The mean (SD) age of patients was 39 (16) with a range of 1-75. Prior to diagnosis, the top 10 comorbidities found among both iMCD and UCD patients included common chronic diseases observed in the general US population, such as diabetes, hypertension, GERD, obesity, asthma, anxiety, and depression. Among UCD patients, the top common comorbidities remained unchanged after diagnosis. Among iMCD patients, however, a number of other comorbidities emerged as top-most common, such as acute renal failure (20%), pneumonia (11%), sepsis (8%), chronic kidney disease (8%), thrombotic microangiopathy (7%), acute cholecystitis (7%), and diverticulitis (6%). We also found that the iMCD patients spent a significantly longer time hospitalized in the 1st year following diagnosis (mean 34.3 days) compared to UCD (mean 14 days) (p<0.05), but there was no significant difference from patients with an Other diagnosis (22 days). We saw a similar trend in days hospitalized per year since diagnosis, with iMCD patients hospitalized for a significantly greater time than UCD (24.2 vs. 10.5 average days hospitalized per year of diagnosis, p<0.001). There was no difference with the Other group (16.2 days). iMCD patients also spent an average of 12.1 days hospitalized before the first iMCD-treating drug and 44.7 days after the administration of the first iMCD-treating drug. Further, a large proportion of iMCD patients required supportive interventions, such as dialysis (23.6%, n=20) and mechanical ventilation (16.5%, n=14). This compares to 7% (n=3) of Other patients and no UCD patients who required dialysis and 9.3% (n=4) of Other patients and 4.6% (n=3) UCD patients who required mechanical ventilation. Discussion: Overall, these data demonstrate that iMCD patients face a significant disease burden, even years after a diagnosis is rendered and treatment is initiated. While siltuximab can effectively control symptoms in a subset of iMCD patients, not all patients receive siltuximab and not all patients treated respond to siltuximab. We found that patients require hospitalization and costly intervention such as dialysis and mechanical ventilation for extended periods of time. These findings have real implications for patient healthcare costs and hospital systems. iMCD patients demonstrate relatively common comorbidities prior to diagnosis and subsequently develop life-threatening conditions such as acute kidney failure and sepsis following diagnosis. These data highlight the importance of continuing research into iMCD etiology, subgroups, treatments, and outcomes, to control the burden of disease and improve outcomes and prognosis for this severely ill group of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Clinical Outcomes from a Phase 2 Trial of Posoleucel, an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Clinically Significant Viral Infections Post-HCT

Background: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are highly susceptible to reactivation of double-stranded DNA viruses. Approximately 70% of high-risk allo-HCT recipients develop clinically significant infections (CSI, defined as viremia + treatment or end organ disease). We present results from a phase 2 trial evaluating the safety and efficacy of posoleucel, a partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product, for preventing CSIs due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), or JC virus (JCV). Methods: This open-label trial enrolled high-risk allo-HCT recipients, including those with grafts from haploidentical, umbilical cord blood, mismatched unrelated donors, and matched unrelated donors with lymphocytes <180/mm3 as well as recipients who underwent T cell depletion. To be eligible, patients had to be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD and those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment were ineligible. Patients received up to 7 infusions of posoleucel once every 14 days and were tested weekly for viremia using quantitative PCR assays. The primary endpoint was the number of CSIs due to AdV, BKV, CMV, EBV, HHV-6, or JCV by week 14. IFN-γ ELISpot analysis was performed for each targeted virus on serial peripheral blood samples to assess functional T cell immune reconstitution and determine the frequency of circulating virus-specific T cells detected over time. To evaluate the persistence and potential contribution of posoleucel to antiviral immune reconstitution, T-cell receptor (TCR) β immunosequencing was performed at selected timepoints. TCR sequences unique to posoleucel were identified computationally and used to track in vivo persistence in serial samples. Results: Twenty-six patients were dosed. Posoleucel dosing began a median of 42 days after allo-HCT. Twenty (77%) patients had viral DNA detected in blood (reactivation) from one or more viruses, 13 (50%) had 2 or more viral reactivations, and 7 (27%) had 3 or more viral reactivations in the 14 weeks after the initiation of posoleucel dosing (Figure). However, by week 14, only 3 patients (12%) had CSIs (2 CMV viremia requiring treatment and 1 EBV-post-transplant lymphoproliferative disorder). No patient had a CSI with more than 1 virus. Nine patients (35%) experienced adverse events that were possibly or probably related to treatment. Eight patients (31%) had serious adverse events (SAEs), 2 of which were judged to be possibly related to treatment (skin and pulmonary GVHD) and 1 probably related to treatment (allergic reaction). Overall, 8 patients (31%) had acute GVHD Grade II-IV. One patient (4%) discontinued posoleucel due to a treatment-emergent SAE of chronic pulmonary GVHD. No patient experienced cytokine release syndrome. TCR sequencing data (N=12) indicated that posoleucel was detectable in vivo during the dosing phase of the study and for up to 12 weeks after the last infusion, with polyclonal VSTs detected in all 12 patients. Six of the 7 patients with available ELISpot data demonstrated IFN-γ-producing virus-specific T cell responses coincident with viral replication. The confirmed persistence of posoleucel and expansion of IFN-γ-producing virus-specific T cells directed against reactivating viruses, suggests a contribution of posoleucel to functional immune reconstitution. Conclusion: Results from this open-label phase 2 trial show that high-risk allo-HCT patients who received posoleucel had lower than expected rates of clinically significant viral infections from the 6 targeted viruses despite the observed and expected low-level viral reactivations throughout the study. Repeat dosing of posoleucel was generally safe and well tolerated. Posoleucel VSTs were detected in vivo for up to 26 weeks, and reconstituting T cells demonstrated functional specificity for multiple viruses. A placebo-controlled global phase 3 trial evaluating the safety and tolerability of posoleucel for the prevention of clinically significant AdV, BKV, CMV, EBV, HHV-6, and JCV infections is ongoing (NCT05305040). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis.

Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient’s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient’s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-022-01369-4.

Human herpesvirus 8-negative effusion-based large B-cell lymphoma: a distinct entity with unique clinicopathologic characteristics

AbstractRare cases of human herpesvirus 8 (HHV8)-negative effusion-based large B-cell lymphoma (EB-LBCL) occur in body cavities without antecedent or concurrent solid mass formation. In contrast to HHV8 + primary effusion lymphoma (PEL), EB-LBCL has no known association with HIV or HHV8 infection. However, the small sample sizes of case reports and series worldwide, especially from non-Japanese regions, have precluded diagnostic uniformity. Therefore, we conducted a retrospective, multi-institutional study of 55 cases of EB-LBCL and performed a comprehensive review of an additional 147 cases from the literature to identify distinct clinicopathologic characteristics. In our study, EB-LBCL primarily affected elderly (median age 80 years), immunocompetent patients and manifested as lymphomatous effusion without a solid component. The lymphomatous effusions mostly occurred in the pleural cavity (40/55, 73%), followed by the pericardial cavity (17/55, 31%). EB-LBCL expressed CD20 (53/54, 98%) and PAX5 (23/23, 100%). Most cases (30/36, 83%) were of non-germinal center B-cell subtype per the Hans algorithm. HHV8 infection was absent (0/55, 0%), while Epstein-Barr virus was detected in 6% (3/47). Clinically, some patients were managed with drainage alone (15/34, 44%), while others received rituximab alone (4/34, 12%) or chemotherapy (15/34, 44%). Eventually, 56% (22/39) died with a median overall survival (OS) of 14.9 months. Our findings were similar to those from the literature; however, compared to the non-Japanese cases, the Japanese cases had a significantly higher incidence of pericardial involvement, a higher rate of chemotherapy administration, and longer median OS. Particularly, we have found that Japanese residence, presence of pericardial effusion, and absence of MYC rearrangement are all favorable prognostic factors. Our data suggest that EB-LBCL portends a worse prognosis than previously reported, although select patients may be managed conservatively. Overall, EB-LBCL has distinct clinicopathologic characteristics, necessitating the establishment of separate diagnostic criteria and consensus nomenclature.

S3585 Don’t Forget the Gut: A Case of Gastrointestinal Kaposi Sarcoma

Introduction: Kaposi sarcoma (KS) is a low grade vascular tumor associated with Human Herpesvirus-8 (HHV8) infection. The disease course is indolent with manifestations ranging from cutaneous to fulminant, visceral involvement. In the United States, KS is most often seen in those with AIDS and with increased access to highly active antiretroviral therapy (HAART) the incidence has been decreasing. GI tract involvement of KS is uncommon and few have GI symptoms; therefore, gastrointestinal Kaposi sarcoma (GI-KS) remains under-diagnosed. This case describes a patient with cutaneous involvement of KS found to have GI-KS with no GI symptoms. Case Description/Methods: A 49-year-old African American male presented with shortness of breath, non-productive cough and a 60-lb unintentional weight loss over the past year. He was diagnosed with HIV in 1999 and has been intermittently compliant with HAART therapy. In the past two years, he was started on Bictegravir/emtricitabine/tenofovir alafenamide but was non-compliant. He recently noticed the development of bilateral non-painful and non-pruritic lower skin lesions (Figure a). His CD4 count was low at 88 cells/mm3 with an elevated HIV viral load. His lower extremity skin lesion biopsy showed irregular blood vessels lined by atypical endothelial cells with an infiltrating growth pattern consistent with KS. CT chest demonstrated multiple ground glass opacities and bronchoscopy with FNA were negative for any malignancy. CT abdomen/pelvis was unremarkable. EGD and colonoscopy was done to to rule out systemic involvement which demonstrated scattered moderate mucosal changes characterized by erythema, granular nodularity in the gastric body and nodular mucosa in the rectum (Figure b/c). Biopsies demonstrated spindle cell proliferation involving the lamina propria consistent with KS. Discussion: Kaposi sarcoma is an AIDS-defining rare vascular tumor. Current recommendations for endoscopy are reserved for patients suspicious for GI involvement. This patient had poorly controlled HIV with no GI symptoms and was found to have GI-KS during endoscopy. Management of KS differs based on cutaneous versus systemic involvement. HAART therapy is the first line in management of cutaneous KS while HAART therapy and chemotherapy is first line in management for systemic KS. Therefore, undiagnosed GI-KS in patients with cutaneous KS negatively affects morbidity and mortality. Therefore, clinicians should maintain a high suspicion for GI-KS in those with AIDS and/or cutaneous KS.Figure 1.: a. Lower extremity cutaneous lesions Figure b. Gastric lesions Figure c. Rectal lesions.

Case Report of a Malignant Melanoma Patient with Longitudinally Extensive Transverse Myelitis: Immune-Related Adverse Event or Human Herpesvirus-7 Infection?

Case Report of a Malignant Melanoma Patient with Longitudinally Extensive Transverse Myelitis: Immune-Related Adverse Event or Human Herpesvirus-7 Infection?

Increased expression of human herpes virus 6 receptor CD134/OX40 in skin lesions of patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

CD134/OX40, a member of the tumor necrosis factor receptor superfamily, is a cell-specific receptor for human herpesvirus 6 (HHV-6) variant B. Patients with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) present a significant increase in CD134 expression in peripheral blood CD4+ T cells. We aimed to investigate the frequency of CD134+ CD4 T cells infiltrating skin lesions in patients with DIHS/DRESS and its association with disease severity. We retrospectively included 21 patients with DIHS/DRESS and 11 patients with erythema multiforme (EM). By immunohistochemistry, the frequency of CD134+ CD4 T cells in DIHS was significantly higher than that in EM (p=0.0083). The DIHS/DRESS severity score was significantly correlated with the frequency of CD134+ CD4 T cells (p=0.0272); moreover, there was a significant difference between severe and mild/moderate cases. Double immunofluorescence staining revealed that numerous cells presented CD134/CD4 and CD134/Foxp3 overlap in patients with DIHS/DRESS. These data suggest increased susceptibility to HHV-6 infection at localized skin sites. HHV-6 may be involved in the mechanism underlying the progression and pathophysiology of DIHS/DRESS.

Isolated Kaposi sarcoma of the upper aerodigestive tract in immunocompetent individuals, an underrecognized entity with favorable prognosis.

Kaposi sarcoma (KS) is a rare vascular neoplasm that most commonly arises in the setting of immunosuppression, in areas with high prevalence of Human Herpesvirus-8 infection, and when both situations coexist. Most cases affect the skin, isolated involvement of the upper respiratory tract without skin involvement is extremely rare with only a few cases reported in the literature. We present a case of isolated nasopharyngeal KS in an immunocompetent patient who achieved remission after multimodality therapy. Recent advances in KS-therapy are discussed.

248.5: Development of Serological Tools for Diagnosis of Human Herpesvirus 8 Infection and Their Application to Estimate Antibody Prevalence in English Blood and Organ Donor Populations

Introduction: Human Herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus, is aetiologically associated with all forms of Kaposi’s Sarcoma (KS), including transplant-related, as well as rare neoplastic conditions such as primary effusion lymphomas and multicentric Castleman disease. Solid organ transplant recipients have a much higher risk of KS compared to the general population and the role of serological screening in this setting has been long debated; there is currently no standard method of screening for HHV-8 infection and serology has been largely used for sero-epidemiological purposes. The latent nature of the virus makes determination of HHV-8 infection status complex and investigations may lead to inaccuracies. Methods: To fulfil the critical gaps in the diagnosis of asymptomatic virus infection, a combination of serological tools for the detection of antibody to both HHV-8 lytic and latent antigens have been developed and compared with the commercial lytic antigen-based immunofluorescence assay (IFA, Scimedx Corp), which is commonly used in Europe for the detection of antibodies to HHV-8. The developed assays include an in-house latent IFA assay that utilises latently infected PEL cells as well as two Double Antigen Binding Assays (DABAs) which utilise major HHV-8 antigens; ORF73 and K8.1 e(latent and lytic proteins, respectively). Results: Initial data gained from the testing of samples from identified patients with ongoing HHV-8 disease indicate a good concordance between both latent and lytic antibody assays. Studies are underway to determine the performance of these assays for the identification of asymptomatic infection and are being applied to establish the prevalence of HHV-8 antibodies in donor populations. Conclusion: HHV-8 has a complex serological profile and the availability of tools based on a range of formats which target multiple proteins will better inform on seroprevalence rates both at a population level and within specific at-risk groups.

Epstein-Barr Virus and Human Herpesvirus-6 Reactivation in Acute COVID-19 Patients.

Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein–Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.

New Insights into the Molecular Interplay between Human Herpesviruses and Alzheimer's Disease-A Narrative Review.

Human herpesviruses (HHVs) have been implicated as possible risk factors in Alzheimer’s disease (AD) pathogenesis. Persistent lifelong HHVs infections may directly or indirectly contribute to the generation of AD hallmarks: amyloid beta (Aβ) plaques, neurofibrillary tangles composed of hyperphosphorylated tau proteins, and synaptic loss. The present review focuses on summarizing current knowledge on the molecular mechanistic links between HHVs and AD that include processes involved in Aβ accumulation, tau protein hyperphosphorylation, autophagy, oxidative stress, and neuroinflammation. A PubMed search was performed to collect all the available research data regarding the above mentioned mechanistic links between HHVs and AD pathology. The vast majority of research articles referred to the different pathways exploited by Herpes Simplex Virus 1 that could lead to AD pathology, while a few studies highlighted the emerging role of HHV 6, cytomegalovirus, and Epstein–Barr Virus. The elucidation of such potential links may guide the development of novel diagnostics and therapeutics to counter this devastating neurological disorder that until now remains incurable.

Association between human herpesvirus 6 (HHV-6) and cognitive function in the elderly population in Shenzhen, China.

Human herpesvirus 6 (HHV-6) is neurophilic, and its relationship with Alzheimer's disease (AD) remains controversial. This study aimed to examine the relationships between HHV-6 and cognitive abilities in elderly people aged 60years or above from communities in Shenzhen. We recruited participants from 10 community health service centers in Shenzhen. Participants were divided into case and control groups according to Mini-Mental State Examination (MMSE) scale standards and were included in this study with 1:1 matching based on sex and age (± 3years). The HHV-6 gene was detected by real-time fluorescent quantitative PCR, and the HHV-6 copy number was quantified. A total of 580 participants (cases, n = 290; controls, n = 290), matched for gender and age was included in this study. A positive HHV-6 test was not associated with a significant difference in global cognitive performance (ORadjusted = 1.651, 95% CI = 0.671-4.062). After adjusting for gender, age, education, Pittsburgh Sleep Quality Index (PSQI) score, homocysteine (Hcy) and glycosylated hemoglobin (HbA1c), the results of multiple linear regression showed that there was a statistically negative correlation between HHV-6 copy number and orientation (βadjusted = -0.974, p = 0.013), attention and calculation (βadjusted = -1.840, p < 0.001), and language (βadjusted = -2.267, p < 0.001). The restricted cubic spline (RCS) model results showed that there was a nonlinear dose-response relationship between HHV-6 log10-transformed copies and orientation (poverall = 0.003, pnonliner = 0.045), attention and calculation (poverall < 0.001, pnonliner < 0.001), and language (poverall < 0.001, pnonliner = 0.016). HHV-6 infection significantly associated with orientation, attention and calculation, and language in elderly individuals.

Epidemiologic Implication of the Association between Herpes Simplex Virus Infection and the Risk of Type 1 Diabetes Mellitus: A Nationwide Case-Control Study in Taiwan.

Enterovirus infection is a known risk factor for type 1 diabetes (T1DM). Whether infection with other viruses induces T1DM remains undetermined. This study investigated the association between human herpesvirus (HHV) infection and the development of T1DM, using the data from Taiwan’s National Health Insurance Research Database. Patients with T1DM and age- and sex-matched controls were included. Subjects with HHV infection were subgrouped into those with histories of varicella-zoster virus, herpes simplex virus (HSV), Epstein-Barr virus, and human cytomegalovirus infections. The odds ratio of the risk of T1DM was calculated using a multivariable conditional logistic regression model. Atopic diseases, autoimmune thyroid diseases, and history of enterovirus infection served as adjusted comorbidities. Our findings suggested a significant association between HSV infection and the risk of T1DM (adjusted odds ratio: 1.21; 95% CI: 1.01–1.47, p = 0.048), while infection with other HHVs was not. The result of HSV infection remained significant when subjects were restricted to age ≤ 18 years (adjusted odds ratio: 1.35; 95% CI: 1.08–1.70, p = 0.010). We found a history of HSV infection might be an independent predictive risk factor for T1DM. This could be potentially helpful to the practice in public health.

Abstract LB162: Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers

Abstract Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent. Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT). Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56). Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs. Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.