VZV Reactivation Research Articles

Patients with autoimmune polyendocrine syndrome type 1 have an increased susceptibility to severe herpesvirus infections

Almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) have neutralizing antibodies against type 1 interferons (IFN), important mediators of antiviral defense. Recently, neutralizing anti-IFN antibodies were shown to be a risk factor of severe COVID-19. Here we show in a cohort of 44 patients with APS-1 that higher titers of neutralizing anti-IFNα4 antibodies are associated with a higher and earlier incidence of VZV reactivation (herpes zoster). The patients also present with uncommonly severe clinical sequelae of herpetic infections. APS-1 patients had decreased humoral immune responses to varicella zoster virus, but cellular responses were comparable to healthy controls. These results suggest that blocking the type I interferon pathway in patients with APS-1 patients leads to a clinically significant immune deficiency, and susceptibility to herpesviruses should be taken into account when treating patients with APS-1.

B-Cell Lymphoma Patients Have a 10% Risk of Shingles, 7% in Cutaneous T-Cell Lymphoma

Background: Patients with lymphoma can be immunosuppressed from the disease, treatment or both. One indicator of cellular mediated immunity is reactivation of Varicella Zoster (VZV), a painful viral infection estimated to occur to 30% of U.S. population during a lifetime and associated with a particularly morbid post-herpetic neuralgia. Bortezomib and dexamethasone have been shown to be correlated with increased rates of varicella zoster and other viral infections (Kim SJ et al, Clinical lymphoma & myeloma, 2008). Autologous stem cell transplant depletes cellular- and humoral-immunity (Kamber C et al, BMT, 2015). While the main risk factor for VZV reactivation is age (Harpaz R, MMWR Recomm Rep, 2008), the underlying malignancy might play a large role in the risk of VZV reactivation. There is little data comparing the proportion of VZV in multiple myeloma (MM) with other indolent B and T-cell lymphomas. The purpose of this study is to compare varicella infection in MM patients with chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and follicular lymphoma (FL). Given that VZV is a relatively common infection in patients with MM, we hypothesized that varicella reactivation in MM patients occurs at a higher rate than in patients with CLL, CTCL, or FL.Methods: A retrospective chart review of 3,765 patients was conducted. Patients were eligible if they had been diagnosed with 1 of 4 malignancies - MM (1,210), CLL (2,520), CTCL (434), or FL (809). Patients diagnosed with other malignancies i.e. mantle cell lymphoma were excluded, as were patients with multiple malignancies i.e. MM and FL. All patients had been seen at the Ohio State University Wexner Medical Center during their treatment. For each patient, information on age, gender, length of survival, age at diagnosis of hematologic malignancy, and proportion of patients with shingles was collected. Only patients who were diagnosed with shingles after hematologic cancer diagnosis were included as positive. Associations between malignancy type and development of shingles were analyzed by a chi-square test, and logistic regression was used to calculate odds ratios for shingles between MM and the other malignancies, controlling for age as a possible confounder. Median survival time was calculated in years using the Kaplan-Meier method, calculated as the time from cancer diagnosis to date of last contact if alive, or date of death if deceased. Seven patients were excluded from survival analysis due to having the same date of diagnosis as date of last contact. This study was approved by the cancer institutional review board.Results: Patient demographic information is found in Table 1. Of the 1,210 MM patients, 127 developed shingles after diagnosis (10.5%); of 2520 CLL patients, 326 were positive (12.9%); of 434 CTCL patients, 33 were positive (7.6%); of 809 FL patients, 78 were positive (9.6%). At a significance level of a=0.05, there was a significant association between cancer type and shingles (χ2=15.59, df=3, p-value=0.0014). Odds ratios comparing MM to each of the other lymphomas were not found to be significant. The median survival time in years was 8.8 for MM, 20.7 for CLL, 25.1 for CTCL, and 24.6 for FL (Figure 1).Conclusion: Patients with MM had the lowest median survival (8.8 years), and a significant association between cancer type and shingle incidence was found, with CTCL patients having the lowest incidence of shingles (7.6%) within the retrospective period. However, the odds ratios comparing MM to the other 3 lymphomas was not significant, showing that the MM patients did not have significantly higher rates of shingles as originally hypothesized. These results demonstrate the differences in viral infection incidence and disease course between hematologic malignancies, and that antiviral strategies more specialized to T and B cell lymphomas may be important in reducing the risk of viral infection. [Display omitted] DisclosuresHofmeister:Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Takeda: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Research Funding.

Association of Achalasia With Active Varicella Zoster Virus Infection of the Esophagus

Achalasia is an esophageal motility disorder of unknown etiology. 1 Vaezi M.F. et al. Am J Gastroenterol. 2020; 115: 1393-1411 Crossref PubMed Scopus (33) Google Scholar Case-control analysis has revealed that antecedent viral infections are significantly more prevalent in achalasia than in control patients (P < .0001); moreover, diseases caused by varicella zoster virus (VZV; the cause of varicella and zoster) are by far the most prevalent of viral infections (77.4%; P < .0001). 2 Becker J. et al. Eur J Gastroenterol Hepatol. 2016; 28: 689-695 Crossref PubMed Scopus (14) Google Scholar Antibody titers to VZV in patients with achalasia are significantly higher than those of age- and sex-matched controls and in situ hybridization has revealed VZV DNA in neurons of the achalasia esophagus. 3 Robertson C.S. et al. Gut. 1993; 34: 299-302 Crossref PubMed Scopus (135) Google Scholar VZV establishes latency in peripheral neurons after varicella or administration of live attenuated varicella vaccine. 4 Gershon M. et al. J Infect Dis. 2018; 218: S113-S119 Crossref PubMed Scopus (18) Google Scholar Cutaneous zoster results from VZV reactivation in skin-projecting neurons, however, VZV reactivation in enteric neurons, which lack cutaneous projections, causes enteric zoster, which may lack a rash and thus escape suspicion. 4 Gershon M. et al. J Infect Dis. 2018; 218: S113-S119 Crossref PubMed Scopus (18) Google Scholar ,5 Gershon A.A. et al. Clin Infect Dis. 2015; 61: 536-544 Crossref PubMed Scopus (34) Google Scholar Therefore, we investigated the possibility that VZV (enteric zoster) might be linked to achalasia.

Exploring the Seasonal Drivers of Varicella Zoster Virus Transmission and Reactivation.

Varicella zoster virus (VZV) is a herpesvirus that causes chickenpox and shingles. The biological mechanisms underpinning the multidecadal latency of VZV in the body and subsequent viral reactivation-which occurs in approximately 30% of individuals-are largely unknown. Because chickenpox and shingles are endemic worldwide, understanding the relationship between VZV transmission and reactivation is important for informing disease treatment and control. While chickenpox is a vaccine-preventable childhood disease with a rich legacy of research, shingles is not a notifiable disease in most countries. To date, population-level studies of shingles have had to rely on small-scale hospital or community-level data sets. Here, we examined chickenpox and shingles notifications from Thailand and found strong seasonal incidence in both diseases, with a 3-month lag between peak chickenpox transmission season and peak shingles reactivation. We tested and fitted 14 mathematical models examining the biological drivers of chickenpox and shingles over an 8-year period to estimate rates of VZV transmission, reactivation, and immunity-boosting, wherein reexposure to VZV boosts VZV-specific immunity to reinforce protection against shingles. The models suggested that the seasonal cycles of chickenpox and shingles have different underlying mechanisms, with ambient levels of ultraviolet radiation being correlated with shingles reactivation.

Enhancement of the Trigeminal Nerve by VZV Reactivation.

Enhancement of the Trigeminal Nerve by VZV Reactivation.

Importance of Compliance With Guidelines for the Prevention of Varicella-Zoster Virus Reactivation in Multiple Myeloma.

The importance of compliance with National Comprehensive Cancer Network (NCCN) guidelines for preventing varicella-zoster virus reactivation (VZVr) in multiple myeloma (MM) in a clinical setting has not been well investigated. We retrospectively studied the clinical characteristics and outcomes of 118 patients with MM treated with proteasome inhibitors. Thirty-nine episodes of VZVr were observed in 37 patients (VZVr group). The proportion of prophylactic antiviral prescriptions and compliance with antiviral prophylaxis based on the NCCN Clinical Practice guidelines was 76% and 30% in the VZVr group, and 88% and 74% in the non-VZVr group, respectively. Multivariate analysis showed that compliance with the NCCN guidelines was the only independent risk factor for VZVr (p=0.0017). It is important that prophylactic antivirals are prescribed for an appropriate duration of time to prevent the reactivation of VZV in compliance with existing guidelines.

14992 Chronic inflammatory skin diseases are associated with herpes zoster in United States inpatients

Many high-risk individuals remain unvaccinated and at risk for significant morbidity from herpes zoster (HZ). Patients with chronic inflammatory skin diseases (CISDs) have potential risk factors for HZ, including systemic immunosuppressant use and immune dysregulation. We sought to determine whether CISDs are associated with HZ in US inpatients. Data were analyzed from the 2002-2012 Nationwide Inpatient Sample, a representative 20% cross-sectional cohort of US hospitalizations (n = 68,088,221 children and adults). In multivariable weighted logistic regression models including age, sex, race/ethnicity, insurance, mean household income, and long-term systemic corticosteroid use, hospitalization for HZ was associated with multiple CISDs: atopic dermatitis (OR [95% CI]: 1.38 [1.14-1.68]), psoriasis (4.78 [2.83-8.08]), pemphigus (1.77 [1.01-3.12]), mycosis fungoides (3.79 [2.55-5.65]), dermatomyositis (7.31 [5.27-10.12]), systemic sclerosis (1.92 [1.47-2.53]), cutaneous lupus erythematosus (1.94 [1.10-3.44]), vitiligo (2.00 [1.04-3.85]), and sarcoidosis (1.52 [1.22-1.90]). Bullous pemphigoid (2.76 [1.69-4.51]), lichen planus (2.97 [1.34-6.59]), morphea (2.76 [1.39-5.49]), and pyoderma gangrenosum (2.45 [1.16-5.15]) showed higher odds only in bivariable models, whereas, hidradenitis suppurativa and alopecia areata were not associated with HZ. Sensitivity analyses among ages < 60 and < 50 years showed similar results. Predictors of HZ in CISDs included older age, female sex, non-white race/ethnicity, and long-term systemic corticosteroid use. Inpatient length of stay and cost of care were significantly higher in HZ patients with vs without CISDs. CISDs are associated with increased hospitalization for HZ, even below recommended ages for vaccination with live and recombinant HZ vaccines. Additional studies are needed to confirm these findings, determine mechanisms of VZV reactivation, and establish CISD-specific vaccination guidelines.

Varicella-Zoster Virus Meningitis and Encephalitis: An Understated Cause of Central Nervous System Infections.

BackgroundVaricella-zoster virus (VZV) and herpes zoster cause infections of the central nervous system (CNS) manifesting as meningitis or encephalitis. As compared to enterovirus (EV) and herpes simplex virus 1 (HSV-1) and 2 (HSV-2), it is not often tested in CNS infections due to VZV and herpes zoster. There is a certain tendency to think that the findings in the cerebrospinal fluid in infections of the CNS by viruses are comparable among themselves. The exact proportion of patients with VZV primary and reactivation infection who present with lesions prior to or concomitant to its involvement in the CNS is unknown. It is also not known about the risk factors that lead to the reactivation of VZV and CNS involvement.ObjectiveTo describe the clinical characteristics and laboratory results of patients with a positive VZV polymerase chain reaction (PCR) and neurological signs and symptoms.MethodsA retrospective and descriptive study was performed at the Hospital Universitario de la Pontificia Universidad Católica de Chile (Hospital Clínico UC CHRISTUS) from September 2012 to July 2014. The following parameters were recorded: neurological signs and symptoms, PCR for VZV in cerebrospinal fluid (CSF), comorbidities, personal medical history, cutaneous lesions, CSF characteristics, CNS imaging, electroencephalography (EEG), treatment, mortality, and neurological sequelae. Adult patients with meningitis, encephalitis, or meningoencephalitis due to VZV diagnosed with PCR were included.ResultsOut of 70 CSF samples analyzed in the previously mentioned period, 21 cases were VZV positive, 16 cases that had clinical information available were included. The mean age with VZV CNS reactivation was 47 years (range 19-80 years). Five patients (31.25%) were immunocompromised: three had human immunodeficiency virus (HIV), one had kidney transplantation, and one had primary immunodeficiency. Clinical presentation was meningitis in 11 patients (68.75%) and encephalitis in five patients (31.25%). Pleocytosis in CSF was observed in all the samples. The five immunocompromised patients had cutaneous lesions. All patients received antiviral treatment. Therapy duration was from 10 up to 21 days. The clinical course was positive in most patients and the mean hospitalization time was 15 days (range 5-60 days). No mortality was observed.ConclusionsVZV is a worldwide virus and a common cause of CNS infection. The rising incidence is probably due to a better diagnostic method and a frequent clinical suspicion even in the absence of cutaneous lesions, except in immunocompromised cases, as it was observed in the present study. CNS infection presented as a wide spectrum of clinical manifestations with possible neurological sequelae. There was a reduction in neurological morbidity with antiviral therapy. Nonetheless, both the incidence and the morbidity of CNS VZV infection are expected to be diminished by varicella and herpes zoster vaccination. Additionally, there was no increase in mortality in these patients.

Role of Adoptive T- Cell Therapy in Post Hematopoietic Stem Cells Transplant Viral Infections-: A Systemic Review

Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) used for the treatment of multiple hematological malignancies requires immunosuppression, that can lead to the reactivation of viruses like EBV, CMV, adenovirus (AdV). These viruses pose a life-threatening risk to an individual like Graft vs Host Disease (GVHD) and other virus-specific complications. Adoptive T cell therapy (ATC) is an approach to treat refractory post-Allo-HSCT transplant viral infections. The aim of this study is to assess the efficacy of various ATCs being developed against various viruses. Methods A systematic search on PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in viral infections after stem cell transplantation from inception to May 28, 2020. Out of 604 studies, 13 phase I and II clinical trials were selected for the systematic review. Results A total of 13 studies were included of which two studies included data on the pediatric population (n=13). A total of 335 patients (pts) were enrolled in 13 studies of which 264 were evaluable. CMV Perruccio et al. (2005) in a randomized controlled trial (RCT) assessed the efficacy of ATC against both Aspergillus and CMV after alloSCT. Median follow up (f/u) was six months. For Aspergillus (n=23), 90% and 54% achieved clearance, while for CMV (n=68) 92% and 9% didn't develop CMV reactivation in treatment and control group respectively. Overall Survival (OS) and progression-free survival (PFS) rate at two years were 92% and 80% respectively. Smith et al. (2018) (n=21) in a phase I trial studied the transfusion of virus-specific T cells (VST) (n=13) against CMV infection after undergoing alloSCT. After a median f/u of 28 weeks, overall response rate (ORR) was 85%. Bao et al. (2012) (n=10) conducted a study with VST transfusion against CMV infection (n=7). ORR was 85% of which 3 pts who were on immunosuppressive had shown reactivation. Miej et al. (2012) in phase I/II study (n=6) assessed the response of VST against refractory CMV with CR of 100% Neuenhahn et al. (2017) studied a phase I/II prospective trial (n=17) (CMV Seropositive graft donor (D+) 9/17 and CMV Seronegative graft donor (D-) 8/17) with CR of 62% in D+ group. In D- group only 37% developed T cells after Third-Party Donor transfer and only these achieved CR, while pts with no T cell detection in D- group (63%), only one achieved CR. Micklethwaite et al. (2008) did a phase I clinical trial (n=12) of CMV specific T cells given prophylactically. Only four pts showed CMV reactivation. Adenovirus Feucht et al. (2019) performed a phase I/II clinical trial (n=30) of VST against refractory AdV infection. 47% showed CR, 13% with negative blood AdV cleared virus from other sites, 10% showed PR. OS at six months was 71%. Winnie et al. (2018) (n=8) conducted phase I/II RCT among pediatric pts. Median f/u was six months. All patients have shown a decrease in AdV viral load. Qasim et al. (2013) conducted a prospective trial (n=5) among pediatric pts with CR of 60% until six weeks f/u. 20% died due to AdV viremia. Multi-virus CTLs Gerdemann et al. (2013) (n=36) did a clinical trial by infusing multi-virus cytotoxic T lymphocytes (CTLs) (n=10), reactive against CMV, EBV, and AdV. CR in 80% of the pts. Muranski et al. (2017) performed a phase I trial (n=9) and infused multi-virus CTLs prophylactically. No AdV, BK, or EBV related disease was observed in any pts while 11% pts had asymptomatic AdV viremia. Only those pts who received steroid therapy had CMV reactivation (44%). Ma et al. (2015) performed a phase I/II RCT with an intervention group (n=19, evaluable=10) and control group (n=33) with an infusion of multi-virus CTLs against CMV, EBV, AdV, and VZV after alloSCT, prophylactically. Pts in the intervention group had no reactivation of EBV, AdV, or VZV. 6 (60%) pts with CMV had reactivation; four before T cell therapy and two in the context of steroid therapy. OS at one year was 89% and 81% in the intervention and control group respectively. Third-Party Donor T-cells Tzannou et al. (2017) (n=37) in a phase II study demonstrated ORR of 92% (95% CI, 78.1% to 98.3%) in various viruses with ORR for BK virus 100%, CMV 94%, Adv 71%, EBV 100% and HHV-6 67%. Conclusion Adoptive T cell therapy for viral infections has shown efficacy in Post- allo-SCT pts who achieved complete clearance of infection in many cases, showed only minimal adverse events, and no major risk for GVHD related to this therapy was noted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Non-idiopathic peripheral facial palsy: prognostic factors for outcome

ObjectivesThere is a lack of data on patients’ and diagnostic factors for prognostication of complete recovery in patients with non-idiopathic peripheral facial palsy (FP).MethodsCohort register-based study of 264 patients with non-idiopathic peripheral FP and uniform diagnostics and standardized treatment in a university hospital from 2007 to 2017 (47% female, median age: 57 years). Clinical data, facial grading, electrodiagnostics, motor function tests, non-motor function tests, and onset of prednisolone therapy were assessed for their impact on the probability of complete recovery using univariable and multivariable statistics.ResultsThe most frequent reason for a non-idiopathic peripheral FP was a reactivation of Varicella Zoster Virus (VZV; 36.4%). Traumatic origin had a higher proportion of complete FP (52.9%). Furthermore, in traumatic FP, the mean interval between onset and start of prednisolone therapy was longer than in other cases (5.6 ± 6.2 days). Patients with reactivation of VZV, Lyme disease or otogenic FP had a significant higher recovery rate (p = 0.002, p < 0.0001, p = 0.018, respectively), whereas patients with post-surgery FP and other reasons had a significant lower recovery rate (p < 0.0001). After multivariate analyses voluntary activity in first EMG, Lyme disease and post-surgery cause were identified as independent diagnostic and prognostic factors on the probability of complete recovery (all p < 0.05).ConclusionInfectious causes for non-idiopathic FP like VZV reactivation and Lyme disease had best probability for complete recovery. Post-surgery FP had a worse prognosis.Level of evidence2

Simultaneous VZV and HSV-1 Reactivation after Minor Head Injury.

An 81-year-old patient presented to the emergency department with a dark lesion on his forehead and swelling of his left eye, 3 days after a minor forehead injury and skin laceration. He also showed singular papules on his chin, upper chest, upper arms and back, later evolving into vesicles. Polymerase-chain reaction testing of vesicle content was positive for VZV and HSV-1, confirming a diagnosis of disseminated cutaneous herpes virus infection and concomitant HSV-1 reactivation. Antiviral and antibiotic treatment was initiated for 1 week with an immediate response. This case report highlights the association of head trauma and subsequent reactivation of VZV in patients at risk. Simultaneous reactivation of HSV-1 and VZV is rare in immunocompetent patients.LEARNING POINTSMinor trauma can cause VZV and HSV reactivation.Consider herpes virus reactivation in case of unclear rash; the appearance of vesicles can be delayed for a few days.Screen for immunodeficiency disorders in disseminated herpes virus infection; if non-apparent, close monitoring is recommended.

No Association Between DAA Treatment for HCV Infection and Herpes Zoster Infection in Analysis of Data From 37 Clinical Trials

Recent case series and retrospective studies have raised concerns that patients who receive direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection are at increased risk of developing varicella-zoster virus infection (VZV reactivation). We investigated the relationship between DAA treatment and VZV reactivation by analyzing pooled participant-level data from 37 clinical trials of DAA agents. We obtained demographic, adverse event, and laboratory data from 13,816 participants in 37 clinical trials submitted to the Food and Drug Administration for approval of DAA agents for treatment of HCV infection. Participants received DAAs (n = 12,249), placebo (n = 997), pegylated interferon (n = 243), or a combination of DAAs and pegylated interferon (n = 327). Occurrence of VZV reactivation was identified using systematically reported adverse event data. HCV virologic response was evaluated by measurement of HCV RNA. VZV reactivation occurred in 9.9 cases per 1000 person-years of DAA treatment (95% CI, 6.8-14.0 per 1000 person years) and 13.8 cases per 1000 person-years of placebo (95% CI, 3.5-37.5 per 1000 person years). No participants in the pegylated interferon or combination DAA and pegylated interferon groups experienced VZV reactivation. Within the placebo-controlled trials there was no significant difference in VZV reactivation between DAA treatment and placebo. VZV reactivation was associated with age older than 40 years, female sex, and HIV coinfection. We did not find an association between time of virologic response and time to VZV reactivation. In an analysis of data from 37 trials, we found no evidence for an association between DAA treatment for HCV infection and increased risk of VZV reactivation.

An adult co-presented with varicella and herpes zoster caused by varicella zoster virus genotype J, China: a case report

BackgroundVaricella zoster virus (VZV) causes varicella primarily in childhood, and some rare adults also report varicella. Herpes zoster mainly occurs in adults by endogenous reactivation of latent VZV. Until now, varicella and herpes zoster have seldom been reported simultaneously in one patient. Here, we report a rare case co-presenting with varicella and herpes zoster in a Chinese adult.Case presentationA 44-year-old Chinese man suffered papules and vesicles with pain on the left ear. Five days after onset, he was admitted to the Department of Dermatology of The Third Hospital of Xiamen. Physical examination revealed that small vesicles surrounded by erythema had developed on his trunk, back and neck, and unilateral papules and vesicles in ribbons had also developed on the left ear. This patient was excluded from human immunodeficiency virus and Treponema pallidum infections by ELISA antibody tests. Laboratory tests revealed that the ratio of eosinophils (0.1%) and eosinophil count (0.0 × 109/L) were significantly downregulated. Treatment with valacyclovir, ebastine, mecobalamine, pregabalin and calamine lotion for 5 days was effective therapy for varicella and herpes zoster. Polymerase chain reaction for vesicular fluids from varicella and herpes zoster was positive for VZV, and further phylogenetic analysis and single nucleotide polymorphism variations confirmed that the VZV genotype was type J (clade 2).ConclusionsThis rare case highlights awareness of varicella and herpes zoster caused by VZV infection in adults. Our report provides novel insight into the rare clinical presentation of VZV genotype J.

A microneedle vaccination with glycoprotein E of Varicella Zoster Virus elicits antibody production and polyfuctional T cells in mice

Abstract A microneedle has several benefits in that it is painless, easy to use and preventable from potential cross-contamination by using conventional needle. Besides these advantages, vaccination with microneedle may provide comparable or even higher immune response than vaccination through conventional intramuscular route. Here we have been developing herpes zoster vaccine using microneedle coated with recombinant glycoprotein E (gE) of VZV, which is essential in virus replication and cell-to-cell spread. Microneedles were coated by gE and three different adjuvants: double-mutant heat-labile toxin (dmLT), the combination of TLR1/2 and TLR3 ligands (Lpampo), or mutant cholera toxin A subunit (CTA). C57BL/6 mice were immunized with the coated microneedles two times at 2-week intervals. The overall increase in gE specific antibody titers was observed among adjuvanted groups compare to the non-adjuvanted group. Moreover, the humoral response was IgG1-dominated. Hence, a decreasing tendency of IgG1/IgG2c ratio was observed in gE adjuvanted with dmLT or Lpampo groups whereas relatively high ratio was detected in CTA group. This indicates that Th1 immune response complemented Th2 response in former groups. By conducting ELISPOT, we measured the amount of IFN-gamma secreting T cells as cell-mediated immune response is significant in immunogenicity of HZ vaccination. Moreover, polyfunctional CD4 T cells were increased after injection with gE +Lpampo coated microneedle. In consistent with humoral response, dmLT or Lpampo adjuvanted group exhibited enhanced cell-mediated immune response. Taken together, delivery of HZ subunit vaccine with microneedle may provide a potent immune response against reactivation of VZV.

Development of HHV-6-Specific Immunity after Cord Blood Transplantation in Adults Depends on Reconstitution of Thymopoiesis and Regeneration of CD4+ T Cells

The treatment of hematological malignancies with umbilical cord blood transplantation (UCBT) is rapidly increasing for adult patients. Disadvantages of UCBT include insufficient cell numbers for adult patient reconstitution, a lack of antigen experienced cells, and deficits in T cell signal transduction mechanisms. Consequently, UCBT is frequently associated with impaired immune function and high infection-related mortality. To counter these difficulties, transplantation with two UCB units has been employed to improve immune reconstitution in adult patients. We evaluated both the quantitative and functional reconstitution of cellular immunity in a group of adult patients undergoing UCBT. Thirty-two patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by infusion with two sequential UCB grafts and GvHD prophylaxis with tacrolimus and sirolimus. The grafts were at least a 4/6 match with each other and the recipient. Here we report the results of 27 patients who have completed at least one year of follow up. Assessments were done prior to transplant and at various time intervals until 12 months post UCBT. Neutrophil and platelet engraftment occurred at a median of 21 days and 42 days, respectively. CD3+ populations remained severely depressed until 8 wks post-transplant when they gradually began to re-emerge. However the CD4+ and CD8+ populations demonstrated distinctly different reconstitution kinetics. At 6 months the median value of absolute numbers of CD4+ lymphocytes was 35% of pre-transplant levels increasing to 42% at 1 yr post-transplant, a median value far below the normal range for adults. In contrast, at 6 months post-transplant CD8+ lymphocytes remained severely depressed to 12% of pre-transplant levels, but dramatically increased and reached normal levels by 1 yr after UCBT. Interestingly, both the CD14+ monocyte and the CD16+CD56+ NK cell populations expanded dramatically at 4 wks post-transplant and reached pre-transplant levels and were within the normal range by 6 months. CD20+ B cell repopulation began at 8 wks post-transplant, displayed a striking expansion leading to a 17-fold increase in the median value for B cell numbers over pre-transplant values at 1 year and resulting in a median value of absolute numbers near the top of the normal range. To evaluate functional T cell immune reconstitution in vivo, we performed IFN-γ ELISpot analysis on CMV stimulated PBLs and compared the results to a PCR-based assay for CMV viremia. Additionally, we assessed the reconstitution of thymopoiesis with the T cell receptor excision circle (TREC) assay and real-time PCR. 16/27 patients and 26/52 UCB products were CMV seropositive prior to transplant. In the post-UCB period, development of CMV-specific effectors as determined by ELISpot did not always correlate with clearance of CMV viremia. Specifically, prior to 8 weeks post-UCBT, 8 out of 12 (67%) patients with CMV-positive ELISpot displayed CMV viremia, between 8 weeks and 100 days post-UCBT 4 out of 11 (36%) patients with CMV-positive ELISpot displayed CMV viremia and after 100 days post-UCBT only 3 out of 10 patients (30%) who developed CMV-positive ELISpot remained positive for CMV viremia. Identification of functional CMV effectors was only associated with the numbers of CD8+CD45RA+ cells (p=0.01) and the development of high TREC concentrations (p=0.01) that were detected after 6 months of UCBT, and was independent of GvHD or mixed chimerism. Taken together these results indicate that reconstitution of T cell immunity after UCBT is characterized by delayed recovery of CD4+ and CD8+ T cells and correlates with reconstitution of thymopoiesis and increase of naive CD8+CD45RA+ T cells that can develop into efficient pathogen-specific effectors.

Herpes Zoster Eruption in an Otherwise Healthy Child: A Case Report

Varicella-zoster virus (VZV; human herpesvirus 3) is a herpesvirus that causes infection in humans. The reactivation of latent VZV manifests as herpes zoster or shingles. In immunocompetent children, reactivation is rare, as increasing age is the most common risk factor for reactivation. The complications of infection include post-herpetic neuralgia and neurological sequelae as well as a bacterial infection of the crusted skin. We present a case of an otherwise healthy 13-year-old child with herpes zoster and multiple risk factors, who was managed successfully, in order to expand the limited literature. The patient presented with a painful vesicular rash, which appeared as multiple grouped vesicles on an erythematous base spreading over the right half of the face. The diagnosis of herpetic (varicella) vesiculobullous dermatitis was confirmed by biopsy and the patient was started on acyclovir and clindamycin with gradual improvement and resolution of his symptoms. Reactivation of VZV is considered a consequence of decreased cell-mediated immunity. However, the reason for reactivation in immunocompetent children remains unclear. In the present case, the patient may have become exposed in utero, through vaccination, or as a result of major facial trauma sustained at the age of six years.

Hepatitis C virus and cumulative infections are associated with atherogenic cardiovascular events in HIV-infected subjects

Objectivesto analyze the association between HCV coinfection and cumulative infections with the development of a cardiovascular disease in HIV-infected subjects. MethodsHIV-infected subjects attended at Virgen del Rocio University Hospital, between January 1982 and March 2018, were considered if fulfilled the following criteria: at least two visits to the HIV clinic, clinical records with data about VZV reactivation and bacterial infections, available data on HCV coinfection status. Atherogenic cardiovascular events were registered. To analyze factors associated with the development of cardiovascular event, a logistic regression analysis was performed. Results823 subjects were included in the study. During the observational period, 58/823 (7.05%) developed a cardiovascular event. Advanced age at HIV-1 diagnosis, a low T-CD4 nadir, HCV coinfection and the burden of infections were independently associated with the risk of developing a cardiovascular event, apart from lipid levels and diabetes. Conclusionsboth HCV and the burden of infections are associated with an increased risk of cardivascular event in HIV-infected patients, together with other cardiovascular risk factors. Therapeutic strategies such as HCV erradication or VZV immunization could ameliorate cardiovascular risk in these subjects.

Reactivation of Simian Varicella Virus in Rhesus Macaques after CD4 T Cell Depletion.

Rhesus macaques intrabronchially inoculated with simian varicella virus (SVV), the counterpart of human varicella-zoster virus (VZV), developed primary infection with viremia and rash, which resolved upon clearance of viremia, followed by the establishment of latency. To assess the role of CD4 T cell immunity in reactivation, monkeys were treated with a single 50-mg/kg dose of a humanized monoclonal anti-CD4 antibody; within 1 week, circulating CD4 T cells were reduced from 40 to 60% to 5 to 30% of the total T cell population and remained low for 2 months. Very low viremia was seen only in some of the treated monkeys. Zoster rash developed after 7 days in the monkey with the most extensive CD4 T cell depletion (5%) and in all other monkeys at 10 to 49 days posttreatment, with recurrent zoster in one treated monkey. SVV DNA was detected in the lung from two of five monkeys, in bronchial lymph nodes from one of the five monkeys, and in ganglia from at least two dermatomes in three of five monkeys. Immunofluorescence analysis of skin rash, lungs, lymph nodes, and ganglia revealed SVV ORF63 protein at the following sites: sweat glands in skin; type II cells in lung alveoli, macrophages, and dendritic cells in lymph nodes; and the neuronal cytoplasm of ganglia. Detection of SVV antigen in multiple tissues upon CD4 T cell depletion and virus reactivation suggests a critical role for CD4 T cell immunity in controlling varicella virus latency.IMPORTANCE Reactivation of latent VZV in humans can result in serious neurological complications. VZV-specific cell-mediated immunity is critical for the maintenance of latency. Similar to VZV in humans, SVV causes varicella in monkeys, establishes latency in ganglia, and reactivates to produce shingles. Here, we show that depletion of CD4 T cells in rhesus macaques results in SVV reactivation, with virus antigens found in zoster rash and SVV DNA and antigens found in lungs, lymph nodes, and ganglia. These results suggest the critical role of CD4 T cell immunity in controlling varicella virus latency.

VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs

BackgroundVaricella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells.MethodsCD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro.ResultsUnlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05).ConclusionsDespite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation.