Reactivation Of Latent Virus Research Articles

Ramsay hunt syndrome: case report

Ramsay-Hunt Syndrome is an uncommon disease caused by the reactivation of latent Varicella zoster virus in the geniculate ganglion. It is characterized with a herpes zoster oticus associated with an acute peripheral facial nerve paralysis, and possible other cranial nerve lesions. We describe the case of a 27-year-old man who presented with severe ear pain for two days, with vesicular eruptions on the external ear and ipsilateral peripheric facial paralysis. He was treated with the association of intravenous steroids and acyclovir for 7 days. The evolution showed gratifying results. The one-year follow-up showed no relapse of the syndrome. The purpose of this report is to highlight the importance of a thorough clinical examination and early treatment of the Ramsay-Hunt syndrome.

Mollaret's Meningitis: CSF Cytology to the Rescue

Mollaret's meningitis refers to the classical description by Pierre Mollaret of recurrent episodes of fever and meningism lasting 2-5 days, followed by spontaneous recovery. It remains a rare entity and most often is attributed to reactivation of latent Herpes Simplex virus (HSV)-2 virus. Though considered self-limiting and innocuous, there are exceptional cases in which neurological sequelae have been reported. From a clinician's perspective, narrowing down the diagnosis may not be straightforward and would require judicious use of investigations. Here we report two cases of Mollaret's meningitis, both of whom had negative cerebrospinal fluid (CSF) polymerase chain reaction (PCR) for HSV. These reports also highlight an unusual pattern of presentation of this rare entity and the utility of CSF cytology in clinching the diagnosis.

CMV-encoded GPCR pUL33 activates CREB and facilitates its recruitment to the MIE locus for efficient viral reactivation.

Human cytomegalovirus (HCMV) establishes life-long latent infection in hematopoietic progenitor cells and circulating monocytes in infected individuals. Myeloid differentiation coupled with immune dysregulation leads to viral reactivation, which can cause severe disease and mortality. Reactivation of latent virus requires chromatin reorganization and the removal of transcriptional repressors in exchange for transcriptional activators. While some factors involved in these processes are identified, a complete characterization of the viral and cellular factors involved in their upstream regulation remains elusive. Herein, we show the HCMV-encoded G protein-coupled receptor (GPCR), UL33, is expressed during latency. Although this viral GPCR is not required to maintain latent infection, our data reveal UL33-mediated signaling is important for efficient viral reactivation. Additionally, UL33 signaling induces cellular cyclic AMP response element binding protein (CREB1, referred to here as CREB) phosphorylation, a transcription factor that promotes reactivation when recruited to the major immediate early (MIE) enhancer/promoter. Finally, targeted pharmacological inhibition of CREB activity reverses the reactivation phenotype of the UL33 signaling-deficient mutant. In sum, our data reveal UL33-mediated signaling functions to activate CREB, resulting in successful viral reactivation.

A novel murine model of differentiation-mediated cytomegalovirus reactivation from latently infected bone marrow haematopoietic cells.

CD34+ myeloid lineage progenitor cells are an important reservoir of latent human cytomegalovirus (HCMV), and differentiation to macrophages or dendritic cells (DCs) is known to cause reactivation of latent virus. Due to its species-specificity, murine models have been used to study mouse CMV (MCMV) latency and reactivation in vivo. While previous studies have shown that MCMV genomic DNA can be detected in the bone marrow (BM) of latently infected mice, the identity of these cells has not been defined. Therefore, we sought to identify and enrich for cellular sites of MCMV latency in the BM haematopoietic system, and to explore the potential for establishing an in vitro model for reactivation of latent MCMV. We studied the kinetics and cellular characteristics of acute infection and establishment of latency in the BM of mice. We found that while MCMV can infect a broad range of haematopoietic BM cells (BMCs), latent virus is only detectable in haematopoietic stem cells (HSCs), myeloid progenitor cells, monocytes and DC-enriched cell subsets. Using three separate approaches, MCMV reactivation was detected in association with differentiation into DC-enriched BMCs cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) followed by lipopolysaccharide (LPS) treatment. In summary, we have defined the kinetics and cellular profile of MCMV infection followed by the natural establishment of latency in vivo in the mouse BM haematopoietic system, including the haematopoietic phenotypes of cells that are permissive to acute infection, establish and harbour detectable latent virus, and can be stimulated to reactivate following DC enrichment and differentiation, followed by treatment with LPS.

HIV-1 Latency and Latency Reversal: Does Subtype Matter?

Cells that are latently infected with HIV-1 preclude an HIV-1 cure, as antiretroviral therapy does not target this latent population. HIV-1 is highly genetically diverse, with over 10 subtypes and numerous recombinant forms circulating worldwide. In spite of this vast diversity, much of our understanding of latency and latency reversal is largely based on subtype B viruses. As such, most of the development of cure strategies targeting HIV-1 are solely based on subtype B. It is currently assumed that subtype does not influence the establishment or reactivation of latent viruses. However, this has not been conclusively proven one way or the other. A better understanding of the factors that influence HIV-1 latency in all viral subtypes will help develop therapeutic strategies that can be applied worldwide. Here, we review the latest literature on subtype-specific factors that affect viral replication, pathogenesis, and, most importantly, latency and its reversal.

Salivary antimicrobial proteins and stress biomarkers are elevated during a 6-month mission to the International Space Station.

As the international space community plans for manned missions to Mars, spaceflight-associated immune dysregulation has been identified as a potential risk to the health and safety of the flight crew. There is a need to determine whether salivary antimicrobial proteins, which act as a first line of innate immune defense against multiple pathogens, are altered in response to long-duration (>6 mo) missions. We collected 7 consecutive days of whole and sublingual saliva samples from eight International Space Station (ISS) crewmembers and seven ground-based control subjects at nine mission time points, ~180 and ~60 days before launch (L-180/L-60), on orbit at flight days ~10 and ~90 (FD10/FD90) and ~1 day before return (R-1), and at R+0, R+18, R+33, and R+66 days after returning to Earth. We found that salivary secretory (s)IgA, lysozyme, LL-37, and the cortisol-to-dehydroepiandrosterone ratio were elevated in the ISS crew before (L-180) and during (FD10/FD90) the mission. "Rookie" crewmembers embarking on their first spaceflight mission had lower levels of salivary sIgA but increased levels of α-amylase, lysozyme, and LL-37 during and after the mission compared with the "veteran" crew who had previously flown. Latent herpesvirus reactivation was distinct to the ~6-mo mission crewmembers who performed extravehicular activity ("spacewalks"). Crewmembers who shed at least one latent virus had higher cortisol levels than those who did not shed. We conclude that long-duration spaceflight alters the concentration and/or secretion of several antimicrobial proteins in saliva, some of which are related to crewmember flight experience, biomarkers of stress, and latent viral reactivation.NEW & NOTEWORTHY Spaceflight-associated immune dysregulation may jeopardize future exploration-class missions. Salivary antimicrobial proteins act as a first line of innate immune defense. We report here that several of these proteins are elevated in astronauts during an International Space Station mission, particularly in those embarking on their first space voyage. Astronauts who shed a latent herpesvirus also had higher concentrations of salivary cortisol compared with those who did not shed. Stress-relieving countermeasures are needed to preserve immunity and prevent viral reactivation during prolonged voyages into deep space.

Long-Term Experience with Large Granular Lymphocytic Leukemia Evolving after Solid Organ and Hematopoietic Stem Cell Transplantation

T-cell large granular lymphocyte leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGLL mainly manifest in elderly and is associated with autoimmune diseases including rheumatoid arthritis (RA), B cell dyscrasias, non-hematologic cancers and immunodeficiency (e.g., hypogammaglobulinemia). LGL manifestations often resemble reactive immune processes leading to the dilemmas that LGLs act like CTL expansion during viral infections (for example EBV associated infectious mononucleosis). While studying a cohort of 246 adult patients with T-LGLL seen at Cleveland Clinic over the past 10 years, we encountered 15 cases of overt T-LGLL following transplantation of solid organs (SOT; n=8) and hematopoietic stem cell transplantation (HSCT; n=7). Although early studies reported on the occurrence of LGL post-transplant, these studies focused on the analysis of oligoclonality skewed reactive CTL responses rather than frank T-LGLL. We aimed to characterize post-transplantation T-LGLL in SOT and HSCT simultaneously and compare them to a control group of 231 de novo T-LGLL (cases with no history of SOT or HSCT). To characterize an unambiguous "WHO-defined T-LGLL" we applied stringent and uniform criteria. All cases were diagnosed if 3 out of 4 criteria were fulfilled, including: 1) LGL count >500/µL in blood for more than 6 months; 2) abnormal CTLs expressing CD3, CD8 and CD57 by flow cytometry; 3) preferential usage of a TCR Vβ family by flow cytometry; 4) TCR gene rearrangement by PCR. In addition, targeted deep sequencing for STAT3 mutations was performed and charts of bone marrow biopsies were reviewed to exclude other possible conditions. Diagnosis was made 0.2-27 yrs post-transplantation (median: 4 yrs). At the time of T-LGLL diagnosis, relative lymphocytosis (15-91%), T lymphocytosis (49-99%) and elevated absolute LGL counts (>500 /µL; 93%) were also seen. Post-transplantation T-LGLL were significantly younger than de novo T-LGLL, (median age: 48 vs. 61 yr; P<.0001). Sixty% of post-transplantation T-LGLL patients were males. Fifteen% of patients had more cytogenetic abnormalities compared to de novo T-LGLL, had a lower absolute LGL count (median: 4.5 vs. 8.5 k/µL) and had less frequent neutropenia, thrombocytopenia and anemia (27 vs. 43%, 33 vs. 35% and 20% vs. 55%; P=.01). TCR Vb analysis identified clonal expansion of ≥1 of the Vb proteins in 60% (n=9) of the patients; the remaining 40% (n=6) of the cases had either a clonal process involving a Vb protein not tested in the panel (20%; n=3) or no clear expansion (20%; n=3). Signs of rejection were observed in 20% (n=3/15) and GvHD in 13% (n=2/15) of the patients. Post-transplantation, 27% of cases presented with neutropenia (absolute neutrophil count <1.5 x109/L; n=4), 33% with thrombocytopenia (platelet count <150 x109/L; n=5) and 25% with anemia (hemoglobin <10 g/dL; n=3). T-LGLL evolved in 10 patients (67%; 10/15) despite IST including cyclosporine (n=5), tacrolimus (n=4), mycophenolate mofetil (n=5), cyclophosphamide (n=1), anti-thymocyte globulin (n=1), and corticosteroids (n=6). Lymphadenopathy and splenomegaly were seen in 13% (n=2) and 33% (n=5) of the patients. Other conditions observed were MGUS (20%; n=3) and RA (7%; n=1). Conventional cytogenetic showed normal karyotype in 89% (n=11, tested individuals 13/15). Somatic STAT3 mutations were identified in 2 patients. Sixty% of cases (n=9) were seropositive for EBV when tested at different time points after transplant. Similarly, 53% (n=8) were seropositive for CMV, of which, 5 were positive post-transplantation and 3 pre-/post-transplantation. The complexity of T-LGLL expansion post-transplantation might be due to several mechanisms including active viral infections, latent oncogenic viral reactivation and graft allo-antigenic stimulation. However, in our cohort graft rejection or GvHD was encountered in a few patients (2 allo-HSCT recipients). Autoimmune conditions were present in 50% of SOT recipients (n=4/ 8, including RA, ulcerative colitis, systemic lupus erythematosus). Some of our patients also had low immunoglobulin levels. Overt EBV (post-transplant lymphoproliferative disorder) and CMV reactivation was diagnosed in only 27% (4/15) of the patients. In sum we report the long term follow up of a cohort of T-LGLL and emphasize the expansion of T-LGLL post-transplant highlighting the difficulty in assigning one unique origin of LGLL. Disclosures Hill: Genentech: Consultancy, Research Funding; Takeda: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria; Amgen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria. Majhail:Atara Bio: Consultancy; Mallinckrodt: Honoraria; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Incyte: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Protein inhibitor of activated STAT1 (PIAS1) inhibits IRF8 activation of Epstein-Barr virus lytic gene expression

Epstein-Barr virus (EBV), a major human oncogenic pathogen, establishes life-long persistent infections. In latently infected B lymphocytes, the virus persists as an episome in the nucleus. Periodic reactivation of latent virus is controlled by both viral and cellular factors. Our recent studies showed that interferon regulatory factor 8 (IRF8) is required for EBV lytic reactivation while protein inhibitor of activated STAT1 (PIAS1) functions as an EBV restriction factor to block viral reactivation. Here, we show that IRF8 directly binds to the EBV genome and regulates EBV lytic gene expression together with PU.1 and EBV transactivator RTA. Furthermore, our study reveals that PIAS1 antagonizes IRF8/PU.1-mediated lytic gene activation through binding to and inhibiting IRF8. Together, our study establishes IRF8 as a transcriptional activator in promoting EBV reactivation and defines PIAS1 as an inhibitor of IRF8 to limit lytic gene expression.

2304. Incidence and Risk Factors for Herpes Zoster among Diabetes Patients at Siriraj Hospital; Results from a 10-year Cohort

BackgroundHerpes Zoster (HZ) is the reactivation of latent varicella-zoster virus. Diabetes Mellitus (DM) is one of well-known risk factors for HZ. Nowsday, the knowledge on the incidence of and risk factors for HZ among Thai DM patients is limited.MethodsWe conducted a nested case–control study of DM patients who attended the Siriraj DM clinic for ≥6 consecutive months during 2005–2014. Eligible subjects were identified through the DM clinic registry database (n = 1,427). Cases were those who had ≥1 episode of HZ while controls were those without evidence of HZ during the study period. We captured 40 cases and randomly sampled 175 controls (1 case: 4 controls). All data were obtained via chart-review, the ICD-10, pharmacy and laboratory databasesResultsDuring the 10-year study period, the cumulative incidence and the incidence rate of HZ were 0.28% [95% CI: 0.20–0.38%] and 3.96 [95% CI: 2.90–5.28] per 1,000 person-years. The most common sites were trunk (27.5%), followed by herpes opthalmicus (22.5%). Thirty-five percent had post-herpetic neuralgia and only 1 case required hospitalization. Independent risk factors for HZ [adjusted odd ratio; 95% CI; P-value] identified from multivariate analysis included underlying hypertension [3.48; 1.28–9.43; P = 0.01], number of hypoglycemic drug used [1.46; 1.03–2.08; P = 0.04] and previous use of herbal remedies [3.83; 1.06–13.84; P = 0.04]. Furthermore, higher body mass index was an independent protective factor [0.89;0.81–0.98; P = 0.02].ConclusionThe incidence rate of HZ among DM patients at our institute was comparable to other Asian countries. Risk factors for HZ can be used to identify patients who would benefit the most from preventive interventions.Disclosures All authors: No reported disclosures.

Ultrasound-guided Erector Spinae Plane Block for the Management of Herpes Zoster Pain: Observational Study.

BackgroundHerpes zoster is caused by the reactivation of latent varicella-zoster virus, which promotes acute and chronic pain that may interfere with daily activities and reduce the quality of life. Ultrasound-guided erector spinae plane (ESP) blocks are used for a wide variety of indications in the management of acute, chronic, and postoperative pain. Our aim was to evaluate the efficacy of ultrasound-guided erector spinae plane blocks for the management of pain in herpes zoster.MethodsThe medical records of 34 patients with acute or chronic pain during herpes zoster between May 2017 and June 2018 were investigated at two pain clinic centers. The patients received ultrasound-guided erector spinae plane block: We performed a single injection for the patients having acute pain and a continuous block for the patients having chronic pain. Patient characteristics, block characteristics (needle insertion level, catheter, or single insertion), the volume of given local anesthetics, the intensity of pain before and after the block procedure using a numerical rating score (NRS) between 0 and 10, and the duration of analgesia were evaluated.ResultsAll patients reported a remarkable and rapid resolution of pain immediately after the block procedure. Median (min-max) NRS score before the block procedure was 9 (4-10). The median (min-max) NRS score was 1.5 (0-7) after the block procedure. The difference was found to be statistically significant (p<0.0001). NRS score after the third month was 1 (0-3); the difference is statistically significant (p=0.002). The median value of analgesia time (min-max) was 18 (3-24) hours.ConclusionOur preliminary experience demonstrated that an ESP block provided sufficient analgesia in acute herpetic pain. A combination of ESP block, pregabalin, and tramadol was also effective within the three-months-period after the block performance.

A RARE CASE OF SHINGLES WITH PERSISTENT SINGULTUS AND RESPIRATORY FAILURE

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Herpes zoster, also known as shingles, occurs after reactivation of latent varicella-zoster virus in sensory ganglia. There have been few cases reporting intractable singultus as a complication of shingles; however, none has reported a patient such as ours who presented with intractable hiccups along with hematemesis and acute hypoxic and hypercapneic respiratory failure. CASE PRESENTATION: A 53 year old Caucasian male with a history of Hypertension, GERD, and a recent episode of shingles presented to the ED with a 3 day history of worsening persistent singultus. Five days prior, he developed burning back pain followed by an eruption of a herpetiform rash along the T4-T5 dermatome on the right thorax. He was diagnosed with shingles and started on oral valacyclovir. Two days later, he developed progressively intense paroxysmal hiccup attacks with associated dyspnea and retching that was unresponsive to chlorpromazine. In the ED, he denied URI symptoms, recent travel, neurological deficits, trauma, or recent surgeries. On physical exam, he was afebrile and had a vesicular rash overlying the anteroposterior thorax along the T4-T5 dermatome. He had no electrolyte abnormalities. In the ER, he was started on intravenous acyclovir for herpes zoster; however, the hiccups were refractory to haloperidol, metoclopramide, and lorazepam. After several hours, he became encephalopathic, had hematemesis, and was subsequently intubated and placed on mechanical ventilation for acute hypoxic and hypercapneic respiratory failure. The hiccups terminated when he was sedated. Upon extubation the next day, the singultus resolved. The remainder of the hospital course was uneventful and he was discharged after a couple of days. DISCUSSION: Hiccups represent an involuntary spasmodic contraction of the diaphragm followed by rapid closure of the vocal cords involving the reflex arc and are rarely persistent. Potential causes of persistent singultus include infections, metabolic abnormalities, or structural disorders that irritate the branches of the vagus nerve, phrenic nerve, or the CNS. Treatment of hiccups is aimed at symptomatic relief and addressing the underlying cause. Physical maneuvers such as Valsalva can be initiated as empiric treatment. Pharmacological therapies include chlorpromazine, metoclopramide and muscle relaxants. Persistent hiccups due to Herpes Zoster have only been reported in exceptional few cases. In all previously reported cases, none had persistent hiccups associated with hypoxic and hypercapneic respiratory failure and hematemesis secondary to the retching effect of persistent singultus as a result of herpes zoster as which occurred in our patient. CONCLUSIONS: Physicians should closely monitor the respiratory status of patients who present with persistent singultus in the setting of shingles. Reference #1: Brooks WDW. Zoster, hiccup and varicella. Br Med J 1931;2:298-9 Reference #2: Efrati P. Obstinate hiccup as a prodromal symptom in thoracic herpes zoster. Neurology 1956;601-2 Reference #3: Berlin AL, Muhn CY, Billick RC. Hiccups eructation, and other uncommon prodromal manifestations of herpes zoster. J Am Acad Dermatol 2003;49:1121-4 DISCLOSURES: No relevant relationships by Abilio Arrascaeta Llanes, source=Web Response No relevant relationships by Nikita Cadet, source=Web Response No relevant relationships by Edison Gavilanes, source=Web Response No relevant relationships by Hao kee Ho, source=Web Response No relevant relationships by Princess Mark-Adjeli, source=Web Response No relevant relationships by Zubin Tharayil, source=Web Response

The Detection and Characterization of Herpes Simplex Virus Type 1 in Confirmed Measles Cases

Based on measles surveillance in Shanghai, People’s Republic of China, from 2006 to 2015, we found that measles virus isolates from 40 throat swab samples exhibited atypical cytopathic effects in Vero/hSLAM cells, which was found to be a result of coinfection with measles virus (MeV) and human herpes simplex virus type 1 (HSV-1). Serological and molecular approaches were used to confirm and characterize the coinfections in these patients. Among the 40 measles cases, measles-specific IgM was detected in 37 cases, while measles-specific IgG was detected in 27 cases. HSV-1-specific IgM and IgG were detected in 7 and 34 cases, respectively, suggesting that most of the MeV infections were primary, but that HSV-1 infection was due to the reactivation of latent virus in most cases. The titers of HSV-1 IgG in patients with either measles or measles-HSV-1 coinfection were significantly higher than those in the healthy group (P = 0.0026 and P < 0.0001, respectively); however, there was no significant difference in the titers of HSV-1 IgG in the MeV and MeV-HSV-1 coinfection patients (P = 0.105). Nucleic acids from MeV and HSV-1 were detected in 40 and 39 throat swabs, respectively. Twenty five MeV RNA sequences were genotyped, and all represented genotype H1, which is the endemic genotype in China. Sequences from the glycoprotein G gene of HSV-1 were used to classify the isolates into two distinct phylogenetic groups: 34 belonged to group A and 3 belonged to group B.

American Journal of Transplantation: Volume 19, Number 9, September 2019

On the Cover: This month, AJT presents numerous articles addressing infectious diseases, particularly as they relate to one another and the numerous biological changes associated with clinical transplantation. Zhang et al (page 2421) present a novel model associating CMV reactivation with ischemia–reperfusion injury and a “second hit” of immunosuppression that facilitates latent viral reactivation. Similarly, L'Huillier et al (page 2495) nicely relate CMV to blunted toll-like receptor activation, and through this, an altered response to many other infectious pathogens. Also, see articles by Reischig et al (page 2457), Anesi et al (page 2468) and Giménez et al (page 2479) for studies relating our therapeutic approaches toward infection, namely antiviral prophylaxis and antibiotic exposure, to subsequent infectious disease risk. Several thoughtful editorials provide broader perspectives on these articles, and many others, all addressing the perennial challenges of infectious risk in transplant patients. Also, Al Ammary et al (page 2614) describe an emerging trend of decreasing living related donation in the face of increasing unrelated donation. Cover design by Megan Llewellyn, Duke University Department of Surgery.

MON-168 A CASE REPORT OF HUMAN PARVOVIRUS B19 INFECTION IN A RENAL TRANSPLANT PATIENT

Anaemia after kidney transplant has been linked to infection by Parvovirus (PV) B19. Organ transplant patients can have the B19 virus persisting for years due to impairment of the neutralizing antibody response and/or cellular immunity. Up to 39% of kidney transplant (KT) recipients suffer from chronic anaemia. They may acquire symptomatic PV B19 infection from the donor, the community or from reactivation of endogenous latent or persistent virus. PV B19 infection in KT recipients tend to occur within a 6-month period after transplantation when the immuno-suppression (IS) is at the strongest. This case report describes a 49 year old Malay lady who has End Stage Renal Disease secondary to Systemic Lupus Erythematosus. She was on haemodialysis for 17 years before a deceased donor renal transplant in November 2017. Thymoglobulin was used as her induction agent and maintained with mycophenolate sodium (Myfortic) at 360 mg bd, tacrolimus and prednisolone. Her tacrolimus level ranges from 8 to 10 ng/ml. Her baseline haemoglobin (Hb) prior to the renal transplant was 9.7 g/dL. Post operation Hb ranging from 8.5 to 9 g/dL. Iron studies showed adequate iron stores with ferritin and transferrin saturation level of 770ug/L and 93% respectively. There was no evidence of hemolysis and the reticulocyte was 0.19%. Subcutaneous(SC) erythropoietin stimulating agent ( ESA) was started 2 weeks post operation to maintain her Hb level. Despite regular SC ESA injection, her Hb level did not improve and dropped 6 weeks after the operation and became pancytopenia. Her serum creatinine was 180 umol/L. SLE activity markers were negative . Pre-transplant immunoglobulin G (IgG) studies showed positivity to Cytomegalovirus (CMV). For the next 4 months, she required 3 to 4 pints of Red Blood Cells (RBC) transfusions monthly. Oesophagogastroduodenoscopy(OGDS) showed gastric erosion only. CMV PCR sent repeatedly were negative. In May 2018, Parvovirus PCR was found to be positive with positive IgG and negative IgM level. Bone marrow aspiration and trephine (BMAT) showed normo-cellular marrow spaces. Granulopoiesis was present with all stages of maturation seen. Megakaryocytes was morphologically unremarkable. Erythropoieisis was preserved. There were a few intranuclear inclusions seen. The intranuclear inclusions were suggestive of Parvovirus infection ( Figure 1). She received intravenous immunoglobulin (IVIg) with 2g/kg in total. Her Hb level was successfully maintained above 10g/dL without further RBC transfusion. WCC and platelet counts also normalized. Her immunosuppression was changed to combination of everolimus, tacrolimus and prednisolone. Parvovirus PCR in June and July 2018 were consequently negative. In October 2018 her Hb level started to drop again. Repeated Parvovirus PCR taken was positive and she was given IVIg again and responded to treatment. She was discharged to her hometown hospital with close monitoring of Parvovirus PCR and Hb level. Figure 1: Intranuclear inclusions in BMAT This case report suggests the importance of including parvovirus B19 infection in the differential diagnosis of persistent anaemia in organ transplant patients and the need to monitor the PCR closely for reactivation and the role of IVIg with reduced IS as part of the management.

Viral Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Literature Review

Hematopoietic stem cell transplant (HSCT) recipients are at an increased risk of bacterial, viral, fungal and parasitic infections. Past exposures to infections, the degree of immunosuppression, prolonged neutropenia and presence of graft versus host disease (GVHD) are some of the factors which make HSCT recipients more susceptible to infections. Viral infections have emerged as a major challenge causing high morbidity and mortality in stem cell transplant recipients. Myeloablative conditioning regimens and GVHD prevention strategies which may delay immune reconstitution and serologic status of donors and recipients affect the incidence of viral infections. Community-acquired respiratory and gastrointestinal viral infections like respiratory syncytial virus, rhinovirus adenovirus, influenza, norovirus and reactivation of latent viruses like herpes simplex virus, cytomegalovirus (CMV) are some of the important pathogens increasing the morbidity and mortality in transplant recipients. Clinical manifestations range from asymptomatic carriage to severe disease. Due to lack of effective agents to treat viral infections and emerging resistance patterns, preventive and prophylactic strategies are valuable. Our review article provides an overview of commonly encountered viral infections and their management in an allogeneic stem cell transplant setting in the adult age group.

Disseminated zoster in an adult patient with extensive burns: a case report

BackgroundShingles (localized zoster) and disseminated zoster are caused by the reactivation of latent varicella zoster virus (VZV). Reactivation of VZV is related to impaired cell-mediated immunity. Extensive burns affecting a patient result in burn-related immunosuppression and cytokine storm. Despite immunosuppression in burn patients, the reactivation of VZV is extremely rare, whereas eczema herpeticum, caused by reactivation of latent herpes simplex virus (HSV), is common. We have found only 1 published case of VZV reactivation during burn treatment in the literature.Case presentationA 51-year-old man was burned in a fire, which affected 60% of his total body surface area (TBSA), and also received inhalation injury (day 0). Despite fluid resuscitation, he showed persistent renal failure. Continuous hemodialysis and filtration (CHDF) combined with polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) therapy was used for cytokine modulation. Autologous and allogeneic skin grafting was performed. On day 15, multiple-drug-resistant Pseudomonas aeruginosa (MDRP) was detected from a blood specimen, and the patient developed multiple organ failure (MOF). On day 31, compact aggregations of small vesicles appeared on the intact skin of his left knee and left buttock. The vesicles were located within the 4th lumbar (L4) spinal dermatome. From day 32 to day 34, similar new vesicles arose on his intact skin and epithelializing skin-graft donor sites. We diagnosed disseminated zoster, based on the patient’s age, the characteristic occurrence of the initial vesicles within a limited area of intact skin in the left L4 dermatome, and a positive Tzank smear. Serologic testing on day 36 showed a high level of anti-VZV immunoglobulin (Ig)G with low levels of anti-VZV IgM, anti-HSV IgG, and anti-HSV IgM. The patient was isolated in a negative-pressure room to avoid air-borne spread of VZV. On day 52, the patient died.ConclusionsTo the best of our knowledge, our patient is the second case of reactivation of VZV during burn treatment. It is unclear why reactivation of VZV is rare in patients with burn-related immunosuppression, whereas HSV reactivation is common. Cytokine modulation throughout the treatment period using CHDF combined with PMX-DHP might have been related to the rare reactivation of VZV in our patient. Our case provides an additional information on the relationship between the immune status of a patient with extensive burns and reactivation of latent VZV or HSV.

Recurrent Shingles in a Frail Nonagenarian

Herpes Zoster (HZ) is a neurocutaneous disease caused by reactivation of latent Varicella Zoster Virus (VZV). Although up to 20% of people develop shingles during their lifetime, it predominantly affects older individuals. The lifetime recurrent rate of HZ in the general population is approximately 1-6%, and it is increased in people with advanced age, disease, and compromised immune system. It may progress to post-herpetic neuralgia (PHN), leading to significant dysfunction, debility, and morbidity. It is believed that VZV vaccination renders a cost-effective way of protection from shingles and alleviates post-herpetic complications. However, CDC reported less than 30% target vaccination rate based on Healthy People 2020. We present a case of recurrent shingles in an individual with severe chronic obstructive pulmonary disease on long-term corticosteroid therapy. This case illustrates the importance of vaccinations among older people.

Role of APOBEC3 proteins in proteasome inhibitor-mediated reactivation of latent HIV-1 viruses.

Proteasome inhibitors (PIs) have been identified as an emerging class of HIV-1 latency-reversing agents (LRAs). These inhibitors can reactivate latent HIV-1 to produce non-infectious viruses. The mechanism underlying reduced infectivity of reactivated viruses is unknown. In this study, we analysed PI-reactivated viruses using biochemical and virological assays and demonstrated that these PIs stabilized the cellular expression of HIV-1 restriction factor, APOBEC3G, facilitating its packaging in the released viruses. Using infectivity assay and immunoblotting, we observed that the reduction in viral infectivity was due to enhanced levels of functionally active APOBEC3 proteins packaged in the virions. Sequencing of the proviral genome in the target cells revealed the presence of APOBEC3 signature hypermutations. Our study strengthens the role of PIs as bifunctional LRAs and demonstrates that the loss of infectivity of reactivated HIV-1 virions may be due to the increased packaging of APOBEC3 proteins in the virus.

Anticytomegalovirus Peptides Point to New Insights for CMV Entry Mechanisms and the Limitations of In Vitro Screenings.

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause severe disease following in utero exposure, during primary infection, or latent virus reactivation in immunocompromised populations. These complications lead to a 1- to 2-billion-dollar economic burden, making vaccine development and/or alternative treatments a high priority. Current treatments for HCMV include nucleoside analogues such as ganciclovir (GCV), foscarnet, and cidofovir. Recently, letermovir, a terminase complex inhibitor, was approved for prophylaxis after stem cell transplantation. These treatments have unwanted side effects, and HCMV is becoming resistant to them. Therefore, we sought to develop an alternative treatment that targets a different stage in viral infection. Currently, small antiviral peptides are being investigated as anti-influenza and anti-HIV treatments. We have developed heparan sulfate-binding peptides as tools for preventing CMV infections. These peptides are highly effective at stopping infection of fibroblasts with in vitro-derived HCMV and murine cytomegalovirus (MCMV). However, they do not prevent MCMV infection in vivo Interestingly, these peptides inhibit infectivity of in vivo-derived CMVs, albeit not as well as tissue culture-grown CMVs. We further demonstrate that this class of heparan sulfate-binding peptides is incapable of inhibiting MCMV cell-to-cell spread, which is independent of heparan sulfate usage. These data indicate that inhibition of CMV infection can be achieved using synthetic polybasic peptides, but cell-to-cell spread and in vivo-grown CMVs require further investigation to design appropriate anti-CMV peptides.IMPORTANCE In the absence of an effective vaccine to prevent HCMV infections, alternative interventions must be developed. Prevention of viral entry into susceptible cells is an attractive alternative strategy. Here we report that heparan sulfate-binding peptides effectively inhibit entry into fibroblasts of in vitro-derived CMVs and partially inhibit in vivo-derived CMVs. This includes the inhibition of urine-derived HCMV (uCMV), which is highly resistant to antibody neutralization. While these antiviral peptides are highly effective at inhibiting cell-free virus, they do not inhibit MCMV cell-to-cell spread. This underscores the need to understand the mechanism of cell-to-cell spread and differences between in vivo-derived versus in vitro-derived CMV entry to effectively prevent CMV's spread.

Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth.

Latent herpes virus reactivation has been demonstrated in astronauts during shuttle (10–16 days) and International Space Station (≥180 days) flights. Following reactivation, viruses are shed in the body fluids of astronauts. Typically, shedding of viral DNA is asymptomatic in astronauts regardless of mission duration; however, in some cases, live/infectious virus was recovered by tissue culture that was associated with atopic-dermatitis or skin lesions during and after spaceflight. Hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes activation during spaceflight occurs as indicated by increased levels of stress hormones including cortisol, dehydroepiandrosterone, epinephrine, and norepinephrine. These changes, along with a decreased cell mediated immunity, contribute to the reactivation of latent herpes viruses in astronauts. Currently, 47/89 (53%) astronauts from shuttle-flights and 14/23 (61%) astronauts from ISS missions shed one or more herpes viruses in saliva/urine samples. Astronauts shed Epstein–Barr virus (EBV), varicella-zoster virus (VZV), and herpes-simplex-1 (HSV-1) in saliva and cytomegalovirus (CMV) in urine. Larger quantities and increased frequencies for these viruses were found during spaceflight as compared to before or after flight samples and their matched healthy controls. The shedding did not abate during the longer ISS missions, but rather increased in frequency and amplitude. These findings coincided with the immune system dysregulation observed in astronauts from shuttle and ISS missions. VZV shedding increased from 41% in space shuttle to 65% in ISS missions, EBV increased 82 to 96%, and CMV increased 47 to 61%. In addition, VZV/CMV shed ≤30 days after ISS in contrast to shuttle where VZV/CMV shed up to 5 and 3 days after flight respectively. Continued shedding of infectious-virus post-flight may pose a potential risk for crew who may encounter newborn infants, sero-negative adults or any immunocompromised individuals on Earth. Therefore, developing spaceflight countermeasures to prevent viral reactivation is essential. Our spaceflight-developed technologies for saliva collection/rapid viral detection have been extended to include clinical applications including zoster patients, chicken pox, post-herpetic neuralgia, multiple sclerosis, and various neurological disorders. These protocols are employed in various clinics and hospitals including the CDC and Columbia University in New York, as well as overseas in Switzerland and Israel.