Nyt fra tidsskrifterne

ObjectivesThe under-five mortality (U5M) rate in Kenya (41 per 1000 live births) remains significantly above international goals (25 per 1000 live births). This is further exacerbated by regional inequalities in mortality. We aimed to describe U5M in Migori County, Kenya, and identify associated factors that can serve as programming targets. DesignCross-sectional observational survey. SettingAreas served by the Lwala Community Alliance and control areas in Migori County, Kenya. ParticipantsThis study included 15 199 children born to respondents during the 18 years preceding the survey. Primary and secondary outcome measuresThe primary outcome was mortality in the first 5 years of life. The survey was powered to detect a 10% change in various health metrics over time with 80% power. ResultsA total of 15 199 children were included in the primary analyses, and 230 (1.5%) were deceased before the fifth birthday. The U5M rate from 2016 to 2021 was 32.2 per 1000 live births. Factors associated with U5M included year of birth (HR 0.926, p

by Deborah Schönegger, Armelle Marais, Bisola Mercy Babalola, Chantal Faure, Marie Lefebvre, Laurence Svanella-Dumas, Sára Brázdová, Thierry Candresse High-throughput sequencing (HTS) has proven a powerful tool to uncover the virome of cultivated and wild plants and offers the opportunity to study virus movements across the agroecological interface. The carrot model consisting of cultivated (Daucus carota ssp. sativus) and wild carrot (Daucus carota ssp. carota) populations, is particularly interesting with respect to comparisons of virus communities due to the low genetic barrier to virus flow since both population types belong to the same plant species. Using a highly purified double-stranded RNA-based HTS approach, we analyzed on a large scale the virome of 45 carrot populations including cultivated, wild and off-type carrots (carrots growing within the field and likely representing hybrids between cultivated and wild carrots) in France and six additional carrot populations from central Spain. Globally, we identified a very rich virome comprising 45 viruses of which 25 are novel or tentatively novel. Most of the identified novel viruses showed preferential associations with wild carrots, either occurring exclusively in wild populations or infecting only a small proportion of cultivated populations, indicating the role of wild carrots as reservoir of viral diversity. The carrot virome proved particularly rich in viruses involved in complex mutual interdependencies for aphid transmission such as poleroviruses, umbraviruses and associated satellites, which can be the basis for further investigations of synergistic or antagonistic virus-vector-host relationships.

Proceedings of the National Academy of Sciences, Volume 120, Issue 34, August 2023.

AbstractThe use of soluble recombinant ACE2 (rACE2) as a decoy capable of blocking SARS-CoV-2 entry into cells has been envisaged as a therapeutic strategy to reduce viral loads in patients suffering from severe COVID-19. We engineered a novel form of rACE2, fused to the Epstein-Barr virus (EBV) antigen P18F3 (rACE2-P18F3), to reorient a pre-existing humoral response towards EBV against SARS-CoV-2 particles. Recombinant ACE2-P18F3 was able to bind to the SARS-CoV-2 spike protein, neutralized viral entry into cells and promoted the phagocytosis of spheres coated with different spike variants by monocytic cells. The results position rACE2-P18F3 as a promising therapeutic candidate to universally block coronaviruses cell entry and clear viral particles.

ObjectivesTo examine correlates of Neisseria gonorrhoeae antimicrobial resistance (AMR) to first-line antimicrobials (azithromycin, cefixime and ceftriaxone). Design and settingThe sentinel surveillance network is an open cohort of gonococcal infection cases from Québec, Canada. Cross-sectional results are reported herein. ParticipantsBetween 1 January 2016 and 31 December 2019, data from 886 individuals accounting for 941 gonorrhoea cases were included. MethodsEpidemiological and clinical data were collected using an auto-administered questionnaire, direct case interviews and chart reviews. Antimicrobial susceptibility testing was performed using the agar dilution method. Generalised estimating equations were used for regression. ResultsThe prevalence of azithromycin resistance with a minimal inhibitory concentration (MIC) of ≥2 mg/L was 21.3%. In 2016, men who have sex with men were more likely to be infected with an azithromycin-resistant N. gonorrhoeae isolate (adjusted prevalence ratio (aPR)=4.73, 95% CI 1.48 to 15.19) or with an isolate with increased third-generation cephalosporin (3GC) MIC (aPR=5.32, 95% CI 1.17 to 24.11 for cefixime (MIC≥0.06 mg/L) and aPR=4.38, 95% CI 1.53 to 12.54 for ceftriaxone (MIC≥0.03 mg/L)). However, these associations were not maintained between 2017 and 2019, with increased MIC observed in men who have sex exclusively with women and women. Overall, azithromycin resistance was significantly more likely in cases who self-reported HIV infection (aPR=1.65, 95% CI 1.00 to 2.71). Cefixime increased MIC were more likely in individuals 25–34 years old (aPR=2.23, 95% CI 1.18 to 4.21). Cefixime and ceftriaxone increased MIC were both more likely in cases who reported ≥5 sexual partners (cefixime: aPR=2.10, 95% CI 1.34 to 3.27 and ceftriaxone: aPR=1.62, 95% CI 1.14 to 2.30). ConclusionSignificant correlates of N. gonorrhoeae AMR to first-line antimicrobials were observed. Antimicrobial stewardship may be particularly important for 3GC. Active monitoring and interventions are critical for 3GC non-susceptible strains, especially considering the very low prevalence in Québec. …

Abstract Introduction Haemophagocytic lymphohistiocytosis is a rare and life-threatening condition caused by uncontrolled immune activation leading to excessive inflammation and tissue destruction. It could either be due to a primary genetic defect or be triggered by secondary causes such as infections, autoimmune diseases, rheumatological diseases or post-transplant immunosuppression. We here report the case of a 4-year-old child with a recent AIDS diagnosis who developed a severe systemic inflammation. Case report We here report the case of a 4-year-old child with a recent AIDS diagnosis who was admitted to the ER with acute respiratory failure due to Pneumocystis jiroveci infection and Aspergillosis; the following microbiological assessment also showed a CMV, HSV, EBV and HHV-7 coinfection. On the 51st day after she’d started antiretroviral therapy, 39th after she’d followed a course of Bactrim and Caspofungin for PJI and Ambisome for pulmonary Aspergillosis, she started presenting fever, unresponsive to broad-spectrum antibiotic therapy. She also presented worsening of her clinical conditions, with evidence at the laboratory assessments of progressive raise in inflammatory indexes, coagulopathy, trilinear cytopenia and hyperferritinemia. To perform the differential diagnosis between IRIS and HLH, HLA-DR on T cells was studied, turning out negative for IRIS. Therefore, in the suspicion of HLH, a bone marrow aspirate and biopsy were performed with evidence of trilinear cytopenia, prevalence of T-cells and macrophages with signs of phagocytosis. She was started on high-dose steroids and Anakinra for a total of 29 days, resulting in prompt apyrexia and progressive improvement of her clinical conditions and laboratory results. Conclusion To the best of our knowledge there is poor literature available about the differential diagnosis of HLH and IRIS, therefore medical management in the concurrence of these two conditions needs to be further investigated, especially in a setting where immunological testing is not quickly available. The clinical differences between these pathologies are blurred and the bone marrow biopsy within marker for IRIS helped us to distinguish these two entities. …

Abstract Introduction Haemophagocytic lymphohistiocytosis is a rare and life-threatening condition caused by uncontrolled immune activation leading to excessive inflammation and tissue destruction. It could either be due to a primary genetic defect or be triggered by secondary causes such as infections, autoimmune diseases, rheumatological diseases or post-transplant immunosuppression. We here report the case of a 4-year-old child with a recent AIDS diagnosis who developed a severe systemic inflammation. Case report We here report the case of a 4-year-old child with a recent AIDS diagnosis who was admitted to the ER with acute respiratory failure due to Pneumocystis jiroveci infection and Aspergillosis; the following microbiological assessment also showed a CMV, HSV, EBV and HHV-7 coinfection. On the 51st day after she’d started antiretroviral therapy, 39th after she’d followed a course of Bactrim and Caspofungin for PJI and Ambisome for pulmonary Aspergillosis, she started presenting fever, unresponsive to broad-spectrum antibiotic therapy. She also presented worsening of her clinical conditions, with evidence at the laboratory assessments of progressive raise in inflammatory indexes, coagulopathy, trilinear cytopenia and hyperferritinemia. To perform the differential diagnosis between IRIS and HLH, HLA-DR on T cells was studied, turning out negative for IRIS. Therefore, in the suspicion of HLH, a bone marrow aspirate and biopsy were performed with evidence of trilinear cytopenia, prevalence of T-cells and macrophages with signs of phagocytosis. She was started on high-dose steroids and Anakinra for a total of 29 days, resulting in prompt apyrexia and progressive improvement of her clinical conditions and laboratory results. Conclusion To the best of our knowledge there is poor literature available about the differential diagnosis of HLH and IRIS, therefore medical management in the concurrence of these two conditions needs to be further investigated, especially in a setting where immunological testing is not quickly available. The clinical differences between these pathologies are blurred and the bone marrow biopsy within marker for IRIS helped us to distinguish these two entities. …

Enterobacterales bloodstream infections (BSI) are common life-threatening conditions. Prompt and appropriate antimicrobial therapy is an essential part of the treatment and has demonstrated a significant reduction in mortality [1, 2]. AmpC β-lactamase-hyperproducing Enterobacterales (ABLHE) are frequently isolated in healthcare-associated infections, which leads to the prescription of carbapenems. ABLHE refers to Enterobacterales that have derepressed AmpC and are therefore third-generation cephalosporin (3GC)-resistant.

AbstractObjectiveThe two co-factors in the etiology of Burkitt lymphoma (BL) are Epstein Barr virus (EBV) and repeated Plasmodium falciparum malaria infections. This study evaluated EBV loads in mucosal and systemic compartments of children with malaria and in community controls. Age was analyzed as a covariate as immunity to malaria in endemic regions is age dependent.MethodsChildren (2-10 years) with clinical malaria from Western Kenya and community controls without malaria were enrolled. Saliva and blood samples were collected, EBV viral load was assessed by quantitative-PCR and EpiTYPER MassARRAY was used to assess methylation of 3 different EBV genes.ResultsRegardless of the compartment, we detected EBV more frequently in malaria cases compared to controls although not significant. When EBV was detected, there were no differences in viral load between cases and controls. However, EBV methylation was significantly lower in the malaria group compared to controls in both plasma and saliva (p-value 

Abstract Background Chronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD) considered to be associated with a genetic immunological abnormality, although its cause is still unclear. EBV is usually detected in T cells or NK cells in CAEBV patients with only a few cases involving B cells described in East Asia, which may be due to differences in genetic and environmental factors. Case description A 16-year-old boy who seemed to be diagnosed as CAEBV of B cell type was studied. The patient had IM-like symptoms persisting for more than 3 months, high levels of EBV DNA in the PB, and positive EBER in situ hybridization in B cells. In addition, to exclude underlying genetic disorders, we performed next-generation sequencing (NGS) and whole-exome sequencing (WES), which identified the missense mutation in PIK3CD (E1021K), ADA (S85L) and CD3D (Q140K) in the patient while no same genetic mutation was detected in his parents and sister. However, there is no diagnosis of CAEBV of B cell type in the most recent World Health Organization classification of tumors of hematopoietic and lymphoid tissues, therefore we finally diagnosed this patient as EBV-B-LPD. Conclusions This study shows a rare case of a patient meeting the definition of CAEBV B-cell disease in East Asia. Meanwhile, the case indicates that the missense mutation and the disease are related. …

Protein post‐translational modifications (PTMs) are reversible processes that regulate the function of target proteins without altering their sequences. High‐throughput sequencing surveys have provided insights into the patterns of PTMs, such as ubiquitination, SUMOylation, and phosphorylation. After primary infection, the Epstein‐Barr virus (EBV), a ubiquitous herpesvirus, establishes a life‐long latent infection. EBV can establish a delicate balance to regulate its proliferation and host cell survival. Owing to the limited gene products of EBV, interfering with the host PTM machinery is an effective way to alter host immune responses and physiological status and establish infection. In this review, we focus on the current knowledge of the mechanisms by which EBV products manipulate host ubiquitination, SUMOylation, and phosphorylation to establish a latent infection or favour viral replication and pathogenesis.

Abstract Background Chronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD) considered to be associated with a genetic immunological abnormality, although its cause is still unclear. EBV is usually detected in T cells or NK cells in CAEBV patients with only a few cases involving B cells described in East Asia, which may be due to differences in genetic and environmental factors. Case description A 16-year-old boy who seemed to be diagnosed as CAEBV of B cell type was studied. The patient had IM-like symptoms persisting for more than 3 months, high levels of EBV DNA in the PB, and positive EBER in situ hybridization in B cells. In addition, to exclude underlying genetic disorders, we performed next-generation sequencing (NGS) and whole-exome sequencing (WES), which identified the missense mutation in PIK3CD (E1021K), ADA (S85L) and CD3D (Q140K) in the patient while no same genetic mutation was detected in his parents and sister. However, there is no diagnosis of CAEBV of B cell type in the most recent World Health Organization classification of tumors of hematopoietic and lymphoid tissues, therefore we finally diagnosed this patient as EBV-B-LPD. Conclusions This study shows a rare case of a patient meeting the definition of CAEBV B-cell disease in East Asia. Meanwhile, the case indicates that the missense mutation and the disease are related. …

AbstractMultiple sclerosis is characterised by the chronic inflammatory destruction of myelinated axons in the central nervous system. Several ideas have been put foward to clarify the roles of the peripheral immune system and neurodegenerative events in such destruction. Yet, none of the resulting models appears to be consistent with all the experimental evidence. They also do not answer the question why MS is exclusively seen in humans, how Epstein-Barr virus contributes to its development but does not immediately trigger it, and why optic neuritis is such a frequent early manifestation in MS.Here we describe a scenario for the development of MS that unifies existing experimental evidence as well as answer the above questions. We propose that all manifestions of MS are caused by a series of unfortunate events that usually unfold over a longer period of time after a primary EBV infection and involves periodic weakening of the blood-brain barrier, antibody-mediated CNS disturbances, accumulation of the oligodendrocyte stress protein αB-crystallin and self-sustaining inflammatory damage.

Journal of Medical Virology, Volume 95, Issue 5, May 2023.

To provide a comprehensive systematic review and meta‐analysis regarding the cumulative incidence (incidence proportion) of human herpesvirus (HHV) reactivation among patients with coronavirus disease 2019 (COVID‐19), we searched PubMed/MEDLINE, Web of Science, and EMBASE up to 25 September 2022, with no language restrictions. All interventional and observational studies enrolling patients with confirmed COVID‐19 and providing data regarding HHV reactivation were included. The random‐effects model was used in the meta‐analyses. We included information from 32 studies. HHV reactivation was considered a positive polymerase chain reaction result taken at the time of COVID‐19 infection. Most of the included patients were severe COVID‐19 cases. The pooled cumulative incidence estimate was 38% (95% Confidence Intervals [CI], 28%–50%,  = 86%) for herpes simplex virus (HSV), 19% (95% CI, 13%–28%,  = 87%) for cytomegalovirus (CMV), 45% (95% CI, 28%–63%,  = 96%) for Epstein‐Barr virus (EBV), 18% (95% CI, 8%–35%) for human herpesvirus 6 (HHV‐6), 44% (95% CI, 32%–56%) for human herpesvirus 7 (HHV‐7), and 19% (95% CI, 14%–26%) for human herpesvirus 8 (HHV‐8). There was no evidence of funnel plot asymmetry based on visual inspection and Egger\'s regression test for the results of HSV ( = 0.84), CMV ( = 0.82), and EBV ( = 0.27) reactivation. In conclusion, the identification of HHV reactivation in severe COVID‐19 patients is helpful in the management of patients as well as the prevention of complications. Further research is required to elucidate the interaction between HHVs and COVID‐19. Systematic review registration: PROSPERO CRD42022321973.

Abstract Background Viral reactivations and co-infections have been reported among COVID-19 patients. However, studies on the clinical outcomes of different viral reactivations and co-infections are currently in limit. Thus, the primary purpose of this review is to perform an overarching investigation on the cases of latent virus reactivation and co-infection in COVID-19 patients to build collective evidence contributing to improving patient health. The aim of the study was to conduct a literature review to compare the patient characteristics and outcomes of reactivations and co-infections of different viruses. Methods Our population of interest included confirmed COVID-19 patients who were diagnosed with a viral infection either concurrently or following their COVID-19 diagnosis. We extracted the relevant literature through a systematic search using the key terms in the online databases including the EMBASE, MEDLINE, Latin American Caribbean Health Sciences Literature (LILACS), from inception onwards up to June 2022. The authors independently extracted data from eligible studies and assessed the risk of bias using the Consensus-based Clinical Case Reporting (CARE) guidelines and the Newcastle–Ottawa Scale (NOS). Main patient characteristics, frequency of each manifestation, and diagnostic criteria used in studies were summarized in tables. Results In total, 53 articles were included in this review. We identified 40 reactivation studies, 8 coinfection studies, and 5 studies where concomitant infection in COVID-19 patients was not distinguished as either reactivation or coinfection. Data were extracted for 12 viruses including IAV, IBV, EBV, CMV, VZV, HHV-1, HHV-2, HHV-6, HHV-7, HHV-8, HBV, and Parvovirus B19. EBV, HHV-1, and CMV were most frequently observed within the reactivation cohort, whereas IAV and EBV within the coinfection cohort. In both reactivation and coinfection groups, patients reported cardiovascular disease, diabetes, and immunosuppression as comorbidities, acute kidney injury as complication, and lymphopenia and elevated D-dimer and CRP levels from blood tests. Common pharmaceutical interventions in two groups included steroids and antivirals. Conclusion Overall, these findings expand our knowledge on the characteristics of COVID-19 patients with viral reactivations and co-infections. Our experience with current review indicates a need for further investigations on virus reactivation and coinfection among COVID-19 patients. …

Journal of Medical Virology, Volume 95, Issue 4, April 2023.

Journal of Medical Virology, Volume 95, Issue 4, April 2023.

There are nine HHVs, including three alpha-herpesviruses [herpes simplex viruses type 1 (HSV-1; HHV-1) and 2 (HSV-2; HHV-2) and VZV (HHV-3)]; four beta-herpesviruses [HHV-6A, HHV-6B, HHV-7, and human cytomegalovirus (HCMV; HHV-5)]; and two gamma-herpesviruses [Kaposi’s sarcoma-associated herpesviruses (KSHV; HHV-8) and Epstein–Barr virus (EBV; HHV-4)]. HHVs are ubiquitous in human populations and their latent or lytic infections cause various diseases [1]. In addition to known HHV pathologies, recent studies linked HSV-1 and VZV with Alzheimer’s disease, and EBV with multiple sclerosis [2–5].

Journal of Medical Virology, Accepted Article.

AbstractWe report sustained remission of chronic active EBV infection in a 27-year-old female patient treated with third-party EBV-specific T-cells followed by allogeneic HSCT. The viremia cleared after administration of anti-T-lymphocyte globulin for GvHD prophylaxis. Subsequent expansion of EBV-infected host T-cells was controlled by transfusion of donor-derived EBV-specific T-cells.

ObjectivesInfectious mononucleosis (IM) is a clinical syndrome that is characterised by lymphadenopathy, fever and sore throat. Although generally not considered a serious illness, IM can lead to significant loss of time from school or work due to profound fatigue, or the development of chronic illness. This study aimed to derive and externally validate clinical prediction rules (CPRs) for IM caused by Epstein-Barr virus (EBV).DesignProspective cohort study.Setting and participants328 participants were recruited prospectively for the derivation cohort, from seven university-affiliated student health centres in Ireland. Participants were young adults (17–39 years old, mean age 20.6 years) with sore throat and one other additional symptom suggestive of IM. The validation cohort was a retrospective cohort of 1498 participants from a student health centre at the University of Georgia, USA.Main outcome measuresRegression analyses were used to develop four CPR models, internally validated in the derivation cohort. External validation was carried out in the geographically separate validation cohort.ResultsIn the derivation cohort, there were 328 participants, of whom 42 (12.8%) had a positive EBV serology test result. Of 1498 participants in the validation cohort, 243 (16.2%) had positive heterophile antibody tests for IM. Four alternative CPR models were developed and compared. There was moderate discrimination and good calibration for all models. The sparsest CPR included presence of enlarged/tender posterior cervical lymph nodes and presence of exudate on the pharynx. This model had moderate discrimination (area under the receiver operating characteristic curve (AUC): 0.70; 95% CI: 0.62–0.79) and good calibration. On external validation, this model demonstrated reasonable discrimination (AUC: 0.69; 95% CI: 0.67–0.72) and good calibration.ConclusionsThe alternative CPRs proposed can provide quantitative probability estimates of IM. Used in conjunction with serological testing for atypical lymphocytosis and immunoglobulin testing for viral capsid antigen, CPRs can enhance diagnostic decision-making for IM in community settings.…

by Wipas Loengbudnark, Vibuntita Chankitisakul, Wuttigrai BoonkumSustainable poultry production in adverse weather conditions is a widely debated issue, which has led to research into the development of breeds of poultry that are genetically resistant to heat. This study aimed to investigate the effects of heat stress on the genetics of monthly egg production and examine the threshold point of heat stress for preventing thermal stress and its effects on chicken productivity. The data of 5,965 monthly egg production records of 629 Thai native Pradu Hang dum chickens were used for analysis in combination with the temperature-humidity index (THI) calculated by meteorological data near the testing station. The average THI throughout the year was 76.6, and the highest was 82. The THI data were subsequently used to find the threshold point of heat stress. The THI equation used in this study was chosen by its highest correlation (-0.306) between THI values and monthly egg production. At a THI of 74, the lowest -2 logL was found and was considered the threshold point of heat stress. This means that monthly egg production would start decreasing when the THI was 74. Heritability was 0.15±0.03, and genetic and permanent environmental correlations were -0.29 and -0.48, respectively. The threshold point was used to estimate the estimated breeding values (EBVs) of the monthly egg production and heat stress individually, and EBVs were calculated into the selection index. The selection index values when the animal was selected for the replacement herd for all chickens (top 50%, 30%, 20%, and 10%) were 0.14, 0.90, 1.27, 1.53, and 1.91, respectively, and the genetic progress was 0.55, 0.60, 0.68, 0.75, and 0.77, respectively. This shows that the selection index values are lower if there are many selected animals. The recommendation for animal genetic selection is that the top 10% is appropriately because it seems to be most preferred. Therefore, using a selection index for high egg production and heat tolerance in Thai native chickens is possible to achieve genetic assessment in a large population.

Abstract Background Epstein Barr virus (EBV) infects ~ 95% of the population worldwide and is known to cause adverse health outcomes such as Hodgkin’s, non-Hodgkin’s lymphomas, and multiple sclerosis. There is substantial interest and investment in developing infection-preventing vaccines for EBV. To effectively deploy such vaccines, it is vital that we understand the risk factors for infection. Why particular individuals do not become infected is currently unknown. The current literature, describes complex, often conflicting webs of intersecting factors—sociodemographic, clinical, genetic, environmental-, rendering causality difficult to decipher. We aimed to use Mendelian randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of EBV. Methods We mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal. Results Our GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed shorter time in education, an increase in number of sexual partners, and a lower age of smoking commencement, to be causal risk factors for EBV serostatus. Conclusions Given the current interest and likelihood of a future EBV vaccine, these factors can inform vaccine development and deployment strategies by completing the puzzle of causality. Knowing these risk factors allows identification of those most likely to acquire EBV, giving insight into what age to vaccinate and who to prioritise when a vaccine is introduced. …

Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NK-cell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation.

by Faith Dickerson, Emily Katsafanas, Andrea Origoni, Theresa Newman, Kelly Rowe, Rita S. Ziemann, Kamal Bhatia, Emily Severance, Glen Ford, Robert YolkenIntroduction Herpesviruses are recognized as major causes of human diseases. Following initial infection, Herpesviruses can undergo cycles of reactivation controlled largely by the immune system. Cigarette smoking is an important modulator of the immune system particularly in individuals with serious mental illness where smoking is associated with increased rates of cardiopulmonary diseases and mortality. However, the effect of smoking on Herpesviruses has not been extensively studied. Methods In this nested cohort study, cigarette smoking was assessed in 1323 persons with serious mental illness or without a psychiatric disorder ascertained in a psychiatric health care system and the adjacent community. Participants provided a blood sample from which were measured IgG class antibodies to five human Herpesviruses: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus-Type 1 (HSV-1); Varicella Zoster Virus (VZV); and Human Herpes Virus-Type 6 (HHV-6). The associations between smoking variables and antibody levels to the Herpesviruses were analyzed among diagnostic groups in multiple regression models adjusted for age, sex, and race. Results Current smoking was significantly associated with higher levels of antibodies to CMV (coefficient .183, 95% CI .049, .317, p…

In Reply We agree with Ms Hu and Dr Kao that the current NCCN guidelines recommend definitive radiotherapy with or without concurrent chemotherapy for NPC with stage II and T3N0 disease, and in this subset, induction or adjuvant chemotherapy only for patients with high-risk features including bulky tumor volume or high serum EBV DNA copy number. Our study excluded patients who had NPC with high-risk features, so all patients with low-risk NPC were not treated with induction or adjuvant chemotherapy. Although triweekly delivery of cisplatin has been the standard regimen for concurrent chemotherapy, a phase 2 clinical trial comparing weekly and triweekly cisplatin during radiotherapy reported that the therapeutic effect and acute reactions of triweekly regimen were similar to that of the weekly regimen. However, other studies have reported significantly greater hematological toxicity but lower gastrointestinal reactions with a weekly cisplatin regimen.

Journal of Medical Virology, Accepted Article.

Journal of Medical Virology, Accepted Article.

Introduction

Suspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. Peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis might rule out MDS for up to 35% of patients referred for suspected disease, without requiring bone marrow aspiration. Yet laboratory-developed liquid antibody cocktails have practical limitations, because of lack of standardisation and poor stability. This research project aims to estimate the level of agreement and comparative accuracy between a single-use flow cytometry tube of lyophilised reagents (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart in quantifying peripheral blood neutrophil myeloperoxidase expression, among adult patients referred for suspected MDS.

Methods and analysis

The MPO-MDS-Develop project is a cross-sectional diagnostic accuracy study of two index tests by comparison with a reference standard in consecutive unselected adult patients conducted at a single university hospital. Flow cytometry analysis of peripheral blood samples will be performed by independent operators blinded to the reference diagnosis, using either Lyotube Stain 468 or laboratory-developed liquid reagent cocktail. The reference diagnosis of MDS will be established by cytomorphological evaluation of bone marrow aspirate by two independent haematopathologists blinded to the index test results. Morphologic assessment will be complemented by bone marrow flow cytometric score, karyotype and targeted next-generation sequencing panel of 43 genes, where relevant. The target sample size is 103 patients.

Ethics and dissemination

An institutional review board (Comité de Protection des Personnes Sud Est III, Lyon, France) approved the protocol prior to study initiation (reference number: 2020-028-B). Participants will be recruited using an opt-out approach. Efforts will be made to release the primary results within 6 months of study completion.

Trial registration number

NCT04399018.

…

Over 95% of humans have been infected with Epstein-Barr virus (EBV) and develop anti-EBV IgG antibodies conferring immunity. However, in specific populations, EBV may induce a range of B-cell lymphoproliferative disorders (LPDs). EBV may also contribute to T cell and NK Cell lymphoproliferation. The immune system is essential to prevent infection and development of cancer. Inborn errors of immunity (IEI) are a heterogenous group of over 450 genetic disorders predisposing to severe and/or recurrent infection, autoimmunity, autoinflammation or early-onset/severe neoplasia or lymphoproliferation.

Journal of Medical Virology, Accepted Article.

by Arthur Daniel Rocha Alves, Jéssica Vasques Raposo, Rafaela Moraes Pereira de Sousa, Claudete Aparecida Araújo Cardoso, Pâmela Karla Simões de Freitas Costa, Julienne Martins Araújo, Sabrina Teresinha Alvim Barreiro, Clarisse da Silveira Bressan, Guilherme Amaral Calvet, Rogério Valls de Souza, Patrícia Brasil, Rita de Cássia Nasser Cubel Garcia, Marcelo Alves Pinto, Vanessa Salete de Paula, Luciane Almeida Amado

Introduction A wide variety of viruses can cause rash diseases (RDs) or acute febrile illness (AFIs) in children, adolescents and adults; however, approximately 19% of RD cases and 40% of AFI cases remain without a defined etiology. Parvovirus B19 (B19V) and herpesvirus infection can also cause RD and/or AFI, and in some risk groups, these infections can become persistent (or latent) and may require hospital treatment. Since these infections do not have mandatory reporting, they can be hidden by other diseases, such as those caused by arboviruses (e.g., dengue virus). In this context, the aim of this study was to pursue the differential laboratory diagnoses of B19V and herpesvirus infections in patients with RD and AFI, without a defined etiology, seen in hospitals and/or reference centers for infectious diseases in Rio de Janeiro. Methods A total of 114 participants were enrolled in the study, including 54 children and 60 adults. B19V infection was assessed by real-time PCR (qPCR) and ELISA (anti-B19V IgM and IgG). EBV was assessed through qPCR, and betaherpesviruses (HCMV, HHV-6 and HHV-7) were assessed through multiplex qPCR. Sociodemographic and clinical data were obtained from the medical record data of these participants. Results The median age of children with RD was 2 years (interquartile range (IQR): 5), and 55.6% were male. Among adults with AFI, the median age was 38 years (IQR: 21), and 56.7% were female. Regarding RD patients, viral prevalence (and load) were 5.5%(104IU/mL), 3.4%(104IU/mL), 5.5%(104IU/mL) and 11.1%(105IU/mL) for B19V, EBV, HCMV and HHV-6 infection, respectively, and in AFI patients they were 6.6%(105IU/mL), 1.6%(103IU/mL), 3.3%(104IU/mL) for B19V, HCMV and HHV-6, respectively. HHV-7 was not detected in RD or AFI patients. Conclusion These results suggest the importance of including B19V and herpesviruses in the differential laboratory diagnoses for patients with RD and AFI, not only for epidemiological purposes but also for the proper management of the patient.…

Journal of Medical Virology, Accepted Article.

The diffusion of the SARS-CoV-2 delta (B.1.617.2) variant and the waning of immune response after primary Covid-19 vaccination favoured the breakthrough SARS-CoV-2 infections in vaccinated subjects. To assess the impact of vaccination, we determined the severity of infection in hospitalised patients according to vaccine status.

Emergency departments (EDs) were on the front line for the diagnostic workup of patients with COVID-19 like symptoms during the first wave. Chest imaging was the key to rapidly identifying COVID-19 before administering RT-PCR which was time-consuming.The objective of our study was to compare the costs and organizational benefits of triage strategies in ED during the first wave of the COVID-19 pandemic.

AbstractHPV-related oropharyngeal cancer (OPC) incidence is increasing among men. Biomarkers that can identify oral HPV 16/18 infections likely to persist, the obligate precursor for HPV-OPC, are needed. Control of oral co-infections, including Epstein-Barr virus (EBV), could serve as a biomarker of immune competence and the ability to control oral HPV. We assessed the association between oral EBV and oral HPV 16/18 persistence among 63 men in the HIM Study who tested HPV16/18 positive. Detection of oral EBV was significantly associated with oral HPV 16/18 ≥ 12-month persistence and deserves evaluation as a biomarker for oral HPV persistence and related OPC.

Nature Medicine, Published online: 19 May 2022; doi:10.1038/d41591-022-00061-9Nanoparticle vaccines show promise in preclinical models; clinical evaluation is warranted to assess whether they could help reduce the burden of disease associated with EBV in humans.

Background:

There is a need for a specific atherosclerotic risk assessment for people living with HIV (PLWH).

Setting:

A machine learning classification model was applied to PLWH and control subjects with low-to-intermediate cardiovascular risks to identify associative predictors of diagnosed carotid artery plaques. Associations with plaques were made using strain elastography in normal sections of the common carotid artery (CCA) and traditional cardiovascular risk factors.

Methods:

One hundred and two PLWH and 84 control subjects were recruited from the prospective Canadian HIV and Aging Cohort Study (57±8 years; 159 men). Plaque presence was based on clinical ultrasound scans of left and right CCA and internal carotid arteries (ICA). A classification task for identifying subjects with plaque was defined using random forests and logistic regression models. Receiver operating characteristic curves (AUC-ROC) were applied to select 5 among 50 combinations of 4 or less features yielding the highest AUC-ROCs.

Results:

To retrospectively classify individuals with and without plaques, the 5 most discriminant combinations of features had AUC-ROCs between 0.76 and 0.79. AUC-ROCs from random forests were statistically significantly higher than those obtained with logistic regressions (p=0.0001). The most discriminant features of random forests classifications in PLWH were age, smoking status, maximum axial strain and pulse pressure (equal weights), and sex and antiretroviral therapy exposure (equal weights). When considering the whole population, the HIV status was identified as a co-factor associated with carotid artery plaques.

Conclusion:

Strain elastography adds to traditional cardiovascular risk factors for identifying individuals with carotid artery plaques.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

The microbiological anorectal cure rate was significantly lower among women who received a single dose of azithromycin than among those who received a 1-week course of doxycycline. This finding suggests that doxycycline should be the first-line therapy for C trachomatis infection in women.

Nature Medicine, Published online: 05 May 2022; doi:10.1038/s41591-022-01785-4A comparison of Sars-Cov-2 vaccine platforms: the CoviCompare project…

by Jonathan Poh, Kao Chin Ngeow, Michelle Pek, Kian-Hin Tan, Jing Shan Lim, Hao Chen, Choon Kiat Ong, Jing Quan Lim, Soon Thye Lim, Chwee Ming Lim, Boon Cher Goh, Yukti Choudhury

Next-generation sequencing of circulating tumor DNA presents a promising approach to cancer diagnostics, complementing conventional tissue-based diagnostic testing by enabling minimally invasive serial testing and broad genomic coverage through a simple blood draw to maximize therapeutic benefit to patients. LiquidHALLMARK® is an amplicon-based next-generation sequencing assay developed for the genomic profiling of plasma-derived cell-free DNA (cfDNA). The comprehensive 80-gene panel profiles point mutations, insertions/deletions, copy number alterations, and gene fusions, and further detects oncogenic viruses (Epstein-Barr virus (EBV) and hepatitis B virus (HBV)) and microsatellite instability (MSI). Here, the analytical and clinical validation of the assay is reported. Analytical validation using reference genetic materials demonstrated a sensitivity of 99.38% for point mutations and 95.83% for insertions/deletions at 0.1% variant allele frequency (VAF), and a sensitivity of 91.67% for gene fusions at 0.5% VAF. In non-cancer samples, a high specificity (≥99.9999% per-base) was observed. The limit of detection for copy number alterations, EBV, HBV, and MSI were also empirically determined. Orthogonal comparison of epidermal growth factor receptor (EGFR) variant calls made by LiquidHALLMARK and a reference allele-specific polymerase chain reaction (AS-PCR) method for 355 lung cancer specimens revealed an overall concordance of 93.80%, while external validation with cobas® EGFR Mutation Test v2 for 50 lung cancer specimens demonstrated an overall concordance of 84.00%, with a 100% concordance rate for EGFR variants above 0.4% VAF. Clinical application of LiquidHALLMARK in 1,592 consecutive patients demonstrated a high detection rate (74.8% circulating tumor DNA (ctDNA)-positive in cancer samples) and broad actionability (50.0% of cancer samples harboring alterations with biological evidence for actionability). Among ctDNA-positive lung cancers, 72.5% harbored at least one biomarker with a guideline-approved drug indication. These results establish the high sensitivity, specificity, accuracy, and precision of the LiquidHALLMARK assay and supports its clinical application for blood-based genomic testing.

Science Advances, <a href='https://www.science.org/toc/sciadv/8/17'>Volume 8, Issue 17</a>, April 2022. …

Nature Reviews Microbiology, Published online: 26 April 2022; doi:10.1038/s41579-022-00741-wAn in vitro study shows that the nuclear lamina regulates Epstein–Barr virus latency and viral gene expression.

by Mai Abdel Haleem Abusalah, Ahmad Adebayo Irekeola, Rafidah Hanim Shueb, Mu’taman Jarrar, Chan Yean Yean

Background The EBV-associated epithelial tumours consist 80% of all EBV-associated cancer, where the nasopharyngeal cancer (NPC) and EBV-associated gastric carcinoma (EBVaGC) are considered as the most frequent EBV-associated epithelial tumours. It has been shown that the BART-encoded miRNAs are abundantly expressed in EBV-associated epithelial tumours, hence, these miRNAs may serve as diagnostic and prognostic biomarkers for EBV-associated epithelial tumours. Therefore, the purpose of this systematic review and meta-analysis is to assess these EBV miRNAs as prognostic biomarkers for NPC and GC. Method This systematic review was developed based on PRISMA guidelines and utilizing PubMed, Web of Science, Scopus, Cochrane, and Google scholar databases. The retrieved articles were thoroughly screened in accordance with the selection criteria. The hazard ratio (HR) and 95% confidence interval (CI) for patient survival outcomes were used to evaluate EBV miRNA expression levels. To assess the risk of bias, funnel plot symmetry and Egger’s bias test were employed. Result Eleven studies met the selection criteria for inclusion, and four were included in the meta-analysis. Most of the articles considered in this study were from China, with one study from South Korea. The overall pooled effect size estimation (HR) for upregulated EBV miRNAs was 3.168 (95% CI: 2.020–4.969), demonstrating that upregulated EBV miRNA expression enhanced the mortality risk in NPC and GC patients by three times. Conclusion To the best of our knowledge, this is the first meta-analysis that investigates the significance of EBV miRNAs as prognostic biomarkers in NPC and GC patients. The pooled effect estimates of HR of the various studies revealed that higher EBV miRNA expression in NPC and GC may result in a worse survival outcome. To assess the clinical significance of EBV miRNAs as prognostic biomarkers, larger-scale prospective studies are needed.…

Journal of Medical Virology, Accepted Article.

Objective:

Widespread use of the measles vaccine should lead to the elimination of this disease. Here we study the seroprevalence of measles in a cohort of adults living with HIV born after the introduction of measles vaccine in France and attempt to identify risk factors for the absence of serum measles antibody.

Design:

In this multicenter cross-sectional study, adult outpatients born after 1980 were screened for the presence of measles IgG antibody. Demographic and clinical data were obtained from the standardised electronic medical record system. Univariate and multivariate logistic regressions were performed to identify factors associated with the absence of measles antibodies.

Results:

Between April 2019 and April 2020, 648 participants were enrolled. The median age was 33 years, 53.6% were born outside of France, and 74% were considered as socially deprived. Plasma HIV RNA was undetectable in 86% of patients. Among 603 evaluable patients, measles serology was positive in 87.2%. Only 81.8% of the patients with documented vaccination tested positive for measles IgG. Younger age was significantly associated with the absence of measles serum antibodies (P = 0.004 for each 10-year lower), as was birth in France (P …

Abstract

Background

Epstein-Barr virus (EBV) infects more than 90% of the population worldwide. However, chronic active EBV infection (CAEBV) is one of the EBV-positive T- or NK-lymphoproliferative diseases with high morbidity and mortality. Here, we report a case of a 9-year girl with CAEBV, successively presenting with polymyositis and coronary artery dilation (CAD).

Case presentation

The girl complained of fatigue for more than 1 month. Muscle strength examinations had no abnormal findings. Blood chemistries showed elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK). Magnetic resonance imaging (MRI) showed spotty high-intensity signals in thigh muscles, and electromyogram suggested myogenic damage. The significant findings were positive EBV antibodies (EBVEA-IgG, EBVCA-IgG, and EBVNA-IgG), increased EBV DNA copies in B, T, and NK cells, and positive EBV-encoded small RNA in biopsy muscle specimen. The girl received ganciclovir, intravenous immunoglobulin, and methylprednisolone, and her symptoms improved. On the 45th day of hospitalization, echocardiograph revealed CAD. She received additional anticoagulants and Tocilizumab. Her condition improved and continued to be followed up at the clinic preparing for hematopoietic stem cell transplantation.

Conclusions

This is the first reported case of CAEBV successively with polymyositis and CAD. This case makes the diagnoses of autoimmune diseases in children more complicated. Careful investigation of hidden CAEBV should be recommended in children with atypical polymyositis or CAD.

…

AbstractBackgroundHIV-exposed, uninfected (HEU) children have a higher risk of severe infection than HIV-unexposed children, though the causes are poorly understood. Emerging data point to altered antibody transfer in women with HIV (WHIV), however, specific perturbations and the influence of ART and viremia remain unclear.MethodsWe evaluated antigen-specific transplacental antibody transfer across 14 antigens in paired maternal and umbilical cord plasma from 352 Ugandan women; 176 were WHIV taking ART. We measured antigen-specific IgG subclass (IgG1, 2, 3, 4) levels and antibody Fcγ receptor (FcγRn, 2a, 2b, 3a, 3b) binding profiles. We used Partial Least Squares Discriminant Analysis to define antigen-specific transplacental antibody transfer features.ResultsGlobal antibody transfer patterns were similar by maternal HIV serostatus, pointing to effective placental function in WHIV on ART. However, HEU umbilical cord antibody profiles were altered, driven by perturbed maternal seroprofiles. WHIV and paired HIV-exposed umbilical cord plasma had higher levels of chronic herpesvirus antibodies (P<0.01 for EBV, HSV) and lower levels of classic vaccine-induced antibodies (P<0.01 for tetanus, polio, HiB), suggesting that umbilical cord antibody profile differences arise from imbalanced WHIV immunity. Multivariate regression analysis demonstrated abnormal WHIV antibody profiles were associated with HIV viremia, lower CD4 count and post-conception ART initiation (P=0.01).ConclusionsPreserved placental antibody transfer and perturbed immune-dominance profiles in WHIV shift the balance of immunity delivered to neonates, pointing to HIV-associated changes in maternal antibody profiles as a key determinant of compromised neonatal immunity. Maternal vaccination interventions may promote transfer of relevant, effective antibodies to protect HEU children against early-life infections.