Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence.

Human cytomegalovirus (CMV) is a herpes virus with poorly understood transmission dynamics. Person-to-person transmission is thought to occur primarily through transfer of saliva or urine, but no quantitative estimates are available for the contribution of different infection routes. Using data from a large population-based serological study (n = 5,179), we provide quantitative estimates of key epidemiological parameters, including the transmissibility of primary infection, reactivation, and re-infection. Mixture models are fitted to age- and sex-specific antibody response data from the Netherlands, showing that the data can be described by a model with three distributions of antibody measurements, i.e. uninfected, infected, and infected with increased antibody concentration. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males are infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males have increased antibody concentration. Merging the statistical analyses with transmission models, we find that models with infectious reactivation (i.e. reactivation that can lead to the virus being transmitted to a novel host) fit the data significantly better than models without infectious reactivation. Estimated reactivation rates increase from low values in children to 2%-4% per year in women older than 50 years. The results advance a hypothesis in which transmission from adults after infectious reactivation is a key driver of transmission. We discuss the implications for control strategies aimed at reducing CMV infection in vulnerable groups

Prevalence of Cytomegalovirus infection among Egyptian patients with fever of unknown origin

Background: Diagnosis of prolonged febrile illness of unknown origin (FUO) is challenging even with the advances in the diagnostic techniques. As common as the infection with cytomegalovirus (CMV) is, most health care providers would not suspect CMV infection as a cause of FUO unless mononucleosis syndrome is evident. The aim of this study is to investigate the rate of CMV infection among patients with FUO and shed light on IgG avidity as a diagnostic tool.  Patients and methods: Two hundred and twenty three (223) immune competent patients with FUO were included in our study. They were subjected to all routine laboratory investigations, fever agglutinins, tuberculin and abdominal ultrasound along with IgG and IgM for CMV and IgG avidity test. Results:  This study shows that the 92.8% of the overall studied population were positive for CMV IgG. However, only 74(33.2%) of the studied population was found positive for IgM. Only one patient had positive IgM with negative IgG. IgG avidity was high in almost all of them. Only 3 patients showed low IgG avidity denoting that they have primary infection. Conclusion: CMV infection was found to be the cause of 33.2% of prolonged febrile illness experienced by immuncompetent adults. Only 1.8% of patients had primary CMV infection and the majority of them had detectable IgG level and were diagnosed with primary infection depending mainly on IgG avidity test

Life Course Socioeconomic Status and Immune Response to Persistent Infection in Mexican Americans.

Immune response to persistent infections, such as cytomegalovirus (CMV), herpes simplex virus-1 (HSV-1), Toxoplasma gondii (T. gondii), and Helicobacter pylori (H. pylori), are patterned by socioeconomic status (SES) in the U.S. Though persistent infections are often acquired early in life, studies of social exposures and these pathogens in adults are often limited to concurrent measures of SES. Further, significant disparities in persistent infections exist by race/ethnicity, indicating that Mexican Americans are more likely to experience the detrimental effects of life course socioeconomic disadvantage on immune response, however, early life cultural exposures are rarely examined. Using data from the Sacramento Area Latino Study on Aging (SALSA), a longitudinal cohort study of community-dwelling Mexican Americans, this dissertation examines the life course mechanisms by which early life SES may influence immune response to persistent pathogens and pathogen burden later in life. Additionally, nativity and acculturation, important components of social and racial/ethnic disparities in health, are investigated as independent predictors and modifiers of the life course social patterning of immune response to persistent infections later in life. The main findings indicate that 1) early life SES indirectly influences later life immune response and pathogen burden by a chain of risk mechanism, 2) nativity is independently associated with CMV, but not HSV-1, T. gondii, H. pylori immune response or pathogen burden, 3) acculturation is not independently associated with immune response or pathogen burden, and 4) nativity and acculturation modify the association between life course SES and immune response to CMV and T. gondii. This work contributes new knowledge and understanding of the life course mechanisms by which early life social conditions act to influence later life immune response to persistent infections and the early life cultural factors that impact these exposures. The results from these studies provide insight on points of intervention during the life course where addressing social disadvantage may improve immunological response to persistent infections later in life. Given the link between persistent infections examined in these studies and adverse health outcomes, this work may have broad implications for disrupting the development of social disparities in chronic health conditions and mortality.PhDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111550/1/hspink_1.pd

Pathogenesis of human cytomegalovirus in the immunecompromised

Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by a vigorous immune response so that infections are asymptomatic or symptoms are mild. However, if the immune system is compromised, HCMV can replicate to high levels and cause serious end organ disease. Substantial progress is being made in understanding the natural history and pathogenesis of HCMV infection and disease in the immunocompromised host. Serial measures of viral load defined the dynamics of HCMV replication and are now used routinely to allow intervention with antiviral drugs in individual patients. They are also used as pharmacodynamic read-outs to evaluate prototype vaccines that may protect against HCMV replication and to define immune correlates of this protection. This novel information is informing the design of randomized controlled trials of new antiviral drugs and vaccines currently under evaluation. In this Review, we discuss immune responses to HCMV and countermeasures deployed by the virus, the establishment of latency and reactivation from it, exogenous reinfection with additional strains, pathogenesis, development of end organ disease, indirect effects of infection, immune correlates of control of replication, current treatment strategies and the evaluation of novel vaccine candidates

Characterizing the transitioning epidemiology of herpes simplex virus type 1 in the USA: Model-based predictions

Background: Herpes simplex virus type 1 (HSV-1) is a prevalent lifelong infection that appears to be undergoing an epidemiologic transition in the United States (US). Using an analytical approach, this study aimed to characterize HSV-1 transitioning epidemiology and estimate its epidemiologic indicators, past, present, and future. Methods: An age-structured mathematical model was developed to describe HSV-1 transmission through oral and sexual modes of transmission. The model was fitted to the National Health and Nutrition Examination Surveys, 1976-2016 data series. Results: HSV-1 seroprevalence was projected to decline from 61.5% in 1970 to 54.8% in 2018, 48.5% in 2050, and 42.0% in 2100. In 30% for those aged 0-19 years, but 60. Meanwhile, the number of new infections per year (oral and genital) was persistent at 2,762,000 in 1970, 2,941,000 in 2018, 2,933,000 in 2050, and 2,960,000 in 2100. Of this total, genital acquisitions contributed 252,000 infections in 1970, 410,000 in 2018, 478,000 in 2050, and 440,000 in 2100 - a quarter of which are symptomatic with clinical manifestations. For those aged 15-49 years, nearly 25% of incident infections are genital. Most genital acquisitions (> 85%) were due to oral-to-genital transmission through oral sex, as opposed to genital-to-genital transmission through sexual intercourse. Conclusion: HSV-1 epidemiology is undergoing a remarkable transition in the US, with less exposure in childhood and more in adulthood, and less oral but more genital acquisition. HSV-1 will persist as a widely prevalent infection, with ever-increasing genital disease burden.This publication was made possible by NPRP grant number 9-040-3-008 from the Qatar National Research Fund (a member of Qatar Foundation). The findings achieved herein are solely the responsibility of the authors. The authors are also grateful for pilot funding provided by the Biomedical Research Program and infrastructure support provided by the Biostatistics, Epidemiology, and Biomathematics Research Core, both at Weill Cornell Medicine in Qatar

Human cytomegalovirus infections are associated with elevated biomarkers of vascular injury

Background: Human cytomegalovirus (HCMV) infects ~50% of adults in the United States. HCMV infections may cause vascular inflammation leading to cardiovascular disease, but the existing evidence is inconsistent. Objective: We investigated demographic predictors of HCMV infection and explored associations between HCMV infection status, the intensity of anti-HCMV Immunoglobulin G (IgG) antibody response, and biomarkers of inflammation and endothelial function which are known predictors of cardiovascular disease. Methods: We conducted a cross-sectional study of 694 adults residing in the Raleigh-Durham-Chapel Hill, NC metropolitan area. Serum samples were tested for IgG antibody response to HCMV, and for biomarkers of vascular injury including soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), C-reactive protein (CRP), and serum amyloid A (SAA). Associations between HCMV and biomarker levels were analyzed using two approaches with HCMV serostatus modeled as a binary variable and as an ordinal variable with five categories comprised of seronegative individuals and quartiles of anti-HCMV antibody responses in seropositive individuals. Results: HCMV seroprevalence in the study population was 56%. Increased body mass index, increased age, female gender, racial/ethnic minority status, and current smoking were significantly associated with HCMV seropositivity in a multivariate regression analysis. HCMV seropositivity was also associated with 9% (95% confidence interval 4–15%) and 20% (0.3–44%) increases in median levels of sICAM-1 and CRP, respectively, after adjusting for covariates. The association between HCMV seropositivity and median levels of sVCAM-1 and SAA were positive but not statistically significant. Significant positive associations were observed between the intensity of anti-HCMV IgG responses and levels of sICAM-1 and sVCAM-1 (p-values 0.0008 and 0.04 for linear trend, respectively). To our knowledge, this is the first epidemiological study to show a relationship between anti-HCMV IgG responses and vascular injury biomarkers sICAM-1 and sVCAM-1 in the general population. Conclusion: HCMV infections are associated with vascular injury and inflammation biomarkers in adult residents of North Carolina

Herpes simplex virus type 1 epidemiology in the Middle East and North Africa: systematic review, meta-analyses, and meta-regressions.

This study aimed at characterizing herpes simplex virus type 1 (HSV-1) epidemiology in the Middle East and North Africa (MENA). HSV-1 records were systematically reviewed. Findings were reported following the PRISMA guidelines. Random-effects meta-analyses were implemented to estimate pooled mean HSV-1 seroprevalence. Random-effects meta-regressions were conducted to identify predictors of higher seroprevalence. Thirty-nine overall seroprevalence measures yielding 85 stratified measures were identified and included in the analyses. Pooled mean seroprevalence was 65.2% (95% CI: 53.6-76.1%) in children, and 91.5% (95% CI: 89.4-93.5%) in adults. By age group, seroprevalence was lowest at 60.5% (95% CI: 48.1-72.3%) in <10 years old, followed by 85.6% (95% CI: 80.5-90.1%) in 10-19 years old, 90.7% (95% CI: 84.7-95.5%) in 20-29 years old, and 94.3% (95% CI: 89.5-97.9%) in ≥30 years old. Age was the strongest predictor of seroprevalence explaining 44.3% of the variation. Assay type, sex, population type, year of data collection, year of publication, sample size, and sampling method were not significantly associated with seroprevalence. The a priori considered factors explained 48.6% of the variation in seroprevalence. HSV-1 seroprevalence persists at high levels in MENA with most infections acquired in childhood. There is no evidence for declines in seroprevalence despite improving socio-economic conditions