Risk For Primary Cytomegalovirus Infection Research Articles

Epidemiology of cytomegalovirus infection in pregnancy in Israel: Real-world data from a large healthcare organization.

Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss among newborns. Women newly acquiring cytomegalovirus infection (CMVi) during pregnancy have the highest risk of vertical transmission. This study aimed to describe the epidemiology of CMVi in pregnancy in a large healthcare database. A retrospective cohort study was performed using the Maccabi Healthcare Services database (Israel). Women aged 18-44 years old on July 1, 2013 with no record of pregnancy in the prior 6 months were followed through December 31, 2017 for first pregnancy occurrence. Pregnancy outcomes (live birth, spontaneous/therapeutic abortions, stillbirth, and uncertain outcomes) were captured. CMV test results were obtained to assess serostatus at the start of pregnancy (SoP) and primary CMV infection (CMVi) during pregnancy. Associations of demographic and reproductive factors with pCMVi were investigated (multivariable logistic regression). The study included 84 699 pregnant women (median age = 31 years; interquartile range = 28-35). Live birth, fetal loss, and uncertain pregnancy outcomes accounted for 76.8%, 18.2%, and 5.0%, respectively. The seroprevalence of CMV at the start of pregnancy in this cohort was 63.4% (95% confidence interval [CI]: 63.1-63.7). Among seronegative women with available test results (n = 10 657), CMVi incidence was 14.5 per 1000 (95% CI = 12.2-16.7). In multivariate logistic regression models adjusting for maternal age, CMVi was significantly associated with having one or more prior live births (odds ratio [OR]: 3.8 [95% CI: 2.6-5.4]) and having a child less than 6 years of age (OR: 4.3 [95%CI: 3.0-6.1]). One in three pregnant women in Israel is at risk for primary CMVi. This study demonstrates that real-world electronic healthcare data can be leveraged to support clinical management and development of interventions for congenital CMV by identifying women at high risk for CMVi during pregnancy.

Geographic Disparities in Cytomegalovirus Infection During Pregnancy.

Cytomegalovirus (CMV) is the most common infectious cause of fetal malformations and childhood hearing loss. CMV is more common among socially disadvantaged groups, and it clusters geographically in poor communities. We conducted a geospatial analysis of chronic and primary CMV infection among pregnant women around Durham, NC. We performed a geospatial analysis of subjects from an ongoing study of CMV infection among pregnant women using geographic information systems and spatial statistics. Subjects were categorized on the basis of results of their CMV immunoglobulin G avidity testing as seronegative, seropositive, or primary infection. We used generalized additive models to analyze the spatial distributions of individuals who fell into each category and to control for confounders such as race and age. We used a generalized estimating equation to correlate community-level variables with CMV status. Of 3527 pregnant women aged 15 to 59 years, 93.4% were either white or black. CMV seropositivity was significantly more common among non-Hispanic white subjects than among minority subjects (odds ratio, 3.76 [95% confidence interval, 3.25-4.34]). We identified a cluster in which women had elevated odds of CMV seropositivity in the urban neighborhoods of Durham. Cases of primary CMV infection were more common in areas with higher-than-average CMV seroprevalence. Neighborhood median family income was associated inversely with the prevalence of chronic CMV. We found a high prevalence of CMV seropositivity in urban low-income neighborhoods among pregnant women, particularly among racial and ethnic minorities. Seronegative pregnant women from these communities might be at heightened risk for primary CMV infection.

Seroprevalence of cytomegalovirus IgG antibodies among pregnant women in Japan from 2009-2014

Human cytomegalovirus (CMV) is a major cause of congenital infection. The seroprevalence of maternal CMV IgG antibodies among Japanese women is decreasing. In this study, we assessed the rate of and risk factors for CMV infection. This article includes a description of a method for the prevention of CMV infection. Medical records of 7,074 women who delivered a baby at our hospital were retrospectively reviewed. For seronegative patients, preventive educational materials were provided, and CMV IgG antibody levels were reassessed during late pregnancy. Congenital infection in neonates from seroconverted mothers was determined by urine analysis. The overall CMV IgG seropositivity rate was 69.1%. The prevalence of CMV IgG increased with age and parity. In a multivariate logistic regression analysis, parity remained an independent determinant of CMV IgG seropositivity. The seroconversion rate for CMV IgG antibody during pregnancy was 0.37%. Neonatal congenital CMV infection occurred in 37.5% of seroconverted women. The risk of primary CMV infection in mothers during their first pregnancy was 7.0%, with an average follow-up period of 2.1years. We found that parity was an independent determinant of CMV IgG seropositivity, suggesting that child-rearing may be a high risk factor for maternal CMV infection. The provision of information on hygiene may be an effective and inexpensive method for preventing CMV infection.

Intragraft Cytomegalovirus Infection: A Randomized Trial of Valacyclovir Prophylaxis versus Pre-Emptive Therapy in Renal Transplant Recipients

In a randomized study, we observed a higher incidence of biopsy-proven acute rejection with pre-emptive valganciclovir therapy as compared with valacyclovir prophylaxis for prevention of cytomegalovirus (CMV) disease after renal transplantation (RTx). Persistence of the virus within the allograft could stimulate the alloimmune response. The aim of our study was to evaluate intragraft CMV infection in patients randomized to the trial. RTx recipients at risk of CMV were randomized to pre-emptive therapy with valganciclovir (n=36) for significant CMV viraemia (> or =2,000 copies/ml by quantitative PCR in whole blood samples) or 3-month prophylaxis with valacyclovir (n=34). Renal biopsies performed during 12 months post-RTx were analysed for the presence of CMV by real-time PCR and immunohistochemical staining. A total of 35 patients (59 biopsies) in the pre-emptive group and 31 patients (57 biopsies) with valacyclovir prophylaxis had > or =1 biopsy specimen with sufficient material for intragraft CMV determination. Cumulative incidence of intragraft CMV infection was 14% and 7% (P=0.315) with pre-emptive therapy and prophylaxis, respectively. Patients at risk for primary CMV infection (CMV serological donor-positive and recipient-negative) were at higher risk for intragraft CMV infection (40% versus 5%; P=0.008). CMV viraemia at the time of biopsy was associated with the presence of CMV within the allograft (P<0.001). During the first year after RTx, the incidence of intragraft CMV infection was relatively low with comparable rates in patients managed by pre-emptive valganciclovir therapy and valacyclovir prophylaxis.

Cytomegalovirus Prophylaxis With Intravenous Polyvalent Immunoglobulin in High-Risk Renal Transplant Recipients

Cytomegalovirus (CMV) seronegative renal allograft recipients (R−), particularly those with a graft from a CMV-seropositive donor (D+), are at high risk for primary CMV infection. CMV resistance to antiviral oral therapy is an emerging problem in renal transplantation, prompting development of new prophylactic strategies. We retrospectively studied the 1-year posttransplantation incidence of CMV infection in high-risk renal transplant recipients, in whom polyvalent intravenous immunoglobulins (IVIg) were used as prophylaxis. Forty R− patients received immunoprophylaxis by polyvalent IVIg (0.25 g/kg weekly for 8 weeks, starting on the operative day). CMV serological tests remained negative in eight patients (20%). Eight patients (20%) had asymptomatic CMV infection while 24 (60%) developed CMV syndrome and were treated with gancyclovir (10 mg/kg/day intravenously for 3 weeks). None had CMV disease or opportunistic infection. Six patients (15%) had biopsy-proven acute rejection, which followed CMV syndrome in three cases. One-year renal allograft and patient survivals were 95% and 97.5%, respectively. Mean serum creatinine level was 124 ± 33 μmol/L at 1 year. Clinical tolerance of IVIg was excellent, without any episode of acute renal failure. Polyvalent IVIg provides effective prophylaxis in renal transplant recipients at high risk for CMV infection and is associated with excellent 1-year allograft survival. Because of their immunomodulatory functions, IVIg may have a beneficial effect on the incidence of acute and chronic rejection and allograft survival. A randomized prospective study is required to evaluate long-term effects of CMV prophylaxis with polyvalent IVIg compared to antiviral agents in renal transplant recipients.

Continuous cytomegalovirus seroconversion in a large group of healthy blood donors.

Transmission of cytomegalovirus (CMV) to seronegative, immunocompromised recipients can cause serious and fatal complications. Although the seroprevalence of CMV is high, the risk of primary CMV infection among healthy blood donors has not yet been analysed in a large population. We developed an algorithm to determine the rate of CMV seroconversion in an overall cohort of 24,260 subjects who donated 176,474 blood units during an 11-year observation period. We detected CMV seroconversion in all relevant age groups (18-60 years) with an overall seroconversion rate of 0.55% per year. Both CMV seroconversion and seroprevalence occurred more frequently in female donors (P = 0.02 and P < 0.001, respectively). We identified 30-35-year-old blood donors as the group with the highest rate of CMV seroconversion per year (1.33% vs. 0.46%; P < 0.0001). We conclude that the risk of primary CMV infection is a continuous lifelong event and correlates with age and female gender.

Prevalence of maternal cytomegalovirus (CMV) antibody and detection of CMV DNA in amniotic fluid.

The prevalence of cytomegalovirus (CMV) IgG antibody was determined in 573 pregnant women in the first trimester. The overall prevalence of CMV IgG antibody was 77.5%. The rate of seropositivity was 67.7% in women < 25 yr, and increased with age to 85.7% in women 40 yr. These results imply that young women in Japan are at increased risk for primary CMV infection during pregnancy and that congenital CMV infection rates might increase in the future. We conducted a prospective study of 75 pregnant women who underwent amniocentesis for various indications to determine if CMV DNA could be detected in the amniotic fluid. None had symptoms associated with CMV infection, CMV IgM antibody, or seroconversion to CMV IgG antibody during pregnancy. CMV DNA was not detected in the amniotic fluid using a polymerase chain reaction assay. The 65 fetuses, including 3 sets of twins, were followed through birth. CMV DNA was not detected in urine samples obtained within the first 2 weeks of life. In conclusion, CMV DNA was not detected in the amniotic fluid of women who did not have CMV infection. These results, however, suggest that the negative predictive value of prenatal amniotic fluid analysis is high and that the presence of CMV DNA in the amniotic fluid has clinical significance for the diagnosis of congenital CMV infection if detected in pregnant women.

Evaluation of a novel immunoglobulin A capture enzyme immunoassay for diagnosis of cytomegalovirus infection in renal and heart transplant recipients.

In a retrospective cohort study of 68 organ transplant patients, the usefulness of a new commercial immunoglobulin A (IgA) antibody capture enzyme immunoassay (EIA) specific to human cytomegalovirus (CMV) for the early diagnosis of CMV disease was investigated. The results were compared with those obtained with the CMV pp65 antigen assay in peripheral blood leukocytes, an IgM immunoblot assay, and six other commercial EIAs. In 21 of 28 patients with CMV disease, the pp65 antigen assay and the immunoblot assay identified patients before the onset of disease more frequently than any other serological test method (17 and 13 patients, respectively; p = 0.0029). In patients at risk for primary CMV infection, the pp65 antigen assay was the only method that identified all patients prior to the onset of CMV disease (p = 0.008). For the other patients who were at risk for CMV infection, the pp65 antigen assay and the immunoblot assay detected infection before CMV disease more frequently than any other test system (p = 0.026). With respect to CMV disease, both immunoblotting and the pp65 antigen assay showed excellent sensitivity (100% and 89%, respectively). However, the specificity of the immunoblot was poor (41%), while the specificity of the pp65 antigen assay was reasonably good (68%). The IgA capture EIA showed moderate sensitivity (61%) and reasonable specificity (76%). In conclusion, the pp65 antigen assay, which detects pp65 antigen in leukocytes, is the method of choice for diagnosis of either primary or recurrent CMV infection. The specificity of the pp65 antigen assay was improved by additional testing for specific IgA and IgM antibodies (95% vs. 68%). The IgA assay is of limited value in renal and heart transplant patients, since it detected IgA antibodies only sporadically, and even then, too late for a timely therapy.

Eradication of cytomegalovirus reactivation disease using high-dose acyclovir and targeted intravenous ganciclovir in kidney and kidney/pancreas transplantation.

The attack rate of cytomegalovirus (CMV) is over 50% in solid organ transplant recipients at risk for primary CMV infection and in those receiving antilymphocyte antibody therapy. Various CMV prophylaxis regimens over the last few years have reduced the attack rate to around 20% overall. We report our results using high-dose acyclovir for 3 months after transplant, with targeted intravenous ganciclovir for the duration of any antilymphocyte antibody therapy, in our kidney and simultaneous pancreas/kidney transplant recipients. Records of 109 consecutive patients over a 2-year period were reviewed. Six cases of CMV disease were identified. Five cases occurred in 21 patients at risk for primary CMV disease (24%), whereas only one case occurred in 73 patients at risk for CMV reactivation (1.4%). We conclude that high-dose acyclovir and targeted ganciclovir is excellent prophylaxis against CMV reactivation in kidney and simultaneous pancreas/kidney transplantation.

Failure of acyclovir to prevent cytomegalovirus infection in renal allograft recipients.

Cytomegalovirus (CMV) is the most common opportunistic pathogen following renal transplantation and remains a major concern in transplantation centers owing to its high morbidity and impact on renal allografts. Pending more effective antiviral drugs, efforts have been directed toward prevention strategies. We conducted a retrospective analysis to evaluate the efficacy of various prophylactic options used at our institution during the period April 1986 to August 1990. All CMV-negative patients with CMV-negative kidneys (D-R-) received screened, CMV-negative blood products (n = 19). CMV-specific immunoglobulins (CMV Ig) were used in 6 patients at increased risk for primary CMV infection and acyclovir was administered to 21 patients at an initial intravenous dose of 5 mg/kg body weight; then oral doses of 800-3200 mg per day were given according to the patients' estimated creatinine clearance. Thirty-two patients did not receive any CMV prophylactic treatment and served as controls. CMV monitoring of the patients during the first 6 months after transplantation showed an overall infection and disease rate of 81% and 38.1%, respectively, in the acyclovir-treated group. Compared with controls, the incidences of infection and disease were higher in the acyclovir-treated patients, with a significant difference for CMV infection (P = 0.002, generalized Wilcoxon test). Only 1 of the 19 D-R- patients presented with CMV infection. CMV Ig-treated patients tended to have less severe disease without any apparent reduction in infection incidence. Given the high rate of infection in patients at risk, we infer that high-dose acyclovir does not prevent CMV infection in our setting of renal transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of acyclovir to prevent cytomegalovirus infection in renal allograft recipients*

Cytomegalovirus (CMV) is the most common opportunistic pathogen following renal transplantation and remains a major concern in transplantation centers owing to its high morbidity and impact on renal allografts. Pending more effective antiviral drugs, efforts have been directed toward prevention strategies. We conducted a retrospective analysis to evaluate the efficacy of various prophylactic options used at our institution during the period April 1986 to August 1990. All CMV-negative patients with CMV-negative kidneys (D- R-) received screened, CMV-negative blood products (n=19). CMV-specific immunoglobulins (CMV Ig) were used in 6 patients at increased risk for primary CMV infection and acyclovir was administered to 21 patients at an initial intravenous dose of 5 mg/kg body weight; then oral doses of 800–3200 mg per day were given according to the patients' estimated creatinine clearance. Thirty-two patients did not receive any CMV prophylactic treatment and served as controls. CMV monitoring of the patients during the first 6 months after transplantation showed an overall infection and disease rate of 81 % and 38.1 %, respectively, in the acyclovir-treated group. Compared with controls, the incidences of infection and disease were higher in the acyclovir-treated patients, with a significant difference for CMV infection (P = 0.002, generalized Wilcoxon test). Only 1 of the 19 D- R- patients presented with CMV infection. CMV Ig-treated patients tended to have less severe disease without any apparent reduction in infection incidence. Given the high rate of infection in patients at risk, we infer that high-dose acyclovir does not prevent CMV infection in our setting of renal transplantation. We advocate the use of screened, CMV-negative blood products in D- R- patients.

Ethnic and gender differences in the prevalence of anti-cytomegalovirus antibodies among young adults in Israel.

The population of Israel comprises offspring of immigrants from countries of high and low incidence of cytomegalovirus infection. To evaluate possible ethnic differences in the prevalence of antibodies against cytomegalovirus in young adults, blood samples were taken from a random sample of 422 Israel military recruits aged 18-19 years, during 1987. Antibodies against cytomegalovirus were determined by means of ELISA. Subjects originating from North Africa or Asia had higher prevalences than those originating from Western countries (84.0% and 74.0% versus 60.0%, P < 0.001) and the differences persisted after adjustment for gender, education and socioeconomic status. The prevalence of antibodies was significantly lower in men than in women (63.1% versus 76.5%). These findings identify subpopulations who are at increased risk of primary cytomegalovirus infection during adulthood and may be candidates for future anti-cytomegalovirus vaccines.

The Occupational Risk of Cytomegalovirus Infection Among Day-care Providers

We prospectively studied day-care providers at six day-care centers in south-eastern Iowa to determine their occupational risk for primary cytomegalovirus infection and to define epidemiologic risk factors. Ninety-six (38%) of 252 day-care providers were seropositive for cytomegalovirus by latex agglutination at entry into the study. Among 82 seronegative providers available for follow-up, seven seroconversions occurred at only two of the six participating centers, yielding an annualized seroconversion rate of 7.9%. Median time to seroconversion among these providers was 13 months. Using Kaplan-Meier estimates of risk, we determined that the overall risk of seroconversion among providers at various centers ranged from 0% to 22% by 12 months and from 0% to 40% by 16 months. Risk of cytomegalovirus acquisition by providers was independent of race, age, education, the presence of a child at home, or caring for children younger than 2 or 3 years in the day-care center. However, the risk of seroconversion among day-care providers appeared to parallel rates of cytomegalovirus excretion and acquisition among children at each center.

Cytomegalovirus transmission in a Midwest day care center: Possible relationship to child care practices

The epidemiology of cytomegalovirus (CMV) infection and transmission in a large Iowa day care center was studied. Over the 9 months of the study the overall CMV prevalence rates were 21% to 22%, with rates as high as 71% in toddlers. Titers of CMV in the urine or saliva of infected children were as high as 3 X 10(4) plaque-forming units of CMV per milliliter, similar to titers of CMV observed in some congenitally infected infants. Restriction enzyme analysis of CMV isolates from children in the center demonstrated two major clusters with similar patterns, one among 2- and 3-year-old children and another among infants. The clustering of similar CMV isolates among nonambulatory infants suggests that child care or hygienic practices may contribute to the spread of CMV infection in day care centers. Furthermore, the relatively high prevalence of CMV excretion in this center and the low seropositivity rates to CMV among adults in Iowa suggest that adults in the Midwest who have contact with children in day care centers may be at risk for primary CMV infection.

Occupational risk for primary cytomegalovirus infection among pediatric healthcare workers: Dworsky, M. E. et al. 1983. N. Engl. J. Med. 309:950–953

Occupational risk for primary cytomegalovirus infection among pediatric healthcare workers: Dworsky, M. E. et al. 1983. N. Engl. J. Med. 309:950–953

Occupational risk for primary cytomegalovirus infection among pediatric health-care workers.

The risk of acquiring cytomegalovirus (CMV) from infected infants concerns pediatric health-care workers, particularly those who may be pregnant. We determined the prevalence of CMV antibody, and thus of past infection, in groups of medical students and house staff, nurses, and physicians, and in groups of pregnant and nonpregnant young women in the community. Although age, sex, and race influenced the results, occupation did not. We then estimated the exposure of the health-care workers by determining the prevalence of CMV infection in three groups of asymptomatic infants for whom they provided care; CMV was shed in urine or saliva of 1.6 per cent of newborns, 13 per cent of premature infants hospitalized for over a month, and 5 per cent of older infants seen in outpatient settings. When we determined the incidence of primary infection in the adult groups by retesting the seronegative members about two years later, we found that the annual attack rates in the medical students (0.6 per cent), house staff (2.7 per cent), and nurses (3.3 per cent) were not higher than in young women in the community (2.5 per cent during pregnancy and 5.5 per cent between pregnancies). We conclude that although pediatric health-care workers frequently and unknowingly care for infants shedding CMV, this occupational contact confers no greater risk than that faced by young women in the community at large.