Early childhood outcomes of NICU graduates with cytomegalovirus infection in California.

BACKGROUND: To assess demographics and outcomes up to 3 years of age among children with cytomegalovirus (CMV) infection in California neonatal intensive care units (NICUs) during 2010-2021. METHODS: The California Perinatal Quality Care Collaborative (CPQCC) collects data on all very low birth weight (VLBW, birth weight ≤ 1500 g) and acutely ill infants with birth weight > 1500 g across 92% of NICUs in California. VLBW infants and those with neurological conditions are referred to a statewide high-risk infant follow-up (HRIF) program. CMV infection was defined as a positive culture or PCR identified during the NICU hospitalization. RESULTS: During 2010-2021, CMV reporting rates averaged 3.5/1000 VLBW infants (n = 205) and 1.1/1000 infants >1500 g (n = 128). Among all 333 infants with CMV, 314 (94%) were discharged home alive, 271 (86%) were referred for HRIF and 205 (65%) had ≥1 visit. Whereas infants born to mothers <20 years of age had highest CMV reporting rates and those born to Hispanic mothers comprised 49% of all infected infants, they had the highest loss of follow-up. At the 12-month visit (n = 152), 19 (13%) infants with CMV had bilateral blindness and 18 (12%) had hearing loss. At the 24-month visit, 5 (5%) of 103 had severe cerebral palsy. CONCLUSIONS: Among infants admitted to the NICU, those with CMV diagnoses may over represent infants with more severe CMV disease and outcomes. The CPQCC and HRIF program findings may help inform implementation of surveillance for congenital CMV infection in other U.S. states and guide strategies to reduce disparities in access to services.

Detection of Cytomegalovirus in Urine Dried on Filter Paper.

Urine is the best specimen for the diagnosis of congenital cytomegalovirus, but collection and processing of liquid urine are impractical for screening. Urine dried on filter paper was processed by the same convenient, low-cost method used by newborn screening to test blood spots and showed high sensitivity and specificity.

Economic assessments of the burden of congenital cytomegalovirus infection and the cost-effectiveness of prevention strategies.

OBJECTIVE: This is a critical review of published economic analyses on congenital cytomegalovirus infection and strategies for its detection and prevention. FINDINGS: The review identified four cost-of-illness studies and nine cost-effectiveness analyses: three of vaccination of young women, two of prenatal screening, and four of newborn screening. All reported either large economic costs or favorable cost-effectiveness of interventions. However, sensitivity analyses did not address some of the most critical assumptions. CONCLUSIONS: Reviewed economic analyses overattributed certain adverse long-term outcomes to congenital cytomegalovirus infection, while other long-term costs were not included. Overall, limited conceptual frameworks, unrepresentative data sources, and unsupported or inadequately documented assumptions regarding outcomes and costs hinder the ability of policymakers to draw conclusions. A major challenge is the limited information on long-term outcomes and costs for representative cohorts of individuals with congenital cytomegalovirus, which further research could helpfully address.

Sensitivity of Dried Blood Spot Testing for Detection of Congenital Cytomegalovirus Infection.

Importance: The sensitivity of dried blood spots (DBS) to identify newborns with congenital cytomegalovirus (cCMV) infection has not been evaluated in screening studies using the current, higher-sensitivity methods for DBS processing. Objective: To assess the sensitivity of DBS polymerase chain reaction (PCR) for newborn screening for cCMV infection using saliva as the reference standard for screening, followed by collection of a urine sample for confirmation of congenital infection. Design, Setting, and Participants: This population-based cohort study took place at 5 newborn nurseries and 3 neonatal intensive care units in the Minneapolis/Saint Paul area in Minnesota from April 2016 to June 2019. Newborns enrolled with parental consent were screened for cCMV using DBS obtained for routine newborn screening and saliva collected 1 to 2 days after birth. Dried blood spots were tested for CMV DNA by PCR at both the University of Minnesota (UMN) and the US Centers for Disease Control and Prevention (CDC). Saliva swabs were tested by CMV DNA PCR at the UMN laboratory only. Newborns who screened positive by saliva or DBS had a diagnostic urine sample obtained by primary care professionals, tested by PCR within 3 weeks of birth. Analysis began July 2019. Exposures: Detection of CMV from a saliva swab using a PCR assay. Main Outcomes and Measures: Number of children with urine-confirmed cCMV and the proportion of them who were CMV positive through DBS screening. Results: Of 12 554 individuals enrolled through June 2019 (of 25 000 projected enrollment), 56 newborns were confirmed to have cCMV (4.5 per 1000 [95% CI, 3.3-5.7]). Combined DBS results from either UMN or CDC had a sensitivity of 85.7% (48 of 56; 95% CI, 74.3%-92.6%), specificity of 100.0% (95% CI, 100.0%-100.0%), positive predictive value (PPV) of 98.0% (95% CI, 89.3%-99.6%), and negative predictive value (NPV) of 99.9% (95% CI, 99.9%-100.0%). Dried blood spot results from UMN had a sensitivity of 73.2% (95% CI, 60.4%-83.0%), specificity of 100.0% (100.0%-100.0%), PPV of 100.0% (95% CI, 91.4%-100.0%), and NPV of 99.9% (95% CI, 99.8%-99.9%). Dried blood spot results from CDC had a sensitivity of 76.8% (95% CI, 64.2%-85.9%), specificity of 100.0% (95% CI, 100.0%-100.0%), PPV of 97.7% (95% CI, 88.2%-99.6%), and NPV of 99.9% (95% CI, 99.8%-99.9%). Saliva swab results had a sensitivity of 92.9% (52 of 56; 95% CI, 83.0%-97.2%), specificity of 99.9% (95% CI, 99.9%-100.0%), PPV of 86.7% (95% CI, 75.8%-93.1%), and NPV of 100.0% (95% CI, 99.9%-100.0%). Conclusions and Relevance: This study demonstrates relatively high analytical sensitivity for DBS compared with previous studies that performed population-based screening. As more sensitive DNA extraction and PCR methods continue to emerge, DBS-based testing should remain under investigation as a potential low-cost, high-throughput option for cCMV screening.

Epidemiology of cytomegalovirus Infection among mothers and infants in Colombia.

We assessed maternal and infant cytomegalovirus (CMV) infection in Colombia. Maternal serum was tested for CMV immunoglobulin G antibodies at a median of 10 (interquartile range: 8-12) weeks gestation (n = 1501). CMV DNA polymerase chain reaction was performed on infant urine to diagnose congenital (≤21 days of life) and postnatal (>21 days) infection. Maternal CMV seroprevalence was 98.1% (95% confidence interval [CI]: 97.5%-98.8%). Congenital CMV prevalence was 8.4 (95% CI: 3.9%-18.3%; 6/711) per 1000 live births. Among 472 infants without confirmed congenital CMV infection subsequently tested at age 6 months, 258 (54.7%, 95% CI: 50.2%-59.1%) had postnatal infection.

Infiltrating Kaposi sarcoma presenting as acute kidney injury: An unexpected consequence of deliberate hepatitis C-positive organ transplantation.

Kaposi sarcoma (KS) following kidney transplantation can result from recipient reactivation of latent human herpesvirus 8 (HHV-8) infection or activation of donor-acquired HHV-8 infection. Post-transplant KS typically manifests with cutaneous pathology, but rare cases of renal allograft involvement have been reported. We describe two cases of donor-derived HHV-8 infection in two hepatitis C (HCV) viremia-negative transplant recipients who each received a kidney from a donor with HCV viremia. One recipient did not develop KS while the other presented with acute kidney injury caused by extensive KS infiltration of the renal parenchyma and metastatic disease. This report reviews the literature for cases of KS involving the renal allograft and highlights an unexpected consequence of deliberate HCV-positive organ transplantation.

Donor-derived human herpesvirus 8 and development of Kaposi sarcoma among 6 recipients of organs from donors with high-risk sexual and substance use behavior.

Kaposi sarcoma (KS) can develop following organ transplantation through reactivation of recipient human herpesvirus 8 (HHV-8) infection or through donor-derived HHV-8 transmission. We describe 6 cases of donor-derived HHV-8 infection and KS investigated from July 2018 to January 2020. Organs from 6 donors, retrospectively identified as HHV-8-positive, with a history of drug use disorder, were transplanted into 22 recipients. Four of 6 donors had risk factors for HHV-8 infection reported in donor history questionnaires. Fourteen of 22 organ recipients (64%) had evidence of posttransplant HHV-8 infection. Lung recipients were particularly susceptible to KS. Four of the 6 recipients who developed KS died from KS or associated complications. The US opioid crisis has resulted in an increasing number and proportion of organ donors with substance use disorder, and particularly injection drug use history, which may increase the risk of HHV-8 transmission to recipients. Better awareness of the risk of posttransplant KS for recipients of organs from donors with HHV-8 infection risk could be useful for recipient management. Testing donors and recipients for HHV-8 is currently challenging with no validated commercial serology kits available. Limited HHV-8 antibody testing is available through some US reference laboratories and the Centers for Disease Control and Prevention.

The impact of maternal HIV and malaria infection on the prevalence of congenital cytomegalovirus infection in Western Kenya.

BACKGROUND: Data on congenital cytomegalovirus (CMV) infection in Africa are limited. OBJECTIVE: To describe the prevalence of congenital CMV infection in a population with high prevalence of maternal HIV and malaria infection in western Kenya. STUDY DESIGN: We screened newborns for CMV by polymerase chain reaction assay of saliva swabs and dried blood spots (DBS), and assessed maternal CMV immunoglobulin G (IgG) status by testing serum eluted from newborn's DBS. We calculated adjusted prevalence ratios (aPRs) using log-binomial regression models. RESULTS: Among 1066 mothers, 210 (19·7%) had HIV infection and 207 (19·4%) had malaria infection; 33 (3·1%) mothers had both. Maternal CMV IgG prevalence was 93·1% (95% confidence interval [CI]: 88·3%-96·0%). Among 1078 newborns (12 sets of twins), 39 (3·6%, 95% CI: 2·7-4·9%) were CMV positive. The prevalence of congenital CMV infection by maternal HIV and malaria infection status was 5·0% (95% CI: 2·7-9·2%) for HIV only, 5·1% (95% CI: 2·7-9·4%) for malaria only, 8·8 (95% CI: 3·1-23·0) for HIV and malaria co-infection, and 2·6% (95% CI: 1·7-4·1%) for none. Congenital CMV infection was independently associated with maternal HIV infection (aPR=2·1; 95% CI: 1·0-4·2), adjusting for maternal age, parity, and malaria infection. CONCLUSIONS: The prevalence of congenital CMV infection was higher than the 0·2-0·7% in developed countries. Maternal HIV infection may increase the risk of congenital CMV infection, but the role of maternal malaria on intrauterine transmission of CMV remains unclear.

CMV on surfaces in homes with young children: results of PCR and viral culture testing.

BACKGROUND: Caring for young children is a known risk factor for cytomegalovirus (CMV) infection mainly through exposure to their saliva and urine. In a previous study, 36 CMV-seropositive children 2 mo. to 4 years old were categorized as CMV shedders (n = 23) or non-shedders (n = 13) based on detection of CMV DNA in their saliva and urine. The current study evaluated the presence of CMV on surfaces in homes of the children. METHODS: Study staff made 4 visits to homes of the 36 enrolled children over 100 days. Saliva was collected by swabbing the mouth and urine was collected on filter paper inserted into diapers. In addition, five surface specimens were collected: three in contact with children's saliva (spoon, child's cheek, washcloth) and two in contact with children's urine (diaper changing table, mother's hand). Samples were tested by PCR and viral culture to quantify the presence of CMV DNA and viable virus. RESULTS: A total of 654 surface samples from 36 homes were tested; 136 were CMV DNA positive, 122 of which (90%) were in homes of the children shedding CMV (p < 0.001). Saliva-associated samples were more often CMV positive with higher viral loads than urine-associated samples. The higher the CMV viral load of the child in the home, the more home surfaces that were PCR positive (p = 0.01) and viral culture positive (p = 0.05). CONCLUSIONS: The main source for CMV on surfaces in homes was saliva from the child in the home. Higher CMV viral loads shed by children correlated with more viable virus on surfaces which could potentially contribute to viral transmission.

Valganciclovir Use Among Commercially and Medicaid-insured Infants With Congenital CMV Infection in the United States, 2009-2015.

PURPOSE: The aim of this study was to assess the clinical characteristics and trends in valganciclovir use among infants diagnosed with congenital cytomegalovirus (CMV) disease in the United States. METHODS: We analyzed data from medical claims dated 2009-2015 from the Truven Health MarketScan® Commercial Claims and Encounters and Medicaid databases. We identified infants with a live birth code in the first claim who were continuously enrolled for at least 45 days. Among infants diagnosed with congenital CMV disease, identified by an ICD-9-CM or ICD-10-CM code for congenital CMV infection or CMV disease within 45 days of birth, we assessed data from claims containing codes for any CMV-associated clinical condition within the same period, and data from claims for hearing loss and/or valganciclovir within the first 180 days of life. FINDINGS: In the commercial and Medicaid databases, we identified 257 (2.5/10,000) and 445 (3.3/10,000) infants, respectively, diagnosed with congenital CMV disease, among whom 135 (53%) and 282 (63%) had ≥1 CMV-associated condition, 30 (12%) and 32 (7%) had hearing loss, and 41 (16%) and 78 (18%) had a claim for valganciclovir. Among infants with congenital CMV disease who had a claim for valganciclovir, 37 (90%) among commercially insured infants and 68 (87%) among Medicaid-insured infants had ≥1 CMV-associated condition and/or hearing loss. From 2009 to 2015, the percentages with a claim for valganciclovir increased from 0% to 29% among commercially insured infants and from 4% to 37% among Medicaid-insured infants (P < 0.0001). IMPLICATIONS: During 2009-2015, there was a strong upward trend in valganciclovir claims among insured infants who were diagnosed with congenital CMV disease, the majority of whom had CMV-associated conditions and/or hearing loss.

Urinary Cytomegalovirus Shedding in the United States: The National Health and Nutrition Examination Surveys, 1999-2004.

Background: There are no data on the prevalence of cytomegalovirus (CMV) shedding from a representative sample of the US population. This information is critical for understanding and preventing CMV. Methods: We tested urine specimens from CMV immunoglobulin (Ig) G-positive participants aged 6-49 years in 3 racial/ethnic groups from the National Health and Nutrition Examination Surveys 1999-2004 for the presence of CMV DNA using real-time polymerase chain reaction assay. We examined the association of sociodemographic characteristics with shedding prevalence and viral loads. Results: Among 6828 CMV IgG-positive participants tested, 537 had CMV DNA detected in urine-a shedding prevalence of 9.70%. Among persons aged 6-49 years, shedding prevalence was 3.83%. The prevalence of urinary shedding was inversely associated with increasing age (26.60%, 6.50%, and 3.45% in CMV IgG-positive participants aged 6-11, 12-19, and 20-49 years, respectively; P < .001 for trend test and pairwise comparisons). Urinary viral load also decreased significantly with age (mean, 2.97, 2.69, and 2.43 log10 copies/mL in those age groups, respectively; P < .001 for trend test and pairwise comparisons). Conclusions: Urinary CMV shedding and viral loads decreased dramatically with age, likely reflecting higher rates of primary CMV infection and longer duration of shedding in younger individuals. The findings demonstrate that children aged 6-11 years continue to shed CMV at higher rates and viral loads than adolescents and adults and thus may still be an important source for CMV transmission.

Cohort study on maternal cytomegalovirus seroprevalence and prevalence and clinical manifestations of congenital infection in China.

Congenital cytomegalovirus (CMV) infection is the leading viral cause of birth defects and developmental disabilities in developed countries. However, CMV seroprevalence and burden of congenital CMV infection are not well defined in China.Cohort of newborns from 5 birthing hospitals in 2 counties of Shandong Province, China, were enrolled from March 2011 to August 2013. Dried blood spots (DBS) and saliva were collected within 4 days after birth for IgG testing for maternal seroprevalence and real-time PCR testing for congenital CMV infection, respectively.Among 5020 newborns tested for CMV IgG, 4827 were seropositive, resulting in CMV maternal seroprevalence of 96.2% (95% confidence interval [CI]:95.6%-96.7%). Of the 10,933 newborns screened for congenital CMV infection, 75 had CMV detected, resulting in an overall prevalence of 0.7% (95% CI: 0.5%-0.9%), with prevalences of 0.4% (14/3995), 0.6% (66/10,857), and 0.7% (52/7761) for DBS, wet saliva, and dried saliva specimens screened, respectively. Prevalence of congenital CMV infection decreased with increasing maternal age (0.9%, 0.6%, and 0.3% among newborns delivered from mothers aged 16-25, 26-35, and >35 years, respectively; P = 0.03), and was higher among preterm infants than full term infants (1.3% vs 0.6%, P = 0.04), infants with intrauterine growth restriction (IUGR) than those without (1.8% vs 0.7%, P = 0.03), and twins or triplets than singleton pregnancies (2.8% vs 0.7%, P = 0.04). None of the 75 newborns exhibited symptomatic congenital CMV infection, and there was no difference in clinical characteristics and newborn hearing screening results between infants with and without congenital CMV infection at birth.Congenital CMV infection prevalence was lower and the clinical manifestations were milder in this relatively developed region of China compared to populations from other countries with similarly high maternal seroprevalence. Follow-up on children with congenital CMV infection will clarify the burden of disabilities from congenital CMV infection in China.

Cytomegalovirus IgM Seroprevalence among Women of Reproductive Age in the United States.

Cytomegalovirus (CMV) IgM indicates recent active CMV infection. CMV IgM seroprevalence is a useful marker for prevalence of transmission. Using data from the National Health and Nutrition Examination Survey (NHANES) III 1988-1994, we present estimates of CMV IgM prevalence by race/ethnicity, provide a comparison of IgM seroprevalence among all women and among CMV IgG positive women, and explore factors possibly associated with IgM seroprevalence, including socioeconomic status and exposure to young children. There was no difference in IgM seroprevalence by race/ethnicity among all women (3.1%, 2.2%, and 1.6% for non-Hispanic white, non-Hispanic black and Mexican American, respectively; P = 0.11). CMV IgM seroprevalence decreased significantly with increasing age in non-Hispanic black women (P<0.001 for trend) and marginally among Mexican American women (P = 0.07), while no apparent trend with age was seen in non-Hispanic white women (P = 0.99). Among 4001 IgG+ women, 118 were IgM+, resulting in 4.9% IgM seroprevalence. In IgG+ women, IgM seroprevalence varied significantly by age (5.3%, 7.3%, and 3.7% for women of 12-19, 20-29, and 30-49 years; P = 0.04) and race/ethnicity (6.1%, 2.7%, and 2.0% for non-Hispanic white, non-Hispanic black, and Mexican American; P<0.001). The factors reported associated with IgG seroprevalence were not associated with IgM seroprevalence. The patterns of CMV IgM seroprevalence by age, race/ethnicity, and IgG serostatus may help understanding the epidemiology of congenital CMV infection as a consequence of vertical transmission and are useful for identifying target populations for intervention to reduce CMV transmission.