Publications by authors named "Suresh B Boppana"

56 Publications

Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines.

Methods Mol Biol 2021 ;2244:403-463

Departments of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA.

Human cytomegalovirus is the largest human herpesvirus and shares many core features of other herpesviruses such as tightly regulated gene expression during genome replication and latency as well as the establishment of lifelong persistence following infection. In contrast to stereotypic clinical syndromes associated with alpha-herpesvirus infections, almost all primary HCMV infections are asymptomatic and acquired early in life in most populations in the world. Although asymptomatic in most individuals, HCMV is a major cause of disease in hosts with deficits in adaptive and innate immunity such as infants who are infected in utero and allograft recipients following transplantation. Congenital HCMV is a commonly acquired infection in the developing fetus that can result in a number of neurodevelopmental abnormalities. Similarly, HCMV is a major cause of disease in allograft recipients in the immediate and late posttransplant period and is thought to be a major contributor to chronic allograft rejection. Even though HCMV induces robust innate and adaptive immune responses, it also encodes a vast array of immune evasion functions that are thought aid in its persistence. Immune correlates of protective immunity that prevent or modify intrauterine HCMV infection remain incompletely defined but are thought to consist primarily of adaptive responses in the pregnant mother, thus making congenital HCMV a potentially vaccine modifiable disease. Similarly, HCMV infection in allograft recipients is often more severe in recipients without preexisting adaptive immunity to HCMV. Thus, there has been a considerable effort to modify HCMV specific immunity in transplant recipient either through active immunization or passive transfer of adaptive effector functions. Although efforts to develop an efficacious vaccine and/or passive immunotherapy to limit HCMV disease have been underway for nearly six decades, most have met with limited success at best. In contrast to previous efforts, current HCMV vaccine development has relied on observations of unique properties of HCMV in hopes of reproducing immune responses that at a minimum will be similar to that following natural infection. However, more recent findings have suggested that immunity following naturally acquired HCMV infection may have limited protective activity and almost certainly, is not sterilizing. Such observations suggest that either the induction of natural immunity must be specifically tailored to generate protective activity or alternatively, that providing targeted passive immunity to susceptible populations could be prove to be more efficacious.
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http://dx.doi.org/10.1007/978-1-0716-1111-1_19DOI Listing
April 2021

Severe Neonatal Coronavirus Disease 2019 Presenting as Acute Respiratory Distress Syndrome.

Pediatr Infect Dis J 2020 11;39(11):e367-e369

From the Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.

Since initial identification of severe acute respiratory syndrome coronavirus 2 in 2019, the virus has proved to be highly transmissible, resulting in a global pandemic with emerging reports of infected neonates. This report highlights a severe case of neonatal coronavirus disease 2019 with acute respiratory distress syndrome.
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http://dx.doi.org/10.1097/INF.0000000000002864DOI Listing
November 2020

Comparing Nasopharyngeal and Midturbinate Nasal Swab Testing for the Identification of Severe Acute Respiratory Syndrome Coronavirus 2.

Clin Infect Dis 2021 04;72(7):1253-1255

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Testing of paired midturbinate (MT) nasal and nasopharyngeal (NP) swabs, collected by trained personnel from 40 patients with coronavirus disease 2019 (COVID-19), showed that more NP (76/95 [80%]) than MT swabs tested positive (61/95 [64%]) (P = .02). Among samples collected a week after study enrollment, fewer MT than NP samples were positive (45% vs 76%; P = .001).
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http://dx.doi.org/10.1093/cid/ciaa882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337631PMC
April 2021

Clinical Diagnostic Testing for Human Cytomegalovirus Infections.

J Infect Dis 2020 03;221(Suppl 1):S74-S85

Viral Vaccine Preventable Diseases Branch, Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Human cytomegalovirus (HCMV) infections are among the most common complications arising in transplant patients, elevating the risk of various complications including loss of graft and death. HCMV infections are also responsible for more congenital infections worldwide than any other agent. Congenital HCMV (cCMV) infections are the leading nongenetic cause of sensorineural hearing loss and a source of significant neurological disabilities in children. While there is overlap in the clinical and laboratory approaches to diagnosis of HCMV infections in these settings, the management, follow-up, treatment, and diagnostic strategies differ considerably. As yet, no country has implemented a universal screening program for cCMV. Here, we summarize the issues, limitations, and application of diagnostic strategies for transplant recipients and congenital infection, including examples of screening programs for congenital HCMV that have been implemented at several centers in Japan, Italy, and the United States.
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http://dx.doi.org/10.1093/infdis/jiz601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057790PMC
March 2020

Correction to: Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2020 Feb 10;20(1):111. Epub 2020 Feb 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

After publication of the original article [1], we were notified that Fig. 3 has "Fig. 1" posted on the top of it and Figs. 4 and 5 have "Genomic Position" in a different spot.
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http://dx.doi.org/10.1186/s12879-020-4766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008528PMC
February 2020

Performance of the Alethia CMV Assay for Detection of Cytomegalovirus by Use of Neonatal Saliva Swabs.

J Clin Microbiol 2020 03 25;58(4). Epub 2020 Mar 25.

Meridian Bioscience Inc., Cincinnati, Ohio, USA.

Congenital cytomegalovirus (cCMV) infection is a major cause of childhood hearing loss and neurodevelopmental delay. Identification of newborns with cCMV infection allows provision of beneficial interventions. However, most infants with cCMV infection have subclinical infection and go undiagnosed. Thus, expanded neonatal CMV testing is increasingly recommended. Saliva is an attractive sample type for CMV testing of newborns, because it is easier to collect than urine and more sensitive for CMV detection than dried blood spots. We evaluated the Alethia CMV assay, a rapid, easy-to-use loop-mediated isothermal amplification method for qualitative detection of CMV DNA in neonatal saliva samples. Saliva swabs were collected prospectively from newborns <21 days old and tested by the Alethia assay according to the manufacturer's instructions. Archived saliva swabs from newborns with cCMV infection were also tested retrospectively. A composite reference method (CRM; two validated PCR assays followed by bidirectional sequencing of amplicons) was performed on all samples as the reference standard comparator. Of 1,480 prospectively collected saliva swabs, 1,472 (99.5%) were negative by both the Alethia assay and CRM, 5 (0.34%) were positive by both the Alethia assay and CRM, and 3 (0.20%) were positive only by the Alethia assay. All 34 (100%) archived swabs from newborns with cCMV infection were positive by both the CRM and the Alethia assay. Overall, the Alethia assay showed 100% and 99.8% positive and negative agreement with the CRM, respectively. The Alethia CMV assay is an accurate method for identifying neonates with cCMV infection and, given its simplicity, appears suitable for CMV testing using neonatal saliva outside a reference laboratory, including remote and resource-limited settings.
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http://dx.doi.org/10.1128/JCM.01951-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098765PMC
March 2020

Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2019 Dec 10;19(1):1046. Epub 2019 Dec 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

Background: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and a leading cause of long-term neurological and sensory sequelae, the most common being sensorineural hearing loss (SNHL). Despite extensive research, clinical or laboratory markers to identify CMV infected children with increased risk for disease have not been identified. This study utilizes viral whole-genome next generation-sequencing (NGS) of specimens from congenitally infected infants to explore viral diversity and specific viral variants that may be associated with symptomatic infection and SNHL.

Methods: CMV DNA from urine specimens of 30 infants (17 asymptomatic, 13 symptomatic) was target enriched and next generation sequenced resulting in 93% coverage of the CMV genome allowing analysis of viral diversity.

Results: Variant frequency distribution was compared between children with symptomatic and asymptomatic cCMV and those with (n = 13) and without (n = 17) hearing loss. The CMV genes UL48A, UL88, US19 and US22 were found to have an increase in nucleotide diversity in symptomatic children; while UL57, UL20, UL104, US14, UL115, and UL35 had an increase in diversity in children with hearing loss. An analysis of single variant differences between symptomatic and asymptomatic children found UL55 to have the highest number, while the most variants associated with SNHL were in the RL11 gene family. In asymptomatic infants with SNHL, mutations were observed more frequently in UL33 and UL20.

Conclusion: CMV genomes from infected newborns can be mapped to 93% of the genome at a depth allowing accurate and reproducible analysis of polymorphisms for variant and gene discovery that may be linked to symptomatic and hearing loss outcomes.
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http://dx.doi.org/10.1186/s12879-019-4681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905059PMC
December 2019

Cytomegalovirus Genetic Diversity Following Primary Infection.

J Infect Dis 2020 02;221(5):715-720

Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.

Background: Infection with multiple cytomegalovirus (CMV) strains (mixed infection) was reported in a variety of hosts. As the virus genetic diversity in primary CMV infection and the changes over time remain incompletely defined, we examined CMV diversity and changes in diversity over time in healthy adolescent females who participated in a phase 2 CMV gB/MF59 vaccine trial.

Methods: CMV genetic diversity was determined by genotyping of 5 genes-gB (UL55), gH (UL75), gN (UL73), US28, and UL144-in urine, saliva, and plasma samples from 15 study subjects.

Results: At the time of primary infection, 5 of 12 (42%) urine samples had multiple virus strains, and 50% of vaccine recipients were infected with gB1 genotype (vaccine strain). Mixed infection was documented in all 15 subjects within 3 months after primary infection, and the majority had different CMV genotypes in different compartments. Changes in genotypes over time were observed in all subjects.

Conclusions: Infection with multiple CMV genotypes was common during primary infection and further diversification occurred over time. Infection with gB1 genotype in vaccine recipients suggests a lack of strain-specific protection from the vaccine. As only 5 polymorphic genes were assessed, this study likely underestimated the true genetic diversity in primary CMV infection.
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http://dx.doi.org/10.1093/infdis/jiz507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026889PMC
February 2020

Contribution of Congenital Cytomegalovirus Infection to Permanent Hearing Loss in a Highly Seropositive Population: The Brazilian Cytomegalovirus Hearing and Maternal Secondary Infection Study.

Clin Infect Dis 2020 03;70(7):1379-1384

Department of Pediatrics, Otorhinolaryngology, and Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Background: The exact contribution of congenital cytomegalovirus infection (cCMVI) to permanent hearing loss (HL) in highly seropositive populations is unknown. We determined the contribution of cCMVI to HL and estimated the effectiveness of newborn hearing screening (HS) in identifying neonates with CMV-related HL.

Methods: A total of 11 900 neonates born from a population with ≥97% maternal seroprevalence were screened for cCMVI and HL. cCMVI was confirmed by detection of CMV-DNA in saliva and urine at age <3 weeks.

Results: Overall, 68 (0.6%; 95% confidence interval [CI], 0.4-0.7) neonates were identified with cCMVI. Of the 91 (0.8%) newborns who failed the HS, 24 (26.4%) were confirmed with HL, including 7 (29.2%; 95% CI, 17.2-59.3) with cCMVI. Another newborn with cCMVI passed the HS but was confirmed with HL at age 21 days. Of the 62 neonates with cCMVI who underwent a complete hearing evaluation, 8 (12.9%; 95% CI, 6.7-23.4) had HL and most (7/8; 87.5%; 95% CI, 46.6-99.7) were identified by HS. The rate of CMV-related HL was 8 per 11 887 neonates (0.7 per 1000 live births). The prevalence ratio of HL among neonates with cCMVI compared to CMV-uninfected neonates was 89.5 (95% CI, 39.7-202.0). No late-onset cCMVI-related HL was detected during a median follow-up of 36 months.

Conclusions: cCMVI is an important cause of HL in childhood in all settings. Integrating targeted cCMVI screening among neonates who fail a HS could be a reasonable, cost-effective strategy to identify newborns with early-onset cCMVI-related HL.
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http://dx.doi.org/10.1093/cid/ciz413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931844PMC
March 2020

Maternal Cytomegalovirus Infection and Fetal Impairment: Uncertainty Remains.

Clin Infect Dis 2020 01;70(1):174

Department of Pediatrics, University of Alabama at Birmingham, Tampa, Florida.

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http://dx.doi.org/10.1093/cid/ciz400DOI Listing
January 2020

Invasive Disease Caused by Haemophilus influenzae Type A.

Clin Pediatr (Phila) 2019 04 2;58(4):470-473. Epub 2019 Jan 2.

1 University of Alabama at Birmingham, AL, USA.

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http://dx.doi.org/10.1177/0009922818821887DOI Listing
April 2019

Vaccination against the human cytomegalovirus.

Vaccine 2019 11 3;37(50):7437-7442. Epub 2018 Apr 3.

UAB School of Medicine, CHB 114, 1600 7th Avenue South, Birmingham, AL 35233, United States. Electronic address:

The human cytomegalovirus (HCMV) is the most important infectious cause of congenital abnormalities and also of infectious complications of transplantation. The biology of the infection is complex and acquired immunity does not always prevent reinfection. Nevertheless, vaccine development is far advanced, with numerous candidate vaccines being tested, both live and inactivated. This article summarizes the status of the candidate vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2018.02.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892274PMC
November 2019

Congenital cytomegalovirus infection.

Semin Perinatol 2018 04 2;42(3):149-154. Epub 2018 Mar 2.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.

Each year, thousands of children are born with or develop permanent disabilities such as hearing loss, vision loss, motor and cognitive deficits from congenital CMV infection (cCMV). However, awareness of cCMV and its associated sequelae is very low in pregnant women and healthcare providers. Both targeted and universal approaches to screen newborns for CMV infection are now achievable due to recent scientific advances including the development of a rapid, high-throughput method for detecting CMV in saliva, the efficacy of antiviral treatment in symptomatic infants, and the demonstration of cost effectiveness of CMV screening. Future studies are needed to address gaps in our understanding on the role of non-primary maternal CMV infections, the evaluation of antiviral treatment in asymptomatic infants, and the implementation of prevention strategies for cCMV.
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http://dx.doi.org/10.1053/j.semperi.2018.02.002DOI Listing
April 2018

Contribution of Breastfeeding to False-Positive Saliva Polymerase Chain Reaction for Newborn Congenital Cytomegalovirus Screening.

J Infect Dis 2018 04;217(10):1612-1615

Department of Pediatrics, Philadelphia, Pennsylvania.

Real-time polymerase chain reaction (PCR) of saliva is highly sensitive for newborn congenital cytomegalovirus (CMV) screening. This study uses nationally published CMV seroprevalence and breastfeeding rates to estimate the contribution of CMV DNA in breast milk to false-positive saliva PCR results. The false-positive rates adjusted for breastfeeding ranged from 0.03% in white Hispanic persons to 0.14% in white non-Hispanic persons. Saliva CMV PCR for newborn screening is highly sensitive, and the low false-positive rates in this study suggest that saliva PCR results are unlikely to be significantly influenced by breastfeeding or other perinatal exposures.
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http://dx.doi.org/10.1093/infdis/jiy057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913650PMC
April 2018

Pathogenesis of Non-Zika Congenital Viral Infections.

J Infect Dis 2017 12;216(suppl_10):S912-S918

Division of Pediatric Infectious Diseases, University of Alabama at Birmingham.

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 from South and Central America and the Caribbean. Although the full spectrum of ZIKV infection of the newborn has yet to be determined, other maternal viral infections resulting in transmission to the fetus provide instructive lessons that can be applied to the prospective evaluation of individuals with ZIKV infection. This review focuses on those other congenital infections, including rubella, congenital cytomegalovirus, human immunodeficiency virus, hepatitis B virus, and neonatal herpes simplex virus, from which lessons for the evaluation of ZIKV in the newborn can be applied.
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http://dx.doi.org/10.1093/infdis/jix431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853682PMC
December 2017

Insight Into Long-term Neurodevelopmental Outcomes in Asymptomatic Congenital CMV Infection.

Pediatrics 2017 11;140(5)

Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama.

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http://dx.doi.org/10.1542/peds.2017-2526DOI Listing
November 2017

Breast Milk Human Cytomegalovirus (CMV) Viral Load and the Establishment of Breast Milk CMV-pp65-Specific CD8 T Cells in Human CMV Infected Mothers.

J Infect Dis 2017 11;216(9):1176-1179

Department of Medicine, University of Alabama at Birmingham.

The role of human cytomegalovirus (HCMV)-specific T-cell responses in breast milk of HCMV-seropositive mothers is not well defined. In these studies, we demonstrate that the frequency of cytomegalovirus (CMV)-pp65-specific T-cell responses in peripheral blood mononuclear cells (PBMCs) and breast milk cells (BMCs) is increased for CD8+ T cells in both sample sources when compared with CD4+ T cells. The frequency of pp55-specific CD8 T cells producing interferon γ (IFN-γ) alone or dual IFN-γ/granzyme rB producers is increased in breast milk compared with PBMCs. Lastly, we observed a positive correlation between breast milk viral load and the CD8 pp65-specific response, suggesting that local virus replication drives antigen-specific CD8 T cells into the breast.
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http://dx.doi.org/10.1093/infdis/jix457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853445PMC
November 2017

Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy.

Lancet Infect Dis 2017 06 11;17(6):e177-e188. Epub 2017 Mar 11.

Serology & Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, NSW, Australia.

Congenital cytomegalovirus is the most frequent, yet under-recognised, infectious cause of newborn malformation in developed countries. Despite its clinical and public health importance, questions remain regarding the best diagnostic methods for identifying maternal and neonatal infection, and regarding optimal prevention and therapeutic strategies for infected mothers and neonates. The absence of guidelines impairs global efforts to decrease the effect of congenital cytomegalovirus. Data in the literature suggest that congenital cytomegalovirus infection remains a research priority, but data are yet to be translated into clinical practice. An informal International Congenital Cytomegalovirus Recommendations Group was convened in 2015 to address these questions and to provide recommendations for prevention, diagnosis, and treatment. On the basis of consensus discussions and a review of the literature, we do not support universal screening of mothers and the routine use of cytomegalovirus immunoglobulin for prophylaxis or treatment of infected mothers. However, treatment guidelines for infected neonates were recommended. Consideration must be given to universal neonatal screening for cytomegalovirus to facilitate early detection and intervention for sensorineural hearing loss and developmental delay, where appropriate. The group agreed that education and prevention strategies for mothers were beneficial, and that recommendations will need continual updating as further data become available.
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http://dx.doi.org/10.1016/S1473-3099(17)30143-3DOI Listing
June 2017

Newborn Dried Blood Spot Polymerase Chain Reaction to Identify Infants with Congenital Cytomegalovirus-Associated Sensorineural Hearing Loss.

J Pediatr 2017 05 22;184:57-61.e1. Epub 2017 Feb 22.

Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL; Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL.

Objective: To determine the utility of dried blood spot (DBS) polymerase chain reaction (PCR) in identifying infants with cytomegalovirus (CMV) infection-associated sensorineural hearing loss (SNHL).

Study Design: Newborns at 7 US hospitals between March 2007 and March 2012 were screened for CMV by saliva rapid culture and/or PCR. Infected infants were monitored for SNHL during the first 4 years of life to determine sensitivity, specificity, and positive and negative likelihood ratios of DBS PCR for identifying CMV-associated SNHL.

Results: DBS at birth was positive in 11 of 26 children (42%) with SNHL at age 4 years and in 72 of 270 children (27%) with normal hearing (P = .11). The sensitivity (42.3%; 95% CI, 23.4%-63.1%) and specificity (73.3%; 95% CI, 67.6%-78.5%) was low for DBS PCR in identifying children with SNHL at age 4 years. The positive and negative likelihood ratios of DBS PCR positivity to detect CMV-associated SNHL at age 4 years were 1.6 (95% CI, 0.97-2.6) and 0.8 (95% CI, 0.6-1.1), respectively. There was no difference in DBS viral loads between children with SNHL and those without SNHL.

Conclusions: DBS PCR for CMV has low sensitivity and specificity for identifying infants with CMV-associated hearing loss. These findings, together with previous reports, demonstrate that DBS PCR does not identify either the majority of CMV-infected newborns or those with CMV-associated SNHL early in life.
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http://dx.doi.org/10.1016/j.jpeds.2017.01.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459403PMC
May 2017

A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening.

Pediatrics 2017 Feb 3;139(2). Epub 2017 Jan 3.

Department of Pediatrics and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.

Background And Objective: Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL).

Methods: Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss.

Results: Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period.

Conclusions: A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS.
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http://dx.doi.org/10.1542/peds.2016-2128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260148PMC
February 2017

Congenital Cytomegalovirus Infection and Permanent Hearing Loss in Rural North Indian Children.

Pediatr Infect Dis J 2017 07;36(7):670-673

From the *Department of Microbiology, †Department of Otolaryngology, ‡Department of Center for Community Medicine, and §Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India; ¶Department of Pediatrics, ‖Department of Epidemiology, and **Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Congenital cytomegalovirus infection (cCMV) is a leading nongenetic cause of permanent congenital or early-onset hearing loss (PCEHL). Although cCMV rates are high despite near-universal seroimmunity, the contribution of cCMV to PCEHL in the developing world is unclear.

Methods: Neonates at a rural North Indian hospital were screened for cCMV by saliva polymerase chain reaction and hearing by distortion-product otoacoustic emission testing. Cytomegalovirus (CMV)-positive infants and those not passing newborn hearing screening (NHS) were evaluated by auditory brainstem response to confirm PCEHL. Infants with cCMV and those with PCEHL were tested for mutations within the GJB2 gene.

Results: Of the 1720 infants screened, 40 (2.3%) did not pass NHS and 20 (1.2%) were CMV positive. Auditory brainstem evoked response testing confirmed unilateral or bilateral PCEHL in 11 (0.64%) children who either did not pass NHS or CMV positive. PCEHL was 20-fold higher in neonates with cCMV (2/20, 10%) than those without (9/1700, 0.5%; P < 0.01). None of 11 infants with PCEHL had connexin 26 mutations.

Conclusion: PCEHL incidence is high in India, with cCMV contributing significantly despite near-universal seroimmunity. Our findings also demonstrate the feasibility and the utility of simultaneous newborn screening for both cCMV and hearing loss in a resource-limited setting.
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http://dx.doi.org/10.1097/INF.0000000000001527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468472PMC
July 2017

Methicillin-resistant Staphylococcus aureus as a Cause of Lemierre's Syndrome.

Pediatr Infect Dis J 2017 04;36(4):429-431

From the Departments of*Pediatrics and †Microbiology, University of Alabama at Birmingham, AL; and ‡Department of Pediatrics, University of California, San Diego.

Lemierre's syndrome (LS) or jugular vein suppurative thrombophlebitis is well described in literature. The organisms most often responsible are Fusobacterium necrophorum or anaerobic flora. We present a case of LS with an atypical microbiologic cause, methicillin-resistant Staphylococcus aureus. We also present retrospective review of all LS cases from our institution and identified 2 additional children with LS caused by methicillin-resistant S. aureus.
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http://dx.doi.org/10.1097/INF.0000000000001460DOI Listing
April 2017

Cost-effectiveness of Universal and Targeted Newborn Screening for Congenital Cytomegalovirus Infection.

JAMA Pediatr 2016 12;170(12):1173-1180

Department of Pediatrics, University of Alabama, Birmingham9Department of Epidemiology, University of Alabama, Birmingham.

Importance: Congenital cytomegalovirus (cCMV) infection is a major cause of childhood deafness. Most cCMV infections are not diagnosed without newborn screening, resulting in missed opportunities for directed care.

Objective: To estimate the cost-effectiveness of universal and targeted newborn cCMV screening programs compared with no cCMV screening.

Design, Setting, And Participants: Models were constructed using rates and outcomes from prospective cohort studies of newborn cCMV screening in US postpartum care and early hearing programs. Costs of laboratory testing, treatment, and hearing loss were drawn from Medicaid data and published estimates. The benefits of cCMV screening were assumed to come from antiviral therapy for affected newborns to reduce hearing loss and from earlier identification of hearing loss with postnatal onset. Analyses were performed from July 2014 to March 2016.

Interventions: Models compared universal or targeted cCMV screening of newborns with a failed hearing screen, with standard care for cCMV infection.

Main Outcomes And Measures: The incremental costs of identifying 1 cCMV infection, identifying 1 case of cCMV-related hearing loss, and preventing 1 cochlear implant; the incremental reduction in cases of severe to profound hearing loss; and the differences in costs per infant screened by universal or targeted strategies under different assumptions about the effectiveness of antiviral treatment.

Results: Among all infants born in the United States, identification of 1 case of cCMV infection by universal screening was estimated to cost $2000 to $10 000; by targeted screening, $566 to $2832. The cost of identifying 1 case of hearing loss due to cCMV was as little as $27 460 by universal screening or $975 by targeted screening. Assuming a modest benefit of antiviral treatment, screening programs were estimated to reduce severe to profound hearing loss by 4.2% to 13% and result in direct costs of $10.86 per newborn screened. However, savings of up to $37.97 per newborn screened were estimated when costs related to functionality were included.

Conclusions And Relevance: Newborn screening for cCMV infection appears to be cost-effective under a wide range of assumptions. Universal screening offers larger net savings and the greatest opportunity to provide directed care. Targeted screening also appears to be cost-effective and requires testing for fewer newborns. These findings suggest that implementation of newborn cCMV screening programs is warranted.
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http://dx.doi.org/10.1001/jamapediatrics.2016.2016DOI Listing
December 2016

Clinical Predictors of Sensorineural Hearing Loss and Cognitive Outcome in Infants with Symptomatic Congenital Cytomegalovirus Infection.

Pediatr Infect Dis J 2016 Aug;35(8):924-6

From the *Division of General Pediatrics, Department of Pediatrics, University of Nebraska Medical Center/Children's Hospital and Medical Center, Omaha, Nebraska; †Division of Neonatology, Department of Pediatrics, Brookwood Medical Center, Birmingham, Alabama; and; ‡Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.

The objective of this study was to determine newborn clinical findings predictive of adverse clinical outcomes in infants with symptomatic congenital cytomegalovirus infection. Of 160 infants, significantly more children with central nervous system involvement had sensorineural hearing loss (P = 0.0007) and an IQ ≤70 (P < 0.0001) compared with infants with transient findings or only a petechial rash.
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http://dx.doi.org/10.1097/INF.0000000000001194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979986PMC
August 2016

Urine Collection Method for the Diagnosis of Congenital Cytomegalovirus Infection.

Pediatr Infect Dis J 2015 Aug;34(8):903-5

From the *Department of Pediatrics, †Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama; ‡Department of Pediatrics, Carolinas Medical Center, Charlotte, North Carolina; §Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi; ¶Department of Pediatrics, The Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania; ‖Department of Pediatrics, The Ohio State University-Nationwide Children's Hospital, Columbus, Ohio; **Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, Texas; ††Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio; ‡‡Saint Peter's University Hospital, New Brunswick, New Jersey; and §§Department of Epidemiology, The University of Alabama at Birmingham, Birmingham, Alabama.

Congenital cytomegalovirus infection is traditionally diagnosed by virus detection in saliva or urine. Virus culture was positive in significantly fewer urine samples collected using cotton balls in diapers (55.2%) than with samples collected by bags (93.2%) from newborns screened positive for CMV in saliva. However, polymerase chain reaction was positive in 95% of urine samples regardless of the collection method.
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http://dx.doi.org/10.1097/INF.0000000000000757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573797PMC
August 2015

Comparison of saliva PCR assay versus rapid culture for detection of congenital cytomegalovirus infection.

Pediatr Infect Dis J 2015 May;34(5):536-7

From the *University of Alabama at Birmingham, Birmingham, AL; †Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS; ‡Department of Pediatrics, Carolinas Medical Center, Charlotte, NC; §Department of Pediatrics, Saint Peter's University Hospital, New Brunswick, NJ; ¶Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH; ‖Department of Pediatrics, University of Pittsburgh and the Children's Hospital of Pittsburgh, Pittsburgh, PA; and **Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH.

As part of the CMV and Hearing Multicenter Screening (CHIMES) study, 72,239 newborns were screened for cytomegalovirus by rapid culture and real-time PCR of saliva samples. Of the 266 infants with congenital cytomegalovirus infection, discordance between rapid culture and PCR was observed in 14 children, and 13 were identified only by PCR, demonstrating the superiority of the PCR assay.
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http://dx.doi.org/10.1097/INF.0000000000000609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400866PMC
May 2015

Prevalence of congenital cytomegalovirus infection in Nigeria: a pilot study.

Pediatr Infect Dis J 2015 Mar;34(3):322-4

From the *Centre for Healthy Start Initiative, Lagos, Nigeria; †Department of Pediatrics, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota; ‡Department of Pediatrics; and §Department of Microbiology, University of Alabama at Birmingham, Alabama.

Dried saliva specimens from 263 neonates in Lagos, Nigeria, were tested for cytomegalovirus (CMV) using real-time polymerase chain reaction. The results for 10 infants (3.8%, 95% confidence interval, 2.1-6.8) were found to be positive. Congenital CMV infection was not associated with any of the demographic or maternal factors including HIV. These data demonstrate the high prevalence of congenital CMV infection and the feasibility of CMV screening by real-time polymerase chain reaction testing.
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http://dx.doi.org/10.1097/INF.0000000000000555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352715PMC
March 2015

Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens.

J Infect Dis 2014 Nov 5;210(9):1415-8. Epub 2014 May 5.

Department of Pediatrics Department of Microbiology.

Viral culture of urine or saliva has been the gold standard technique for the diagnosis of congenital cytomegalovirus (CMV) infection. Results of rapid culture and polymerase chain reaction (PCR) analysis of urine and saliva specimens from 80 children were compared to determine the clinical utility of a real-time PCR assay for diagnosis of congenital CMV infection. Results of urine PCR were positive in 98.8% of specimens. Three PCR-positive urine samples were culture negative. Results of saliva PCR and culture were concordant in 78 specimens (97.5%). Two PCR-positive saliva samples were culture negative. These findings demonstrate that PCR performs as well as rapid culture of urine or saliva specimens for diagnosing congenital CMV infection and saliva specimens are easier to collect. Because PCR also offers more rapid turnaround, is unlikely to be affected by storage and transport conditions, has lower cost, and may be adapted to high-throughput situations, it is well suited for targeted testing and large-scale screening for CMV.
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http://dx.doi.org/10.1093/infdis/jiu263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271051PMC
November 2014

Recent approaches and strategies in the generation of antihuman cytomegalovirus vaccines.

Methods Mol Biol 2014 ;1119:311-48

Departments of Pediatrics and Microbiology, The University of Alabama at Birmingham, Birmingham, AL, USA.

The development of prophylactic and to lesser extent therapeutic vaccines for the prevention of disease associated with human cytomegalovirus (HCMV) infections has received considerable attention from biomedical researchers and pharmaceutical companies over the previous 15 years, even though attempts to produce such vaccines have been described in the literature for over 40 years. Studies of the natural history of congenital HCMV infection and infection in allograft recipients have suggested that prophylaxis of disease associated with HCMV infection could be possible, particularly in hosts at risk for more severe disease secondary to the lack of preexisting immunity. Provided a substantial understanding of immune response to HCMV together with several animal models that faithfully recapitulate aspects of human infection and immunity, investigators seem well positioned to design and test candidate vaccines. Yet more recent studies of the role of a maternal immunity in the natural history of congenital HCMV infection, including the recognition that reinfection of previously immune women by genetically distinct strains of HCMV occur in populations with a high seroprevalence, have raised several questions about the nature of protective immunity in maternal populations. This finding coupled with observations that have documented a significant incidence of damaging congenital infections in offspring of women with immunity to HCMV prior to conception has suggested that vaccine development based on conventional paradigms of adaptive immunity to viral infections may be of limited value in the prevention of damaging congenital HCMV infections. Perhaps a more achievable goal will be prophylactic vaccines to modify HCMV associated disease in allograft transplant recipients. Although recent descriptions of the results from vaccine trials have been heralded as evidence of an emerging success in the quest for a HCMV vaccine, careful analyses of these studies have also revealed that major hurdles remain to be addressed by current strategies.
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http://dx.doi.org/10.1007/978-1-62703-788-4_17DOI Listing
November 2014