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Cytomegalovirus (CMV) infection is the most common congenital viral infection in U.S. children, with a frequency between 0.5% and 1% of newborn infants resulting in approximately 30,000 infected children annually. A small minority (approximately 10%) can be identified in the neonatal period as symptomatic with jaundice (from direct hyperbilirubinemia), petechiae (from thrombocytopenia), hepatosplenomegaly, microcephaly, or other manifestations. The vast majority are asymptomatic at birth, yet 15% will have or develop sensorineural hearing loss (SNHL) during the first few years of life; others (1%-2%) will develop vision loss associated with retinal scars. Congenital CMV accounts for 20% of those with SNHL detected at birth and 25% of children with SNHL at 4 years of age.
Screening for congenital CMV has been an ongoing subject of debate. The challenges of implementing screening programs are related both to the diagnostics (collecting urine samples on newborns) as well as with the question of whether we have treatment and interventions to offer babies diagnosed with congenital CMV across the complete spectrum of clinical presentations.
Current screening programs implemented in some hospitals, called “targeted screening,” in which babies who fail newborn screening programs are tested for CMV, are not sufficient to achieve the goal of identifying babies who will need follow-up for early detection of SNHL or vision abnormalities, or possibly early antiviral therapy (Valcyte; valganciclovir), because only a small portion of those who eventually develop SNHL are currently identified by the targeted screening programs.1
However, its availability only has added to the debate as to whether the time has arrived for universal screening.
Vertical transmission of CMV occurs in utero (during any of the trimesters), at birth by passage through the birth canal, or postnatally by ingestion of breast milk. Neonatal infection (in utero and postnatal) occurs in both mothers with primary CMV infection during gestation and in those with recurrent infection (from a different viral strain) or reactivation of infection. Severe clinically symptomatic disease and sequelae is associated with primary maternal infection and early transmission to the fetus. However, it is estimated that nonprimary maternal infection accounts for 75% of neonatal infections. Transmission by breast milk to full-term, healthy infants does not appear to be associated with clinical illness or sequelae; however, preterm infants or those with birth weights less than 1,500 g have a small risk of developing clinical disease.
The polymerase chain reaction–based saliva CMV test (Alethia CMV Assay Test System) was licensed by the Food and Drug Administration in November 2018 after studies demonstrated high sensitivity and specificity, compared with viral culture (the gold standard). In one study, 17,327 infants were screened with the liquid-saliva PCR assay, and 0.5% tested positive for CMV on both the saliva test and culture. Sensitivity and specificity of the liquid-saliva PCR assay were 100% and 99.9%, respectively.2 The availability of an approved saliva-based assay that is both highly sensitive and specific overcomes the challenge of collecting urine, which has been a limiting factor in development of pragmatic universal screening programs. To date, most of the focus in identification of congenital CMV infection has been linking newborn hearing testing programs with CMV testing. For some, these have been labeled “targeted screening programs for CMV.” To us, these appear to be best practice for medical evaluations of an infant with identified SNHL. The availability of saliva-based CMV testing should enable virtually all children who fail newborn screening to be tested for CMV. In multiple studies,3,4 6% of infants with confirmed hearing screen failure tested positive for CMV. A recent study5 identified only 1 infant among the 171 infants who failed newborn screening, however only approximately 15% of the infants were eventually confirmed as hearing impaired at audiology follow-up, suggesting that programmatically testing for CMV might be limited to those with confirmed hearing loss if such can be accomplished within a narrow window of time.
The major challenge with linking CMV testing with newborn hearing screening is whether treatment with valganciclovir would be of value in congenital CMV infection and isolated hearing loss. Studies of children with symptomatic central nervous system congenital CMV disease provide evidence of improvement (or lack of progression) in hearing loss in those treated with valganciclovir. Few, if any of these children had isolated hearing loss in this pivotal study.6 An observational study reported improved outcomes in 55 of 59 (93%) children with congenital CMV and isolated SNHL treated with valganciclovir between birth to 12 weeks of life.7 Hearing improved in nearly 70% of ears, 27% showed no change, and only 3% demonstrated progression of hearing loss; most of the improved ears returned to normal hearing. Currently, a National Institutes of Health study (ValEAR) is recruiting CMV-infected infants with isolated SNHL and randomizing them to treatment with valganciclovir or placebo. The goal is to determine if infants treated with valganciclovir will have better hearing and language outcomes.
Linking CMV testing to those who fail newborn hearing screening programs is an important step, as it appears such children are at least five times more likely to be infected with CMV than is the overall birth cohort. However, such strategies fall short of identifying the majority of newborns with congenital CMV infection, who are completely asymptomatic yet are at risk for development of complications that potentially have substantial impact on their quality of life. Although the availability of sensitive and specific PCR testing in saliva provides a pragmatic approach to identify infected children, many questions remain. First, would a confirmatory test be necessary, such as urine PCR (now considered the gold standard by many CMV experts)? Second, once identified, what regimen for follow-up testing would be indicated to identify those with early SNHL or retinopathy, and until what age? Third, is there a role for treatment in asymptomatic infection? Would that treatment be prophylactic, prior to the development of clinical signs, or implemented once early evidence of SNHL or retinopathy is present?
The Valgan Toddler study – sponsored by NIH and the University of Alabama as part of the Collaborative Antiviral Study Group – will enroll children who are aged 1 month through 3 years and who had a recent diagnosis of hearing loss (within the prior 12 weeks) and evidence of congenital CMV infection. The purpose of this study is to compare the effect on hearing and neurologic outcomes in infants aged 1 month through 4 years with recent onset SNHL who receive 6 weeks of valganciclovir versus children who do not receive this drug. The results of such studies will be critical for the development of best practices.
In summary, the licensure of a rapid PCR-based tool for diagnosis of CMV infection from saliva adds to our ability to develop screening programs to detect asymptomatic infants with congenital CMV infection. The ability to link newborns who fail hearing screening programs with CMV testing will lead to more detection of CMV-infected neonates, both with isolated hearing loss, and subsequently with no signs or symptoms of infection. There is an urgent need for evidence from randomized clinical trials to enable the development of best practices for such infants.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and senior attending physician at Boston Medical Center. Dr. Lapidot is a senior fellow in pediatric infectious diseases, Boston Medical Center. Neither Dr. Pelton nor Dr. Lapidot have any relevant financial disclosures. Email them at pdnews@mdedge.com.
References
1. J Pediatric Infect Dis Soc. 2019 Mar 28;8(1):55-9.
2. N Engl J Med 2011 Jun 2; 364:2111-8.
3. Pediatrics. 2008 May;121(5):970-5
4. J Clin Virol. 2018 May;102:110-5.
5. J Pediatric Infect Dis Soc. 2019 Mar;8(1):55-9.
6. J Pediatr. 2003 Jul;143(1):16-25.
7. J Pediatr. 2018 Aug;199:166-70.
Cytomegalovirus (CMV) infection is the most common congenital viral infection in U.S. children, with a frequency between 0.5% and 1% of newborn infants resulting in approximately 30,000 infected children annually. A small minority (approximately 10%) can be identified in the neonatal period as symptomatic with jaundice (from direct hyperbilirubinemia), petechiae (from thrombocytopenia), hepatosplenomegaly, microcephaly, or other manifestations. The vast majority are asymptomatic at birth, yet 15% will have or develop sensorineural hearing loss (SNHL) during the first few years of life; others (1%-2%) will develop vision loss associated with retinal scars. Congenital CMV accounts for 20% of those with SNHL detected at birth and 25% of children with SNHL at 4 years of age.
Screening for congenital CMV has been an ongoing subject of debate. The challenges of implementing screening programs are related both to the diagnostics (collecting urine samples on newborns) as well as with the question of whether we have treatment and interventions to offer babies diagnosed with congenital CMV across the complete spectrum of clinical presentations.
Current screening programs implemented in some hospitals, called “targeted screening,” in which babies who fail newborn screening programs are tested for CMV, are not sufficient to achieve the goal of identifying babies who will need follow-up for early detection of SNHL or vision abnormalities, or possibly early antiviral therapy (Valcyte; valganciclovir), because only a small portion of those who eventually develop SNHL are currently identified by the targeted screening programs.1
However, its availability only has added to the debate as to whether the time has arrived for universal screening.
Vertical transmission of CMV occurs in utero (during any of the trimesters), at birth by passage through the birth canal, or postnatally by ingestion of breast milk. Neonatal infection (in utero and postnatal) occurs in both mothers with primary CMV infection during gestation and in those with recurrent infection (from a different viral strain) or reactivation of infection. Severe clinically symptomatic disease and sequelae is associated with primary maternal infection and early transmission to the fetus. However, it is estimated that nonprimary maternal infection accounts for 75% of neonatal infections. Transmission by breast milk to full-term, healthy infants does not appear to be associated with clinical illness or sequelae; however, preterm infants or those with birth weights less than 1,500 g have a small risk of developing clinical disease.
The polymerase chain reaction–based saliva CMV test (Alethia CMV Assay Test System) was licensed by the Food and Drug Administration in November 2018 after studies demonstrated high sensitivity and specificity, compared with viral culture (the gold standard). In one study, 17,327 infants were screened with the liquid-saliva PCR assay, and 0.5% tested positive for CMV on both the saliva test and culture. Sensitivity and specificity of the liquid-saliva PCR assay were 100% and 99.9%, respectively.2 The availability of an approved saliva-based assay that is both highly sensitive and specific overcomes the challenge of collecting urine, which has been a limiting factor in development of pragmatic universal screening programs. To date, most of the focus in identification of congenital CMV infection has been linking newborn hearing testing programs with CMV testing. For some, these have been labeled “targeted screening programs for CMV.” To us, these appear to be best practice for medical evaluations of an infant with identified SNHL. The availability of saliva-based CMV testing should enable virtually all children who fail newborn screening to be tested for CMV. In multiple studies,3,4 6% of infants with confirmed hearing screen failure tested positive for CMV. A recent study5 identified only 1 infant among the 171 infants who failed newborn screening, however only approximately 15% of the infants were eventually confirmed as hearing impaired at audiology follow-up, suggesting that programmatically testing for CMV might be limited to those with confirmed hearing loss if such can be accomplished within a narrow window of time.
The major challenge with linking CMV testing with newborn hearing screening is whether treatment with valganciclovir would be of value in congenital CMV infection and isolated hearing loss. Studies of children with symptomatic central nervous system congenital CMV disease provide evidence of improvement (or lack of progression) in hearing loss in those treated with valganciclovir. Few, if any of these children had isolated hearing loss in this pivotal study.6 An observational study reported improved outcomes in 55 of 59 (93%) children with congenital CMV and isolated SNHL treated with valganciclovir between birth to 12 weeks of life.7 Hearing improved in nearly 70% of ears, 27% showed no change, and only 3% demonstrated progression of hearing loss; most of the improved ears returned to normal hearing. Currently, a National Institutes of Health study (ValEAR) is recruiting CMV-infected infants with isolated SNHL and randomizing them to treatment with valganciclovir or placebo. The goal is to determine if infants treated with valganciclovir will have better hearing and language outcomes.
Linking CMV testing to those who fail newborn hearing screening programs is an important step, as it appears such children are at least five times more likely to be infected with CMV than is the overall birth cohort. However, such strategies fall short of identifying the majority of newborns with congenital CMV infection, who are completely asymptomatic yet are at risk for development of complications that potentially have substantial impact on their quality of life. Although the availability of sensitive and specific PCR testing in saliva provides a pragmatic approach to identify infected children, many questions remain. First, would a confirmatory test be necessary, such as urine PCR (now considered the gold standard by many CMV experts)? Second, once identified, what regimen for follow-up testing would be indicated to identify those with early SNHL or retinopathy, and until what age? Third, is there a role for treatment in asymptomatic infection? Would that treatment be prophylactic, prior to the development of clinical signs, or implemented once early evidence of SNHL or retinopathy is present?
The Valgan Toddler study – sponsored by NIH and the University of Alabama as part of the Collaborative Antiviral Study Group – will enroll children who are aged 1 month through 3 years and who had a recent diagnosis of hearing loss (within the prior 12 weeks) and evidence of congenital CMV infection. The purpose of this study is to compare the effect on hearing and neurologic outcomes in infants aged 1 month through 4 years with recent onset SNHL who receive 6 weeks of valganciclovir versus children who do not receive this drug. The results of such studies will be critical for the development of best practices.
In summary, the licensure of a rapid PCR-based tool for diagnosis of CMV infection from saliva adds to our ability to develop screening programs to detect asymptomatic infants with congenital CMV infection. The ability to link newborns who fail hearing screening programs with CMV testing will lead to more detection of CMV-infected neonates, both with isolated hearing loss, and subsequently with no signs or symptoms of infection. There is an urgent need for evidence from randomized clinical trials to enable the development of best practices for such infants.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and senior attending physician at Boston Medical Center. Dr. Lapidot is a senior fellow in pediatric infectious diseases, Boston Medical Center. Neither Dr. Pelton nor Dr. Lapidot have any relevant financial disclosures. Email them at pdnews@mdedge.com.
References
1. J Pediatric Infect Dis Soc. 2019 Mar 28;8(1):55-9.
2. N Engl J Med 2011 Jun 2; 364:2111-8.
3. Pediatrics. 2008 May;121(5):970-5
4. J Clin Virol. 2018 May;102:110-5.
5. J Pediatric Infect Dis Soc. 2019 Mar;8(1):55-9.
6. J Pediatr. 2003 Jul;143(1):16-25.
7. J Pediatr. 2018 Aug;199:166-70.
Cytomegalovirus (CMV) infection is the most common congenital viral infection in U.S. children, with a frequency between 0.5% and 1% of newborn infants resulting in approximately 30,000 infected children annually. A small minority (approximately 10%) can be identified in the neonatal period as symptomatic with jaundice (from direct hyperbilirubinemia), petechiae (from thrombocytopenia), hepatosplenomegaly, microcephaly, or other manifestations. The vast majority are asymptomatic at birth, yet 15% will have or develop sensorineural hearing loss (SNHL) during the first few years of life; others (1%-2%) will develop vision loss associated with retinal scars. Congenital CMV accounts for 20% of those with SNHL detected at birth and 25% of children with SNHL at 4 years of age.
Screening for congenital CMV has been an ongoing subject of debate. The challenges of implementing screening programs are related both to the diagnostics (collecting urine samples on newborns) as well as with the question of whether we have treatment and interventions to offer babies diagnosed with congenital CMV across the complete spectrum of clinical presentations.
Current screening programs implemented in some hospitals, called “targeted screening,” in which babies who fail newborn screening programs are tested for CMV, are not sufficient to achieve the goal of identifying babies who will need follow-up for early detection of SNHL or vision abnormalities, or possibly early antiviral therapy (Valcyte; valganciclovir), because only a small portion of those who eventually develop SNHL are currently identified by the targeted screening programs.1
However, its availability only has added to the debate as to whether the time has arrived for universal screening.
Vertical transmission of CMV occurs in utero (during any of the trimesters), at birth by passage through the birth canal, or postnatally by ingestion of breast milk. Neonatal infection (in utero and postnatal) occurs in both mothers with primary CMV infection during gestation and in those with recurrent infection (from a different viral strain) or reactivation of infection. Severe clinically symptomatic disease and sequelae is associated with primary maternal infection and early transmission to the fetus. However, it is estimated that nonprimary maternal infection accounts for 75% of neonatal infections. Transmission by breast milk to full-term, healthy infants does not appear to be associated with clinical illness or sequelae; however, preterm infants or those with birth weights less than 1,500 g have a small risk of developing clinical disease.
The polymerase chain reaction–based saliva CMV test (Alethia CMV Assay Test System) was licensed by the Food and Drug Administration in November 2018 after studies demonstrated high sensitivity and specificity, compared with viral culture (the gold standard). In one study, 17,327 infants were screened with the liquid-saliva PCR assay, and 0.5% tested positive for CMV on both the saliva test and culture. Sensitivity and specificity of the liquid-saliva PCR assay were 100% and 99.9%, respectively.2 The availability of an approved saliva-based assay that is both highly sensitive and specific overcomes the challenge of collecting urine, which has been a limiting factor in development of pragmatic universal screening programs. To date, most of the focus in identification of congenital CMV infection has been linking newborn hearing testing programs with CMV testing. For some, these have been labeled “targeted screening programs for CMV.” To us, these appear to be best practice for medical evaluations of an infant with identified SNHL. The availability of saliva-based CMV testing should enable virtually all children who fail newborn screening to be tested for CMV. In multiple studies,3,4 6% of infants with confirmed hearing screen failure tested positive for CMV. A recent study5 identified only 1 infant among the 171 infants who failed newborn screening, however only approximately 15% of the infants were eventually confirmed as hearing impaired at audiology follow-up, suggesting that programmatically testing for CMV might be limited to those with confirmed hearing loss if such can be accomplished within a narrow window of time.
The major challenge with linking CMV testing with newborn hearing screening is whether treatment with valganciclovir would be of value in congenital CMV infection and isolated hearing loss. Studies of children with symptomatic central nervous system congenital CMV disease provide evidence of improvement (or lack of progression) in hearing loss in those treated with valganciclovir. Few, if any of these children had isolated hearing loss in this pivotal study.6 An observational study reported improved outcomes in 55 of 59 (93%) children with congenital CMV and isolated SNHL treated with valganciclovir between birth to 12 weeks of life.7 Hearing improved in nearly 70% of ears, 27% showed no change, and only 3% demonstrated progression of hearing loss; most of the improved ears returned to normal hearing. Currently, a National Institutes of Health study (ValEAR) is recruiting CMV-infected infants with isolated SNHL and randomizing them to treatment with valganciclovir or placebo. The goal is to determine if infants treated with valganciclovir will have better hearing and language outcomes.
Linking CMV testing to those who fail newborn hearing screening programs is an important step, as it appears such children are at least five times more likely to be infected with CMV than is the overall birth cohort. However, such strategies fall short of identifying the majority of newborns with congenital CMV infection, who are completely asymptomatic yet are at risk for development of complications that potentially have substantial impact on their quality of life. Although the availability of sensitive and specific PCR testing in saliva provides a pragmatic approach to identify infected children, many questions remain. First, would a confirmatory test be necessary, such as urine PCR (now considered the gold standard by many CMV experts)? Second, once identified, what regimen for follow-up testing would be indicated to identify those with early SNHL or retinopathy, and until what age? Third, is there a role for treatment in asymptomatic infection? Would that treatment be prophylactic, prior to the development of clinical signs, or implemented once early evidence of SNHL or retinopathy is present?
The Valgan Toddler study – sponsored by NIH and the University of Alabama as part of the Collaborative Antiviral Study Group – will enroll children who are aged 1 month through 3 years and who had a recent diagnosis of hearing loss (within the prior 12 weeks) and evidence of congenital CMV infection. The purpose of this study is to compare the effect on hearing and neurologic outcomes in infants aged 1 month through 4 years with recent onset SNHL who receive 6 weeks of valganciclovir versus children who do not receive this drug. The results of such studies will be critical for the development of best practices.
In summary, the licensure of a rapid PCR-based tool for diagnosis of CMV infection from saliva adds to our ability to develop screening programs to detect asymptomatic infants with congenital CMV infection. The ability to link newborns who fail hearing screening programs with CMV testing will lead to more detection of CMV-infected neonates, both with isolated hearing loss, and subsequently with no signs or symptoms of infection. There is an urgent need for evidence from randomized clinical trials to enable the development of best practices for such infants.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and senior attending physician at Boston Medical Center. Dr. Lapidot is a senior fellow in pediatric infectious diseases, Boston Medical Center. Neither Dr. Pelton nor Dr. Lapidot have any relevant financial disclosures. Email them at pdnews@mdedge.com.
References
1. J Pediatric Infect Dis Soc. 2019 Mar 28;8(1):55-9.
2. N Engl J Med 2011 Jun 2; 364:2111-8.
3. Pediatrics. 2008 May;121(5):970-5
4. J Clin Virol. 2018 May;102:110-5.
5. J Pediatric Infect Dis Soc. 2019 Mar;8(1):55-9.
6. J Pediatr. 2003 Jul;143(1):16-25.
7. J Pediatr. 2018 Aug;199:166-70.