Who actually gains from nationwide new born diagnosis for cerebral cytomegalovirus illness

Editorial Who Actually Gains from Nationwide New Born Diagnosis for Cerebral Cytomegalovirus Illness? Jourdes Jary Waniel* National University of Singapore, Singapore *Corresponding Author : Jourdes Jary Waniel, Adjunct Associate Professor, Duke-NUS Medical School and Yong Loo Lin School of Medicine, National University of Singapore, Sin- gapore. Received : October 22, 2023 Accepted: October 23, 2023 Published : November 25, 2023 Editorial Congenital hypothyroidism (0.25–0.5 per 1000) and sensori- neural hearing loss (SNHL, 1.1/1000 neonates) are less com- mon than congenital cytomegalovirus (cCMV) infection, which has a higher reported prevalence of 6/1000 newborns [1-3]. Similar to the range of SNHL severities found in newborn hear- ing screens, which range from mild unilateral loss to bilateral profound hearing loss, cCMV also presents with a wide range of outcomes, such as varying degrees of SNHL loss, visual im- pairment, developmental delay, and cognitive impairments [4]. Children that are affected may also not show many symptoms. The diagnosis of cCMV infection may only be made within a spe- cific timeframe, which makes it distinct from other infections. It will become impossible to differentiate between congenital and postnatal infections after 3–4 weeks, as the former typically does not result in negative consequences to hearing, vision, or development. The use of polymerase chain reaction with dried blood spots obtained at or soon after birth for screening of met- abolic diseases is the only way to address this diagnostic conun- drum in the absence of newborn CMV screening, despite the fact that Ross et al. have demonstrated that this method has low sensitivity and specificity for identifying cCMV [5,6]. Which kids will benefit from cCMV screening universally? Of the 25488 children with cCMV, only 3262 (12.8%) were symptomatic at birth, according to estimates made by Cannon et al [1]. Only 815 of them would have a clinical diagnosis of cCMV at delivery. These kids will not gain anything from screening. Additional- ly, it was shown by Dollard et al. that 8.10 cCMV babies had a 12.7% symptom rate [7]. Regretfully, a systematic method for diagnosing symptomatic cCMV at birth does not exist. Not one of the symptoms is unique to cCMV; instead, there are several that are related to the brain (microcephaly, seizures), growth (intrauterine growth retardation [IUGR]), haematological and systemic involvement (petechia, jaundice, anaemia, splenomeg- aly, hepatomegaly), and respiratory infection (pneumonia). The amount of symptoms that require cCMV study in the various clinical contexts affects clinical diagnosis as well. Dollard et al. ruled out IUGR, a sign that infected newborns frequently expe- rience [7]. However, Rivera et al. demonstrated that IUGR was a separate risk factor for congenital or late-onset hearing loss in cases of symptomatic cCMV infection [8]. In order to identify a symptomatic disease and recruit participants for the valgan- cylovir therapy of cCMV trial, Kimberlin et al. took into account at least one or more of a set of symptoms [9]. It follows that a large number of kids with vague or minimal symptoms would not receive a diagnosis. According to Cannon et al., 87.2 percent of cCMV are asymptomatic at birth and would go undiagnosed if universal screening wasn’t implemented, and 75% of children with symptomatic cCMV are not clinically diagnosed as CMV at birth. Sensorineural Hearing loss Kennedy et al. came to the conclusion that newborn CMV screening would be beneficial for these children because their research demonstrated that children diagnosed prior to this age had considerably higher receptive and expressive language scores than those diagnosed later. Between the ages of 9 and 24 months, 256 (1%) children were identified as having hearing loss [11]. They came to the conclusion that SNHL would be de- tected earlier than if CMV had gone undiagnosed, and that new born screening would therefore also help this group [12] using www.directivepublications.org Page - 1 The Journal of Clinical Pathology

Editorial data from the pre-new born hearing screening era, when only 18% of children were diagnosed before the age of 2 years. Is it possible to identify newborns with SNHL who would benefit from antiviral treatment through newborn screening? Children with SNHL and CNS involvement participated in the first phase III randomised control trial of Gancylovir therapy, which demon- strated improvement in hearing outcomes after six months of treatment [13]. Given the high probability of a clinical diagno- sis in the context of CNS involvement, newborn screening may not be beneficial for this group. Infants having one symptom at least, possibly more, were included in a later trial by Kimberlin et al. using valganciclovir [9]. One of the symptoms may have been hearing loss alone. This work opens the prospect of treat- ing isolated SNHL, even if the authors later stated that children with only SNHL without additional clinical evidence of symptom- atic disease were not enrolled in substantial numbers [14]. 75% of symptomatic newborns (2447 infants, or 9.6% of the entire cohort) did not receive a cCMV diagnosis, according to research by Cannon et al. [1]. Hence, treatment may have been beneficial for the 2447 symptomatic but undiagnosed cCMV infants (14.5 percent of all infants with cCMV) and the 1245 asymptomatic but SNHL at birth children, as Kimberlin et al. demonstrated that a 6-month course improved hearing outcomes at 12 and 24 months in comparison to a 6-week course. Developmental and cognitive difficulties According to Cannon et al., 763 (or 3% of all cCMV children) of the 815 symptomatic children who were clinically confirmed as having the disease experienced developmental delay or cog- nitive impairment [1]. These kids will not gain anything from screening. 574 (2.3%) of the 2447 symptomatic children who did not receive a cCMV diagnosis experienced these issues. In comparison to a 6-week period, Kimberlin et al. demonstrated that a 6-month course of treatment increased the neurodevel- opmental scores on the Bayley –III at 24 months in symptom- atic infants with at least one symptom [9]. As a result, these kids who would have benefited from treatment may have ben- efited from screening. These issues were also present in 1045 youngsters (4.1%) who were asymptomatic. It is possible that some of these kids had congenital hearing loss, in which case antiviral therapy would have been necessary. The incidence of these problems is the same in controls and asymptomatic cCMV [15]. The potential advantages of universal screening for these kids stem from the clinical recommendation, as well as potential legal mandate, of close developmental follow-up for high-risk kids from the American Academy of Paediatrics [16, 17]. Therefore, there’s a good chance that developmental issues will be noticed and treated sooner rather than later if they go undiagnosed. The diagnostic process may take far less time for impacted children who show up later on with developmental delay and/or cognitive delay than it would for children who do not have a previous diagnosis. A youngster with cCMV is not likely to experience any of these issues. Later pregnancies won’t raise the risk of genetic issues. Having a diagnosis is also likely to improve prognosis. However, given the absence of a devel- opmental follow-up framework for CMV, whether symptomatic or not, the advantages of newborn screening might not be as clear for this particular set of infants. Economic considerations Any programme aimed at universal screening must take cost into account. Screening programmes have the potential to reduce severe to profound hearing loss by 4.2-13%, with a di- rect cost of $10.86 per screened infant. Gantt et al. based their findings on the assumption that the benefits of screening stem from early identification of postnatal hearing loss and antiviral therapy for affected newborns to reduce hearing loss [18]. Ac- cording to their estimates, the lifetime expenses of a child with severe or profound hearing loss come to almost US$ 1.2 million. Overall, they came to the conclusion that screening newborns for cCMV is justified because it is typically linked to cost savings or is cost neutral when considering net public spending. With about 40,000 new cases reported annually, the estimated yearly cost of cCMV in the US is currently higher than $3 billion [19]. While acknowledging the drawbacks and moral dilemmas as- sociated with newborn screening generally, universal newborn CMV screening offers notable benefits, chief among which is the decrease in the incidence of SNHL [20]. Determining whether treating isolated and late-onset SNHL is beneficial is crucial. The significance of universal screening will increase if this treatment window can be established. References 1. Cannon MJ, Griffiths PD, Aston V, Rawlinson WD (2014) Universal newborn screening for congenital CMV infec- tion: what is the evidence of potential benefit? Rev Med Virol 24: 291-307. 2. Rastogi MV, LaFranchi SH (2010) Congenital hypothyroid- www.directivepublications.org Page - 2 The Journal of Clinical Pathology

Editorial ism. Orphanet J Rare Dis 10: 17. 3. Mehra S, Eavey RD, Keamy DG Jr (2009) The epidemiolo- gy of hearing impairment in the United States: newborns, children, and adolescents. Otolaryngol Head Neck Surg 140: 461-472. 4. Lanzieri TM, Leung J, Caviness AC, Chung W, Flores M, et al. (2017) Long-term outcomes of children with symptom- atic congenital cytomegalovirus disease J Perinatol 37: 875-880. 5. Meyer L, Sharon B, Huang TC, Meyer AC, Gravel KE, et al. (2017) Analysis of archived newborn dried blood spots (DBS) identifies congenital cytomegalovirus as a major cause of unexplained pediatric sensorineural hearing loss. Am J Otolaryngol. 38: 565-570. 6. Ross SA, Ahmed A, Palmer AL, Michaels MG, Sánchez PJ, et al. (2017) Blood Spot Polymerase Chain Reaction to Iden- tify Infants with Congenital Cytomegalovirus-Associated Sensorineural Hearing Loss. J Pediatr 184: 57-61. 7. Dollard SC, Grosse SD, Ross DS (2017) New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus in- fection. Rev Med Virol 17: 355-363. 8. Rivera LB, Boppana SB, Fowler KB, Britt WJ, Stagno S, et al. (2002) Predictors of hearing loss in children with symp- tomatic congenital cytomegalovirus infection. Pediatrics 110: 762-767. 9. Kimberlin DA, Jester PM, Sánchez PJ for the National Insti- tute of Allergy and Infectious Diseases Collaborative Anti- viral Study Group. (2015) Valganciclovir for Symptomatic Congenital Cytomegalovirus Disease. N Engl J Med 372: 933-943. 10. Lanzieri TM, Chung W, Flores M, Blum P, Caviness AC, et al. (2017) Hearing Loss in Children With Asymptomatic Congenital Cytomegalovirus Infection. Pediatrics 139: e20162610. 11. Kennedy CR, McCann DC, Campbell MJ, Law CM, Mullee M, et al. (2006) Language ability after early detection of permanent childhood hearing impairment. N Engl J Med 354: 2131-2141. 12. Drews CD, Allsopp YM, Murphy CC, Decouflé P (1994) Hearing impairment among 10-year-old children: metro- politan Atlanta, 1985 through 1987. Am J Public Health. 84: 1164-1166. 13. Kimberlin DW, Lin CY, Sánchez PJ, Demmler GJ, Dankner W, et al. (2003) Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involv- ing the central nervous system: a randomized, controlled trial. J Pediatr 143: 16-25. 14. KImberlin DW, Aban I, Acosta EP (2015) Valganciclovir for Congenital Cytomegalovirus. N Engl J Med 372: 2462-2463 15. Bartlett AW, McMullan B, Rawlinson WD, Palasanthiran P (2017) Hearing and neurodevelopmental outcomes for children with asymptomatic congenital cytomegalovirus infection: A systematic review. Rev Med Virol. 16. American Academy of Pediatrics, Council on Children With Disabilities, Section on Developmental Behavioral Pediat- rics, Bright Futures Steering Committee, Medical Home Initiatives for Children With Special Needs Project Adviso- ry Committee (2006) Identifying Infants and Young Chil- dren With Developmental Disorders in the Medical Home: An Algorithm for Developmental Surveillance and Screen- ing. Pediatrics 118: 405-420 17. American Academy of Pediatrics. Council on Children With Disabilities (2007) Role of the Medical Home in Fam- ily-Centered Early Intervention Services. Pediatrics 120: 1153-1158. 18. Gantt S, Dionne F, Kozak FK, Goshen O, Goldfarb DM, et al. (2016) Cost-effectiveness of Universal and Targeted New- born Screening for Congenital Cytomegalovirus Infection. JAMA Pediatr 170: 1173-1180. 19. Marsico C, Kimberlin KW (2017) Congenital Cytomegalovi- rus infection: advances and challenges in diagnosis, pre- vention and treatment. Ital J Pediatr 43: 38. 20. Tarini BA, Goldenberg AJ (2012) Ethical issues with new- born screening in the genomics era. Annu Rev Genomics Hum Genet 13: 381-393. www.directivepublications.org Page - 3 The Journal of Clinical Pathology

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