Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Awareness and Education in Pregnancy
3.2. Maternal Screening
3.3. Neonatal Screening
3.3.1. Universal Screening
Author, Year, Ref, Country | Study Design and Time of Enrollment | Population | Method of Universal Screening | Results | Symptomatic Newborns at Birth (Other than Isolated HL) | Isolated HL Confirmed Cases | Treatment | Outcome | Comments |
---|---|---|---|---|---|---|---|---|---|
Schlesinger, 2005 [49] Israel | Multicenter prospective study From May 98 to August 99 | Live-born infants | PCR on urine | 14 diagnosed/2000 screened for CMV | 2 symptomatic (microcephaly, hepatitis) | no HL found | n.a. | n.a. | This study did not identify any isolated SNHL, no information about follow-up for LO-SNHL was provided. |
Lorenzoni, 2013 [48] Italy | Monocenter prospective From January 2012 to July 2013 | Premature newborns (<37 gw) and SGA term infants (weight <3rd percentile) | PCR on urine | 12 (10 preterms, 2 SGA)/383 screened/504 premature or SGA | 1 preterm (lissencephaly) | 2 | n.a. | n.a. | Increased incidence of cCMV and isolated SHL (17%) in this populations. |
Barkai, 2014 [50] Israel | Single-center prospective study From May 2011 to May 2012 | Live-born infants | PCR on saliva confirmed by urine | 48 cCMV/9845 screened for CMV/10,137 live-born infants | 0 | 1 | 4 infants | 1 LO-SNHL at 3 months of age | Incidence of neonatal hearing loss: 2%. The infant diagnosed with HL passed the OAE screening and was confirmed on ABR. |
Fowler, 2017 [47] USA | Multicenter prospective From March 2007 to March 2012 | Live-born infants | PCR on saliva or DBS | 443 cCMV identified out of 100,332 tested | n.a. | 35 confirmed | n.a. | n.a. | Incidence of neonatal hearing loss: 8%. The lack of CMV confirmation on urine may give some FP patients. 15 cCMV cases with confirmed SNHL passed the OAE screening. |
Dar, 2017 [51] India | Multicenter, prospective study From December 2010 to May 2012 | Live-born infants | PCR on saliva | 20 diagnosed/1720 screened | 1 | 2 | n.a. | n.a. | Incidence of neonatal hearing loss: 10%. 1 out of 2 neonates with cCMV and SNHL passed the initial HS. The lack of CMV confirmation on urine may give some FP patients. |
Yamamoto, 2020 [52] Brazil | Multicenter, prospective study From September 2013 to April 2017 | Live-born infants | PCR on saliva, confirmed on urine | 68 diagnosed/11,900 tested | 4 | 4 | 7 | Neonatal SNHL: between the 4 isolated SNHL, 1 progressed and 1 was stable at 18–48 months at follow-up For the 4 symptomatic babies, all had SNHL, one progressive and 3 stable at follow-up. For the other 49 cases, no late-onset HL was detected at a median 36-month follow-up | Incidence of neonatal hearing loss: 5.8%. 1 neonate with cCMV and SNHL passed the initial HS. Targeted screening would have missed 12.5% of infants with SNHL. |
Yamada, 2020 [53] Japan | Multicenter prospective study From November 2009 to March 2018 | Live-born infants | PCR on urine | 56 diagnosed/11,736 tested for CMV | 19 | 4 | n.a. | Between the 4 isolated SNHL, 2 normal development and 2 mild sequele. | The incidence of isolated SNHL in this population is 7.1%. |
Blazquez-Gamero, 2020 [54] Spain | Prospective, monocenter From February 2017 to February 2018 | Live-born infants | PCR on saliva, confirmed by urine | 15 positive out of 3190 tested | 2 | 0 | n.a. | No infants (13 available at follow-up) developed SNH at 25 months | The incidence of isolated SNHL in this population is 0%. |
Letamendia-Richard, 2022 [55] France | Monocenter, retrospective From single unit, 2016–2020 | Live-born infants | PCR on saliva at birth, confirmed by urine | 63 confirmed infections/15,341 tested/15,649 live-born infants | 8 infants small for gestational age, no one with HL | 1 | n.a. | n.a. | The child with isolated SNHL had hepatomegaly at prenatal US and his mother had known seroconversion, so it would have been diagnosed without intervention. |
Chiereghin, 2022 [56] Italy | Multicenter prospective study From February 2019 to July 2020 | Live-born infants | PCR on saliva confirmed by urine | 21 confirmed cCMV/3151 screened for CMV | 1 case with severe CNS disease and HL | 1 | 2 (6 months) | 1 asymptomatic infant developed LO-SNHL at 5 months of age | Incidence of neonatal hearing loss: 4.7%. No information regarding hearing screening test. |
3.3.2. Targeted Screening
Author, Year, Ref, Country | Study Design and Time of Enrollment | Patient | Method of Targeted Screening | Results | Symptomatic Newborns at Birth (Other than Isolated HL) | Isolated HL Confirmed Cases | Treatment | Outcomes of cCMV Cases | Comments |
---|---|---|---|---|---|---|---|---|---|
Stehel, 2008 [60] Texas (USA) | Monocenter, retrospective From September 1999 to August 2004 | Patients failing HS, mother infected with HIV, clinical or lab signs suggestive | PCR on urine | 24 confirmed/483 screened/572 failing HS. | 9 | 8 | n.a. | n.a. | The inclusion criteria for screening were not stringent. It was hard to predict if the screening would be different to normal clinical practice. |
Williams, 2014 [61] UK | Multicenter prospective From August 2010 to October 2012 | Infants < 22 days old failing NHS. Known cCMV excluded | PCR on urine or saliva | 6 diagnosed/407 screened/411 recruited after failing NHS | n.a. | 3 | n.a. | n.a. | Clinical data and outcome missing. |
Kawada, 2015 [62] Japan | Prospective study From January 2011 to December 2013 | Infants failing NHS | PCR on saliva or urine | 6 confirmed out fo 127 failing NHS | 0 | 6 | valgancyclovir for 6 weeks | only 1 out of 6 improved at 1-year follow-up | Valganciclovir did not show to significantly improved hearing function. |
Roth, 2017 [63] Israel | Single-center retrospective study From 2014 to 2015 | Infants failing NHS | PCR on saliva confirmed by urine | 4 confirmed cCMV/180 tested for CMV/200 failing NHS | 2 | 3 | n.a. | n.a. | Targeted screening identified 1 child (out of 200 failing NHS) who needed treatment. Outcomes missing. |
Diener, 2017 [58] Utah (USA) | Retrospective multicenter From 2013 to 2015 | Live-born infants failing NHS. Infants with suggestive symptoms were excluded | PCR on saliva, confirmed on urine | 14 diagnosed/314 screened for CMV/509 failing HS | 0 | 6 | n.a. | n.a. | No information on follow-up and outcome. |
Rawlinson, 2018 [59] Australia | Monocenter, retrospective study From October 2009 to Oct 2016 | Infants failing HS and formal audiological testing (ABR) | PCR on saliva up to 2011, after 2011, positivity on saliva was confirmed on urine | 19 diagnosed/323 screened/502 infants with confirmed HL | 4 | 15 | 6 out of 19 (only 4 started within the first month of life) | n.a. | No clinical outcome, no follow-up. Symptomatic infants were not excluded from the study (4 out of 19 confirmed) and were reasonably diagnosed without this intervention. |
Beswick, 2019 [64] Australia | Multicenter, retrospective From August 2014 to April 2016 | Neonates failing NHS (twice OAE) | PCR on saliva, confirmed by urine and blood | 3 diagnosed out of 234 screened/347 failing NHS | 0 | 2 | 1, valganciclovir | n.a. | Intervention allowed diagnosis and treatment of one otherwise asymptomatic infant. No clinical outcome provided. |
Pellegrinelli, 2019 [65] Italy | Observational single-center study From 2014 to 2018 | Infants failing NHS (AOE) | PCR on DBS | 5 DBS tested positive/82 DBS screened/89 failing NHS | n.a. | 5 | n.a. | n.a. | DBS method may have missed some CMV diagnoses. |
Ronner, 2021 [57] Massachusetts (USA) | Monocenter, retrospective chart review, From 2013 to 2020 (screening from 2015). Targeted screening was implemented in 2015 for 2 nurseries, from 2016 to all nurseries | Infants failing NHS | Primary PCR on saliva | 8 confirmed/528 tested for CMV/891 failing NHS | n.a. | 6 | valganciclovir | hearing stable in 3, progressed in 2, improved in 1. | Hearing function improved in 1 patient out of 6 diagnosed and treated for isolated SNHL. Not specified if symptomatic infants were excluded from the study. |
Khi Chung, 2022 [66] Netherlands | National, prospective observational From 2012 to 2016 | Infants failing NHS (three rounds: two OAEs, one ABR) | PCR on DBS | 54 confirmed/1374 DBS screened/1381 infants failing NHS | n.a. | n.a. (48 infants had confirmed HL, but other concurrent symptoms were not excluded or specified in the study) | n.a | n.a. | Symptomatic children were not excluded and granular data about clinical scenario were not provided. |
Fourgeaud, 2022 [67] France | Multicenter, prospective study From 2014 to 2017 | Newborns failing NHS (twice OAE in 3 centers, twice ABR in 2 centers) | PCR on saliva Confirmatory test on saliva and blood | 2 confirmed/231 screened for CMV/236 failing NHS | n.a. | n.a. (2 cases of HL but no information on other symptoms) | valganciclovir | n.a. | No granular data about clinical scenario of confirmed cases. Not specified if symptomatic infants were excluded from the study. |
Webb, 2022 [68] Australia | Prospective, multicenter From June 2019 to March 2020 | Infants failing NHS | PCR on saliva, confirmed on urine and plasma | 1 positive out of 96 tested | 0 | 1 | valganciclovir started at 32 days of life for 6 months | n.a. | Good feasibility and acceptability. |
Zhang, 2023 [69] Japan | Single-center observational prospective study From October 2018 to October 2021 | Newborns with suggestive perinatal conditions, including failing NHS (twice ABR) | PCR on urine | 1 positive out of 12 failing NHS, 1 positive screened because of abnormal CNS findings, 1 positive screened for suspected maternal infection during pregnancy | n.a. | 1 | 2 treated with valgancyclovir | n.a. | No clinical outcome. |
3.4. Vaccinations
Vaccine | Author, Year or Trial ID Number | Study Design | Population | Outcome | Enrolment Time | Results |
---|---|---|---|---|---|---|
bB-MF59: MF59 adjuvated recombinant CMV envelope glicoproteinB subunit | Pass, 2009 [74] | Phase 2, placebo-controlled, randomized, double-blind trial. | Post-partum, seronegative women, aged 14–40 years and healthy. | Effectiveness in preventing CMV infection during a 42-month period | August 1999 to April 2006 | 464 subject enrolled. Vaccine recipients were more likely to remain uninfected than placebo recipients (p = 0.02). |
bB-MF59: MF59 adjuvated recombinant CMV envelope glicoproteinB subunit | Bernstein, 2017 [75] | Phase 2, multicenter, randomized, double-blind, controlled study. | Healthy adolescent females. | Effectiveness in preventing CMV infection, immunogenicity, safety. | June 2006–June 2013 | 402 subjects enrolled. CMV infection occurred without significant differences between vaccinated and control individuals. |
V160: whole-virus vaccine that is derived from the live-attenuated AD169 strain | Das, 2023 [76] | Phase 2b, multicenter, randomized, double-blind, placebo-controlled study. | Healthy, CMV-seronegative, non-pregnant, 16–35-year-old women of childbearing potential with exposure to children aged 5 years or younger. | Efficacy of three doses of V160 in reducing the incidence of primary CMV infection during the follow-up period starting 30 days after the last dose of vaccine; vaccine safety. | April 2018–August 2019 | 2220 enrolled. The vaccine efficacy for the V160 three-dose group was 44.6% (95% CI −15.2 to 74.8) at the final testing of the primary efficacy hypothesis, a result corresponding to failure to demonstrate the primary efficacy hypothesis. The study was terminated due to futility. |
mRNA-1647 | NCT04232280 [78] | Phase 2, randomized, observer-blind, placebo-controlled, dose-finding trial. Part 1: to inform the selection of the middle dose level for further development. Part 2: to further evaluate the safety and immunogenicity of the middle dose level of mRNA-1647 vaccine or placebo. | Healthy participants seropositive or seronegative, males or females, 18 to 40 years of age. | Safety, immunogenicity (NAb titers) | September 2020–April 2023 | 315 subjects enrolled. No results reported. |
mRNA-1647 | Ongoing trial NCT05085366 [79] | Phase 3, randomized, observer-blind, placebo-controlled study. | Participants aged ≥20 years, has or anticipates having direct exposure within 7 months after the planned first dose (in the home, socially, or occupationally) to at least 1 child ≤5 years of age. Enrollment estimated 6900 subjects. | Efficacy (seroconversion from a negative to a positive result) in females and in all participants. Safety. | October 2021–April 2024 | Enrolled 7454 patients, no results reported. |
4. Final Considerations and Future Prospectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Liberati, C.; Sturniolo, G.; Brigadoi, G.; Cavinato, S.; Visentin, S.; Cosmi, E.; Donà, D.; Rampon, O. Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions. Viruses 2024, 16, 1311. https://doi.org/10.3390/v16081311
Liberati C, Sturniolo G, Brigadoi G, Cavinato S, Visentin S, Cosmi E, Donà D, Rampon O. Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions. Viruses. 2024; 16(8):1311. https://doi.org/10.3390/v16081311
Chicago/Turabian StyleLiberati, Cecilia, Giulia Sturniolo, Giulia Brigadoi, Silvia Cavinato, Silvia Visentin, Erich Cosmi, Daniele Donà, and Osvalda Rampon. 2024. "Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions" Viruses 16, no. 8: 1311. https://doi.org/10.3390/v16081311
APA StyleLiberati, C., Sturniolo, G., Brigadoi, G., Cavinato, S., Visentin, S., Cosmi, E., Donà, D., & Rampon, O. (2024). Burden of Congenital CMV Infection: A Narrative Review and Implications for Public Health Interventions. Viruses, 16(8), 1311. https://doi.org/10.3390/v16081311