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Neonatal and long-term ophthalmological findings in infants with symptomatic and asymptomatic congenital cytomegalovirus infection
Journal of Clinical Virology 97 (2017) 59–63
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Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Full length article
Neonatal and long-term ophthalmological findings in infants with symptomatic and asymptomatic congenital cytomegalovirus infection
MARK
⁎
Maria Grazia Caprettia, , Concetta Marsicoa, Simonetta Guidelli Guidib, Antonio Ciardellab, Giuliana Simonazzic, Silvia Gallettia, Liliana Gabriellid, Tiziana Lazzarottod, Giacomo Faldellaa a
Department of Medical and Surgical Sciences, Neonatology Unit,St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy Ophthalmology Unit, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy c Department of Medical and Surgical Sciences, Division of Obstetrics and Prenatal Medicine, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy d Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Microbiology and Virology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy b
A R T I C L E I N F O
A B S T R A C T
Keywords: Congenital CMV infection Chorioretinitis Visual function Long-term outcomes
Background: Congenital cytomegalovirus (cCMV) infection is responsible of a high burden of neurosensory impairment in children. Objectives: To report incidence and consequences of ophthalmological abnormalities in infants with cCMV infection and better define their long-term ophthalmological management. Study design: Infants with cCMV infection were enrolled in a 6-year follow-up. Infants were classified as symptomatic or asymptomatic based on complete clinical, laboratory and instrumental evaluations. All infants underwent funduscopic evaluation in neonatal period, and yearly complete ophthalmological evaluation, including funduscopic, motility and visual acuity assessments. Results: Forty-eight infants were enrolled, 18/48 (37.5%) symptomatic and 30/48 (62.5%) asymptomatic. Mean duration of follow-up was 34.9 ± 22.2 vs. 34.8 ± 20.1 months (P = 0.98). Funduscopic abnormalities were identified in neonatal period in 7/18 (39%) symptomatic infants and in none of the infants without other clinical and instrumental abnormalities at birth (P < 0.001); chorioretinal scars were the most common finding (5/18 cases, 28%). Strabismus was detected in 1/18 (5.5%) symptomatic infants during the first years of life. Visual impairment at last follow-up evaluation was suspected or detected in 4/18 (22%) symptomatic infants and in none of the asymptomatic infants at birth (P = 0.01). Ophthalmological abnormalities were associated with other signs of central nervous system (CNS) involvement (P < 0.001). No correlation was found with the type of maternal infection. Conclusions: Ophthalmological abnormalities were common in symptomatic infants though often not associated with long-term visual impairment, and correlated with the presence of CNS involvement. Neonatal and periodical ophthalmological evaluations throughout childhood seem prudential for symptomatic babies. No ophthalmological abnormalities were detected in asymptomatic infants, who might therefore undergo more deferred evaluations.
1. Background Congenital cytomegalovirus (CMV) infection is the most common congenital viral infection, with an estimated incidence of 0.6-2% of all live births [1,2]. It contributes to a high burden of disease and is recognized as the leading non-genetic cause of sensorineural hearing loss (SNHL) in children [3–6].
Ocular abnormalities and visual impairment have been reported in a high percentage of symptomatic infants with congenital CMV (cCMV) infection, whereas they are considered uncommon in asymptomatic infants [7–11]. These data though are based on few studies, since large follow-up studies have mainly focused on hearing and neurodevelopmental outcomes. This paucity of data has made difficult to reach clear recommendations on the ophthalmological follow-up that should be
Abbreviations: BAERs, auditory brainstem responses; cCMV, congenital cytomegalovirus; CMV, cytomegalovirus; CNS, central nervous system; cUS, cranial ultrasound; GCV, ganciclovir; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging; SNHL, sensorineural hearing loss; VEPs, visual evoked potentials; VGCV, valganciclovir; WM, white matter ⁎ Corresponding author at: Neonatology Unit, St. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 11, 40138 Bologna, Italy. E-mail address: [email protected] (M.G. Capretti). https://doi.org/10.1016/j.jcv.2017.11.001 Received 1 July 2017; Received in revised form 1 November 2017; Accepted 6 November 2017 1386-6532/ © 2017 Elsevier B.V. All rights reserved.
Journal of Clinical Virology 97 (2017) 59–63
M.G. Capretti et al.
Neonates with CNS involvement were treated with intravenous ganciclovir (GCV) or oral valganciclovir (VGCV) for at least 6 weeks, after informed consent from parents or legal guardians was obtained.
provided to infants with cCMV infection [12]. Specifically, it is unclear if it should be equally directed to all congenitally infected infants or if it may be adjusted on the basis of the neonatal presentation of CMV infection. Recently, a European panel of experts in the field suggested that, based on the few available studies, ophthalmological follow-up should be provided annually in symptomatic babies at least until children can talk, but not in the asymptomatic babies (article in press). These points are of major interests, both to adequate counsel parents and to have a cost-effective management of infants.
3.2. Ophthalmological evaluation
All infants with cCMV infection referred to the Outpatient Clinic of the Neonatal Division of St. Orsola-Malpighi Hospital, Bologna, Italy between January 2006 and December 2015 were enrolled in a prospective observational study. Infants were identified because of suspected/confirmed maternal CMV infection during pregnancy or because of the presence of symptoms consistent with cCMV infection at birth. Data regarding timing and type (primary vs. non-primary) of maternal infection, neonatal and follow-up evaluations (physical, neurodevelopmental, audiological and ophthalmological assessments) were prospectively collected during routine visits. The follow-up was scheduled for 6 years: only infants followed for at least 12 months were included.
All ophthalmological examinations were adapted to the age of the patient and performed by experienced ophthalmologists. Dilated funduscopic examination with cycloplegic refraction was performed at birth, 1, 3, 6 and 12 months and then annually. Cycloplegia was obtained with a single instillation of a solution of tropicamide/phenylephrine hydrochloride. Visual function was defined according to the International Classification of Diseases, 10th Revision: blindness was defined as a corrected visual acuity of < 1/20 (or corresponding visual field loss) in the better eye, and low vision corresponded to a best corrected visual acuity of < 3/10 but ≥ 1/20 in the better eye [14]. For the purpose of this study also unilateral findings were reported. For younger preverbal infants, visual function was estimated on the basis of the fixation behavior, considering a moderate impairment as a poor but demonstrable fixation and a severe visual impairment as no demonstrable fixation behavior. Measurement of visual acuity with optotypes was used in older children. All infants received motility examination and testing of anterior segment. Infants with funduscopic abnormalities and/or abnormal visual function underwent visual evoked potentials (VEPs). VEPs were elicited using a flash stimulus and/or a pattern-reversal stimulus and recorded at the scalp over the occipital cortex. The VEPs waveform was analyzed for both amplitude and latency of onset of a peak after stimulus. A complete ophthalmological examination was performed yearly until 6 years.
3.1. Definition and monitoring of cCMV infection
3.3. Statistical methods
Maternal primary infection was diagnosed based on clinical and laboratory history and CMV IgM-positive and low/moderate CMV IgG avidity results as well as positive DNAemia and/or seroconversion for CMV. Maternal non-primary infection was diagnosed, within the first 16 weeks of gestation, according to blot-confirmed IgM-positivity with high avidity CMV IgG and presence of CMV DNA in blood and/or urine and/or saliva [13]. cCMV infection was diagnosed by CMV detection in urine within the first three weeks of life by viral culture until 2012 and by real-rime Polymerase Chain Reaction (PCR) from 2012 to 2015; for infants who were referred to our Center beyond the third week of life, cCMV infection was diagnosed by detection of CMV-DNA by real-time PCR on the Guthrie card stored at 48 h of life. Blood viral load was assessed on whole blood using real-time PCR, and expressed as number of copies/mL, as previously described [13]. All infants underwent a complete clinical, laboratory and instrumental evaluation during the first month of life to define the infection as symptomatic or asymptomatic. Infants were considered symptomatic if showing: intrauterine growth restriction (IUGR), hepatomegaly, splenomegaly, petechiae, thrombocytopenia, elevated serum transaminases, jaundice with conjugated hyperbilirubinemia, central nervous system (CNS) involvement (as denoted by microcephaly, seizures or other neurological signs, neuroimaging abnormalities consistent with CMV infection detected by cranial ultrasound [cUS] and/or Magnetic Resonance Imaging [MRI], ophthalmological abnormalities detected by funduscopic examination or SNHL detected by Brainstem Auditory Evoked Responses [BAERs]). SNHL was defined as a threshold > 20 dB for pure tones, confirmed at two consecutive BAERs, and after exclusion of middle ear disorders. Infants were considered asymptomatic if clinical, laboratory and instrumental evaluations were all normal at birth.
Statistical analyses were conducted using IBM SPSS software version 20. Categorical data were summarized using frequency counts and percentages. The chi-square test or Fisher’s exact test were used for comparison between groups for categorical data. For continuous data, data distribution was checked for normality by the Shapiro-Wilk test. Being data normally distributed, the T-test was used to compare mean ( ± standard deviation) between groups. The Mann-Whitney test was used to compare blood viral load between groups. P-values < 0.05 were considered statistically significant.
2. Objectives The aim of this study was to evaluate ophthalmological findings and visual function in the neonatal period and during a long-term follow-up in infants with cCMV infection. The ocular involvement in relation to type and timing of maternal infection was also explored. 3. Study design
4. Results Forty-eight infants with cCMV infection were enrolled, including 18/48 (37.5%) symptomatic and 30/48 (62.5%) asymptomatic infants (Table 1). In the symptomatic group 11/18 infants (61%) were born to mothers with a primary CMV infection, diagnosed during the first trimester of pregnancy in 6/11 (55%) cases and during the second trimester in the other 5/11 (45%) cases. Instead, 5/18 (28%) infants were born to mothers with a non-primary CMV infection. For two infants, maternal serology during pregnancy was not available. In the asymptomatic group 27/30 (90%) infants were born to mothers with a primary CMV infection, diagnosed during the first trimester in 6/27 (22%) cases, during the second trimester in 11/27 (41%) cases and during the third trimester in 10/27 (37%) cases. Instead, 3/30 (10%) infants were born to mothers with a non-primary CMV infection. Mean gestational age, birth weight and age at the last evaluation were similar between groups (Table 1). Blood viral load was available for 13/18 (72%) symptomatic infants and for 22/30 (73%) asymptomatic infants. Blood viral load at birth was significantly higher in symptomatic as compared with 60
Journal of Clinical Virology 97 (2017) 59–63
M.G. Capretti et al.
61
72 months
24 months
16 months
36 months
72 months
72 months
Thrombocytopenia, petechiae Ventriculomegaly, periventricular calcifications
– Normal
– WM abnormalities
8
7
6
Macular chorioretinal scars, exoforia, abnormal VEPs, suspected low vision Macular chorioretinal scars, unilateral low vision Pale and small optic disc, abnormal VEPs, poor fixation behavior Gray optic disc, initially abnormal VEPs, normal vision Normal funduscopic evaluation, unilateral exotropia, normal vision 4
5
Peripheral chorioretinal scars, normal vision 3
Abbreviations: GCV ganciclovir; IUGR intrauterine growth restriction; L left; R right; SNHL sensorineural hearing loss; VEPs visual evoked potentials; VGCV valganciclovir; WM white matter.
GCV 6 weeks GCV 6 weeks VGCV 6 weeks VGCV 6 months VGCV 6 weeks GCV 6 weeks
Peripheral chorioretinal scars, initial poor fixation behavior Peripheral chorioretinal scars, abnormal VEPs, exoforia, low vision 1
All enrolled infants underwent at least one funduscopic evaluation during the neonatal period. None had active chorioretinitis. Abnormalities were found in 7/18 (39%) symptomatic infants (Table 2, patients nos.1–7). Five out of 18 symptomatic infants (28%) had unilateral chorioretinal scars at the first evaluation (Table 2, patients nos. 1–5); 2 of these 5 infants were born to mothers with a primary first-trimester CMV infection, two infants were born to mothers with a non-primary CMV infection and for one infant maternal serology was not available. Retinal lesions evolved into atrophic chorioretinal scars during the followup period (median last follow-up evaluation 44 months, range 12–72 months), without evidence of active retinitis (Fig. 1). The remaining two infants with funduscopic abnormalities (Table 2, patients nos. 6, 7) were born to a mother with a non-primary CMV infection and to a mother with a primary first-trimester infection respectively; the first one had a funduscopic evaluation consistent with optic nerve hypoplasia, and the other one had a gray optic disc at first
Ocular findings
4.2. Funduscopic evaluation
Patient
Table 2 Characteristics of the symptomatic infants with ocular involvement at birth and during follow-up.
In the symptomatic group, the most common finding in the neonatal period was the presence of neuroimaging abnormalities, detected in 14/ 18 infants (78%): white matter abnormalities (10/14), temporal pseudocysts (4/14), calcifications (3/14), ventriculomegaly (3/14), migrational abnormalities (1/14). The other most common neonatal manifestation was thrombocytopenia, detected in 4/18 (22%) infants; all these 4 infants also had CNS involvement. Twelve out of 18 (67%) infants had SNHL at the last evaluation; SNHL was diagnosed at birth in 8/12 (67%) infants, while it was late-onset in 4/12 (33%) cases. Seven of these 12 infants with SNHL had ocular involvement during the neonatal period or during follow-up (Table 2, patients nos. 2–8). Five out of 18 (28%) subjects had a poor neurodevelopmental outcome at the last evaluation; 4 of these 5 subjects with neurodevelopmental delay had ocular involvement during the neonatal period or during follow-up (Table 2, patients nos. 2,4,6,8). No cases of SNHL were reported among asymptomatic infants.
Neuroimaging findings
Other signs at birth
4.1. Non-ocular manifestations of cCMV infection
Microcephaly, thrombocytopenia, hepatosplenomegaly, IUGR –
asymptomatic babies (36,644 copies/mL [range 2580–628,808] vs. 2600 copies/mL [range 620–148,694], P = 0.006). No difference was found in the blood viral load between symptomatic infants with and without ocular involvement (33,088 copies/mL [range 2580–628,808] vs. 36,644 copies/mL [range 5156–530,000], P = 0.92).
Migrational abnormalities, ventriculomegaly, periventricular calcifications Periventricular cysts, WM abnormalities
Data are number of infants unless otherwise indicated. ^ the trimester of maternal infection is available only for primary CMV infections. * the type of maternal infection is not available for 2 symptomatic infants.
–
0.98
Multiple small periventricular cysts
0.10
72 months
27 3 34.8 ± 20.1
Delayed onset SNHL (no responses L; 50 dB R) Delayed onset SNHL (normal L; 50 dB R) SNHL (no response L and R) SNHL (70 dB L; normal R) SNHL (90 dB L; 90 dB R) SNHL (25 dB L; 55 dB R) SNHL (no response L; 70 dB R)
11 5 34.9 ± 22.2
–
0.06 1 0.03
2
6 11 10
12 months
6 5 0
VGCV 6 months GCV 6 weeks
0.55 0.09 0.20
Normal
18/12 39 ± 1.2 3249 ± 417
Thrombocytopenia, petechiae, hepatitis
8/10 38.4 ± 1.1 3067 ± 551
Mild ventriculomegaly, periventricular cysts, WM abnormalities WM abnormalities
P value
Antiviral therapy
Asymptomatic (N = 30)
Hearing function
M/F Gestational age (weeks) Birth weight (grams) - Trimester of CMV infection^ - First - Second - Third - Type of maternal infection* - Primary - Non-primary Last follow-up evaluation (months)
Symptomatic (N = 18)
Last follow-up evaluation
Table 1 Demographical data of the study population.
Journal of Clinical Virology 97 (2017) 59–63
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Fig. 1. Funduscopic evaluation of a symptomatic infant showing peripheral chorioretinal scars.
evaluation that progressively evolved to normality. None of the enrolled infants showed isolated funduscopic abnormalities.
Table 3 Visual findings in symptomatic and asymptomatic congenital CMV infected infants. Symptomatic (N = 18)
4.3. Visual function
Vision - Normal 14 - Impaired 4^ Retinal scars - Unilateral 5* - Bilateral – - Late onset – Optic atrophy/hypoplasia - Unilateral 1 - Bilateral 1 Strabismus - Exotropia 1 - Esotropia –
At the last follow-up evaluation, 4/18 (22%) symptomatic infants had suspected or demonstrable visual impairment (Table 2, patients nos. 2, 4, 5, 6). One of these 4 infants was not able to cooperate for a complete visual acuity examination because of severe neurodevelopmental delay related to extensive CNS involvement. This infant was considered to have visual impairment because of unilateral macular scars, bilateral increased latency at the VEPs (146 ms) compatible with optic atrophy and microphthalmia (Table 2, patient no.4). The other 3 infants with demonstrable visual impairment had ophthalmological abnormalities detected during the neonatal period. One of these three infants (Table 2, patient no.2) had bilateral low vision first diagnosed at 48 months of life; one (Table 2, patient no. 5) had unilateral low vision related to a macular scar; one (Table 2, patient no. 6) had a poor fixation behavior at 16 months of age. One out of 18 infants (5.5%) had an initial demonstrable but poor fixation behavior at the age of 6 months, but his fixation behavior improved over the time, and at 12 months of age he seems to have a normal visual function (Table 2, patient no.1). None of the enrolled infants showed isolated visual impairment.
Asymptomatic (N = 30)
P value
30 –
0.01
– – –
0.005
– –
0.13
– –
0.37
Data are number of infants unless otherwise indicated. ^ one case of suspected vision impairment; one case of bilateral low vision; one case of unilateral low vision; one case of poor fixation behavior. * in 3 cases peripheral scars; in 2 cases macular scars.
Instead, the risk of occurrence of ocular disease and the ophthalmological management of these infants is not completely clear. It is known that the risk of symptomatic infections is related to the timing of maternal infection [18,19]: our study confirms the lack of symptoms and of late-onset sequelae among infants born to mothers with third-trimester CMV infections (P = 0.03), while it apparently does not confirm the highest risk of symptoms in infants born to mothers with first-trimester infections. This finding however is likely influenced by the possibility of volunteer interruption of pregnancy in the early stages of pregnancy, which may lead to an underestimation of the symptomatic cases, particularly for fetuses with severe involvement. Notably, the rate of symptomatic infections following maternal primary and non-primary infections was similar. Overall 17% of infants with cCMV infection showed ophthalmological involvement, which is in line with previous studies reporting ocular involvement in 5–30% of infected infants [10]. When considering only symptomatic infants, 45% had some degree of ocular involvement, a rate comparable to that of CMV-related SNHL, underlying that the total number of affected infants is not negligible. Nonetheless, the long-term visual morbidity was of major concern only in a minority of infants (22%). It is possible that antiviral therapy had an impact on ameliorating the visual outcome, since all infants with neonatal ophthalmological pathological findings were treated; however, this point is only speculative and falls outside the purpose of this study. None of the enrolled infants had isolated ocular involvement, which means that none of the asymptomatic infants showed ocular involvement either in the neonatal period or during follow-up. This finding is partially in contrast with a recent study where moderate visual impairment did not differ between symptomatic and asymptomatic infants and chorioretinal scars were reported in 4% of asymptomatic infants [11]. A possible explanation of this difference is related to the definition of symptomatic infection we used. As mentioned above, we routinely perform cerebral MRI in all CMV congenitally infected infants during the first month of life, regardless of cUS findings and/or other signs of infection, and we use neuroimaging findings to classify infants
4.4. Strabismus Unilateral exotropia was noted at 16 months of age in 1/18 (5.5%) of symptomatic infants (Table 2, patient no.8). No cases of esotropia were recorded. 4.5. Other ophthalmological findings One symptomatic infant (5.5%) with severe CNS involvement had bilateral microphthalmia (Table 2, patient no.4). No other ocular abnormalities were found in both groups. Ophthalmological findings of enrolled infants are summarized in Table 3. 5. Discussion Natural history studies of cCMV infection reported variable rates of long-term morbidity, up to 60% in symptomatic infants [3,5,15,16]. The long-term prognosis of cCMV infection however remains a matter of speculation for some aspects; first, since in most countries a systematic neonatal screening program for cCMV does not exist, the rate of sequelae might differ from what currently accepted, because it is likely that most asymptomatic patients are missed, and thus not enrolled in follow-up studies. Second, although chorioretinitis, neuroimaging abnormalities and microcephaly at birth correlate with a poor neurological outcome [17], reliable predictors of SNHL have not been yet identified. The risk of occurrence of SNHL during childhood however is well defined, and thus the evaluation of hearing function throughout childhood is recommended in all patients with cCMV infection [12]. 62
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as symptomatic or asymptomatic [20,21]. In our cohort, 7/18 neonates (39%) were considered symptomatic because of the isolated presence of MRI abnormalities. Some patients (Table 2, patients nos. 2, 3) were considered symptomatic because of the isolated association of cerebral MRI abnormalities and ocular involvement. However, there is currently no consensus on the best neuroimaging approach in the neonatal period, nor in the criteria used for the definition of symptomatic versus asymptomatic infection worldwide. We also considered in the symptomatic group infants with isolated SNHL (Table 2, patient no.7). These clarifications should be taken into account when interpreting results of follow-up studies. Our results also suggest that it is likely that we are currently missing opportunities to treat symptomatic babies. Without universal screening programs for cCMV, it is understandable that most of the asymptomatic babies go undiagnosed; though, our series seems to suggest that also many symptomatic babies might be missed. In this series only a minority of subjects had clinical signs consistent with cCMV at birth, but CNS involvement and/or SNHL were detected in some subjects without clinical detectable disease at birth. The implementation of universal screening programs for cCMV urgently requires further considerations. The most common ophthalmological finding was the presence of peripheral chorioretinal scars, reported in 28% of symptomatic neonates. This percentage is in line with previous studies conducted on a cohort of infants enrolled during 1982–1992, where chorioretinal scars were found in 26% of symptomatic infants [11]. Interestingly funduscopic abnormalities were always associated with other signs of infection, and specifically all infants had other signs of CNS involvement. Ophthalmological abnormalities were strongly associated with CNS involvement and SNHL (P < 0.001). In contrast with previous data reporting an incidence of strabismus of 19–29% among symptomatic infants [10,11,22], strabismus was not a common finding in our series, with only one case of exotropia; this infant had a severe CNS involvement at birth, and thus received antiviral therapy. Also, although the possibility of late-onset retinal lesions and of reactivations of chorioretinitis during childhood was previously described [11,23,24], we did not identify new lesions during the followup period neither in the asymptomatic nor in the symptomatic group. Though this finding might be related to the relatively small number of subjects enrolled in this study. Some symptomatic infants were diagnosed with visual impairment, altered VEPs and strabismus during the follow-up, underlying the importance of the systematic ophthalmological evaluations in symptomatic infants. A limitation of our investigation is the lack of a control group; we hypothesize however that given the absence of ophthalmological findings in asymptomatic infants, our results would not be significantly altered by the presence of a control group. In conclusion, ocular involvement seems to be common, even if often not severe, among symptomatic infants, while is rare among asymptomatic infants. Ophthalmological involvement is more common in infants with CNS involvement at birth, and both primary and nonprimary maternal infections may be associated with symptomatic infections and ocular disease. Even if the sample size was small, this study suggests that a close ophthalmological follow-up throughout childhood is prudential for symptomatic infants, while asymptomatic infants might undergo more deferred evaluations.
The findings presented in this study are not experimental investigations, as the proposed protocol overlaps with the clinical management of babies, and performed at physician’s discretion. Infant’s parents or guardians had given consent to utilize collected data. References [1] A. Kenneson, M.J. Cannon, Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection, Rev. Med. Virol. 17 (2007) 253–276. [2] S. Manicklal, V.C. Emery, T. Lazzarotto, et al., The silent global burden of congenital cytomegalovirus, Clin. Microbiol. Rev. 26 (2013) 86–102. [3] S.B. Boppana, S.A. Ross, K.B. Fowler, Congenital cytomegalovirus infection: clinical outcome, Clin. Infect. Dis. 57 (Suppl. (4)) (2013) S178–S181. [4] C.C. Morton, W.E. Nance, Newborn hearing screening – a silent revolution, N. Engl. J. Med. 354 (2006) 2151–2164. [5] S.C. Dollard, S.D. Grosse, D.S. Ross, New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection, Rev. Med. Virol. 17 (2007) 355–363. [6] K.B. Fowler, S. Boppana, Congenital cytomegalovirus (CMV) infection and hearing deficit, J. Clin. Virol. 35 (2006) 226–231. [7] S. Ghekiere, K. Allegaert, V. Cossey, et al., Ophthalmological findings in congenital cytomegalovirus infection: when to screen, when to treat? J. Pediatr. Ophthalmol. Strabismus 49 (2012) 274–282. [8] S.B. Boppana, R.F. Pass, W.J. Britt, et al., Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality, Pediatr. Infect. Dis. J. 11 (1992) 93–99. [9] K.S. Anderson, C.S. Amos, S. Boppana, et al., Ocular abnormalities in congenital cytomegalovirus infection, J. Am. Optom. Assoc. 67 (1996) 273–278. [10] D.K. Coats, G.J. Demmler, E.A. Paysse, et al., Ophthalmologic findings in children with congenital cytomegalovirus infection, J. AAPOS 4 (2000) 110–116. [11] H. Jin, G.J. Demmler-Harrison, D.K. Coats, et al., Long-term visual and ocular sequelae in patients with congenital cytomegalovirus infection, Pediatr. Infect. Dis. J. (April (10)) (2017) 10.10.1097/IFN.0000000000001599. [12] W.D. Rawlison, S.B. Boppana, K.B. Fowler, et al., Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy, Lancet Infect. Dis. (2017), http://dx.doi.org/10.1016/ S1473-3099(17)30143-3. [13] R. Rizzo, L. Gabrielli, D. Bortolotti, et al., Study of soluble HLA-G in congenital human cytomegalovirus infection, J Immunol Res 2016 (2016) 3890306. [14] World Health Organization, International Statistical Classification of Diseases and Related Health Problems, 10th revision, World Health Organization, Geneva, Switzerland, 2010 Available at: www.who.int/classifications/icd/ICD10Volume2_ en_2010.pdf . (Accessed 6 September 2016). [15] K.B. Fowler, S. Boppana, Congenital cytomegalovirus (CMV) infection and hearing deficit, J. Clin. Virol. 35 (2006) 226–231. [16] C.L. Townsend, M. Forsgren, K. Ahlfors, et al., Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom, Clin. Infect. Dis. 56 (2013) 1232–1239. [17] D.E. Noyola, G.J. Demmler, C.T. Nelson, et al., Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection, J. Pediatr. 138 (2001) 325–331. [18] R.F. Pass, K.B. Fowler, S.B. Boppana, et al., Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome, J. Clin. Virol. 35 (2006) 216–220. [19] G. Enders, A. Daiminger, U. Bäder, et al., Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age, J. Clin. Virol. 52 (2011) 244–246. [20] R. Manara, L. Balao, C. Baracchini, et al., Brain magnetic resonance findings in symptomatic congenital cytomegalovirus infection, Pediatr. Radiol. 41 (2011) 962–970. [21] M.G. Capretti, M. Lanari, G. Tani, et al., Role of cerebral ultrasound and magnetic resonance imaging in newborns with congenital cytomegalovirus infection, Brain Dev. 36 (2014) 203–211. [22] K. Teär Fahnehjelm, M. Olsson, C. Fahnehjelm, et al., Chorioretinal scars and visual deprivation are common in children with cochlear implants after congenital cytomegalovirus infection, Acta Paediatr. 104 (2015) 693–700. [23] S. Boppana, C. Amos, W. Britt, et al., Late onset and reactivation of chorioretinitis in children with congenital cytomegalovirus infection, Pediatr. Infect. Dis. J. 13 (1994) 1139–1142. [24] L.E. Coors, R. Spencer, Delayed presentation of cytomegalovirus retinitis in an infant with severe congenital cytomegalovirus infection, Retina 30 (Suppl. (4)) (2010) S59–62.
Funding None. Competing interests None declared.
63
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Full length article
Neonatal and long-term ophthalmological findings in infants with symptomatic and asymptomatic congenital cytomegalovirus infection
MARK
⁎
Maria Grazia Caprettia, , Concetta Marsicoa, Simonetta Guidelli Guidib, Antonio Ciardellab, Giuliana Simonazzic, Silvia Gallettia, Liliana Gabriellid, Tiziana Lazzarottod, Giacomo Faldellaa a
Department of Medical and Surgical Sciences, Neonatology Unit,St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy Ophthalmology Unit, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy c Department of Medical and Surgical Sciences, Division of Obstetrics and Prenatal Medicine, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy d Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Microbiology and Virology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy b
A R T I C L E I N F O
A B S T R A C T
Keywords: Congenital CMV infection Chorioretinitis Visual function Long-term outcomes
Background: Congenital cytomegalovirus (cCMV) infection is responsible of a high burden of neurosensory impairment in children. Objectives: To report incidence and consequences of ophthalmological abnormalities in infants with cCMV infection and better define their long-term ophthalmological management. Study design: Infants with cCMV infection were enrolled in a 6-year follow-up. Infants were classified as symptomatic or asymptomatic based on complete clinical, laboratory and instrumental evaluations. All infants underwent funduscopic evaluation in neonatal period, and yearly complete ophthalmological evaluation, including funduscopic, motility and visual acuity assessments. Results: Forty-eight infants were enrolled, 18/48 (37.5%) symptomatic and 30/48 (62.5%) asymptomatic. Mean duration of follow-up was 34.9 ± 22.2 vs. 34.8 ± 20.1 months (P = 0.98). Funduscopic abnormalities were identified in neonatal period in 7/18 (39%) symptomatic infants and in none of the infants without other clinical and instrumental abnormalities at birth (P < 0.001); chorioretinal scars were the most common finding (5/18 cases, 28%). Strabismus was detected in 1/18 (5.5%) symptomatic infants during the first years of life. Visual impairment at last follow-up evaluation was suspected or detected in 4/18 (22%) symptomatic infants and in none of the asymptomatic infants at birth (P = 0.01). Ophthalmological abnormalities were associated with other signs of central nervous system (CNS) involvement (P < 0.001). No correlation was found with the type of maternal infection. Conclusions: Ophthalmological abnormalities were common in symptomatic infants though often not associated with long-term visual impairment, and correlated with the presence of CNS involvement. Neonatal and periodical ophthalmological evaluations throughout childhood seem prudential for symptomatic babies. No ophthalmological abnormalities were detected in asymptomatic infants, who might therefore undergo more deferred evaluations.
1. Background Congenital cytomegalovirus (CMV) infection is the most common congenital viral infection, with an estimated incidence of 0.6-2% of all live births [1,2]. It contributes to a high burden of disease and is recognized as the leading non-genetic cause of sensorineural hearing loss (SNHL) in children [3–6].
Ocular abnormalities and visual impairment have been reported in a high percentage of symptomatic infants with congenital CMV (cCMV) infection, whereas they are considered uncommon in asymptomatic infants [7–11]. These data though are based on few studies, since large follow-up studies have mainly focused on hearing and neurodevelopmental outcomes. This paucity of data has made difficult to reach clear recommendations on the ophthalmological follow-up that should be
Abbreviations: BAERs, auditory brainstem responses; cCMV, congenital cytomegalovirus; CMV, cytomegalovirus; CNS, central nervous system; cUS, cranial ultrasound; GCV, ganciclovir; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging; SNHL, sensorineural hearing loss; VEPs, visual evoked potentials; VGCV, valganciclovir; WM, white matter ⁎ Corresponding author at: Neonatology Unit, St. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 11, 40138 Bologna, Italy. E-mail address: [email protected] (M.G. Capretti). https://doi.org/10.1016/j.jcv.2017.11.001 Received 1 July 2017; Received in revised form 1 November 2017; Accepted 6 November 2017 1386-6532/ © 2017 Elsevier B.V. All rights reserved.
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Neonates with CNS involvement were treated with intravenous ganciclovir (GCV) or oral valganciclovir (VGCV) for at least 6 weeks, after informed consent from parents or legal guardians was obtained.
provided to infants with cCMV infection [12]. Specifically, it is unclear if it should be equally directed to all congenitally infected infants or if it may be adjusted on the basis of the neonatal presentation of CMV infection. Recently, a European panel of experts in the field suggested that, based on the few available studies, ophthalmological follow-up should be provided annually in symptomatic babies at least until children can talk, but not in the asymptomatic babies (article in press). These points are of major interests, both to adequate counsel parents and to have a cost-effective management of infants.
3.2. Ophthalmological evaluation
All infants with cCMV infection referred to the Outpatient Clinic of the Neonatal Division of St. Orsola-Malpighi Hospital, Bologna, Italy between January 2006 and December 2015 were enrolled in a prospective observational study. Infants were identified because of suspected/confirmed maternal CMV infection during pregnancy or because of the presence of symptoms consistent with cCMV infection at birth. Data regarding timing and type (primary vs. non-primary) of maternal infection, neonatal and follow-up evaluations (physical, neurodevelopmental, audiological and ophthalmological assessments) were prospectively collected during routine visits. The follow-up was scheduled for 6 years: only infants followed for at least 12 months were included.
All ophthalmological examinations were adapted to the age of the patient and performed by experienced ophthalmologists. Dilated funduscopic examination with cycloplegic refraction was performed at birth, 1, 3, 6 and 12 months and then annually. Cycloplegia was obtained with a single instillation of a solution of tropicamide/phenylephrine hydrochloride. Visual function was defined according to the International Classification of Diseases, 10th Revision: blindness was defined as a corrected visual acuity of < 1/20 (or corresponding visual field loss) in the better eye, and low vision corresponded to a best corrected visual acuity of < 3/10 but ≥ 1/20 in the better eye [14]. For the purpose of this study also unilateral findings were reported. For younger preverbal infants, visual function was estimated on the basis of the fixation behavior, considering a moderate impairment as a poor but demonstrable fixation and a severe visual impairment as no demonstrable fixation behavior. Measurement of visual acuity with optotypes was used in older children. All infants received motility examination and testing of anterior segment. Infants with funduscopic abnormalities and/or abnormal visual function underwent visual evoked potentials (VEPs). VEPs were elicited using a flash stimulus and/or a pattern-reversal stimulus and recorded at the scalp over the occipital cortex. The VEPs waveform was analyzed for both amplitude and latency of onset of a peak after stimulus. A complete ophthalmological examination was performed yearly until 6 years.
3.1. Definition and monitoring of cCMV infection
3.3. Statistical methods
Maternal primary infection was diagnosed based on clinical and laboratory history and CMV IgM-positive and low/moderate CMV IgG avidity results as well as positive DNAemia and/or seroconversion for CMV. Maternal non-primary infection was diagnosed, within the first 16 weeks of gestation, according to blot-confirmed IgM-positivity with high avidity CMV IgG and presence of CMV DNA in blood and/or urine and/or saliva [13]. cCMV infection was diagnosed by CMV detection in urine within the first three weeks of life by viral culture until 2012 and by real-rime Polymerase Chain Reaction (PCR) from 2012 to 2015; for infants who were referred to our Center beyond the third week of life, cCMV infection was diagnosed by detection of CMV-DNA by real-time PCR on the Guthrie card stored at 48 h of life. Blood viral load was assessed on whole blood using real-time PCR, and expressed as number of copies/mL, as previously described [13]. All infants underwent a complete clinical, laboratory and instrumental evaluation during the first month of life to define the infection as symptomatic or asymptomatic. Infants were considered symptomatic if showing: intrauterine growth restriction (IUGR), hepatomegaly, splenomegaly, petechiae, thrombocytopenia, elevated serum transaminases, jaundice with conjugated hyperbilirubinemia, central nervous system (CNS) involvement (as denoted by microcephaly, seizures or other neurological signs, neuroimaging abnormalities consistent with CMV infection detected by cranial ultrasound [cUS] and/or Magnetic Resonance Imaging [MRI], ophthalmological abnormalities detected by funduscopic examination or SNHL detected by Brainstem Auditory Evoked Responses [BAERs]). SNHL was defined as a threshold > 20 dB for pure tones, confirmed at two consecutive BAERs, and after exclusion of middle ear disorders. Infants were considered asymptomatic if clinical, laboratory and instrumental evaluations were all normal at birth.
Statistical analyses were conducted using IBM SPSS software version 20. Categorical data were summarized using frequency counts and percentages. The chi-square test or Fisher’s exact test were used for comparison between groups for categorical data. For continuous data, data distribution was checked for normality by the Shapiro-Wilk test. Being data normally distributed, the T-test was used to compare mean ( ± standard deviation) between groups. The Mann-Whitney test was used to compare blood viral load between groups. P-values < 0.05 were considered statistically significant.
2. Objectives The aim of this study was to evaluate ophthalmological findings and visual function in the neonatal period and during a long-term follow-up in infants with cCMV infection. The ocular involvement in relation to type and timing of maternal infection was also explored. 3. Study design
4. Results Forty-eight infants with cCMV infection were enrolled, including 18/48 (37.5%) symptomatic and 30/48 (62.5%) asymptomatic infants (Table 1). In the symptomatic group 11/18 infants (61%) were born to mothers with a primary CMV infection, diagnosed during the first trimester of pregnancy in 6/11 (55%) cases and during the second trimester in the other 5/11 (45%) cases. Instead, 5/18 (28%) infants were born to mothers with a non-primary CMV infection. For two infants, maternal serology during pregnancy was not available. In the asymptomatic group 27/30 (90%) infants were born to mothers with a primary CMV infection, diagnosed during the first trimester in 6/27 (22%) cases, during the second trimester in 11/27 (41%) cases and during the third trimester in 10/27 (37%) cases. Instead, 3/30 (10%) infants were born to mothers with a non-primary CMV infection. Mean gestational age, birth weight and age at the last evaluation were similar between groups (Table 1). Blood viral load was available for 13/18 (72%) symptomatic infants and for 22/30 (73%) asymptomatic infants. Blood viral load at birth was significantly higher in symptomatic as compared with 60
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72 months
24 months
16 months
36 months
72 months
72 months
Thrombocytopenia, petechiae Ventriculomegaly, periventricular calcifications
– Normal
– WM abnormalities
8
7
6
Macular chorioretinal scars, exoforia, abnormal VEPs, suspected low vision Macular chorioretinal scars, unilateral low vision Pale and small optic disc, abnormal VEPs, poor fixation behavior Gray optic disc, initially abnormal VEPs, normal vision Normal funduscopic evaluation, unilateral exotropia, normal vision 4
5
Peripheral chorioretinal scars, normal vision 3
Abbreviations: GCV ganciclovir; IUGR intrauterine growth restriction; L left; R right; SNHL sensorineural hearing loss; VEPs visual evoked potentials; VGCV valganciclovir; WM white matter.
GCV 6 weeks GCV 6 weeks VGCV 6 weeks VGCV 6 months VGCV 6 weeks GCV 6 weeks
Peripheral chorioretinal scars, initial poor fixation behavior Peripheral chorioretinal scars, abnormal VEPs, exoforia, low vision 1
All enrolled infants underwent at least one funduscopic evaluation during the neonatal period. None had active chorioretinitis. Abnormalities were found in 7/18 (39%) symptomatic infants (Table 2, patients nos.1–7). Five out of 18 symptomatic infants (28%) had unilateral chorioretinal scars at the first evaluation (Table 2, patients nos. 1–5); 2 of these 5 infants were born to mothers with a primary first-trimester CMV infection, two infants were born to mothers with a non-primary CMV infection and for one infant maternal serology was not available. Retinal lesions evolved into atrophic chorioretinal scars during the followup period (median last follow-up evaluation 44 months, range 12–72 months), without evidence of active retinitis (Fig. 1). The remaining two infants with funduscopic abnormalities (Table 2, patients nos. 6, 7) were born to a mother with a non-primary CMV infection and to a mother with a primary first-trimester infection respectively; the first one had a funduscopic evaluation consistent with optic nerve hypoplasia, and the other one had a gray optic disc at first
Ocular findings
4.2. Funduscopic evaluation
Patient
Table 2 Characteristics of the symptomatic infants with ocular involvement at birth and during follow-up.
In the symptomatic group, the most common finding in the neonatal period was the presence of neuroimaging abnormalities, detected in 14/ 18 infants (78%): white matter abnormalities (10/14), temporal pseudocysts (4/14), calcifications (3/14), ventriculomegaly (3/14), migrational abnormalities (1/14). The other most common neonatal manifestation was thrombocytopenia, detected in 4/18 (22%) infants; all these 4 infants also had CNS involvement. Twelve out of 18 (67%) infants had SNHL at the last evaluation; SNHL was diagnosed at birth in 8/12 (67%) infants, while it was late-onset in 4/12 (33%) cases. Seven of these 12 infants with SNHL had ocular involvement during the neonatal period or during follow-up (Table 2, patients nos. 2–8). Five out of 18 (28%) subjects had a poor neurodevelopmental outcome at the last evaluation; 4 of these 5 subjects with neurodevelopmental delay had ocular involvement during the neonatal period or during follow-up (Table 2, patients nos. 2,4,6,8). No cases of SNHL were reported among asymptomatic infants.
Neuroimaging findings
Other signs at birth
4.1. Non-ocular manifestations of cCMV infection
Microcephaly, thrombocytopenia, hepatosplenomegaly, IUGR –
asymptomatic babies (36,644 copies/mL [range 2580–628,808] vs. 2600 copies/mL [range 620–148,694], P = 0.006). No difference was found in the blood viral load between symptomatic infants with and without ocular involvement (33,088 copies/mL [range 2580–628,808] vs. 36,644 copies/mL [range 5156–530,000], P = 0.92).
Migrational abnormalities, ventriculomegaly, periventricular calcifications Periventricular cysts, WM abnormalities
Data are number of infants unless otherwise indicated. ^ the trimester of maternal infection is available only for primary CMV infections. * the type of maternal infection is not available for 2 symptomatic infants.
–
0.98
Multiple small periventricular cysts
0.10
72 months
27 3 34.8 ± 20.1
Delayed onset SNHL (no responses L; 50 dB R) Delayed onset SNHL (normal L; 50 dB R) SNHL (no response L and R) SNHL (70 dB L; normal R) SNHL (90 dB L; 90 dB R) SNHL (25 dB L; 55 dB R) SNHL (no response L; 70 dB R)
11 5 34.9 ± 22.2
–
0.06 1 0.03
2
6 11 10
12 months
6 5 0
VGCV 6 months GCV 6 weeks
0.55 0.09 0.20
Normal
18/12 39 ± 1.2 3249 ± 417
Thrombocytopenia, petechiae, hepatitis
8/10 38.4 ± 1.1 3067 ± 551
Mild ventriculomegaly, periventricular cysts, WM abnormalities WM abnormalities
P value
Antiviral therapy
Asymptomatic (N = 30)
Hearing function
M/F Gestational age (weeks) Birth weight (grams) - Trimester of CMV infection^ - First - Second - Third - Type of maternal infection* - Primary - Non-primary Last follow-up evaluation (months)
Symptomatic (N = 18)
Last follow-up evaluation
Table 1 Demographical data of the study population.
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Fig. 1. Funduscopic evaluation of a symptomatic infant showing peripheral chorioretinal scars.
evaluation that progressively evolved to normality. None of the enrolled infants showed isolated funduscopic abnormalities.
Table 3 Visual findings in symptomatic and asymptomatic congenital CMV infected infants. Symptomatic (N = 18)
4.3. Visual function
Vision - Normal 14 - Impaired 4^ Retinal scars - Unilateral 5* - Bilateral – - Late onset – Optic atrophy/hypoplasia - Unilateral 1 - Bilateral 1 Strabismus - Exotropia 1 - Esotropia –
At the last follow-up evaluation, 4/18 (22%) symptomatic infants had suspected or demonstrable visual impairment (Table 2, patients nos. 2, 4, 5, 6). One of these 4 infants was not able to cooperate for a complete visual acuity examination because of severe neurodevelopmental delay related to extensive CNS involvement. This infant was considered to have visual impairment because of unilateral macular scars, bilateral increased latency at the VEPs (146 ms) compatible with optic atrophy and microphthalmia (Table 2, patient no.4). The other 3 infants with demonstrable visual impairment had ophthalmological abnormalities detected during the neonatal period. One of these three infants (Table 2, patient no.2) had bilateral low vision first diagnosed at 48 months of life; one (Table 2, patient no. 5) had unilateral low vision related to a macular scar; one (Table 2, patient no. 6) had a poor fixation behavior at 16 months of age. One out of 18 infants (5.5%) had an initial demonstrable but poor fixation behavior at the age of 6 months, but his fixation behavior improved over the time, and at 12 months of age he seems to have a normal visual function (Table 2, patient no.1). None of the enrolled infants showed isolated visual impairment.
Asymptomatic (N = 30)
P value
30 –
0.01
– – –
0.005
– –
0.13
– –
0.37
Data are number of infants unless otherwise indicated. ^ one case of suspected vision impairment; one case of bilateral low vision; one case of unilateral low vision; one case of poor fixation behavior. * in 3 cases peripheral scars; in 2 cases macular scars.
Instead, the risk of occurrence of ocular disease and the ophthalmological management of these infants is not completely clear. It is known that the risk of symptomatic infections is related to the timing of maternal infection [18,19]: our study confirms the lack of symptoms and of late-onset sequelae among infants born to mothers with third-trimester CMV infections (P = 0.03), while it apparently does not confirm the highest risk of symptoms in infants born to mothers with first-trimester infections. This finding however is likely influenced by the possibility of volunteer interruption of pregnancy in the early stages of pregnancy, which may lead to an underestimation of the symptomatic cases, particularly for fetuses with severe involvement. Notably, the rate of symptomatic infections following maternal primary and non-primary infections was similar. Overall 17% of infants with cCMV infection showed ophthalmological involvement, which is in line with previous studies reporting ocular involvement in 5–30% of infected infants [10]. When considering only symptomatic infants, 45% had some degree of ocular involvement, a rate comparable to that of CMV-related SNHL, underlying that the total number of affected infants is not negligible. Nonetheless, the long-term visual morbidity was of major concern only in a minority of infants (22%). It is possible that antiviral therapy had an impact on ameliorating the visual outcome, since all infants with neonatal ophthalmological pathological findings were treated; however, this point is only speculative and falls outside the purpose of this study. None of the enrolled infants had isolated ocular involvement, which means that none of the asymptomatic infants showed ocular involvement either in the neonatal period or during follow-up. This finding is partially in contrast with a recent study where moderate visual impairment did not differ between symptomatic and asymptomatic infants and chorioretinal scars were reported in 4% of asymptomatic infants [11]. A possible explanation of this difference is related to the definition of symptomatic infection we used. As mentioned above, we routinely perform cerebral MRI in all CMV congenitally infected infants during the first month of life, regardless of cUS findings and/or other signs of infection, and we use neuroimaging findings to classify infants
4.4. Strabismus Unilateral exotropia was noted at 16 months of age in 1/18 (5.5%) of symptomatic infants (Table 2, patient no.8). No cases of esotropia were recorded. 4.5. Other ophthalmological findings One symptomatic infant (5.5%) with severe CNS involvement had bilateral microphthalmia (Table 2, patient no.4). No other ocular abnormalities were found in both groups. Ophthalmological findings of enrolled infants are summarized in Table 3. 5. Discussion Natural history studies of cCMV infection reported variable rates of long-term morbidity, up to 60% in symptomatic infants [3,5,15,16]. The long-term prognosis of cCMV infection however remains a matter of speculation for some aspects; first, since in most countries a systematic neonatal screening program for cCMV does not exist, the rate of sequelae might differ from what currently accepted, because it is likely that most asymptomatic patients are missed, and thus not enrolled in follow-up studies. Second, although chorioretinitis, neuroimaging abnormalities and microcephaly at birth correlate with a poor neurological outcome [17], reliable predictors of SNHL have not been yet identified. The risk of occurrence of SNHL during childhood however is well defined, and thus the evaluation of hearing function throughout childhood is recommended in all patients with cCMV infection [12]. 62
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Ethical approval
as symptomatic or asymptomatic [20,21]. In our cohort, 7/18 neonates (39%) were considered symptomatic because of the isolated presence of MRI abnormalities. Some patients (Table 2, patients nos. 2, 3) were considered symptomatic because of the isolated association of cerebral MRI abnormalities and ocular involvement. However, there is currently no consensus on the best neuroimaging approach in the neonatal period, nor in the criteria used for the definition of symptomatic versus asymptomatic infection worldwide. We also considered in the symptomatic group infants with isolated SNHL (Table 2, patient no.7). These clarifications should be taken into account when interpreting results of follow-up studies. Our results also suggest that it is likely that we are currently missing opportunities to treat symptomatic babies. Without universal screening programs for cCMV, it is understandable that most of the asymptomatic babies go undiagnosed; though, our series seems to suggest that also many symptomatic babies might be missed. In this series only a minority of subjects had clinical signs consistent with cCMV at birth, but CNS involvement and/or SNHL were detected in some subjects without clinical detectable disease at birth. The implementation of universal screening programs for cCMV urgently requires further considerations. The most common ophthalmological finding was the presence of peripheral chorioretinal scars, reported in 28% of symptomatic neonates. This percentage is in line with previous studies conducted on a cohort of infants enrolled during 1982–1992, where chorioretinal scars were found in 26% of symptomatic infants [11]. Interestingly funduscopic abnormalities were always associated with other signs of infection, and specifically all infants had other signs of CNS involvement. Ophthalmological abnormalities were strongly associated with CNS involvement and SNHL (P < 0.001). In contrast with previous data reporting an incidence of strabismus of 19–29% among symptomatic infants [10,11,22], strabismus was not a common finding in our series, with only one case of exotropia; this infant had a severe CNS involvement at birth, and thus received antiviral therapy. Also, although the possibility of late-onset retinal lesions and of reactivations of chorioretinitis during childhood was previously described [11,23,24], we did not identify new lesions during the followup period neither in the asymptomatic nor in the symptomatic group. Though this finding might be related to the relatively small number of subjects enrolled in this study. Some symptomatic infants were diagnosed with visual impairment, altered VEPs and strabismus during the follow-up, underlying the importance of the systematic ophthalmological evaluations in symptomatic infants. A limitation of our investigation is the lack of a control group; we hypothesize however that given the absence of ophthalmological findings in asymptomatic infants, our results would not be significantly altered by the presence of a control group. In conclusion, ocular involvement seems to be common, even if often not severe, among symptomatic infants, while is rare among asymptomatic infants. Ophthalmological involvement is more common in infants with CNS involvement at birth, and both primary and nonprimary maternal infections may be associated with symptomatic infections and ocular disease. Even if the sample size was small, this study suggests that a close ophthalmological follow-up throughout childhood is prudential for symptomatic infants, while asymptomatic infants might undergo more deferred evaluations.
The findings presented in this study are not experimental investigations, as the proposed protocol overlaps with the clinical management of babies, and performed at physician’s discretion. Infant’s parents or guardians had given consent to utilize collected data. References [1] A. Kenneson, M.J. Cannon, Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection, Rev. Med. Virol. 17 (2007) 253–276. [2] S. Manicklal, V.C. Emery, T. Lazzarotto, et al., The silent global burden of congenital cytomegalovirus, Clin. Microbiol. Rev. 26 (2013) 86–102. [3] S.B. Boppana, S.A. Ross, K.B. Fowler, Congenital cytomegalovirus infection: clinical outcome, Clin. Infect. Dis. 57 (Suppl. (4)) (2013) S178–S181. [4] C.C. Morton, W.E. Nance, Newborn hearing screening – a silent revolution, N. Engl. J. Med. 354 (2006) 2151–2164. [5] S.C. Dollard, S.D. Grosse, D.S. Ross, New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection, Rev. Med. Virol. 17 (2007) 355–363. [6] K.B. Fowler, S. Boppana, Congenital cytomegalovirus (CMV) infection and hearing deficit, J. Clin. Virol. 35 (2006) 226–231. [7] S. Ghekiere, K. Allegaert, V. Cossey, et al., Ophthalmological findings in congenital cytomegalovirus infection: when to screen, when to treat? J. Pediatr. Ophthalmol. Strabismus 49 (2012) 274–282. [8] S.B. Boppana, R.F. Pass, W.J. Britt, et al., Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality, Pediatr. Infect. Dis. J. 11 (1992) 93–99. [9] K.S. Anderson, C.S. Amos, S. Boppana, et al., Ocular abnormalities in congenital cytomegalovirus infection, J. Am. Optom. Assoc. 67 (1996) 273–278. [10] D.K. Coats, G.J. Demmler, E.A. Paysse, et al., Ophthalmologic findings in children with congenital cytomegalovirus infection, J. AAPOS 4 (2000) 110–116. [11] H. Jin, G.J. Demmler-Harrison, D.K. Coats, et al., Long-term visual and ocular sequelae in patients with congenital cytomegalovirus infection, Pediatr. Infect. Dis. J. (April (10)) (2017) 10.10.1097/IFN.0000000000001599. [12] W.D. Rawlison, S.B. Boppana, K.B. Fowler, et al., Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy, Lancet Infect. Dis. (2017), http://dx.doi.org/10.1016/ S1473-3099(17)30143-3. [13] R. Rizzo, L. Gabrielli, D. Bortolotti, et al., Study of soluble HLA-G in congenital human cytomegalovirus infection, J Immunol Res 2016 (2016) 3890306. [14] World Health Organization, International Statistical Classification of Diseases and Related Health Problems, 10th revision, World Health Organization, Geneva, Switzerland, 2010 Available at: www.who.int/classifications/icd/ICD10Volume2_ en_2010.pdf . (Accessed 6 September 2016). [15] K.B. Fowler, S. Boppana, Congenital cytomegalovirus (CMV) infection and hearing deficit, J. Clin. Virol. 35 (2006) 226–231. [16] C.L. Townsend, M. Forsgren, K. Ahlfors, et al., Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom, Clin. Infect. Dis. 56 (2013) 1232–1239. [17] D.E. Noyola, G.J. Demmler, C.T. Nelson, et al., Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection, J. Pediatr. 138 (2001) 325–331. [18] R.F. Pass, K.B. Fowler, S.B. Boppana, et al., Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome, J. Clin. Virol. 35 (2006) 216–220. [19] G. Enders, A. Daiminger, U. Bäder, et al., Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age, J. Clin. Virol. 52 (2011) 244–246. [20] R. Manara, L. Balao, C. Baracchini, et al., Brain magnetic resonance findings in symptomatic congenital cytomegalovirus infection, Pediatr. Radiol. 41 (2011) 962–970. [21] M.G. Capretti, M. Lanari, G. Tani, et al., Role of cerebral ultrasound and magnetic resonance imaging in newborns with congenital cytomegalovirus infection, Brain Dev. 36 (2014) 203–211. [22] K. Teär Fahnehjelm, M. Olsson, C. Fahnehjelm, et al., Chorioretinal scars and visual deprivation are common in children with cochlear implants after congenital cytomegalovirus infection, Acta Paediatr. 104 (2015) 693–700. [23] S. Boppana, C. Amos, W. Britt, et al., Late onset and reactivation of chorioretinitis in children with congenital cytomegalovirus infection, Pediatr. Infect. Dis. J. 13 (1994) 1139–1142. [24] L.E. Coors, R. Spencer, Delayed presentation of cytomegalovirus retinitis in an infant with severe congenital cytomegalovirus infection, Retina 30 (Suppl. (4)) (2010) S59–62.
Funding None. Competing interests None declared.
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