Congenital Cytomegalovirus
Congenital cytomegalovirus (cCMV) is the most common congenital infection in the developed world. Reported prevalence varies between cohorts but is approximately 7 per 1000 births.1 About half of cytomegalovirus (CMV)-infected babies with clinically detectable disease at birth are destined to have significant impairments in their development, and cCMV infection is implicated in approximately 25% of all children with sensorineural hearing loss (SNHL).1,2 Meta-analysis shows that although long-term sequelae, especially SNHL, are more common in those with clinically detectable disease at birth, they are also found in 13% of those without clinical features attributable to CMV on initial examination.1 Despite the significant long-term impact of cCMV infection, there is limited evidence on which to base many treatment decisions in clinical practice. In an era of enhanced perinatal screening, fetuses and newborns are increasingly tested for CMV after abnormalities were detected during routine ultrasonography or maternal serology. Furthermore, otherwise “asymptomatic”, congenitally CMV-infected, newborns are being identified after detection of SNHL through newborn hearing screening programs. Because of earlier diagnosis, babies with cCMV now presenting to pediatricians differ from those primarily included in clinical trials of treatment reported in the literature. A symposium was convened during the 2015 conference of the European Society of Paediatric Infectious Diseases to discuss the current management of cCMV. In attendance were clinicians from throughout Europe, many of whom are involved in policy for cCMV for their region/country. This article summarizes the discussions at this meeting alongside the evidence informing them. A balanced perspective of the controversies in this area is presented and areas of consensus highlighted. Finally, where evidence is lacking, suggestions are made for future research efforts to address areas of unmet medical need. The authors acknowledge the coexisting need for studies on the management of babies with symptoms consistent with cCMV, but in whom this diagnosis cannot be firmly established, and of those with symptomatic postnatal CMV infection; this article does not, however, address these groups. The internationally accepted GRADE system for evaluating evidence has been used to illustrate points where relevant (Table 1).3TABLE 1.: Grade System of Evaluating Evidence3DEFINITIONS OF SYMPTOMATIC DISEASE Classically, cCMV infection is categorized as “symptomatic” or “asymptomatic” at birth. Differing definitions and opinions on what constitutes “symptomatic” CMV infection, however, makes interpreting the literature challenging. Indeed, some of the largest cohort studies include babies with SNHL at birth in the group described as being “asymptomatic” because no “clinically apparent disease” was detectable during newborn examination.4 In modern healthcare systems, whereby cCMV is increasingly detected through screening for other conditions, alongside increased accessibility of investigations, such as magnetic resonance imaging (MRI), the traditional dichotomy between clinically “apparent” and “inapparent” disease is becoming less meaningful. Table 2 summarizes the accepted clinical features of cCMV disease with those symptoms detectable on newborn examination listed separately to those detectable only if specific investigations are conducted, for example, when cCMV is already suspected.5–8TABLE 2.: Possible Signs and Symptoms in Children With Congenital CMV5–8Full Consensus Within This Expert Group Was That 1. For the purposes of research and publication, newborns identified as having cCMV disease after abnormal clinical examination at birth (such as microcephaly, small for gestational age (SGA), widespread petechiae, hepatosplenomegaly) should be differentiated from those babies identified through screening or investigation for other disorders, for example, those tested for CMV after known/likely maternal infection or abnormal newborn hearing screening. This differentiation would allow for more accurate assessment of the prognostic value of individual manifestations of “symptomatic” disease on longer-term outcomes as already shown in other publications.9 2. “Symptomatic” cCMV should be considered as “severe,” “moderate” or “mild” disease. a. “Mild” disease includes those with isolated (1 or 2 at most), otherwise, clinically insignificant or transient findings, such as petechiae, mild hepatomegaly or splenomegaly or biochemical/hematologic abnormalities (such as thrombocytopenia, anemia, leukopenia, borderline raised liver enzyme abnormalities or conjugated hyperbilirubinemia) or SGA (defined as weight for gestational age <−2 standard deviations) without microcephaly. b. “Severe” disease includes those with central nervous system (CNS) involvement (abnormal neurologic or ophthalmologic examination, microcephaly or neuroimaging consistent with cCMV disease [such as calcifications, moderate to severe ventriculomegaly, cysts, white matter changes, cerebral or cerebellar hypoplasia, hippocampal dysplasia, neuronal migration abnormalities])10 or with life-threatening disease. The Majority Agreed That 2b. “Severe” disease also includes babies with evidence of severe single-organ disease (including those with clinically significant liver enzyme abnormalities [liver “failure”] and marked hepatosplenomegaly) or those with significant multiorgan involvement. Babies with transient or otherwise clinically insignificant abnormalities (ie, the babies are not “sick”) that resolve spontaneously over a few weeks are not included in this group even if these abnormalities are multiple. 2c. A further group exists that may be considered to have “moderate” disease. This group is heterogeneous and includes, for example, those with persistent (eg, more than 2 weeks duration) abnormalities of hematologic/biochemical indices or more than 2 “mild” disease manifestations (as listed earlier). Because of lack of evidence, full consensus could not be reached on how to approach this group, and treatment decisions are currently made on a case by case basis. Development of a validated clinical scoring system for disease severity at presentation and risk of sequelae would be beneficial for both counseling parents and informing treatment decisions. 3. Defining CNS involvement a. It remains uncertain whether some, nonspecific findings detected on cranial ultrasound (CrUSS) and MRI (particularly isolated lenticulostriatal vasculopathy [LSV]) constitute clinically significant CNS disease. LSV has been detected in 0.4%–5.8% of all neonates undergoing an ultrasound, and only 5% has been associated with cCMV.11,12 Some have suggested isolated LSV as a marker of risk for SNHL.11 Others have found only more extensive neuroimaging abnormalities to be of prognostic value.13,14 The majority at this meeting would not consider LSV in isolation to be a notable CNS manifestation of disease. It is suggested that neuroradiologic abnormalities not known to be clearly associated with CMV disease and adverse outcomes are discussed with a suitably experienced neuroradiologist, particularly, if the results of these discussions might influence treatment decisions. b. The exact pathophysiology of SNHL is not clear but is likely secondary to infection and degradation of sensory structures within the inner ear.15,16 It is therefore debated whether isolated SNHL should truly be considered a CNS manifestation of infection and, as a consequence, whether such children should be considered comparable to those with CNS disease included in published clinical trials. No studies have addressed this specific population, but a nonrandomized cohort study observing the effects of valganciclovir in isolated SNHL is in progress (clinicaltrials.gov NCT02005822). The majority of experts at this meeting would categorize babies with isolated, confirmed SNHL in the “severe”/CNS group because bilateral SNHL is not only associated with likely long-term impairments but was also included in the criteria for recruitment in the only randomized controlled trials (RCTs) in cCMV. However, consensus was not reached because the spectrum of hearing loss is wide, and treatment of isolated SNHL has not been evaluated in any RCTs. WHEN SHOULD TESTING FOR CONGENITAL CMV BE CONSIDERED? Indications for testing for cCMV are based on the presence of one or more of the most frequently observed clinical features (Table 3).17 Unfortunately, predictive values for each of these features are not available.TABLE 3.: Clinical Features That Should Lead to Testing for Congenital CMVFull Consensus Within This Expert Group Was That Testing for cCMV Should be Performed in 1. Fetuses with ultrasound/MRI imaging consistent with cCMV disease (by appropriately timed antenatal testing of amniotic fluid).18 (Quality C, Level 1) 2. Newborns where there is a maternal history of suspected primary CMV infection during pregnancy. If antenatal testing of amniotic fluid has been conducted, it is suggested that cCMV infection should still be confirmed at birth because both false-positive and -negative results have been reported.18 (Quality C, Level 1) 3. Newborns with signs/symptoms consistent with cCMV disease (see Table 2; including those with findings consistent with cCMV on antenatal imaging). (Quality B, Strength 1) 4. Children with confirmed SNHL.16 Systems need to be established to ensure testing for cCMV occurs, where possible, in the first 21 days of life because dried blood spot (DBS) are not always readily available for testing (see below). (Quality B, Strength 1) The Majority Agreed That 5. Newborns who are SGA should not routinely be tested. Studies in SGA newborns have shown the prevalence of cCMV to be 0%–5.2%.19–22 However, the majority of studies report a prevalence of 1.4%–1.8%, which is not significantly higher than the prevalence of cCMV in the general population. Therefore, evidence is insufficient to justify screening all newborns with isolated SGA for cCMV. None of these studies distinguish between asymmetrical (with normal head circumference) and symmetrical SGA, but when head circumference was mentioned, most SGA babies with cCMV had microcephaly (head circumference <−2 standard deviations).21,22 Because of this, and the poor prognostic outcome of children with cCMV and microcephaly, many present at this meeting test those babies with symmetrical SGA but not those with preserved head growth.14(Quality C, Strength 2) 6. Prematurity. Evidence that premature babies have a higher incidence of cCMV is limited.20,23 Testing extremely premature babies (<28 weeks gestational age) at birth does, however, assist in differentiating between congenital and postnatal infection. This may be very helpful in guiding the management of these babies that are particularly vulnerable to symptomatic postnatal infection. However, consensus was not reached regarding practice in this area, with cost being a factor among other considerations.24 (Quality C, Strength 2) 7. Testing of babies born to mothers who are known to be CMV seropositive at the establishment of pregnancy. Although maternal nonprimary CMV infection is known to be important when considering the overall burden of cCMV disease, testing all babies born to these women, particularly in populations with high maternal seroprevalence, is tantamount to universal neonatal screening.25,26 Identifying women with nonprimary CMV who are at highest risk of transmitting infection to their fetus remains elusive. It was agreed that individual case discussion and local policy should therefore dictate practice in this area. Further research is clearly needed. LABORATORY DIAGNOSIS OF CONGENITAL CMV INFECTION Testing for cCMV using CMV polymerase chain reaction (PCR) in urine is highly reliable: sensitivity is 100% and specificity 99%.27 One negative urine specimen in a neonate is therefore sufficient to exclude infection, and repeat sampling is not necessary. After 21 days, a urine positive for CMV could be because of CMV acquired postnatally from, for example, passage through the birth canal or through breast milk. As CMV PCR techniques are becoming more sensitive, earlier testing, before the age of 14 days, is recommended.27 CMV PCR testing of saliva is an alternative and is easy to perform. Samples should be taken immediately before feeding in breastfed newborns, and confirmed with urine, as false-positive results have been reported.28–31 PCR assay of neonatal DBS can be performed retrospectively in an attempt to diagnose cCMV after the first 21 days of life. Sensitivity is around 84% in meta-analysis but is highly variable on the techniques used and the being a negative DBS PCR be used to exclude a diagnosis of Consensus Within This Expert Group Was That 1. Testing for cCMV should be performed using a CMV PCR of urine within 21 days of birth but within 14 days of birth (Quality B, Strength 2. PCR testing can be an but a positive should be confirmed using urine (Quality B, Strength 3. After the age of 21 days, CMV PCR of DBS can be used to diagnose cCMV sensitivity is and a negative test cannot be used to exclude a diagnosis of cCMV (Quality B, Strength A DIAGNOSIS OF CONGENITAL CMV INFECTION After a diagnosis of cCMV infection has been investigations are to the of disease and to assist with discussions regarding and Consensus Within This Expert Group Was That 1. The investigations are in any in whom a diagnosis of cCMV is for the manifestations of disease (Table blood liver (Quality Strength 1) testing some screening such as are not sufficient to central hearing loss in (Quality Strength 1) (Quality Strength 1) 2. If imaging to is to be MRI is the neuroimaging MRI can be performed in neonates without the need for and both highly and of the of which (Quality C, Strength 1) 3. MRI should be performed in babies with clinically detectable neurologic findings or The Majority Agreed That 4. MRI should be performed in any babies with cCMV and evidence of CMV disease (see Table (Quality C, Strength 1) 5. CMV PCR should be performed in blood at studies have shown the of CMV to be associated with long-term and this may be when evaluating babies without any other manifestations of cCMV CMV PCR should not, however, be used to cCMV infection the of CMV in blood has been described even in babies with severe cCMV (Quality C, Strength 2) 6. of fluid No current evidence examination of as of routine Studies have shown detectable CMV in and such as a poor However, have shown no prognostic value from in the clinical Despite this lack of evidence, there was a majority that although a area of for future should not be performed routinely in babies with cCMV infection (Quality C, Strength a Agreed That 7. MRI should be performed in all Although there is no evidence that MRI prognostic to in those without evidence of CMV disease at birth, some that it is to MRI in all babies because can be identified as with (Quality Strength No are currently for the treatment of cCMV. Although many case and cohort studies have reported on treatment for cCMV, there are results from only 2 The first of these studies evaluated treatment in neonates of gestational age weeks and clinically apparent disease in the newborn with evidence of CNS disease (including microcephaly, abnormal indices for hearing and hearing and outcomes were but there was significant loss to A more to treatment with valganciclovir and included babies with any evidence of symptomatic (including cCMV babies however, had isolated, mild clinical and in the treatment group had isolated SNHL A on both hearing and outcomes was shown with the treatment The treatment of hearing outcomes most in those with CNS involvement. of was only however, for hearing as to hearing is of and only for CNS involvement. the of some features of cCMV disease in published alongside the of hearing loss and in SNHL reported in cCMV, it is even more to any regarding treatment from Clinical trials to not, evidence on which to base treatment decisions for many of the presenting to clinicians in clinical practice. Table on which should be treatment after a risk discussion with the This and associated areas where consensus was discussion around the treatment of babies with less severe cCMV disease and whether the shown in the treatment was sufficient to justify such a of Although clinical findings such as SGA and have been shown in cohorts to risk for SNHL, more of that these findings in isolation are associated with outcomes in babies presenting without other manifestations of symptomatic on the or of symptoms treatment remains and it is therefore that clinicians discuss treatment and with an in this of Consensus Within This Expert Group Was That 1. Babies with evidence of CNS disease should treatment (Quality Strength should be for (Quality B, Strength 2. Babies with no findings consistent with CMV disease should not treatment because no evidence exists to treatment in this group (Quality Strength to 3. Babies with evidence of life-threatening disease or severe single-organ disease or multiorgan involvement should Although evidence is particularly for life-threatening disease, consensus was that treatment should be considered in this group (Quality B, Strength Consensus could not be reached on of treatment in this 4. valganciclovir is now the of should be used in babies to or where is uncertain (Quality Strength The Majority Agreed That 5. Babies with “mild” cCMV disease (as should not No studies have clearly addressed treatment in this present at this meeting would not, babies with or 2 isolated or clinically manifestations of disease (Quality C, Strength 6. Babies with “moderate” cCMV disease (as earlier). Evidence for babies with but not manifestations of disease (including without significantly raised liver is It that these are discussed on a with a with of babies with cCMV (such as a disease (Quality B, Strength 7. of isolated The majority at this meeting would include SNHL at birth in their for treatment because this was in the criteria for treatment in RCTs. Furthermore, the of treatment is in hearing than hearing with outcomes reported in studies (with likely was not, however, and it is that no have addressed treatment in this group of babies who are now identified through newborn hearing screening C, Strength and Although valganciclovir is now treatment in most it is currently whether valganciclovir areas as as where should be (eg, CNS or inner because no studies have the 2 In those with severe disease, particularly if is by some in of treatment can be (Quality C, Strength in without CNS In those in whom the is taken to the majority would for However, there was no consensus on this in of the shown for treatment in the only (Quality B, Strength babies than of children has not been addressed in any although it is that the is also not evidence case of small of babies the newborn have reported Babies found to have SNHL after hearing screening at birth not have a diagnosis of cCMV confirmed the of for No consensus was reached on how it might be to treatment in this or in the of hearing are currently evaluating the of treatment in children with cCMV and SNHL (clinicaltrials.gov and which may this for the newborn Strength OF of the around less babies to the effects of currently available is frequently observed during treatment in This is reported less with valganciclovir than with with during the first of with no increased observed after weeks in those randomized to treatment with in the only evaluating The of valganciclovir also the burden of and risk of and central observed during treatment with has been reported in to of those with and in a In the most study of treatment with liver was but this was clinically significant when with In all abnormal and after effects have not been evaluated in neonates with or studies the risk of and Although this has not been observed in to parents should be these particularly when considering treatment in those in which has not been clearly No adverse long-term effects have been in a small cohort of babies in neonatal studies and to OF Table summarizes a for babies for cCMV. are based on the and from the published and to are no to however, have a when is a (eg, in those with or where there are treatment Consensus Within This Expert Group Was That treatment is babies should have weight and to of (see Table Strength 1) treatment is parents should be both the known and effects of treatment with current (Quality Strength for no published Although there are of treatment no cohorts have been to this to be evaluated in during life. possible, children treatment be a to a Agreed That Some report to assist in decisions regarding and detection of however, most experts at this meeting not this is not by any and of after treatment is with no with long-term outcomes (Quality Strength If is after it is suggested that parents are of the that be detectable and that this is of Table summarizes of babies with cCMV and The for is based on long-term studies of SNHL in is suggested during the first 2 of life because this is the of highest risk for of hearing loss and a for detection of SNHL during this is also most likely to long-term should however, because in hearing throughout (Quality B, Strength is suggested at and 2 of age with This is not, however, routinely in all and there is no in this group, although detection of impairments is agreed to be is at children can in those with clinically detectable disease at birth, but not in those because in has been observed in this group (Quality C, Strength should be for where these (see cCMV are not parents of children with hearing loss may from for those with hearing FOR Clinical trials treatment of those with more manifestations of clinically detectable disease at birth and those with isolated Clinical studies of antenatal to of infection and cCMV disease infection is to cCMV should it clear how those included were identified (ie, babies presenting with clinically detected babies identified through antenatal or postnatal screening including hearing screening or after further investigation of such as thrombocytopenia, found when blood sampling is performed for other Development of clinical to categorize severity of disease and babies with findings of and associated outcomes to assist counseling of Studies of particularly and value with to long-term impairments particularly in those without clinically detectable disease at birth through studies cCMV Clinical trials of alternative treatment and when It that a of treatment be beneficial in babies with such clinical manifestations of disease and likely variable burden and The of both and of long-term outcomes would of future and more accurate counseling and children treatment should be in a to for any long-term effects of of risk for maternal particularly, in those mothers with known to CMV As at the this article the consensus of a group of with a in cCMV. It that of practice is based on limited but areas where there is consensus have shown cost of screening at birth for cCMV, although these are by the raised in this article regarding of of treatment and agreed treatment in It be to address many of the research raised through the significant and long-term alongside in such studies when treatment is being more accurate on disease manifestations and treatment outcomes in alongside maternal however, treatment as shown very for the management of This a approach to initial definitions of and which is currently being addressed by a of clinicians with an in this area through both and European such as Paediatric European for of Infectious the European Congenital CMV and European Society of Paediatric Infectious Diseases and European Society for Clinical It should also be that this article on postnatal of diagnosis and is an associated and need for alongside and to address in of antenatal It is that through such progress be made in infection and disease in newborns and children with cCMV. The children and their who have for and who on a to and consistent including those parents who are involved with other parents through local or including not CMV