Joppe Nijman

Postnatally acquired cytomegalovirus infection in preterm infants: a prospective study on risk factors and cranial ultrasound findings

Objective To study risk factors and cranial ultrasound (cUS) findings in a large cohort of preterm infants, admitted to a neonatal intensive care unit and diagnosed with postnatally acquired cytomegalovirus (CMV) infection. Study design This prospective, observational study was performed from April 2007 until June 2009 among 315 infants born <32 weeks of gestation. Postnatal CMV infection was diagnosed by CMV PCR on urine collected at term-equivalent age. In CMV-positive infants, congenital infection was excluded. The authors compared the clinical and demographic data, feeding pattern and cUS results of infected and non-infected patients. Logistic regression analysis was performed. Results In 39 of 315 infants, the diagnosis of postnatal CMV infection has been made. The majority of CMV-infected infants (33/39.85%) did not develop any symptoms of CMV infection. The most important, independent risk factors of postnatal CMV infection were non-native Dutch maternal origin (OR 9.6 (95% CI 4.3 to 21.5)) and breast milk (OR 13.2 (95% CI 1.7 to 104.5)). The risk of infection significantly increased in infants with lower gestational age (GA) (OR 0.7 (95% CI 0.5 to 0.9)). Lenticulostriate vasculopathy (LSV) was significantly more often present in infants with CMV infection (OR 4.1 (95% CI 1.9 to 8.8)). Conclusions Postnatal CMV infection is an asymptomatic infection among preterm infants. Infants with lower GA are at greatest risk of postnatal CMV infection, especially when fed with fresh breast milk from their non-native Dutch mother. LSV not present at birth but confirmed at term-equivalent age can suggest a postnatal CMV infection.

Urine viral load and correlation with disease severity in infants with congenital or postnatal cytomegalovirus infection

BACKGROUND A correlation between cytomegalovirus (CMV) load in urine and severity of disease in congenitally infected infants has previously been reported. CMV load in postnatally infected infants has not been studied before. OBJECTIVE To investigate CMV load in urine of infants with postnatal or congenital infection and correlate this with clinical symptoms of CMV disease and cerebral abnormalities. STUDY DESIGN Infants admitted to our NICU between July 2000 and February 2010, and diagnosed with congenital or postnatal CMV infection were included. Clinical symptoms of CMV infection, cranial ultrasonography (cUS) and magnetic resonance imaging (MRI) findings were evaluated. CMV urine loads of postnatally infected infants were analyzed and compared with CMV urine loads of congenitally infected infants. RESULTS Seventeen infants with congenital CMV infection and 45 infants with postnatal CMV infection were included. Thirteen/17 (76%) congenitally infected infants had clinical symptoms of CMV infection at birth and 11/17 (65%) had cerebral abnormalities diagnosed by neuro-imaging. None of the four asymptomatic infants had cerebral abnormalities. Of the postnatally infected infants 43/45 (96%) did not develop any clinical symptoms of CMV infection, but in 23/45 (51%) cerebral abnormalities such as lenticulostriate vasculopathy and germinolytic cysts were identified. The median CMV load in postnatally infected infants was significantly lower than in congenitally infected infants (1.0×10(5)copies/ml versus 8.5×10(6)copies/ml, p<0.001, respectively). CONCLUSIONS CMV load in urine is significantly lower in infants with postnatal CMV infection than in infants with congenital CMV infection irrespective of clinical symptoms of CMV infection or cerebral abnormalities.

Neuro-Imaging Findings in Infants with Congenital Cytomegalovirus Infection: Relation to Trimester of Infection

Background: Congenital cytomegalovirus (cCMV) infection early in pregnancy may result in major disabilities. Cerebral abnormalities detected using cranial ultrasound (cUS) and magnetic resonance imaging (MRI) have been related to neurological sequelae. Objective: To evaluate the additional value of MRI and assess the relationship between time of infection during pregnancy and outcome in infants with cCMV infection. Methods and Study Design: Demographic and clinical data were collected in infants with cCMV infection (1992-2013). Trimester of infection, neuro-imaging results and outcome were reviewed. Cerebral abnormalities were categorized into none, mild (lenticulostriate vasculopathy, germinolytic cysts, high signal intensity on T2-weighted images) and severe (migrational disorder, ventriculomegaly, cerebellar hypoplasia). Results were statistically analysed. Results: Thirty-six infants were eligible for analysis. cUS was performed in all and cranial MRI in 20 infants. Migrational disorders were only diagnosed using MRI (p < 0.01). In 17 infants trimester of infection was ascertained. Seven out of 10 infants infected during the first trimester had severe abnormalities on cUS (5 confirmed on MRI) and adverse sequelae; 3 had no/mild abnormalities on cUS/MRI and normal outcome. Two out of 3 infants infected during the second trimester with no/mild abnormalities on cUS/MRI had normal outcome; 1 with mild cUS and MRI abnormalities developed sensorineural hearing loss. Four infants infected during the third trimester with no/mild abnormalities on cUS/MRI had normal outcome. Conclusion: Infants with a first trimester cCMV infection are most at risk of severe cerebral abnormalities and neurological sequelae. MRI, and not cUS, enables an early diagnosis of migrational disorders, which can improve prediction of outcome.

Genotype Distribution, Viral Load and Clinical Characteristics of Infants with Postnatal or Congenital Cytomegalovirus Infection

Background Congenital cytomegalovirus infection is a leading cause of long-term sequelae. Cytomegalovirus is also frequently transmitted to preterm infants postnatally, but these infections are mostly asymptomatic. A correlation between cytomegalovirus genotypes and clinical manifestations has been reported previously in infants with congenital infection, but not in preterm infants with postnatal infection. Objectives The main objective of this study was to investigate cytomegalovirus genotype distribution in postnatal and congenital cytomegalovirus infection and its association with disease severity. Methods Infants admitted to the neonatal intensive care unit of the University Medical Center Utrecht, The Netherlands between 2003–2010 and diagnosed with postnatal or congenital cytomegalovirus infection were included. Classification of cytomegalovirus isolates in genotypes was performed upon amplification and sequencing of the cytomegalovirus UL55 (gB) and UL144 genes. Clinical data, cerebral abnormalities, neurodevelopmental outcome and viral load were studied in relation to genotype distribution. Results Genotyping results were obtained from 58 preterm infants with postnatal cytomegalovirus infection and 13 infants with congenital cytomegalovirus infection. Postnatal disease was mild in all preterm infants and all had favourable outcome. Infants with congenital infection were significantly more severely affected than infants with postnatal infection. Seventy-seven percent of these infants were symptomatic at birth, 2/13 died and 3/13 developed long-term sequelae (median follow-up 6 (range 2–8) years). The distribution of cytomegalovirus genotypes was comparable for postnatal and congenital infection. UL55 genotype 1 and UL144 genotype 3 were predominant genotypes in both groups. Conclusions Distribution of UL55 and UL144 genotypes was similar in asymptomatic postnatal and severe congenital CMV infection suggesting that other factors rather than cytomegalovirus UL55 and UL144 genotype are responsible for the development of severe disease.

Cerebral white matter and neurodevelopment of preterm infants after coagulase-negative staphylococcal sepsis.

Objective: Coagulase-negative staphylococci are the most common pathogens causing lateonset sepsis in the neonatal intensive care unit. Neonatal sepsis can be associated with cerebral white matter damage in preterm infants. Neurodevelopment has been shown to be correlated with apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivities of the white matter. Design: Prospective cohort study. Setting: Twenty-eight–bed neonatal intensive care unit at a tertiary care children’s hospital. Patients: Seventy preterm infants (gestational age <32 wks), 28 with coagulase-negative staphylococcal sepsis (group 1) and 42 without sepsis (group 2). Intervention: The values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of three white matter regions (parietal, frontal, and occipital), estimated with diffusiontensor magnetic resonance imaging with a 3.0-T magnetic resonance imaging system, were obtained at termequivalent age. Neurodevelopmental outcome assessments were performed at 15 months (Griffiths Mental Developmental Scales) and 24 months (Bayley Scales of Infant and Toddler Development, Third Edition) corrected age. Measurements and Main Results: Values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of the left and right white matter regions were equal in all patients. There was no significant difference in apparent diffusion coefficient values (mean of total: 1.593 ± 0.090 × 10−3mm2/sec and 1.601 ± 0.117 × 10−3mm2/sec, respectively, p = .684), fractional anisotropy values (mean of total: 0.19 ± 0.04 and 0.19 ± 0.03, respectively, p = .350), radial diffusivity (mean of total: 1.420 ± 0.09 × 10−3mm2/sec and 1.425 ± 0.12 × 10−3mm2/sec, respectively, p = .719), and axial diffusivity (mean of total: 1.940 ± 0.12 × 10−3mm2/sec and 1.954 ± 0.13 × 10−3mm2/sec, respectively, p = .590) in the three combined regions between the two groups. No significant differences were found in neurodevelopmental outcome at 24 months. Conclusions: No association was found between coagulase-negative staphylococcal sepsis in preterm infants and cerebral white matter damage as determined by values of apparent diffusion coefficients, fractional anisotropy, and radial and axial diffusivity at termequivalent age, and no adverse effect was seen on early neurodevelopmental outcome.

Maternal and neonatal anti-cytomegalovirus IgG level and risk of postnatal cytomegalovirus transmission in preterm infants.

Immunological mechanisms influencing the risk of mother‐to‐child cytomegalovirus (CMV) transmission in preterm infants have not been studied sufficiently. In this study, the correlation between maternal and neonatal serum anti‐CMV IgG levels and risk of postnatal CMV transmission in preterm infants was assessed. Anti‐CMV IgG levels of 79 CMV seropositive mothers and their 94 infants were determined in peripheral blood samples collected within 3 days after delivery. Postnatal CMV infection was detected in 39/94 (41%) infants by PCR on urine at term‐equivalent age (gestational age 40 weeks) after congenital infection was excluded. Maternal or infant anti‐CMV IgG levels were not significantly different between infants with and without postnatal CMV infection. The anti‐CMV IgG infant–mother ratio showed a significant positive correlation with gestational age (range 25–32 weeks, R2 = 0.218, P < 0.001), reaching 1.0 at 32 weeks of gestation. Anti‐CMV IgG infant–mother ratio was significantly lower in infants with postnatal CMV infection (P = 0.015). In conclusion, the risk of postnatal CMV transmission is related to low gestational age and low anti‐CMV IgG infant–mother ratio. J. Med. Virol. 85:689–695, 2013.

Urine is superior to saliva when screening for postnatal CMV infections in preterm infants

BACKGROUND Cytomegalovirus (CMV) is the most frequently contracted virus in preterm infants. Postnatal infection is mostly asymptomatic but is sometimes associated with severe disease. To diagnose an infection, urine or saliva samples can be tested for CMV-DNA by real-time polymerase chain reaction (rtPCR). Although the diagnostic accuracy of testing saliva samples has not been determined in preterm infants, saliva is widely used because it is easier to obtain than urine. OBJECTIVES To determine whether screening of saliva is equivalent to urine to detect a postnatal CMV infection in preterm infants. STUDY DESIGN Between 2010 and 2013 saliva and urine samples were collected from infants admitted to the Neonatal Intensive Care Unit of the University Medical Center Utrecht and born with a gestational age (GA) below 32 weeks. Urine samples were obtained within three weeks after birth and urine and saliva samples at term equivalent age (40 weeks GA) and tested for CMV-DNA by rtPCR. Infants with a congenital CMV infection were excluded. RESULTS Of 261 preterm infants included in the study, CMV-DNA was detected in urine of 47 and in saliva of 43 children. Of 47 infants with postnatal CMV infection, CMV was detected in 42 saliva samples (sensitivity 89.4%; CI 76.9-96.5). Of 214 children without postnatal CMV infection, one saliva sample tested positive for CMV (specificity 99.5%; CI 97.4-99.9). CONCLUSIONS Screening saliva for CMV-DNA by rtPCR is inferior to urine to diagnose postnatal CMV infections in preterm infants.

Outcome of Preterm Infants With Postnatal Cytomegalovirus Infection

In this prospective study, we investigate neurodevelopmental outcomes, including hearing, of a large cohort of preterm infants with pCMV infection until early childhood. OBJECTIVES: To assess whether preterm infants with postnatal cytomegalovirus infection develop neurologic sequelae in early childhood. METHODS: Infants <32 weeks’ gestation were prospectively screened for cytomegalovirus (CMV) at term-equivalent age. Neurodevelopment was compared between CMV-positive and CMV-negative infants by using the Griffiths Mental Development Scales (GMDS) at 16 months’ corrected age (CA); the Bayley Scales of Infant and Toddler Development, Third Edition or the GMDS at 24 to 30 months’ CA; and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition and Movement Assessment Battery for Children, Second Edition at 6 years of age. At 6 years old, hearing was assessed in CMV-positive children. RESULTS: Neurodevelopment was assessed in 356 infants at 16 months’ CA, of whom 49 (14%) were infected and 307 (86%) were noninfected. Infected infants performed significantly better on the GMDS locomotor scale. There were no differences at 24 to 30 months’ CA on the Bayley Scales of Infant and Toddler Development, Third Edition or GMDS. At 6 years of age, infected children scored lower on the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, but mean scores were within normal range, reaching significance only in verbal IQ (96 [SD 17] vs 103 [SD 15] points; P = .046). Multiple regression indicated no impact of CMV status but significant influence of maternal education and ethnicity on verbal IQ. No significant differences in motor development were found and none of the infected children developed sensorineural hearing loss. CONCLUSIONS: In this cohort study, postnatal cytomegalovirus infection in preterm children did not have an adverse effect on neurodevelopment within the first 6 years of life.

Predictors of severity for postnatal cytomegalovirus infection in preterm infants and implications for treatment.

Postnatal cytomegalovirus (CMV) infection is common in neonates and is mostly acquired through infected breast milk from seropositive mothers. In this review, risk factors of postnatal CMV transmission and predictors of severity, preventive measures and treatment of symptomatic postnatal CMV infection in preterm infants are discussed. Several viral, transmission route and host factors have been associated with a higher risk of postnatal CMV transmission from mother to child. Severity predictors of symptomatic postnatal CMV infection may include extreme prematurity (gestational age <26 weeks), timing of postnatal infection as well as comorbidities. Further research in postnatally infected preterm infants at risk for severe symptoms is essential with respect to preventive measures involving the infected breast milk and antiviral treatment.

HEARING IN PRETERM INFANTS WITH POSTNATALLY ACQUIRED CYTOMEGALOVIRUS INFECTION

Cytomegalovirus is an important cause of sensorineural hearing loss in children. In contrast to congenitally infected infants, little is known about hearing in preterm infants with postnatal cytomegalovirus infection. We studied the hearing in 64 preterm infants during the first year of life and in 18 during the second year of life. None of the infants developed sensorineural hearing loss.