Advances in congenital and postnatal cytomegalovirus infections

Abstract

Congenital CMV infection (cCMV) is the most prevalent viral infection worldwide and the leading cause of non-genetic sensorineural hearing loss. Early diagnosis of cCMV infection is advantageous as it allows for regular follow-up and timely intervention in case of late-onset symptoms among symptomatic and asymptomatic children. Recently, it has been questioned if affected infants are adequately recognized due to unfavorable levels of disease knowledge among healthcare providers and low registration numbers in international cCMV registries. In contrast to cCMV, a postnatal CMV (pCMV) infection is usually uneventful. A pCMV infection is most frequently acquired through CMV infected breastmilk. Uncertainties remain about implementation of preventive measures among preterm infants (gestational age 24-32 weeks) due to immunological immaturity and frequent co-morbidities. While full-term infants are unaffected, there are doubts whether cerebral development and (long-term) outcome are equally unaffected in the preterm population. This thesis in Part I (cCMV) aimed at evaluating current recognition and management practices, assess the disease burden of cCMV in the Netherlands through a registry and to evaluate postnatal neuro-imaging findings to neurodevelopment and trimester of maternal CMV infection. In Part II (pCMV), the aim was to evaluate available diagnostics for pCMV screening amongst preterm infants, to identify predictors of clinical severity and to study neuro-imaging findings. Lastly, we aimed to assess the effects of a pCMV infection on short- and long-term neurodevelopment. The findings of this thesis suggest a suboptimal state of recognition and management practices of infants with cCMV infection. Similar to findings from other international cCMV registries, approximately 80% of the expected infants were not reported. It is unclear whether this is due to the difficulties surrounding antenatal or postnatal detection and diagnosis of cCMV infection or due to incomplete comprehension of disease characteristics by health care professionals, as demonstrated in this thesis. Universal screening shortly after birth would circumvent these problems and allow for timely identification, thorough follow-up and implementation of therapy if needed. Moreover, collection of long-term follow-up data will provide accurate population based information on the disease burden. Furthermore, this thesis confirms that the presence of postnatal neuro-imaging abnormalities correlate with a maternal CMV infection early in pregnancy and an adverse neurodevelopmental outcome. In terms of pCMV infections, prematurity and low birthweight may predict an adverse clinical course. We also evaluated the consequence of pCMV infection within a large, prospectively screened cohort of preterm infants until six years of age. Screening was conducted by urine CMV-PCR and saliva CMV-PCR, whereby urine was the most sensitive sample. Analysis of neuro-imaging revealed no gross brain lesions but minor changes in the structural integrity of the occipital white matter in infected infants. At six years of age there was no indication of abnormal visual function or abnormalities in cognitive or motor development that could be attributed to the infection. Likewise, at six years of age none of the infected children had sensorineural hearing loss. On the basis of these findings preventive measures appear not be warranted for preterm infants with a gestational age of 24-32 weeks.