Postnatal Cytomegalovirus Infection Among Preterm Infants

KEY POINTS

• 1.

  Cytomegalovirus (CMV) infection is acquired in the postnatal period primarily from mother’s milk feeding.

• 2.

  Postnatal CMV (pCMV) infection is usually asymptomatic in healthy term infants. Among very low birth weight (VLBW, birth weight <1500 g) infants, infection occurs in ∼6.5% and is associated with a sepsis-like syndrome in ∼1% but is rarely fatal.

• 3.

  Symptomatic pCMV infection is associated with lower gestation, younger age at acquisition, and an increased number of preexisting comorbid conditions.

• 4.

  VLBW pCMV infection has been variably associated with increased risk of chronic lung disease, retinopathy of prematurity, hearing loss, and neurodevelopmental impairment.

• 5.

  There are no standard recommendations for use of antiviral therapies for pCMV infection.

• 6.

  Prevention of pCMV transmission from mother to preterm infant is an area of ongoing research that has focused on methods to inactivate the virus in milk. The risks and benefits of such approaches remain unclear.

Introduction

Human cytomegalovirus (CMV) is a double-stranded DNA virus of the beta-herpes family. Primary infection with CMV commonly occurs via mucosa, but transmission can also occur after a transfusion or transplant or in utero. Like other herpes viruses, CMV persists after primary infection, predominantly by residing in myeloid cells where the virus does not replicate and avoids elimination by the host immune system. During times of altered immune function, such as immunosuppression for transplant therapy, the virus can reactivate, proliferate with multiorgan involvement, and cause substantial morbidity and mortality. In neonates, both congenital CMV infection (cCMV) and postnatally acquired CMV infection (pCMV) occur almost exclusively among infants born to CMV-infected mothers. cCMV may occur in the newborn due to primary maternal infection during pregnancy or with reactivation of a latent maternal infection, with resulting transplacental or intrapartum transmission. In contrast, pCMV is primarily acquired via breast milk feeding. A majority of lactating women with latent CMV infection (positive for CMV-specific immunoglobulin G [IgG] serum antibodies) experience viral reactivation with secretion of CMV in breast milk. This reactivation is localized in mammary tissue without consistent maternal viremia. Although vertical CMV transmission during pregnancy can be devastating for the immune-naïve fetus, primary infection from breast milk in the postnatal period is largely asymptomatic among both term and preterm infants. Preterm and very-low birth weight (VLBW, birth weight <1500 g) infants, however, may manifest acute illness after pCMV, with symptoms ranging from isolated laboratory abnormalities to acute clinical decompensation. ^, In the following, we will address neonatal CMV infection, with an emphasis on pCMV among preterm, VLBW infants.

Viral Pathogenesis

CMV entry into host cells is driven by interactions between glycoprotein complexes present on the outermost lipid envelope of the virus and host receptors ( Fig. 33.1 ). ^, Once intracellular, a tightly regulated sequence of immediate early, early, and late gene expression occurs. Viral effects on the host cell can include a variety of outcomes including lysis, immune evasion, immune activation, and an altered cellular environment, depending on the type of cell, stage of development (especially important in fetal infection), and the immune state of the host. Mechanisms of CMV persistence and immune evasion involve a multipronged approach by viral gene products against each arm of human immune defense. The virus produces cytokines that mimic host interleukin 10 and suppress inflammation; interferes with immune action requiring major histocompatibility complex I and II presentation; slows cell apoptosis; encodes microRNAs that alter cell cycle regulation; and produces a chemokine that is thought to allow dissemination of the virus in the body. ^, CMV establishes latency in specific hematopoietic cell lines, establishing life-long persistence.