Pediatric Cytomegalovirus Infection Clinical Presentation

The history must be tailored to the specific clinical circumstances and disease category. Specific disease categories are considered as follows:

• Congenital cytomegalovirus (CMV) infection: Current estimates suggest that 30,000-40,000 infants are born with congenital cytomegalovirus infection annually in the United States, making cytomegalovirus by far the most common and important of all congenital infections. The likelihood of congenital infection and the extent of disease in the newborn depend on maternal immune status. If primary maternal infection occurs during pregnancy, the average rate of transmission to the fetus is 40%; approximately 65% of these infants have cytomegalovirus disease at birth. With recurrent maternal infection (ie, cytomegalovirus infection that occurs in the context of preconceptual immunity), the risk of transmission to the fetus is lower, ranging from 0.5-1.5%; most of these infants appear normal at birth (ie, silent infection). Hence, congenital infection may be classified as symptomatic or asymptomatic in nature (see the image below). Epidemiology patterns of congenital cytomegalovirus infection. Approximately 10% of cases of congenital cytomegalovirus occur in women with primary infection during pregnancy, and 90% of these infants have neurological sequelae. Although preexisting immunity (eg, maternal recurrent infection) protects against severe disease, approximately 15% of these infants have sequelae, particularly sensorineural hearing loss.

  • Cytomegalic inclusion disease (CID)
    • Approximately 10% of infants with congenital infection have clinical evidence of disease at birth.^[12] The most severe form of congenital CMV infection is referred to as CID.
    • CID almost always occurs in women who have primary cytomegalovirus infection during pregnancy, although rare cases are described in women with preexisting immunity who presumably have reactivation of infection during pregnancy.
    • CID is characterized by intrauterine growth retardation, hepatosplenomegaly, hematological abnormalities (particularly thrombocytopenia), and various cutaneous manifestations, including petechiae and purpura (ie, blueberry muffin baby). However, the most significant manifestations of CID involve the CNS. Microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most common neurological consequences of CID.
    • Intracerebral calcifications typically demonstrate a periventricular distribution and are commonly encountered using CT scanning (see the image below). The finding of intracranial calcifications is predictive of cognitive and audiologic deficits in later life and predicts a poor neurodevelopmental prognosis. Cranial CT scan of infant born with symptomatic congenital cytomegalovirus infection. Neurological involvement is evident, manifest as ventriculomegaly and periventricular calcifications.
    • Most infants who survive symptomatic CID have significant long-term neurological and neurodevelopmental sequelae. Indeed, it has been estimated that congenital cytomegalovirus may be second only to Down syndrome as an identifiable cause of mental retardation in children.
  • Asymptomatic congenital cytomegalovirus
    • Most infants with congenital cytomegalovirus infection are born to women who have preexisting immunity to cytomegalovirus. These infants appear clinically healthy at birth; however, although infants with congenital cytomegalovirus infection appear well, they may have subtle growth retardation compared to uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae.
    • The major consequence of inapparent congenital cytomegalovirus infection is sensorineural hearing loss. Approximately 15% of these infants will have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of cytomegalovirus–associated hearing loss because this deficit may develop months or even years after birth.^[13]
• Acquired cytomegalovirus infection: In contrast to congenital infection, acquired cytomegalovirus infection occurs postnatally. Primary infection in this context is generally asymptomatic, although cytomegalovirus disease may occur in certain risk groups as follows:

  • Perinatal infection
    • Perinatal acquisition of cytomegalovirus usually occurs secondary to exposure to infected secretions in the birth canal or via breastfeeding. Most infections are asymptomatic. Indeed, in some reviews, cytomegalovirus acquired through breast milk has been referred to as a form of natural immunization.
    • Some infants who acquire cytomegalovirus infection perinatally may have signs and symptoms of disease, including lymphadenopathy, hepatitis, and pneumonitis, which may be severe. Disease secondary to acquisition by breast milk is generally limited to premature infants with low birth weight. These infants may suffer considerable morbidity. Whether interventions, such as freezing or pasteurization, are warranted to decrease the risk of transmission to these high-risk infants is unclear. More studies of long-term neurodevelopmental outcomes of premature infants who acquire cytomegalovirus infection perinatally from breast milk are needed.
  • Cytomegalovirus mononucleosis
    • Typical cytomegalovirus mononucleosis is a disease found in young adults. Although cytomegalovirus mononucleosis may be acquired by blood transfusion or organ transplantation, cytomegalovirus mononucleosis is usually acquired via person-to-person transmission.
    • The hallmark symptoms of cytomegalovirus mononucleosis are fever and severe malaise. An atypical lymphocytosis and mild elevation of liver enzymes are present.
    • Clinically differentiating cytomegalovirus mononucleosis from Epstein-Barr virus (EBV)-induced mononucleosis may be difficult. Cytomegalovirus mononucleosis is typically associated with less pharyngitis and less splenomegaly. As with EBV mononucleosis, the use of b-lactam antibiotics in association with cytomegalovirus mononucleosis may precipitate a generalized morbilliform rash.
  • Transfusion-acquired cytomegalovirus infection
    • Posttransfusion cytomegalovirus infection has a presentation similar to that of cytomegalovirus mononucleosis. Incubation periods range from 20-60 days.
    • The use of seronegative blood donors, frozen deglycerolized blood, or leukocyte-depleted blood can decrease the likelihood of transmission and is recommended for high-risk patients (eg, neonates, immunocompromised patients).
• Cytomegalovirus infections in immunocompromised patients: Cytomegalovirus causes various clinical syndromes in immunocompromised patients. Disease manifestations vary in severity depending on the degree of host immunosuppression. Infection may occur because of reactivation of latent viral infection or may be newly acquired via organ or bone marrow transplant from a seropositive donor. Infections may also be mixed in nature, with donor and recipient isolates both present. Viral dissemination leads to multiple organ system involvement, with the most important clinical manifestations consisting of pneumonitis, GI disease, and retinitis.

  • Cytomegalovirus pneumonitis
    • Cytomegalovirus is a major cause of pneumonitis in immunosuppressed children and adults. This disease may be observed in the setting of HIV infection, congenital immunodeficiency, malignancy, and solid organ or bone marrow transplant.
    • The mortality rate is based on the degree of immunosuppression, with mortality rates of at least 90% reported in bone marrow transplant recipients. Solid organ transplant recipients are at risk of developing cytomegalovirus pneumonitis also, although mortality rates are lower.
    • The illness usually begins 1-3 months following transplantation and starts with symptoms of fever and dry, nonproductive cough. The illness progresses quickly with retractions, dyspnea, and hypoxia becoming prominent.
    • The illness is an interstitial pneumonitis, with a radiographic appearance of diffuse bilateral interstitial infiltrates. Because the differential diagnosis of pneumonitis is extensive in immunocompromised patients, consider performing a bronchoalveolar lavage or open lung biopsy to confirm the diagnosis and direct appropriate therapy.
  • Cytomegalovirus GI disease
    • GI tract disease caused by cytomegalovirus can include esophagitis, gastritis, gastroenteritis, pyloric obstruction, hepatitis, pancreatitis, colitis, and cholecystitis. Characteristic signs and symptoms may include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea.
    • Stool may be Hemoccult positive or frankly bloody. Endoscopy and biopsy are warranted, and characteristic cytomegalic inclusion cells may be observed in GI endothelium or epithelium.
    • Although CMV enteritis does not carry the same ominous prognosis as cytomegalovirus pneumonitis, antiviral therapy is warranted.
    • Differentiating cytomegalovirus hepatitis from chronic rejection in liver transplant patients may be difficult, even with biopsy.
  • Cytomegalovirus retinitis
    • Before the advent of highly active antiretroviral therapy (HAART) for HIV infection, cytomegalovirus retinitis was the most common cause of blindness in adult patients with acquired immunodeficiency syndrome (AIDS), with an overall lifetime prevalence of more than 90%.
    • HIV-associated cytomegalovirus retinitis in children, in contrast to adults, has been relatively rare, probably reflecting overall differences in cytomegalovirus seroprevalence between the populations. Retinitis is less common in transplant patients.
    • Cytomegalovirus produces a necrotic rapidly progressing retinitis with characteristic white perivascular infiltrate with hemorrhage (brushfire retinitis).
    • Peripheral lesions may be asymptomatic, and even advanced disease does not cause pain. In children, strabismus or failure to fix and follow objects may be important clues to the diagnosis.
    • The disease can progress to total blindness and retinal detachment if left untreated. Cytomegalovirus chorioretinitis is also observed in symptomatic infants with congenital infection infants, although the disease does not usually progress to vision loss. The presence of chorioretinitis in an infant with congenital infection infant indicates a poor neurodevelopmental prognosis.
  • Other cytomegalovirus syndromes
    • Various syndromes have been attributed to cytomegalovirus infection, although cause and effect relationships are often difficult to establish.
    • Menetrier disease is a rare disorder characterized by hyperplasia and hypertrophy of the gastric mucous glands, which results in massive enlargement of the gastric folds. Most cases appear to be cytomegalovirus associated, although the pathogenesis is unknown.
    • In children with congenital HIV infection, co-infection with cytomegalovirus appears to accelerate the HIV disease progression and HIV-associated neurological disease. Accumulating evidence suggests that cytomegalovirus infection may be a cofactor in the pathogenesis of atherosclerosis. In addition, the phenomena of posttransplant vascular sclerosis and postangioplasty restenosis appear to be cytomegalovirus–induced lesions.
    • The long-term health consequences of cytomegalovirus infection may include atherosclerosis, immunosenescence, and an increased risk of malignancy. These associations require further study but provide a potential justification for universal vaccination of both sexes against cytomegalovirus.

Physical examination findings depend on age, route of acquisition, and immune status of the patient. Findings are reviewed in a syndrome-specific fashion.

Risk factors for cytomegalovirus–associated illness chiefly include age and immunodeficiency. These points are covered in case-by-case fashion in other sections of this article.