History
The history must be tailored to the specific clinical circumstances and disease category.
Congenital cytomegalovirus (CMV) infection
The risk of intrauterine transmission is highest when primary infection occurs during pregnancy, with a significantly increased risk of adverse fetal effects if fetal infection occurs during the first half of pregnancy. [33]
Among congenitally infected infants, approximately 10% have signs and symptoms of disease at birth, and these symptomatic infants have been reported to have a 40-90% risk of subsequent neurologic sequelae, including mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. [34, 35, 36] Although the remaining 90% of infants are asymptomatic at birth, a range of 7-20% have been reported to subsequently develop permanent sequelae, particularly sensorineural hearing loss. [37, 38, 39]
Congenital CMV infection is the most common cause of nongenetic sensorineural hearing loss. Other complications include cognitive impairment, chorioretinitis, and cerebral palsy. Motor deficits and seizures occur in 23% and 19%, respectively, of pediatric patients with symptomatic congenital CMV infection. [21, 22]
Hence, congenital infection may be classified as symptomatic or asymptomatic in nature (see the image below). Overall, it has been estimated that in a given cohort of 1000 infants with congenital CMV infection, 170-190 will have permanent sequelae, of whom one third are from the symptomatic group and two thirds are from the asymptomatic group.
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. [40] The most severe form of congenital CMV infection is referred to as CID.
CID almost always occurs in women who have primary CMV 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 restriction, 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 neurologic 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 neurologic and neurodevelopmental sequelae. Indeed, it has been suggested that more children have long-term neurodevelopmental handicaps as a result of congenital CMV infection than either Down syndrome or fetal alcohol syndrome. [41]
Asymptomatic congenital CMV
Most infants with congenital CMV infection are born to women who have preexisting immunity to CMV. These infants appear clinically healthy at birth; however, although infants with congenital CMV infection appear well, they may have subtle growth restriction compared with uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae.
The major consequence of inapparent congenital CMV infection is sensorineural hearing loss. Approximately 15% of these infants have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of CMV-associated hearing loss because this deficit may develop months or even years after birth. [42]
Acquired CMV infection
In contrast to congenital infection, acquired CMV infection occurs postnatally. Primary infection in this context is generally asymptomatic, although CMV disease may occur in certain risk groups.
Perinatal infection
Perinatal acquisition of CMV usually occurs secondary to exposure to infected secretions in the birth canal or via breastfeeding. Most infections are asymptomatic. Indeed, in some reviews, CMV acquired through breast milk has been referred to as a form of natural immunization.
Some infants who acquire CMV 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 have 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 are needed on the long-term neurodevelopmental outcomes of premature infants who acquire CMV infection perinatally from breast milk.
CMV mononucleosis
Typical CMV mononucleosis is a disease found in young adults. Although CMV mononucleosis may be acquired by blood transfusion or organ transplantation, CMV mononucleosis is usually acquired via person-to-person transmission. [43]
The hallmark symptoms of CMV mononucleosis are fever and severe malaise. An atypical lymphocytosis and mild elevation of liver enzymes are present.
Clinically differentiating CMV mononucleosis from Epstein-Barr virus (EBV)-induced mononucleosis may be difficult. CMV mononucleosis is typically associated with less pharyngitis and less splenomegaly. As with EBV mononucleosis, the use of beta-lactam antibiotics in association with CMV mononucleosis may precipitate a generalized morbilliform rash.
Transfusion-acquired CMV infection
Posttransfusion CMV infection has a presentation similar to that of CMV 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).
CMV infections in immunocompromised patients
CMV 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 transplantation 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.
CMV pneumonitis
CMV 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 transplantation.
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 also at risk of developing CMV pneumonitis, 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.
CMV GI disease
GI tract disease caused by CMV 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 CMV pneumonitis, antiviral therapy is warranted.
Differentiating CMV hepatitis from chronic rejection in liver transplantation patients may be difficult, even with biopsy.
Evidence of active CMV infection, including viral inclusion–bearing cells, is often observed in patients with exacerbations of inflammatory bowel disease (ulcerative colitis and Crohn disease), although whether this represents a source of active bowel pathology in this setting remains unclear.
CMV retinitis
Before the advent of highly active antiretroviral therapy (HAART) for HIV infection, CMV 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 CMV retinitis in children, in contrast to adults, has been relatively rare, probably reflecting overall differences in CMV seroprevalence between the populations. Retinitis is less common in transplantation patients.
CMV 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. CMV chorioretinitis is also observed in symptomatic infants with congenital infection, although the disease does not usually progress to vision loss. The presence of chorioretinitis in an infant with congenital infection indicates a poor neurodevelopmental prognosis.
Other CMV syndromes
Various syndromes have been attributed to CMV 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 CMV associated, although the pathogenesis is unknown.
In children with congenital HIV infection, co-infection with CMV appears to accelerate the HIV disease progression and HIV-associated neurological disease. Accumulating evidence suggests that CMV infection may be a cofactor in the pathogenesis of atherosclerosis. In addition, the phenomena of posttransplant vascular sclerosis and postangioplasty restenosis appear to be CMV-induced lesions.
The long-term health consequences of CMV infection may include atherosclerosis, immunosenescence, and an increased risk of malignancy. [2] These associations require further study but provide a potential justification for universal vaccination of both sexes against CMV.
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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.
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Cranial CT scan of infant born with symptomatic congenital cytomegalovirus infection. Neurological involvement is evident, manifest as ventriculomegaly and periventricular calcifications.
