Viral Infections
Sandra K. Burchett
INTRODUCTION.
Vertically transmitted (mother-to-child) viral infections of the fetus and newborn can generally be divided into two major categories. The first are congenital infections, which are transmitted to the fetus in utero. The second are perinatal infections, which are acquired intrapartum or in the postpartum period. Infections acquired through breastfeeding are in the latter category. Classifying these infections into congenital and perinatal categories highlights aspects of their pathogenesis in the fetus and newborn infant. Generally, when these infections occur in older children or adults, they are benign. However, if the host is immunocompromised or if the immune system is not yet developed, such as in the neonate, clinical symptoms may be quite severe or even fatal. Congenital infections can have manifestations that are clinically apparent antenatally by ultrasonography or when the infant is born, whereas perinatal infections may not become clinically obvious until after the first few days or weeks of life. Although, classically, the congenital infections have gone by the acronym TORCH (T = toxoplasmosis, O = other, R = rubella, C = cytomegalovirus, H = herpes simplex virus), this term is now archaic and should be avoided. When congenital or perinatal infections are suspected, the diagnosis of each of the possible infectious agents should be considered separately and the appropriate most rapid diagnostic test requested in order to implement therapy as quickly as possible. Useless information is often obtained when the diagnosis is attempted by drawing a single serum sample to be sent for measurement of TORCH titers. These immunoglobulin G (IgG) antibodies are acquired by passive transmission to the fetus and merely reflect the maternal serostatus. Pathogen-specific IgM antibodies do reflect fetal/infant infection status but with variable sensitivity and specificity. The following discussion is divided by pathogen as to the usual timing of acquisition of infection (congenital or perinatal) and in approximate order of prevalence. A summary of the diagnostic evaluation for separate viral infections is shown in Table 48.1.
II. CYTOMEGALOVIRUS (CMV: CONGENITAL AND PERINATAL).
CMV is a double-stranded enveloped DNA virus with lifelong infection. It is a member of the herpesvirus family, is found only in humans, and derives its name from the histopathologic appearance of infected cells, which have abundant cytoplasm and both intranuclear and cytoplasmic inclusions.
Epidemiology. CMV is present in saliva, urine, genital secretions, breast milk, and blood or blood products of infected persons and can be transmitted by exposure to any of these sources. Primary infection (acute infection) is usually asymptomatic in older infants, children, and adults, but may manifest with mononucleosis-like symptoms, including a prolonged fever and a mild hepatitis. Latent infection is asymptomatic unless the host becomes immunocompromised. CMV infection is very common, with seroprevalence in the United States between 50% and 85% by age 40. Forty percent or more of pregnant women in the United States are
infected, with the lowest infection prevalence in young primigravidas. Primary CMV infection occurs in 1% to 3% of pregnant women, with a fetal attack rate of 30% to 40%. About 30,000 infants are born annually in the United States with congenital CMV infection (1 in 150 births) with more than 5,000 infants with permanent problems (1 in 750 births). Eighty percent of infants with congenital
CMV infection will remain asymptomatic. The risk of transmission to the fetus as a function of gestational age is uncertain, but infection during early gestation likely carries a higher risk of severe fetal disease. Vertical transmission can occur at any time in gestation or in the perinatal period, and infants are usually asymptomatic, especially if born to women seropositive before pregnancy. However, as many as 17% of infants with symptomatic CMV are born to women with prior seropositivity. Congenital CMV occurs in at least 1% of all live births in the United States and is the leading infectious cause of sensorineural hearing loss (SNHL) and developmental delay. Annually, of these 40,000 CMV-infected infants, 10% will have symptomatic disease at birth. Additionally, 10% of the asymptomatic neonates will develop significant sequelae in the first year of life. Therefore, at least 8,000 infants are severely affected or die from CMV infection in the United States each year. CMV infection is more common among HIV-1 infected infants, and coinfected infants may have more rapid progression of HIV-1 disease. Therefore, screening for CMV in HIV-exposed infants is advised.
Table 48.1 Diagnostic Techniques for Diagnosis of Perinatal Infections
Pathogen
Test of Choice
Sensitivity
Expense
Turnaround
HSV
DFA skin lesion
High
Moderate
Hours
Parvovirus
PCR blood
High
Moderate
Hours*
Parvovirus
IgM
Moderate
Low
Days
CMV
PCR urine/saliva
High
Moderate
Hours*
CMV
Spin-enhanced urine culture (shell vial)
High
Moderate
Days
HIV
DNA PCR if mother known HIV-infected
High
High
Hours*
HIV
RNA PCR if mother not treated
High
Moderate
Hours*
HBV
HBVSAg
High
Low
Hours
HBV
DNA PCR
High
Moderate
Hours*
HCV
RNA PCR <12 mo
High
Moderate
Hours*
HCV
RIBA >15 mo
High
Low
Hours*
V-ZV
DFA skin lesion
Moderate
Moderate
Hours
EV
RNA PCR blood
High
Moderate
Hours*
EV
Culture urine, oropharynx, stool
Moderate
High
Days
Rubella
Culture urine
Moderate
High
Many days
RSV
DFA
Moderate
Moderate
Hours
HSV = herpes simplex virus; DFA = direct fluorescent antibody; PCR = polymerase chain reaction; IgM = immunoglobulin M; CMV = cytomegalovirus; HBV = hepatitis B virus; HCV = hepatitis C virus; V-ZV = varicella-zoster virus; EV = enterovirus; RSV = respiratory syncytial virus.
* PCRs in general are done within a half day but often are a send-out test to a central lab requiring days to ship and retrieve data.
Clinical disease in congenital infection may present at birth, while both congenital and perinatal infection can manifest with symptoms later in infancy.
Congenital early symptomatic disease can present as an acute fulminant infection involving multiple organ systems with as high as 30% mortality. Signs include petechiae or purpura (79%), hepatosplenomegaly (HSM) (74%), jaundice (63%), prematurity and/or “blueberry muffin spots” reflecting extramedullary hematopoiesis. Laboratory abnormalities include elevated hepatic transaminases and bilirubin levels (as much as half conjugated), anemia, and thrombocytopenia. Hyperbilirubinemia may be present at birth or develop over time and usually persists beyond the period of physiologic jaundice. Approximately one-third of these infants are preterm, and one-third have intrauterine growth restriction (IUGR).
A second early presentation includes infants who are symptomatic but without life-threatening complications. These babies may have IUGR or disproportionate microcephaly (48%) with or without intracranial calcifications. These calcifications may occur anywhere in the brain, but are classically found in the periventricular area. Other findings of central nervous system (CNS) disease can include ventricular dilatation, cortical atrophy, migrational disorders such as lissencephaly, pachygyria, and demyelination as well as chorioretinitis in approximately 10% to 15% of infants. Babies with CNS manifestations almost always have developmental abnormalities and neurologic dysfunction. These range from mild learning and language disability or mild hearing loss to intelligence quotient (IQ) scores below 50, motor abnormalities, deafness, and visual problems. Because SNHL is the most common sequela of CMV infection (60% in symptomatic and 5% in asymptomatic infants at birth), any infant failing the newborn hearing screen also should be screened for CMV infection. Conversely, infants with documented congenital CMV infection should be assessed for hearing loss as neonates and throughout the first year of life.
Asymptomatic congenital infection at birth in 5% to 15% of neonates can manifest as later disease in infancy. Abnormalities include developmental abnormalities, hearing loss, mental retardation, motor spasticity, and acquired microcephaly. Other problems that can be detected later in life include inguinal hernia and dental defects due to abnormal enamel production.
Perinatally acquired CMV infection may occur (i) from intrapartum exposure to the virus within the maternal genital tract, (ii) from postnatal exposure to infected breast milk, (iii) from exposure to infected blood or blood products, or (iv) nosocomially through urine or saliva. The time from infection to disease presentation varies from 4 to 12 weeks. Almost all term infants who are infected perinatally remain asymptomatic, especially if the infection arose from a mother with reactivated viral excretion. While long-term developmental and neurologic abnormalities are rarely seen, an acute infection syndrome, including neutropenia, anemia, HSM, lymphadenopathy, and hearing loss can be found, especially in preterm infants. Data suggest that all infants, regardless of gestational age, should have hearing testing over the first year of life if documented to have acquired CMV.
CMV pneumonitis. CMV has been associated with pneumonitis occurring especially in preterm infants <4 months old. Symptoms and radiographic findings in CMV pneumonitis are similar to those seen in afebrile pneumonia of other causes in neonates and young infants, including Chlamydia trachomatis, Ureaplasma urealyticum, and respiratory syncytial virus (RSV). Symptoms include tachypnea, cough, coryza, and nasal congestion. Intercostal retractions and hypoxemia may be present, and apnea may occur. Radiographically, there is hyperinflation, diffusely increased pulmonary markings, thickened bronchial walls, and focal atelectasis. A small number of infants may have symptoms that are severe enough to require mechanical ventilation, and historically, approximately 3% of infants die if untreated. Laboratory findings in CMV pneumonitis are nonspecific. Long-term sequela includes recurrent pulmonary problems, including wheezing and, in some cases, repeated hospitalizations for respiratory distress. Whether this presentation reflects congenital or perinatal CMV infection is unclear. Conversely, merely finding CMV in respiratory secretions of a preterm infant does not prove causality of symptomatology because CMV is present in saliva of infected infants.
Transfusion-acquired CMV infection. In the past, significant morbidity and mortality could occur in newborn infants receiving CMV-infected blood or blood products. Since both the cellular and humoral maternal immune systems are helpful in preventing infection or in ameliorating clinical disease, those most severely affected were preterm, low birth weight infants born to CMV-seronegative women. Mortality was estimated to be 20% in very low birth weight infants. Symptoms typically developed 4 to 12 weeks after transfusion, lasted for 2 to 3 weeks, and consisted of respiratory distress, pallor, and HSM. Hematologic abnormalities were also seen, including hemolysis, thrombocytopenia, and atypical lymphocytosis. Transfusion-acquired CMV is now rare, prevented by using blood or blood products from CMV-seronegative donors or filtered, leukoreduced products (see Chap. 42).
Diagnosis. CMV infection should be suspected in any infant having typical symptoms of infection or if there is a maternal history of seroconversion or a mononucleosis-like illness in pregnancy. The diagnosis is made if CMV is identified in urine, saliva, blood, or respiratory secretions and defined as congenital infection if found within the first 2 weeks of life and as perinatal infection if negative in the first 2 weeks and positive after 4 weeks of life. Depending upon when the fetus or infant infection occurred, blood is the earliest specimen to become positive, but urine is likely to give the highest sensitivity for diagnosis as CMV
is concentrated in high titers in the urine. CMV is also shed in saliva. A negative viral test from blood cannot rule out CMV infection, but a negative urine test in an untreated infant symptomatic for 4 weeks or more does rule out infection. There are three rapid diagnostic techniques:
CMV polymerase chain reaction (PCR). CMV may be detected by PCR in urine or blood. The sensitivity of using this test for diagnosis is quite high for urine, but a negative PCR in blood does not rule out infection.
Spin-enhanced culture or “shell vial.” Virus can be isolated from saliva and in high titer from urine. Depending upon local laboratory specifications, the specimen is collected with a Dacron swab, inoculated into viral transport medium, and then inoculated into viral tissue culture medium containing a coverslip on which tissue culture cells have been grown and incubated. Viable CMV infects the cells, which are then lysed and stained with antibody to CMV antigens. Virus can be detected with high sensitivity and specificity within 24 to 72 hours of inoculation. It is much more rapid than standard tissue culture, which may take from 2 to 6 weeks for replication and identification. A negative result generally rules out CMV infection except in infants who may have acquired infection within the prior 2 to 3 weeks.
CMV antigen. Peripheral blood can be centrifuged and the buffy coat spread on a slide. The neutrophils are then lysed and stained with an antibody to CMV pp65 antigen. Positive results confirm CMV infection and viremia; however, negative results do not rule out CMV infection. This test is usually used to follow efficacy of therapy.
CMV IgG and IgM. The determination of serum antibody titers to CMV has limited usefulness for the neonate, although negative IgG titers in both maternal and infant sera are sufficient to exclude congenital CMV infection. The interpretation of a positive IgG titer in the newborn is complicated by the presence of transplacentally derived maternal IgG. Uninfected infants usually show a decline in IgG within 1 month and have no detectable titer by 4 to 12 months. Infected infants continue to produce IgG throughout the same time period. Tests for CMV-specific IgM have limited specificity but can help in the diagnosis of an infant infection.
If the diagnosis of congenital CMV infection is made, the infant should have a thorough physical and neurologic examination, magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain, an ophthalmologic examination, and a hearing test. Laboratory evaluation should include a complete blood count, liver function tests, and cerebrospinal fluid (CSF) examination. In CMV-infected infants with symptomatic disease, approximately 90% with abnormal brain imaging will have CNS sequelae. However, about 30% of infants with normal brain imaging will also have sequelae.
Treatment. Ganciclovir (9-[(1,3-dihydroxy-2-propoxy, 3-dihydroxy-2-propoxy)methyl]guanine) and the oral prodrug, valganciclovir, have been effective in the treatment of and prophylaxis against dissemination of CMV in immunocompromised patients. The earliest studies of infants with symptomatic CMV disease showed a strong trend toward efficacy in the ganciclovir-treated infants as assessed by stabilization or improvement of SNHL. Randomized studies are ongoing using oral valganciclovir treatment for symptomatic, congenitally infected infants. Most treated infants will have thrombocytopenia and neutropenia during the course of therapy. Families
should be advised that while evidence is increasing as to antiviral efficacy, questions remain about the potential for future reproductive system effects as testicular atrophy and gonadal tumors were found in some animals treated with pharmacologic doses of ganciclovir. Additionally, although there have been no controlled trials, hyperimmune CMV immunoglobulin (CMVIG) might conceivably benefit infants with congenital CMV, especially those with a fulminant presentation. Treatment should be supervised by a pediatric infectious disease specialist.
Prevention
Screening. Because only 1% to 3% of women acquire primary CMV infection during pregnancy, with the overall risk of symptomatic fetal infection, only 0.2%, screening for women at risk for seroconversion is generally not recommended. Isolation of virus from the cervix or urine of pregnant women cannot be used to predict fetal infection. In cases of documented primary maternal infection or seroconversion, quantitative PCR testing of amniotic fluid can determine whether the fetus acquired infection. However, counseling about a positive finding of fetal infection is difficult because 85% of infected fetuses will only have mild or asymptomatic disease. Some investigators have found that higher CMV viral loads from the amniotic fluid tended to correlate with abnormal neurodevelopmental outcome. One study suggested a protective benefit against severe neonatal disease by administering hyperimmune CMVIG antenatally to women with low-affinity antibody to CMV. Presently, there is not enough information about fetal transmission and outcome to provide guidelines for obstetric management, such as recommendations for therapeutic abortion, even if primary maternal CMV infection is documented. The Centers for Disease Control and Prevention (CDC) recommends that (i) pregnant women practice hand washing with soap and water after contact with diapers or oral secretions; and not share food, utensils, toothbrushes, pacifiers with children; and avoid saliva when kissing a child; (ii) pregnant women who develop a mononucleosis-like illness during pregnancy should be evaluated for CMV infection and counseled about risks to the unborn child; (iii) antibody testing can confirm prior CMV infection; (iv) recovery of CMV from the cervix or urine of women near delivery does not warrant a cesarean section; (v) the benefits of breastfeeding outweigh the minimal risk of acquiring CMV; and (vi) there is no need to screen for CMV or exclude CMVexcreting children from schools or institutions.
Immunization. Passive immunization with hyperimmune anti-CMVIG and active immunization with a live-attenuated CMV vaccine represent attractive therapies for prophylaxis against congenital CMV infections. However, data from clinical trials are lacking. Immune globulin might be considered as prophylaxis of susceptible women against primary CMV infection in pregnancy. Two live-attenuated CMV vaccines have been developed, but their efficacy has not been clearly established. The possibility of reactivation of vaccinestrain CMV in pregnancy with subsequent infection of the fetus must be considered carefully before adequate field trials can be completed in women of childbearing age.
Breast milk restriction. Although breast milk is a common source for perinatal CMV infection in the newborn, symptomatic infection is rare, especially in term infants. In this setting, protection against disseminated disease may be provided by transplacentally derived maternal IgG or antibody in breast milk.
However, there may be insufficient transplacental IgG to provide adequate protection in preterm infants. It remains unclear whether mothers of preterm infants should be recommended to offer breast milk without prior screening for CMV seropositivity. In mothers of extremely premature infants known to be CMV positive, pasteurizing breast milk at 220°C, or freezing breast milk, will reduce the titer of CMV but will not eliminate active virus. At present, there is no recommended method of minimizing the risk of exposure to CMV in infected breast milk.
Environmental restrictions. Day care centers and hospitals are potential highrisk environments for acquiring CMV infection. Not surprisingly, a number of studies confirmed an increased risk for infection in day care workers. However, there does not appear to be an increased risk of infection in hospital personnel. Good hand-washing and infection-control measures practiced in hospital settings generally are sufficient to control the spread of CMV to workers. Unfortunately, such control may be difficult to achieve in day care centers. Good hand-washing technique should be suggested to pregnant women with children in day care, especially if the women are known to be seronegative. The determination of CMV susceptibility of these women by serology may be useful for counseling.
Transfusion product restrictions. The risk of transfusion-acquired CMV infection in the neonate has been almost eliminated by the use of CMV antibody-negative donors, by freezing packed red blood cells (PRBCs) in glycerol or by removing the white blood cells. It is particularly important to use blood from one of these sources in preterm, low birth weight infants (see Chap. 42).
III. HERPES SIMPLEX VIRUS (HSV: PERINATAL).
HSV, a life-long infection, is a double-stranded, enveloped DNA virus with two virologically distinct types: types 1 and 2. HSV-2 is the predominant cause of neonatal disease (75%—80%), but both types produce clinically indistinguishable neonatal syndromes. The virus can cause localized disease of the skin, eye, or mouth, or may disseminate by cell-to-cell contiguous spread or viremia. After adsorption and penetration into host cells, viral replication proceeds, resulting in cellular swelling, hemorrhagic necrosis, formation of intranuclear inclusions, cytolysis, and cell death.
Epidemiology. At least 80% of the U.S. population is infected with HSV type 1, the cause of recurrent orolabial disease and an increasing cause of genital disease. According to the 2005-2008 National Health and Nutrition Examination Survey, the overall seroprevalence of HSV-2, the predominant cause of recurrent genital disease, is 16.2%, increasing with age and number of sexual partners to as high as 48% in African American women and about 21% in Caucasian and Hispanic women. The majority of seropositive persons are unaware of their HSV-2 infection status. Infection in the newborn occurs as a result of direct exposure, most commonly in the perinatal period from maternal genital disease. HSV-2 is more likely to recur in the genital tract and, therefore, accounts for most neonatal HSV infections. In one study, the characteristic ulcerations of the genitalia were present only in two-thirds of the genital tracts from which HSV could be isolated. Others had asymptomatic shedding or atypical lesions. It is estimated that up to 0.4% of all women presenting for delivery are shedding virus, and approximately 1% of all women with a history of recurrent HSV infection asymptomatically shed HSV at delivery. However, when the birth canal is carefully visualized and those with asymptomatic lesions
excluded, this rate of shedding is nearer to 0.5%. It is critical to recognize that most mothers of infants with neonatal HSV do not have a history of HSV. Approximately 30% to 50% of infants will acquire HSV infection if maternal primary infection occurs near delivery; whereas <1% of infants are infected if born to a woman seropositive (recurrent) prior to pregnancy or who acquired infection in the first half of pregnancy. Additionally, one-third of infants born to mothers with newly acquired HSV-2, although already infected with HSV-1 (nonprimary, first episode), may acquire HSV infection. This may well be due to protective maternal type-specific antibodies in the infant’s serum or the birth canal. The overall incidence of newborn infection with HSV is estimated to be from 1 in 3,000 to 1 in 20,000, or from 200 to 1,333 infants per year in the United States.
Transmission
Intrapartum transmission is the most common cause of neonatal HSV infection. It is primarily associated with active shedding of virus from the cervix or vulva at the time of delivery. As many as 95% of newborn infections occur as a result of intrapartum transmission. The amount and duration of maternal virus shedding is likely to be a major determinate of fetal transmission. These are greatest with primary maternal infections. Maternal antibody to HSV is also important and is associated with a decreased risk of fetal or neonatal transmission. In fact, when maternal antibody is present, the risk of acquisition of HSV, even for the newborn exposed to HSV in the birth canal, is very low. The exact mechanism of action of maternal antibody in preventing perinatal infection is not known, but transplacentally acquired antibody has been shown to reduce the risk of severe newborn disease following perinatal HSV exposure. The risk of intrapartum infection increases with ruptured membranes, especially when ruptured longer than 4 hours. Finally, direct methods for fetal monitoring, such as with scalp electrodes, increase the risk of fetal transmission in the setting of active shedding. It is best to avoid these techniques in women with a history of recurrent infection or suspected primary HSV disease.
Antenatal transmission. In utero infection has been documented but is uncommon. Spontaneous abortion has occurred with primary maternal infection before 20 weeks’ gestation, but the true risk to the fetus of early-trimester primary infection is not known. Fetal infections may occur by either transplacental or ascending routes and have been documented in the setting of both primary and rarely recurrent maternal disease. There may be a wide range of clinical manifestations, from localized skin or eye involvement to multiorgan disease and congenital malformations. Chorioretinitis, microcephaly, and hydranencephaly may be found in a small number of patients.
Postnatal transmission. A small percentage of neonatal HSV infections result from postnatal exposure. Potential sources include symptomatic and asymptomatic oropharyngeal shedding by either parent, hospital personnel, or other contacts, and maternal breast lesions. Measures to minimize exposure from these sources are discussed in the subsequent text.
Clinical manifestations. Data from the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG) indicate that morbidity and mortality of neonatal HSV best correlates with three categories of disease. These are infections localized to the skin, eye, and/or mouth; encephalitis with or without localized mucocutaneous disease; and disseminated infection with multiple organ involvement. The NIAID CASG reported on the outcome of
210 infants with HSV infection who were randomized to receive either acyclovir or vidarabine antiviral therapy. Eight babies had congenital infection with signs (chorioretinitis, skin lesions, hydrocephalus) at birth with very high mortality. More than 50% mortality was seen in infants having disseminated disease, with hemorrhagic shock and pneumonitis as the principal causes of death. Of the survivors for whom follow-up was available, significant neurologic sequelae were seen in a high percentage of the infants with encephalitis and disseminated disease.
Skin, eye, and mouth infection. Approximately 50% of infants with HSV have disease localized to the skin, eye, or mucocutaneous membranes. Vesicles typically appear on the sixth to ninth day of neonatal life. A cluster of vesicles often develops on the presenting part of the body, where extended direct contact with virus may occur. Vesicles occur in 90% of infants with localized mucocutaneous infection, and recurrent disease is common. Significant morbidity can occur in these infants despite the absence of signs of disseminated disease at the time of diagnosis. Up to 10% of infants later show neurologic impairment, and infants with keratoconjunctivitis can develop chorioretinitis, cataracts, and retinopathy. Thus, ophthalmologic and neurologic follow-up is important in all infants with mucocutaneous HSV. Infants with three or more recurrences of vesicles, likely reflecting poor cellular or humoral viral control, have an increased risk of neurologic complications.
CNS infection. Approximately one-third of neonates with HSV present with encephalitis in the absence of disseminated disease, and as many as 60% of these infants do not have mucocutaneous vesicles. These infants usually become symptomatic at 10 to 14 days of life with lethargy, seizures, temperature instability, and hypotonia. In the setting of disseminated disease, HSV is thought to invade the CNS from hematogenous spread. However, CNS infection in the absence of disseminated disease can occur, most often in infants having transplacentally derived viral-neutralizing antibodies, which may protect against widespread dissemination but not influence intraneuronal viral replication. Mortality is high without treatment and is approximately 15% with treatment. Late treatment is associated with increased mortality. Approximately two-thirds of surviving infants have impaired neurodevelopment. Long-term sequelae from acute HSV encephalitis include microcephaly, hydranencephaly, porencephalic cysts, spasticity, blindness, deafness, chorioretinitis, and learning disabilities.
Disseminated infection. This is the most severe form of neonatal HSV infection. It accounts for approximately 22% of all infants with neonatal HSV infection and ends in mortality for over half. Pneumonitis and fulminant hepatitis are associated with greater mortality. Symptoms usually begin within the first week of neonatal life. The liver, adrenals, and other visceral organs are usually involved. Approximately two-thirds of infants also have encephalitis. Clinical findings include seizures, shock, respiratory distress, disseminated intravascular coagulation (DIC), and respiratory failure. A typical vesicular rash may be absent in as many as 20% of infants. Forty percent of the infants who survive have long-term morbidity.
Diagnosis. HSV infection should be considered in the differential diagnosis of ill neonates with a variety of clinical presentations. These include CNS abnormalities, fever, shock, DIC, and/or hepatitis. HSV should also be considered in infants with respiratory distress without an obvious bacterial cause or a clinical course and
findings consistent with prematurity. The possibility of concomitant HSV infection with other commonly encountered problems of the preterm infant should be considered. Viral isolation or fluorescent antibody detection of viral proteins in the appropriate clinical setting remains critical to the diagnosis. For the infant with mucocutaneous lesions, tissue should be scraped from vesicles, placed in the appropriate viral transport medium, and promptly processed for culture by a diagnostic virology laboratory. Alternatively, virus can be detected directly when tissue samples are swabbed onto a glass slide and evaluated by direct fluorescent antibody (DFA) technique. Virus can also be isolated from the oropharynx and nasopharynx, conjunctivae, stool, urine, and CSF. In the absence of a vesicular rash, viral isolation from these sites may aid in the diagnosis of disseminated HSV or HSV encephalitis. With encephalitis, an elevated CSF protein level and pleocytosis are often seen, but initial values may be within normal limits. Therefore, serial CSF examinations may be very important. Electroencephalography and CT/MRI are also useful in the diagnosis of HSV encephalitis. Viral isolation from CSF is reported to be successful in as many as 40% of cases, and rates of detection in CSF by PCR may reach close to 100%. Combined HSV-1 and -2 serology is of little value, because many women are infected with HSV-1 and because these tests usually have a relatively slow turnaround time; however, obtaining type-specific antibody (glycoprotein specific) has an 80% to 98% sensitivity and >96% specificity for identifying maternal infection and infant prognosis. Specific IgM is not useful. The number of different viral antigen-specific antibodies produced seems to correlate with the extent of disseminated disease, and the presence of certain antigen-specific antibodies may have long-term prognostic value. Laboratory abnormalities seen with disseminated disease include elevated hepatic transaminase levels, direct hyperbilirubinemia, neutropenia, thrombocytopenia, and coagulopathy. A diffuse interstitial pattern is usually observed on radiographs of infants with HSV pneumonitis.
Treatment. Effective antiviral therapy (acyclovir, a nucleoside analog that selectively inhibits HSV replication) exists, but the timing of therapy is critical. Treatment is indicated for all forms of neonatal HSV disease. Initially, NIAID CASG studies were carried out with vidarabine, which reduced morbidity and mortality. Mortality with encephalitis was reduced from 50% to 15% and in disseminated disease from 90% to 70%. Later, studies from the CASG found that acyclovir is as efficacious as vidarabine for the treatment of neonatal HSV. Furthermore, acyclovir is a selective inhibitor of viral replication with minimal side effects on the host and can be administered in relatively small volumes over short infusion times. Recommendations include treating infants with disease limited to the skin, eye, and mouth disease with 20-mg acyclovir/kg every 8 hours for 14 days, and those with CNS or disseminated disease for at least 21 days, or longer if the CSF PCR remains positive. Infants with ocular involvement should have an ophthalmologic evaluation and treatment with topical ophthalmic agents (1% trifluridine, 0.1% iododeoxyuridine, or 3% vidarabine) in addition to parenteral therapy. Oral therapy such as with valacyclovir is not recommended at this time for initial treatment. Some experts recommend acyclovir suppressive therapy at 300 mg/m2/dose three times a day after the initial treatment period until 6 months of life with careful monitoring for neutropenia and anemia.
Prevention
Pregnancy strategies. Pregnant women known to be HSV-2 seronegative should avoid genital sexual intercourse with a known HSV-2 seropositive
partner in the third trimester. Some experts also suggest avoiding oral—genital contact with partners known to have HSV-2 or -1 if the woman is known to be seronegative since HSV-1 can also result in maternal recurrent genital disease. For women who do acquire primary HSV during pregnancy, several trials have shown efficacy and safety of treating pregnant women with clinically symptomatic primary HSV infection with a 10-day course of acyclovir (oral therapy or IV if more severe disease). It is also recommended that women with HSV-2 be tested for HIV since HSV-2 seropositive persons have a twofold greater risk for acquisition of HIV than those who are seronegative for HSV-2.
Delivery strategies. Women with known clinical or serologic evidence of HSV-2 are often offered acyclovir near term until delivery, enabling a vaginal delivery if there are no visible lesions.
Management of the newborn at risk for HSV (see Table 48.2). The principal problem in developing strategies for the prevention of HSV transmission is the inability to identify maternal shedding of virus at the time of delivery. Viral identification requires isolation in tissue culture, so any attempt to identify
women who may be shedding HSV at delivery would require antenatal cervical cultures. Unfortunately, such screening cultures taken before labor fail to predict active excretion at delivery. Until more rapid techniques such as a screening PCR are made available for the identification of HSV, the only clear recommendation that can be made is to deliver infants by cesarean section if genital lesions are present at the start of labor. The efficacy of this approach may diminish when membranes are ruptured beyond 4 hours. Nevertheless, it is generally recommended that cesarean section be considered even with membrane rupture of longer durations, although data showing efficacy beyond 4 hours are lacking. For women with a history of genital herpes, careful examination should be performed to determine whether lesions are present when labor commences. If lesions are observed, cesarean section should be offered. If no lesions are identified, vaginal delivery is appropriate, but a cervical swab should be obtained for culture. At this time, there are no data to support the prophylactic use of antiviral agents or immunoglobulin to prevent transmission to the newborn infant. Infants inadvertently delivered vaginally in the setting of cervical lesions should be isolated from other infants in the nursery, and cultures should be obtained from the oropharynx/nasopharynx and conjunctivae. If the mother can be identified as having recurrent infection, the resultant neonatal infection rate is low, and parents should be instructed to consult their pediatrician if a rash or other clinical changes (lethargy, tachypnea, poor feeding) develop. Weekly pediatric follow-up during the first month is recommended. Infants with a positive culture from any site or the evolution of clinical symptomatology should immediately have cultures repeated and antiviral therapy started. Before starting acyclovir therapy, the infant should have conjunctival, nasopharyngeal swabs for DFA and culture, urine for culture, and a CSF evaluation for pleocytosis and HSV DNA PCR. Evidence of dissemination should be evaluated with hepatic transaminases and a chest radiograph if respiratory symptoms develop.
Table 48.2 Management of the Child Born to a Woman with Active Genital Herpes Simplex Virus Infection
Maternal primary or first-episode infection:
▪
Consider offering an elective cesarean section, regardless of lesion status at delivery, or if membranes ruptured less than 4 h
▪
Swab infant’s conjunctive and nasopharynx, and possibly collect urine for DFA and culture to determine exposure to HSV
▪
Treat with acyclovir if DFA or culture positive or signs of neonatal HSV
If cesarean section performed after 24 h of ruptured membranes or if vaginal delivery unavoidable:
▪
Swab infant’s conjunctivae and nasopharynx, and collect urine for DFA and culture to determine exposure to HSV
▪
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