Introduction

Neonatal hepatitis refers to a heterogeneous group of disorders that result in a somewhat similar morphologic change in the liver of an infant younger than three months of age in response to various insults. The term neonatal hepatitis has been used at times to include all causes of cholestasis in infancy in which extrahepatic biliary obstruction is excluded. Although in the majority of cases an etiology cannot be found, specific infectious and metabolic causes have been identified that may present as neonatal hepatitis. At final diagnosis, neonatal hepatitis is responsible for approximately 40% of the cases of infants with cholestasis and is the most frequently encountered liver disorder of early infancy. Males usually predominate over females (2:1). Additionally, some familial cases have been reported, suggesting either a maternal environmental factor or autosomal recessive inheritance.

Histologically, there is a loss of the lobular architecture with preservation of the zonal distribution of portal tracts and central veins. There is ballooning degeneration of hepatocytes with fusion of hepatocyte membranes and nuclear transformation into multinucleated giant cells. These multi-nucleated giant cells are believed to be the response of immature hepatocytes to most forms of injury and are a non-specific finding in neonatal liver biopsy samples. There may be abundant extramedullary hematopoiesis and variable inflammation (Figure 10.1). Cholestasis may be marked because the newborn already is in a relative state of physiologic cholestasis. Finding cytoplasmic inclusions, steatosis, or storage material, or elucidating a positive family history, may aid in distinguishing metabolic, viral, and familial causes of neonatal hepatitis.

Figure 10.1 Neonatal hepatitis; needle biopsy at six weeks of age. (a) Portal area with inflammation at top and parenchymal lobular disarray below (original magnification 40×). (b) Ballooned hepatocytes and multinucleated giant cell (original magnification 450×). (c) Extramedullary hematopoiesis (arrow) (original magnification 450×). (d) Necrotic hepatocyte (Councilman body, arrow) (original magnification 450×). (Hematoxylin and eosin stain.)

This chapter reviews known causes of neonatal hepatitis with intrahepatic cholestasis, concentrating in particular on associated congenital infections. It has become increasingly clear that the term neonatal hepatitis is too vague and is no longer clinically or therapeutically appropriate. Hepatitis in a neonate caused by a known etiologic agent that may be amenable to therapy needs to be differentiated from idiopathic neonatal hepatitis, in which etiologic agents are unknown and probably multiple. This becomes increasingly important as new therapeutic regimens are developed.

Routes of Infection

The newborn may acquire infection transplacentally in utero, during delivery, or after birth. The study of transplacental infection has been hampered by the latency of many viruses. It has been well established that transplacental passage may result in congenital syphilis, toxoplasmosis, rubella, and cytomegalovirus (CMV) infections. The secondary liver abnormalities at birth may be inactive because of remote in utero infection, with the consequent scarred cirrhotic liver, or relatively new, with an acute hepatitis. An essential factor in the transmission of the infection from the mother to the fetus is the time of maternal infection during the pregnancy. In general, infectious agents cross the placenta best during the third trimester. This is particularly true for syphilis, toxoplasmosis, and hepatitis B virus (HBV).

Perinatal acquisition of infection may be the result of the upward spread of bacterial agents from vaginitis, endometritis, or placentitis. Inhalation or swallowing of infected amniotic fluid may transmit the infection to the fetus. During labor and delivery, direct contact with pathogens in vaginal or uterine secretions or contaminated blood may result in neonatal infection. Listeria, herpes simplex, and CMV may be transmitted by this route and can cause neonatal hepatitis.

Postnatal infection less frequently results in neonatal hepatitis. Close contact with maternal infecting secretions (oral, nasal, breast milk) is possible. Blood or blood product transfusions may contain agents that could result in a neonatal hepatitis.

Etiologic Agents

Urinary Tract Infection

Neonatal bacterial infections associated with jaundice have frequently been associated with the urinary tract [7]. They commonly present between the second and eighth weeks of postnatal life. These infections are rarely associated with fever or urinary symptoms. There may be a history of lethargy, irritability, poor feeding, and, occasionally, vomiting or diarrhea. Males are more frequently affected than females. Anatomic abnormalities of the genitourinary tract are infrequent. Hepatomegaly is frequently apparent. Laboratory studies reveal a conjugated hyperbilirubinemia, mildly increased aminotransferase levels, and leukocytosis with an increase in polymorphonuclear cells. Urinalysis shows pyuria, and urine culture usually reveals E. coli. Blood cultures may be transiently positive. Hepatic pathology is relatively benign, with non-specific findings of bile stasis, periportal inflammation, and Kupffer cell hyperplasia.

Treatment consists of appropriate antibiotic therapy to avoid significant morbidity and mortality. Resolution of the jaundice may be delayed despite successful bacterial eradication because of the formation of bilirubin–protein conjugates in the serum. An underlying metabolic disease (e.g., galactosemia) must be considered in all infants with cholestasis and gram-negative bacterial infections.

Congenital Syphilis

Despite penicillin and routine maternal screening, congenital syphilis remains a problematic perinatal infection. In utero, transplacental transmission of Treponema pallidum spirochetes to the fetus or with direct contact of infectious lesions during birth may result in a mild to severe range of symptoms [8]. Commonly, patients are asymptomatic. Severe infections may result in prematurity, apnea, hepatosplenomegaly, jaundice, hydrops fetalis, skin and mucosal lesions, rhinitis, osteochondritis, osteomyelitis, periostitis, myocarditis and pseudoparalysis. Findings may be present at birth or may develop over days to months, most often by five weeks. Milder infections may present with anicteric hepatitis, poor weight gain, or purulent nasal discharge. Laboratory abnormalities can include conjugated hyperbilirubinemia, elevated serum aminotransferase levels and a delayed prothrombin time.

Liver histology classically reveals an intralobular dissecting fibrosis with centrilobular mononuclear infiltration. Silver stains may demonstrate spirochetes. In milder infections or in late presentation, the histologic features may not be typical. There may be portal fibrosis and portal inflammation, which are non-specific signs of hepatitis. Unless the clinical history is obtained, the diagnosis could easily be missed. Occasionally, congenital syphilis may lead to fulminant hepatic failure with subsequent liver calcifications [9].

Congenital syphilis should be considered in the differential diagnosis of any neonate with hepatitis. A definitive diagnosis can be made if spirochetes are identified in skin or mucosal lesions. Serologic testing of serum and cerebrospinal fluid analysis using specific treponemal antibody tests (e.g., microhemagglutination test for T. pallidum, fluorescent treponemal antibody absorption) and non-specific non-treponemal reagin and flocculation tests (e.g., Venereal Disease Research Laboratory test, rapid plasma reagin, automated reagin test) may be required to distinguish syphilis from other spirochetal diseases. A lumbar puncture to obtain CSF fluid should be performed to evaluate for central nervous system syphilis in infants if there is confirmed or high suspicion for congenital syphilis. Serology may be positive in normal unaffected infants for up to three months after birth because of passively acquired maternal antibodies confounding the diagnosis.

Treatment includes parenteral penicillin therapy. Erythromycin and ceftriaxone are reserved for penicillin allergy, but efficacy has not been proved and penicillin desensitization is preferable. Tetracycline or doxycycline, although useful in adults, should not be used in pregnant mothers or infants because of effects on developing teeth and bones. If penicillin G cannot be administered, alternative treatment recommendations can be found at the Centers for Disease Control and Prevention website (www.cdc.gov/nchstp/dstd/penicillinG.htm). After appropriate therapy, serology may remain positive for up to two years. Serum aminotransferase levels may remain elevated after onset of therapy for a prolonged period. Prognosis may ultimately depend on the extent of hepatic damage before the institution of therapy. Chronic liver disease has not been reported in infants appropriately treated for congenital syphilis.

Tuberculous Hepatitis

Neonatal infection of the liver with tuberculosis is exceedingly rare. Infection may occur by way of placental spread from miliary tuberculosis in the mother, by inhalation with pulmonary involvement, or by aspiration of contaminated amniotic fluid. Usually, respiratory symptoms predominate. Other clinical features include fever, hepatomegaly, splenomegaly, irritability, lethargy and poor feeding. Hepatic lesions have caseating necrosis with surrounding giant cells and epithelioid cells with tubercle bacilli [10]. The clinical course is usually rapidly fatal. If a newborn is suspected of having congenital tuberculosis, a Mantoux skin test (five tuberculin units of purified protein derivative), chest radiographs, lumbar puncture, and cultures should be obtained rapidly. Regardless of the skin test results, which are frequently negative in congenital tuberculosis, treatment should be initiated promptly with isoniazid, pyrazinamide, rifampin, and streptomycin or kanamycin.

Parasitic Infections

Viral Infections

Cytomegalovirus

Cytomegalovirus may be acquired transplacentally, at delivery, or postnatally from infected secretions (saliva or breast milk) or from transfusion of blood products [15]. The risk of vertical transmission to the fetus is higher with primary maternal infection. Significant congenital CMV disease has been reported in the offspring of liver transplant recipients [16]. Most congenitally infected infants remain asymptomatic. The minority (5–10%) develop clinically apparent infection, but, unfortunately, these may include low birth weight, microcephaly, periventricular cerebral calcifications, chorioretinitis, thrombocytopenia, purpura, deafness, and psychomotor retardation. Hepatosplenomegaly and conjugated hyperbilirubinemia are often seen in neonatal CMV infection [17, 18]. The hepatosplenomegaly may be secondary to significant extramedullary hematopoiesis.

Liver biopsy may reveal significant giant cell transformation. The presence of large intranuclear inclusion bodies in bile duct epithelium and occasionally in hepatocytes or Kupffer cells, and intracytoplasmic inclusion bodies in hepatocytes, confirms the diagnosis (Figure 10.2) [17]. Bile stasis, inflammation, fibrosis, and bile duct proliferation are also featured.

Figure 10.2 Cytomegalovirus infection. Large hard-appearing intranuclear inclusion (arrow). Adjacent portal tract has acute and chronic inflammatory infiltrate. (Hematoxylin and eosin, original magnification 450×.)

Diagnosis of CMV infection includes culture of the nasopharynx, saliva, and urine. Culture of the liver may yield positive results, but the yield is usually not as good as from the urine [19]. The detection of CMV in hepatic tissue can be improved with the use of electron microscopy, viral DNA by PCR, and monoclonal antibody techniques [20, 21]. Serologic tests are also useful for CMV diagnosis and IgM CMV-specific antibodies can be monitored.

Long-term follow-up of congenital CMV-infected patients may show resolution of hepatomegaly but development of portal hypertension despite the absence of cirrhosis [22, 23]. Treatment for congenital CMV infection includes use of the antiviral drug ganciclovir and CMV immunoglobulin intravenously. Foscarnet may be used as an alternative drug in cases of ganciclovir-resistant virus or in patients unable to tolerate ganciclovir therapy. Valganciclovir and cidofovir have also been used in neonates with CMV infection, but side effects must be weighed before use. Effectiveness of therapy is highest if initiated within the first month of life. Liver transplantation also has been used rarely for infants with severe hepatic involvement. Prognosis is poor for infants with severe infection, with neurologic sequelae frequently occurring.

Herpes Hepatitis

Hepatitis from herpes simplex may present as part of a generalized disease in the newborn [24]. Symptoms may not appear until four to eight days of age, which coincides with the incubation period for herpes. Congenital herpes infection may present with microcephaly and necrotic, ulcerative, vesicular, or purpuric lesions on the mucosal surfaces or the skin. Although the liver may be mildly affected, more often there is jaundice, hepatosplenomegaly, and abnormal coagulation factors. Gastrointestinal bleeding, coagulopathy, encephalitis, and seizures may be present in severe cases. Diagnosis may be confirmed by typical cutaneous lesions, by identification of the virus in skin lesions using direct fluorescent antibody staining or enzyme immunoassay detection of herpes antigens, cell culture, and PCR of herpes simplex viral DNA [25]. Acute and convalescent sera may be tested for increases in herpes simplex antibody titers to confirm acute infection, but serologic diagnosis is less helpful than viral isolation, which has become the more rapid diagnostic procedure of choice.

An asymptomatic maternal genital lesion is often the cause of the neonatal infection, with herpes simplex type 2 accounting for the majority of congenital herpes infections. Fetal scalp monitoring, prolonged rupture of membranes, prematurity, and low birth weight may contribute to the risk of infection. Infection in the newborn can be avoided by cesarean section delivery. Other less common sources of neonatal infection include transmission from a parent from a non-genital infection (e.g., from the hands or mouth) or postnatal infection from another infected infant in the nursery, probably from the hands of personnel caring for the infants.

Liver histology reveals necrosis (either multifocal or generalized) with characteristic intranuclear acidophilic inclusions in hepatocytes. Multinucleated giant cells also may be present (Figure 10.3). Culture of liver tissue may confirm the diagnosis but may take up to a week to be positive. Morphologic demonstration of herpesvirus is usually faster. Immunohistochemical staining using commercially available antisera can demonstrate herpesvirus in tissue [26]. The closely related varicella–zoster virus, which can produce an identical histologic appearance in the liver, can be distinguished by the difference in cutaneous rash. The CMV intranuclear inclusions are much larger than those of herpesvirus intranuclear inclusions, and there may be bile duct cell involvement in CMV infection, aiding in the diagnosis [27]. Herpes simplex viral DNA may be detected by PCR.

Figure 10.3 Herpesvirus infection. Viable hepatocytes adjacent to areas of necrosis. A multinucleated giant cell (solid arrow) and pale intranuclear inclusions with rim of chromatin (open arrow) are noted. (Hematoxylin and eosin, original magnification 450×.)

Without treatment, the outcome invariably is death. The use of antiviral therapy (acyclovir) in conjunction with liver transplantation when necessary has significantly improved the outlook for herpes-infected neonates with severe disease limited to the liver [25, 28]. Acyclovir has become the drug of choice because of its ease of administration and lower toxicity. Prophylactic use of acyclovir in exposed newborns is not recommended because of potential drug toxicity and the low risk of disease to most newborns.

Rubella

The incidence of congenital rubella has diminished because of the widespread use of rubella vaccine [29]. Clinical manifestations vary and are dependent on timing of maternal infection, with the highest risk in the first ten weeks of pregnancy. Hepatic involvement in congenital rubella is common [30, 31]. Hepatomegaly is always found, and splenomegaly, jaundice, and cholestasis with a conjugated hyperbilirubinemia and elevated serum alkaline phosphatase and aminotransferases may also feature. Congenital rubella is associated with ophthalmologic (cataracts, microphthalmia, glaucoma, chorioretinitis), cardiac (patent ductus arteriosus, peripheral pulmonic stenosis, atrial or ventricular septal defects), auditory (sensorineural deafness), and neurologic (microcephaly, meningoencephalitis, retardation) anomalies. Growth retardation, thrombocytopenia, and purpuric skin lesions (blueberry muffin) may be observed.

Humans are the sole source of rubella infection. Postnatal rubella is transmitted by direct or droplet contact with nasopharyngeal secretions. Congenitally infected infants may shed rubella virus in nasopharyngeal secretions and urine for up to one year and transmit infection to contacts.

Liver histology reveals mononuclear infiltrates of the portal zones with intralobular fibrosis and extramedullary hematopoiesis (Figure 10.4). There may be giant cell transformation, focal areas of necrosis, cholestasis, and evidence of bile duct proliferation. An increased incidence of biliary atresia has been reported in these infants [18].

Figure 10.4 Congenital rubella infection. Portal and periportal fibrosis and extramedullary hematopoiesis (arrow). (Hematoxylin and eosin, original magnification 100×.)

Diagnosis may be made by isolation of virus from the nose by inoculation of appropriate tissue culture. Throat swabs, urine, blood, and cerebrospinal fluid may yield positive cultures, particularly in congenitally infected infants. Serologic testing is also useful in confirming the diagnosis. Specific rubella IgM antibody is indicative of recent postnatal or congenital infection. The use of PCR for prenatal and postnatal diagnosis of congenital rubella is also being utilized.

Treatment is supportive. Control of rubella has been attempted by the routine immunization of all infants and the testing of all women for evidence of protective antibody to rubella before marriage. Infants with congenital rubella usually recover from the hepatitis without the development of hepatic failure. However, significant morbidity and mortality in these infants usually are the result of the cardiac lesions or hemorrhage.

Hepatitis A

Although hepatitis A virus (HAV) is a frequent cause of hepatitis in childhood, it is not a frequent cause of hepatitis in the newborn [32]. Acquisition of HAV by blood transfusions has been reported in the neonatal period [33]. Most of these neonates developed serologic evidence of acute HAV infection but were clinically and biochemically asymptomatic. Although rare, neonatal cholestasis resulting from vertical transmission of HAV has been reported [34, 35].

In general, HAV is spread by the fecal-oral route. Infection occurs at a younger age in lower socioeconomic groups and is endemic in developing countries. Children usually are anicteric and have a milder course than do adults. No HAV carrier state exists, and chronic HAV infection does not occur.

Serologic testing for IgM- and IgG-specific anti-HAV antibodies is commercially available. Recent infection is denoted by an elevated titer of IgM anti-HAV.

Treatment is supportive. Enteric precautions should be observed. If the mother is not jaundiced, no special care of the infant is recommended. Breast-feeding may occur as long as proper hygiene is practiced. If the mother is jaundiced, immunoglobulin is recommended, although its efficacy in this situation is not proven. Limited data exist on the use of the HAV vaccine in infants; the currently available vaccines in the USA are approved for children over one year of age.

Hepatitis B

Overall in the USA, HBV is an uncommon cause of neonatal hepatitis. However, in certain regions of the USA and in parts of the world, it is common for perinatal transmission of HBV to occur from a chronic HBV carrier mother or the mother with acute HBV infection during the third trimester of pregnancy [36]. Perinatal transmission of HBV is also more likely if the mother is positive for the HBV “e” antigen (HBeAg) and thus has HBV DNA circulating in the bloodstream. If the infant does not acquire HBV infection at birth, close contact with other family members places the infant at high risk for acquisition of the virus, making pre-exposure HBV immunization imperative.

The majority of infants who develop hepatitis B through vertical transmission show evidence of HBV surface antigen (HBsAg) positivity between four and 16 weeks of age and become asymptomatic carriers. However, some infants develop a chronic active form of hepatitis B, and others, with time, develop cirrhosis and hepatocellular carcinoma. A coinfection or superinfection with delta hepatitis virus (hepatitis D (HDV)) is also possible. It is rare for perinatally acquired HBV to result in an acute icteric hepatitis [37]. These infants may have a benign course, with the development of anti-HBsAg and loss of HBsAg, or uncommonly may progress to a rapidly fulminant and fatal hepatitis.

All mothers with the potential for HBV infection should be screened for HBsAg. In many US states, the law requires that all pregnant women have their HBV status investigated during their pregnancy. For infants whose mothers are found to be HBsAg positive, immunoprophylaxis should be instituted at birth. Neonates born to mothers who are HBsAg positive should be bathed carefully soon after birth to remove potentially infected maternal blood or secretions. Hepatitis B immunoglobulin (HBIG) should be administered intramuscularly (0.5 mL) as soon as possible after birth and preferably within 12 hours. Efficacy of HBIG after 12 hours and before 48 hours is presumed but unproved. At another distant injection site, HBV vaccine (0.5 mL) should be administered intramuscularly using a different syringe at the same time as HBIG. The second and third doses of vaccine are given at one to two and six months after the first. For preterm infants who weigh <2 kg at birth born to HBsAg-positive mothers, the initial vaccine dose should not be counted in the required three doses to complete the immunization series, so these preterm infants receive a total of four doses. The need for booster doses of HBV vaccine for children and adults with a normal immune system is not recommended as immune memory remains intact for 15 years or more. The Infectious Disease Advisory Committee of the American Academy of Pediatrics recommends routine immunization with HBV vaccine of all infants regardless of risk factors or maternal HBV status. Although the cost–benefits of this approach will not be immediate, it is anticipated that within 10–20 years of this practice HBV infection could be effectively controlled and potentially eliminated as a significant cause of liver disease within the USA.

Diagnosis of HBV uses commercially available serologic tests for HBV antigens (HBsAg and HBeAg) and antibodies to HBsAg, HBV core antigen (HBcAg), and HBeAg. In acute infection, HBsAg positivity detects the great majority of cases. However, because HBsAg is also positive in chronic infection, IgM anti-HBcAg presence can be used to establish acute or recent HBV infection. Quantitative tests of serum HBV DNA by PCR or branched-chain DNA methods are commercially available and useful in the selection and monitoring of patients for therapy.

Liver biopsy is seldom necessary for the diagnosis of acute HBV infection. Focal or single-cell necrosis with clear cells, balloon cells, and acidophilic bodies is usually evident. There may be centrilobular necrosis with surrounding mononuclear infiltrate as well as bile stasis and Kupffer cell enlargement.

There is no specific treatment for acute HBV infection. For chronic hepatitis B in childhood, interferon-alfa2b therapy and lamivudine have been approved for use in children with evidence of viral replication (HBV DNA or HBeAg positivity) and increased serum aminotransferase levels [38]. Interferon therapy requires an injection three times a week for 24 weeks. Pegylated interferon may be utilized over three years of age and requires once weekly injection. Lamivudine requires 52 weeks of daily oral administration. With interferon, 26% of children became HBeAg negative and 10% lost HBsAg. With lamivudine, 23% had HBeAg seroconversion and only 2% lost HBsAg. Tenofovir disoproxil fumarate and adefovir dipivoxil are approved by the US Food and Drug Administration (FDA) for use in children over 12 years of age. Currently, trials are under way using the orally administered drugs entecavir for children under 16 years of age and tenofovir disoproxil fumarate for children 2 to <12 years of age with chronic hepatitis B. Additionally, trials are underway for the use of tenofovir alafenamide in children and adolescents with chronic hepatitis B. This is anticipated as a preferred therapy in comparison to tenofovir disoproxil fumarate given favored side-effect profile including renal and bone safety.

Hepatitis C

The signs and symptoms of hepatitis C are similar to those of hepatitis A and B. Acute disease is associated with jaundice in only 25% of patients, and abnormalities in serum liver function tests occur less frequently than with hepatitis B infection. Most infections are asymptomatic. Transmission of hepatitis C virus (HCV) can occur by way of parenteral administration of blood or blood products, but the majority of cases in the USA are not associated with blood transfusion. High-risk groups for HCV infection include parenteral drug users, people transfused with blood or blood products, healthcare workers who are frequently exposed to blood, and people with household or sexual contact with an infected person. Perinatal transmission of HCV has been demonstrated [39].

Seroprevalence among pregnant women in the USA is estimated at 1–2%, with maternal–fetal transmission at about 5%. Maternal coinfection with HIV has been associated with an increased risk of perinatal transmission of HCV. Vertical transmission of HCV may depend on the HCV genotype and the serum titer of maternal viral RNA. Serum HCV antibody and HCV RNA have been detected in breast milk, but HCV transmission to infants by breastfeeding has not been demonstrated [40]. The rate of vertical transmission of HCV is identical in breastfed and bottle-fed infants. A key feature of HCV hepatitis is its propensity to progress to chronic hepatitis and more severe hepatic dysfunction. About 60–80% of children with hepatitis C progress to chronicity, and cirrhosis develops in at least 20% of these [41, 42]. Hepatitis C has been associated with the development of hepatocellular carcinoma [43].

The two major tests currently available for the laboratory diagnosis of HCV infections are antibody assays for HCV and those for detecting and quantitating HCV RNA. The antibody test involves a sensitive enzyme-linked immunosorbent assay. If positive, confirmation in the past was made by a recombinant immunoblot assay. Both assays detect IgG antibodies; no IgM assays are available. Highly sensitive PCR assays for detection and quantification of HCV RNA and a nucleic acid-based amplification test are commercially available and have largely replaced the recombinant immunoblot assay for confirmation. These tests are costly, but they may be useful for monitoring patients undergoing therapy and for identifying infection early in infants because maternal antibody can cross the placenta and interfere with the ability to detect antibody produced by the infant.

Children with chronic hepatitis C are clinically monitored and then treated when >3 years of age. Interferon, pegylated interferon, and pegylated interferon in combination with ribavirin have been found to be safe and efficacious in the treatment of chronic hepatitis C in adults and children [44–48]. Combination therapy (interferon with ribavirin) was shown to result in higher rates of sustained virologic, biochemical, and histologic response than interferon alone. Combination pegylated interferon and ribavirin are FDA approved for use in children with chronic HCV infection.

More recently, as in adults, direct acting anti-virals (DAA) have now been approved for use in children with chronic hepatitis C, given their high efficacy and safety profile. DAA medications including ledipasvir/sofosbuvir (Harvoni) are now approved for use in children >3 years or those who weigh >35 kg with genotypes 1, 4, 5 and 6. Glecaprevir/pibrentasvir (Mavyret) is approved for children >3 years of age or >45 kg with genotypes 1–6. Sofosbuvir + ribavirin is approved for patients >12 years of age and >35 kg with genotypes 2 and 3.

The use of immunoglobulin for post-exposure prophylaxis against HCV infection is not recommended based on the lack of clinical efficacy in humans and animal laboratory studies. Furthermore, immunoglobulin is manufactured from plasma documented to be negative for anti-HCV antibodies.

Delta Hepatitis (Hepatitis D)

Delta hepatitis virus requires infection with HBV because the outer coat of the complete HDV is HBsAg. If HDV infection occurs at the same time as HBV infection, this is referred to as a coinfection. If HDV infection occurs in a person who is already chronically infected with HBV, this is referred to as a superinfection. Transmission of HDV can be by parenteral, percutaneous, or mucous membrane inoculation. It may also be transmitted by blood or blood products, intravenous drug use, or sexual contact if HBsAg is present in the person’s blood. Transmission of HDV from mother to newborn infant is unusual. Spread of HDV may also occur among families with HBsAg carriers. Infection with HDV is most commonly found in southern Italy, Eastern Europe, South America, Africa, and the Middle East. Although there is a high prevalence of HBV infection in the Far East, HDV is uncommon there. In the USA, HDV is found most frequently in intravenous drug abusers, hemophiliacs, and immigrants from endemic areas.

Diagnosis of HDV infection can be made using commercially available anti-HDV antibody test, IgM-specific anti-HDV, and delta antigen tests. Differentiation of HDV coinfection from superinfection can be established by use of IgM anti-HBcAg, which is present only with acute HBV infection.

Treatment of HDV infection is usually supportive. In fact, the only approved therapy effective against chronic hepatitis D is currently in adults with pegylated interferon for 12 months in those with elevated HDV-RNA levels and alanine aminotransferase levels [49]. Because HDV cannot be transmitted in the absence of HBV, care in avoiding HDV should be taken by HBV-positive individuals. Successful immunization with HBV vaccine affords protection from HDV infection.

Hepatitis E (Enterically Transmitted Non-A, Non-B Hepatitis)

Transmission of hepatitis E virus is predominantly by the fecal-oral route but can occur via blood transfusions and through mother-to-child transmission. The disease is more common in adults than children and is associated with a significantly high incidence of mortality in pregnant women. Cases have been reported in epidemics and have usually been traced to contaminated water. Endemic enterically transmitted non-A, non-B hepatitis has been reported in the USA, but most reported cases have occurred among travelers to endemic regions.

Diagnosis is established by exclusion of other known causes of acute hepatitis (i.e., HAV, HBV, HCV, and HDV). Serologic tests that detect antibody (IgM) to the hepatitis E virus and hepatitis E viral RNA detection by PCR of stool or serum are available in commercial and research laboratories to confirm the diagnosis. Treatment is supportive. Passive immunoprophylaxis with immunoglobulin prepared in the USA has not been effective.

GB Virus C (Hepatitis G)

Two viruses belonging to the Flaviviridae family, GB virus C and hepatitis G virus (HGV), are variants of the same viral species and distantly related to HCV. Although there is considerable evidence demonstrating persistent viral infection, this virus has not been demonstrated to cause disease in humans or other primates. An association with post-transfusion hepatitis has been reported, but most infected children remain asymptomatic. Mother-to-infant transmission of HGV has been documented, resulting in a high viral persistence rate and lack of immune response to the virus [50, 51]. In mothers co-infected with either HIV or HCV and HGV, HGV transmission is more frequent and occurs at a higher rate than that for HCV. Transmission of HGV can be through blood or blood products, injection drug use, or sexual contact.

No serologic test is commercially available. An indirect immunoassay, which uses the E2 (envelope) protein as an antigenic target, is available for research purposes. GB virus C RNA can be detected in serum samples using a reverse transcriptase PCR method.

Because the virus has not been demonstrated to cause either persistent hepatitis or symptomatic disease, treatment is supportive. Although HGV has been demonstrated to be sensitive to treatment with interferon therapy, the infection frequently recurs once therapy is terminated [52].

Transfusion-Transmitted Virus

Transfusion-transmitted virus (TTV) is an unenveloped, single-stranded DNA virus that has been implicated as a cause of post-transfusion hepatitis [53]. The virus has been found to contaminate blood and blood product transfusions and has been found in the feces [54]. No data have been published on maternal–neonatal transmission of this virus. Co-infection with HCV has been noted. Like HGV, TTV does not seem to be linked to biochemical signs of liver disease.

No serologic test is currently available. The viral DNA has been detected by use of PCR using semi-nested primers [55]. In preliminary studies in adults co-infected with HCV and TTV, interferon therapy seemed useful in TTV eradication.

Enteroviral Hepatitis

Although many viruses may produce disease in the newborn, only a few viruses are frequently encountered. Among the less frequent viruses, which may on occasion result in nursery epidemics of significant clinical illness, are viruses within the enterovirus classification. These generally include non-polio enteroviruses, including coxsackieviruses, echoviruses, and enteroviruses. Transmission may have occurred during the prenatal, intrapartum, or perinatal period. A maternal history of a viral syndrome or fever just before delivery may be elicited. Initially the infant may appear healthy and vigorous. However, poor feeding, fever, lethargy, diarrhea, jaundice, and skin rash signal clinical infection. These non-specific signs, however, do not help to distinguish these viruses from other bacterial or viral etiologies. In the majority of cases, these infections are benign and self-limited. However, there are reports of death resulting from enteroviral infections in neonates [56, 57]. Fatal and massive hepatic necrosis with failure has been reported with infections of coxsackievirus group B and echovirus groups 6, 9, 11, 14, and 19. These patients demonstrated jaundice, markedly elevated serum aminotransferases, disseminated intravascular coagulation, and progressive hepatic failure.

Diagnosis is made by viral isolation from the throat, rectum, or other sites of clinical involvement, or using biopsy material. Tissue culture techniques may not be adequate for viral isolation, and suckling mouse inoculation may be required to isolate the offending virus. Sera for antibody testing during the acute and convalescent periods should be collected and stored because an increase in titer for an isolated virus suggests a causal role. Because no common enterovirus antigen is available, serologic screening without viral isolation is generally not performed. Use of PCR can detect enterovirus RNA in urine, serum and respiratory secretions. Additionally, use of PCR to test for the presence of enteroviral RNA in cerebrospinal fluid is available in several research laboratories.

There is no specific approved therapy for enteroviral infections. Good supportive care, attention to bleeding problems, and treatment of secondary bacterial infections are important considerations. Intravenous immunoglobulin has been used in life-threatening neonatal enteroviral infections in hope of the presence of a high antibody titer to the infecting virus. Pleconaril is an investigational drug that inhibits viral attachment to host cell receptors and uncoating of viral nucleic acid. It has potent anti-enterovirus activity and has shown promise in treatment of neonatal echovirus and coxsackievirus B infections, including severe hepatitis [58].