Etiology and Pathogenesis

EBV is transmitted by oral secretions and sexual intercourse, thus requiring close contact for transmission. After infection, the virus is excreted for many months and then intermittently for life. The incubation period is usually 30 to 50 days. The virus most likely spreads from the epithelial cells of the buccal mucosa to B-lymphocytes and then disseminates to the entire lymphoreticular system, including the liver and spleen. Similar to other herpesviruses, EBV stays latent in the body for life. EBV has been associated with a spectrum of proliferative disorders such as hemophagocytic syndrome, nasopharyngeal carcinoma, Burkitt lymphoma, and lymphoproliferative disorders.

Clinical Presentation

EBV infection causes a wide spectrum of clinical diseases. In many infants and young children, the symptoms are mild or unrecognized. The symptoms of infectious mononucleosis are malaise, fatigue, prolonged fever, sore throat, headache, nausea, and abdominal pain. Patients often have pharyngitis with exudates, lymphadenopathy, hepatomegaly, or splenomegaly. The incidence of dermatitis may be as high as 15% and is even more pronounced in children who were treated with ampicillin or amoxicillin; it is often called “ampicillin rash” (Figure 97-1). Rare complications of mononucleosis include airway obstruction, central nervous system (CNS) disorders, splenic rupture, thrombocytopenia, and hemolytic anemia.

Figure 97-1 Clinical presentation of Epstein-Barr virus.

EBV is also associated with Gianotti-Crosti syndrome in which a symmetric rash is seen on the cheeks, extensor surfaces, or buttocks with multiple erythematous papules, which may coalesce into plaques. This may persist for 15 to 50 days and may sometimes look like atopic dermatitis (see Figure 97-1).

Differential Diagnosis

Several other pathogens may cause a mononucleosis-like illness, including cytomegalovirus (CMV), adenovirus, hepatitis viruses, HIV, rubella, and Toxoplasma gondii. Another infection that causes a similar clinical picture is streptococcal pharyngitis; however, it usually is not associated with hepatosplenomegaly.

Evaluation and Management

In 90% of cases, there is leukocytosis of 10,000 to 20,000 cells/mm³ with a predominance of lymphocytes with 20% to 40% atypical lymphocytes. There may be a mild thrombocytopenia but usually no purpura, and mild elevations of transaminases can occur. A nonspecific test for heterophile antibodies (also called Monospot) can be done. These are immunoglobulin M (IgM) antibodies that agglutinate sheep or horse red blood cells (RBCs) and usually appear during the first 2 weeks of illness and gradually disappear over a 6-month period. This test result is often negative in children younger than 4 years old. EBV can also be detected by serologic antibody testing. In the acute phase, there is a rapid immunoglobulin M (IgM) and IgG response to viral capsid antigen (VCA) and IgG to early antigen(EA). Positive Epstein-Barr virus nuclear antigen (EBNA) (nuclear antigen) antibody indicates past infection because this is not usually present until several weeks to months after infection (Table 97-1).

There is no specific treatment for infectious mononucleosis. Patients should not participate in contact sports until they have recovered or until the spleen normalizes. In severe cases with complications, a short course of corticosteroids may be helpful; however, there are no controlled data showing efficacy.

Future Directions

Further studies need to be done regarding the safety and efficacy of corticosteroids for treating complicated EBV infections. Research regarding treatment of EBV infections in immunocompromised patients is also needed. Investigations into associations between EBV, malignancies, and lymphoproliferative disorders will help elucidate these disease processes.

Etiology and Pathogenesis

Measles is transmitted by direct contact with large droplets or small droplet aerosols that enter through the respiratory tract or conjunctivae. Patients are contagious 3 days before the rash and up to 4 to 6 days afterward. The incubation period is 8 to 12 days. It is very contagious and affects 90% of exposed individuals. The virus causes necrosis of epithelium and a small vessel vasculitis of skin and oral mucosa. Infected cells fuse and cause multinucleated giant cells called Warthin-Finkeldey giant cells that are pathognomonic for measles.

Clinical Presentation

There are four phases to the infection: incubation period, prodrome, exanthem, and recovery. The prodrome period begins with a mild fever that increases to 103° to 105°F, conjunctivitis, coryza, and cough. Koplik spots appear 1 to 4 days before the rash. They appear as red lesions with a bluish white spot in the center and are usually on the inner aspects of the cheek. Rash usually appears after 2 to 4 days and begins on the face as discrete erythematous patches and spreads downward often becoming confluent (Figure 97-2). Lesions are also seen on the palms and soles. Rash fades in about 7 days and may leave desquamation of the skin. Cough can last up to 10 days.

Figure 97-2 Koplik spots.

Complications include otitis media, pneumonia, laryngotracheobronchitis, seizures, and diarrhea. In rare cases, measles may cause acute encephalitis and subacute sclerosing panencephalitis (SSPE), a degeneration of the CNS usually occurring an average of 7 years later.

Differential Diagnosis

Measles may sometimes be confused with other viruses that cause exanthems such as rubella, adenovirus, enterovirus, EBV, human herpesvirus-6 (HHV-6), and parvovirus. Mycoplasma pneumoniae and group A streptococci (GAS) can also produce similar rashes. Several clinical findings are similar in Kawasaki’s disease, but there is a more prominent cough and no thrombocytosis in measles. Drug reactions should also be in the differential diagnosis.

Evaluation and Management

The diagnosis of measles is usually clinical; however, laboratory findings can include decreased white blood cell count, and a normal erythrocyte sedimentation rate and C-reactive protein. IgM antibody can be detected 1 to 2 days after the onset of rash and remains for 1 month and is therefore indicative of acute infection. A fourfold increase in IgG antibodies after 2 to 4 weeks can also be diagnostic. There is no specific treatment for measles; however, low vitamin A levels are associated with increased morbidity and mortality. Therefore, vitamin A supplementation is recommended. No antibiotic prophylaxis is recommended.

Prevention

Vaccination is the best form of prevention. The first dose is recommended between 12 and 15 months followed by a second dose at 4 to 6 years of age. Because the vaccine is a live-attenuated vaccine, it should not be given to pregnant women or severely immunocompromised children. The MMR (mumps, measles, and rubella) vaccine can cause fever (6-12 days after), rash (7-12 days after) and rarely a transient thrombocytopenia. Fortunately, several large and well-designed scientific studies have convincingly shown that there is no evidence that the measles vaccine causes autism.

Postexposure prophylaxis can be administered via vaccine if it is less than 72 hours after exposure or immune globulin up to 6 days after exposure.

Future Directions

Continued educational efforts need to be undertaken to assure parents about the necessity and the safety of the measles vaccine. Preventing measles from becoming endemic again in the United States will require maintenance of a high level of immunity through vaccination. Eliminating measles from developing countries through vaccines remains a continuing effort.

Etiology and Pathogenesis

HSV is ubiquitous and is transmitted through direct contact with infected mucocutaneous surfaces. Even if a person is asymptomatic, the virus can be intermittently shed; however, the greatest concentration of virus is shed during symptomatic primary infections. Although HSV-1 is thought to infect oral mucosa and HSV-2 is thought to cause genital infections, either type can cause initial infections in any mucosa surface. However, HSV-1 is more likely to cause recurrent oral infections, and HSV-2 is more likely to cause recurrent genital infections.

The virus enters through mucosal surfaces and then spreads via nerve endings to sensory ganglia. Some viruses then establish latency in these sensory neurons (Figure 97-3). The incubation period is usually 2 days to 2 weeks.

Figure 97-3 Pathogenesis and clinical presentation of herpes simplex viruses.

Clinical Presentation

The most common clinical manifestation of primary infection in children is gingivostomatitis and is usually caused by HSV-1. It causes sudden onset of pain in the mouth often manifested as refusal to eat, drooling, and high fevers. The gums become very swollen, and vesicles that are usually grouped on an erythematous base are seen throughout the oral cavity, including the gums, lips, tongue, palate, tonsils, and pharynx. The vesicles can progress to ulcers, and lymphadenopathy is often seen (see Figure 97-3). The illness usually resolves in 7 to 14 days.

Herpes labialis (common names include cold sores or fever blisters) is a common manifestation of recurrent HSV-1 infections. Usually, a burning, tingling, itching sensation is felt several hours or days before the development of a herpetic lesion. It usually begins as a small grouping of erythematous papules that progress to small, thin-walled vesicles. The vesicles then form ulcers or become pustular. The most common site of infection is the vermillion border of the lip. Symptoms usually last 6 to 10 days.

HSV infections can occur on any skin surface that may have breakdown or trauma. Herpetic whitlow is a term used for HSV infections of the fingers or toes. Lesions and pain usually last for 10 days, and complete recovery usually occurs in 18 to 20 days. Eczema herpeticum is described in patients with a history of eczema who are superinfected with HSV (see Figure 97-3). In addition to severe rash, patients can present with high fevers, malaise, and lymphadenopathy. Other areas of the body that may be affected by HSV include the conjunctiva, cornea, and retina as well as the CNS, causing encephalitis and aseptic meningitis. Thus, any vesicles around the eyes should prompt an ophthalmologic examination. HSV has also been implicated in erythema multiforme and Bell’s palsy.

Differential Diagnosis

When vesicular lesions are seen, the differential diagnosis should always include infections caused by varicella zoster (VZV). Gingivostomatitis can be confused with hand, foot, and mouth disease caused by coxsackievirus or other causes of pharyngitis such as GAS and infectious mononucleosis. Widespread eczema herpeticum can be confused with Stevens-Johnson syndrome.

Evaluation and Management

The diagnosis of HSV infection can be made by detection of viral antigen or viral DNA by polymerase chain reaction (PCR) as well as by viral culture obtained by vigorous rubbing of vesicular base. In HSV encephalitis, there is usually a pleocytosis with predominance of lymphocytes. Electroencephalography and magnetic resonance imaging may show temporal lobe abnormalities as well.

The treatment of HSV includes three antiviral medications, acyclovir, valacyclovir, and famciclovir. For gingivostomatitis, acyclovir started within 72 hours of onset reduces the severity and duration of illness. For herpes labialis, oral treatment can shorten duration of the episode and can also be used to prevent recurrences. Acyclovir has also been shown to be effective in the treatment of eczema herpeticum.

Future Directions

Further studies need to be conducted regarding the efficacy of acyclovir for prevention of recurrent HSV infections and treatment of various HSV infection. Currently, valacyclovir and famciclovir have not been approved by the Food and Drug Administration for use in children. If they are approved, alternatives to acyclovir will be available and may be more effective in the treatment of HSV infections in children.

Etiology and Pathogenesis

The virus is spread through direct contact with respiratory secretions or fluid of skin lesions as well as by airborne spread of respiratory secretions. The incubation period is 10 to 21 days after exposure. Patients are contagious 1 to 2 days before the onset of rash until all of the vesicles have crusted over. The virus then establishes a latent infection in the dorsal root ganglia.

Clinical Presentation

Chicken pox is characterized by fever, malaise, anorexia, headache, and a classic rash that starts centrally and then spreads outward. The rash begins as erythematous macules that then become very pruritic and vesicular. It is often described as a “dew drop on a rose petal” (Figure 97-4). Crusting of the lesions then occurs as new ones arise, resulting in different stages of rash. A child who has been previously vaccinated but infected with VZV may have “breakthrough varicella” in which the rash is more atypical. The rash may be maculopapular and less vesicular with fewer lesions. Severe neonatal chicken pox can develop if a mother develops the disease 5 days before delivery or 2 days after.

Figure 97-4 Clinical presentations of varicella zoster virus.

Complications of varicella include bacterial superinfections of the skin, thrombocytopenia, arthritis, hepatitis, cerebellar ataxia, encephalitis, meningitis, and glomerulonephritis. These complications are more common in adolescents, adults, infants, and immunocompromised patients. The reactivation of latent VZV causes zoster or shingles and manifests as grouped vesicles within one or two dermatomes (see Figure 97-4). Although the lesions can cause intense pain in adults, children commonly have a mild rash with minimal symptoms that usually resolve in 1 to 2 weeks.

Differential Diagnosis

The differential diagnosis of varicella includes HSV and enterovirus caused by the vesicular lesions. It can often be confused with drug reactions, contact dermatitis, and insect bites.

Evaluation and Management

The diagnosis of VZV can be confirmed using direct fluorescence antigen or PCR. Viral cultures can also be done from tissue sample in 3 to 4 days. A fourfold increase in VZV IgG titer can also be confirmatory. There is usually an initial leukopenia and then a lymphocytosis. In most cases, the liver enzymes are slightly elevated.

Acyclovir can be used to treat varicella infections but is not currently recommended in healthy children. It can be given to adolescents, children older than 12 months old with skin or pulmonary disorders and children receiving chronic salicylates or corticosteroids. Treatment should be started within 72 hours of onset of rash and as soon as possible. Intravenous (IV) acyclovir should be used in any complicated or disseminated cases.

Prevention

A varicella vaccine was introduced in 1995 and is currently recommended to be given with the MMR vaccine at 12 to 18 months and again at 4 to 6 years of age. Postexposure prophylaxis can be given to healthy children via vaccine within 3 to 5 days of exposure. Varicella zoster immune globulin can be given as postexposure prophylaxis to immunocompromised children, pregnant women, and newborns within 96 hours of exposure.

Future Directions

With the new recommendation for an additional vaccine dose, further surveillance will determine if this increases the efficacy of the vaccine and whether this will increase the incidence of herpes zoster. Because of the atypical presentation of varicella after immunization, diagnosis will rely more heavily on laboratory tests. As with HSV, approval for use of famciclovir and valacyclovir in children may provide alternatives for the treatment of varicella infections.

Etiology and Pathogenesis

HHV-6 is likely transmitted to children via asymptomatic shedding in the secretions (such as saliva) of close contacts. The incubation period is 9 to 10 days. After primary infection, HHV-6 becomes latent in peripheral blood mononuclear cells and persists in salivary glands as well as possibly other tissues such as kidneys, lungs, and CNS.

Clinical Presentation

Roseola is characterized by high fever (usually >103°F) that may persist for 3 to 7 days. During this time some infants may be irritable and anorexic, usually without upper respiratory tract infections. Febrile seizure can occur in 10% to 15% of patients. A rose-colored maculopapular rash usually develops on the trunk during defervescence, spreads to the extremities and face, and then fades after 1 to 3 days (Figure 97-5). HHV-6 can also cause nonspecific febrile illnesses without rash accompanied by cervical or post-occipital lymphadenopathy, respiratory or gastrointestinal (GI) symptoms and inflamed tympanic membranes. It is also thought that HHV-6 reactivation may contribute to disease in the immunocompromised host.

Figure 97-5 Roseola.

Differential Diagnosis

Other illnesses causing fever and rash should be considered, including rubella, measles, scarlet fever, and drug hypersensitivity. If children are very irritable, meningitis and encephalitis need to be ruled out.

Evaluation and Management

The diagnosis is usually made clinically but can be confirmed by PCR or serology from the serum. IgM antibodies usually develop on day 5 to 7 of illness and resolves in 2 months, but it can persist in 5% of healthy adults. A fourfold increase in IgG antibody titer can also be used. Plasma PCR has a sensitivity and specificity of 90% and 100%, respectively, for the diagnosis of primary HHV-6 infection in immunocompetent children. There is no recommended antiviral treatment for healthy children except for supportive needs.

Future Directions

HHV-6 has been associated with multiple sclerosis, encephalitis in AIDS, glove and sock syndrome (a benign dermatosis), Gianotti-Crosti syndrome, and pityriasis rosea, but more work is required in these areas. Because of the persistence of the virus, current diagnostic tests cannot differentiate between primary versus reactivation versus latent infection; thus, more research is needed in this area. Currently, ganciclovir and cidofovir are used in the treatment of immunocompromised patients with severe disease. Additional research is needed to determine the most effective antiviral therapy in this population.

Etiology and Pathogenesis

Parvovirus B19 is transmitted by contact with respiratory tract secretions via large droplets from nasopharyngeal viral shedding. Its primary target is the erythroid cell line, leading to progressive depletion of erythroid precursors and a brief decline in erythropoiesis. The incubation period is 4 to 28 days. Children with rash or arthralgia are not considered to be infectious because this usually occurs after viremia. However, individuals with aplastic crisis are considered to be infectious. Populations that are at risk for developing complications secondary to parvovirus infection include those with hematologic disease, immunosuppressed patients, and pregnant women.

Clinical Presentation

Erythema infectiosum usually causes fever, malaise, and rhinorrhea during viral shedding, which precedes the distinctive “slapped cheek” facial rash by 7 to 10 days. A maculopapular lacy or reticular rash, often pruritic, can also appear on the trunk and move peripherally. Arthralgia and arthritis occur much less commonly in children than in adults (10% vs. 60%, respectively). Parvovirus can also cause mild respiratory illnesses with no rash or other types of rashes. Patients with hemoglobinopathies or other anemias that depend on reticulocytosis may develop transient aplastic crisis because of cessation of RBC production. They may present with symptoms of severe anemia, including pallor, tachycardia, and lethargy. Parvovirus B19 has also been found to be a cause of nonimmune hydrops fetalis.

Differential Diagnosis

The differential diagnosis includes rubella, measles, enterovirus infections, and drug reactions. In children with arthritis or arthralgia juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), serum sickness may be considered.

Evaluation and Management

The diagnosis of parvovirus can be confirmed using serologic testing. In an immunocompetent host, diagnosis using IgM antibody is preferred because it can usually be detected by the third day of illness and persists for 6 to 8 weeks. PCR can detect parvovirus in serum for 9 months and thus may not indicate acute infection. However, PCR testing is recommended for detection in immunocompromised patients who may have chronic infections.

The treatment for parvovirus is often supportive, although patients with aplastic crisis may require RBC transfusions. Immunocompromised patients who are at risk for complications can be treated with IV immunoglobulin.

Future Directions

There are ongoing studies linking parvovirus B19 to rheumatologic disorders such as SLE and juvenile idiopathic arthritis. Screening for B19 in blood products may help to prevent complications in immunocompromised children, but currently there is insufficient evidence to recommend universal testing.

Etiology and Pathogenesis

Enteroviruses are spread by fecal-oral and respiratory routes. They may survive on surfaces for periods of time and thus may be transmitted via fomites. The incubation period is 3-10 days. Virus can be shed in the respiratory tract for 1 to 3 weeks but fecal viral shedding can occur for 7 to 11 weeks. There may be 2 stages of viremia and thus a biphasic pattern can be seen.

Clinical Presentation

Enterovirus can cause nonspecific febrile illnesses, which may present as fevers (101°-104°F), malaise, irritability, diarrhea, vomiting, rash, sore throat, or respiratory symptoms. Illness usually lasts for 3 days but can last longer than 1 week. A biphasic pattern may be seen with initial fever for 1 day followed by 2 to 3 days of normal temperatures and recurrence of fever. Rashes vary from maculopapular to urticarial, vesicular, or petechial.

A common manifestation in children is hand, foot, and mouth disease in which children usually have fever, oropharyngeal inflammation, and vesicles with an erythematous ring in the oral cavity usually on the tongue, buccal mucosa, and posterior soft palate. The vesicles can ulcerate and cause anorexia. Often there is also a maculopapular, vesicular, or pustular lesion on the palms, soles, hands, feet, and occasionally buttock and groin (Figure 97-6).

Figure 97-6 Hand, foot, and mouth disease.

Herpangina is another common condition caused by enteroviruses. It is characterized by high fevers (to 106°F), sore throat, dysphagia, and lesions in the oral cavity that are usually discrete, 1- to 2-mm vesicles and ulcers with an erythematous ring. These are typically seen on the anterior tonsillar pillars, soft palate, and posterior pharynx.

The leading cause of aseptic meningitis is nonpolio enterovirus. Less commonly, enterovirus can also cause a number of other illnesses in the respiratory, cardiac, neurologic, and GI systems as well as severe neonatal multisystemic disease.

Differential Diagnosis

The differential diagnosis depends on the clinical presentation, but when exanthems are seen, other infectious agents to consider are GAS, Staphylococcus aureus, HSV, adenovirus, VZV, EBV, measles, rubella, and HHV-6 or -7.

Evaluation and Management

Viral culture or PCR can be done from throat, stool, rectal swab, urine, blood, and cerebrospinal fluid. However, because of long-term shedding of the virus in stool, detection in stool may not indicate acute infection. There is no specific treatment for enterovirus infections, although immune globulin may be used in neonates or immunodeficient patients with severe disease. An antiviral agent called Pleconaril is under evaluation.

Future Directions

More studies need to be done to determine the efficacy of immunoglobulin and other antiviral therapies such as Pleconaril for the treatment of nonpolio enterovirus infections.