Viruses are continually being discovered and associated with diseases that previously had unknown etiologies. New methods for diagnosis and treatment of viral diseases are also being developed. This article focuses on several viruses as they affect infants and children and recent developments in the diagnosis and treatment of these viral infections (Table 1).
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Human Parvovirus B19
The fifth disease of the original six classic exanthems of childhood, erythema infectiosum is now known to be caused by human parvovirus B19. Initial features of this infection are nonspecific and include headache, coryza and mild fever. Symptoms usually occur a few days before the rash appears.
The rash of erythema infectiosum may be accompanied by headache, pharyngitis, mild fever, malaise, myalgias, coryza, diarrhea, nausea, cough and conjunctivitis. The rash is pruritic and frequently begins on the cheeks, where it is confluent, erythematous, symmetric and edematous, giving the classic "slapped-cheek" appearance (Figure 1). The rash may then appear on the trunk and extremities with central fading, giving it a reticular appearance. The rash fades after two to four days.
The typical duration of erythema infectiosum in children is five to nine days, although the rash can recur and fluctuate in intensity with exposure to sunlight. Erythema infectiosum is believed to be transmitted through respiratory secretions. The rash and arthralgias occur when the patient is no longer contagious. Antibodies to IgG parvovirus B19 persist for years and protect the patient from reinfection.
Intravenous immunoglobulin therapy may be helpful in controlling persistent infection in immunocompromised patients. Good hygiene practices, such as careful hand washing to control spread by respiratory secretions, may be the most effective preventive strategy.
Human Herpesvirus Type 6
Human herpesvirus type 6 (HHV-6) is now thought to be the cause of roseola infantum (exanthem subitum). The exact mode of transmission is unknown, but oral secretions may play a role, since HHV-6 is present in the saliva of 63 to 92 percent of healthy adults. Roseola infantum usually occurs sporadically, but it can occur in epidemics. It tends to occur in the spring or fall. The incubation period is believed to be seven to 17 days (usually 10 days). Most cases of roseola occur in children between six and 18 months of age, and occurrence is rare after three years of age.
Roseola is characterized by the sudden onset of fever (up to 40[degrees]C [104[degrees]F]), which may last one to five days but usually lasts three to four days. Attendant clinical findings are usually absent. Mild pharyngitis or coryza may be present, but the child usually looks well despite the fever.
During the first 24 to 36 hours of the fever, the white blood cell count can reach 16,000 to 20,000 per [mm.sup.3] (16.0 to 20.0 x [10.sup.9] per L), with a left shift. Leukopenia appears by the second day, with counts of 3,000 to 5,000 cells per [mm.sup.3] (3.0 to 5.0 x [10.sup.9] per L); on the third or fourth day of the disease, a relative lymphocytosis develops.
The characteristic macular or maculopapular rash (Figure 2) appears on the third or fourth day of the disease, as the fever subsides. The rash usually begins on the trunk and spreads to the neck and arms, occasionally involving the face and the legs. The rash usually lasts 24 hours. Enlarged cervical lymph nodes occasionally may be present. Prognosis is generally good, except in the rare patient who has seizures secondary to the hyperpyrexia.
HHV-6 may establish a persistent infection in the lymphocytes of patients who have recovered from a primary infection. Cases of HHV-6 infection without fever and also without rash have been reported. Also, subsequent attacks of exanthem subitum secondary to HHV-6 infection have been reported. Since HHV-6 is present in the saliva of most adults, prevention is difficult and infection may be unavoidable.
Fever and rash are often the presenting symptoms of chickenpox, which is caused by varicella-zoster virus. Controversy now surrounds the treatment of chickenpox with acyclovir (Zovirax). In one study, patients who received acyclovir defervesced one to two days before the placebo group and had fewer skin lesions. However, treatment with acyclovir did not appear to reduce complications or prevent scar formation or the transmission of infection.
Early treatment appears to be necessary for any clinical effect, since many populations that benefit most from treatment with oral acyclovir (such as adolescents) acquire varicella secondary to household contact. If treatment is started later than the first day of the rash, it will not have a significant effect. Most authorities recommend treatment with acyclovir only for the more complicated and severe cases of varicella that may occur in adolescents, adults or secondary household cases.
A live attenuated varicella vaccine has been licensed for use in Japan since 1987, in Korea since 1988 and in several European countries during the past five years. Licensure is expected in the United States in 1994. A recent trial of this vaccine was performed in 3,303 healthy children in the United States. The study showed a seroconversion rate of 96 percent six weeks after vaccination, with 99 percent of those who responded remaining seropositive one year after vaccination. The incidence of chickenpox in persons who received the vaccine after household exposure was 12 percent. Those who became infected had clinically mild disease.
The vaccine was generally well tolerated, with the most frequent complaint being pain at the injection site. Rashes at the injection site occurred in 4 percent of study subjects. Oral temperatures of 38.8 [degrees]C (102 [degrees]F) or higher occurred in less than 1 percent of the study subjects during the first three days after vaccination.
Attenuation in the live varicella vaccine was assessed in a study of healthy siblings of leukemia patients who had received the varicella vaccine. The authors concluded that the vaccine virus had a lower than normal rate of spread to susceptible children in the household and that the vaccine virus remained attenuated, causing a milder infection than that associated with wild-type varicella and seroconversion in siblings with vaccine-induced infection.
Herpes Simplex Virus-1
Herpes simplex virus-1 (HSV-1) infection results from close contact between susceptible and infected persons, primarily through secretions from active oral or genital lesions. HSV-1 may present as fever and rash. It causes 80 to 90 percent of oral and labial herpes infections. Most primary cases of mucocutaneous infection with HSV occur during infancy and childhood, followed by recurrent infections throughout life. Most of these infections are "cold sores" and are only an inconvenience.
HSV-1 is also the major cause of herpes simplex encephalitis after the neonatal period. Cerebrospinal fluid cultures are rarely positive for HSV. The temporal lobes are the primary target, and necrotizing, hemorrhagic encephalitis results.
Electroencephalography (EEG) can aid in the localization of the encephalitis by the finding of unilateral paroxysmal lateral epileptiform discharges in the area of the herpetic infection. Compared with other acute neurologic disorders, herpes simplex encephalitis is more likely to be accompanied by focality on the EEG, brain scan or computed tomographic (CT) scan. Polymerase chain reaction assays may be useful in identifying HSV DNA in the cerebrospinal fluid. With the availability of acyclovir, a safe and effective agent, many clinicians begin therapy without the benefit of a definitive diagnostic test such as brain biopsy In such a circumstance, however, other diseases that mimic herpes simplex encephalitis must have been ruled out. If the HSV antigen detection remains negative after five days of treatment with acyclovir, biopsy is recommended.
Cytomegalovirus (CMV) rarely causes symptoms of disease in healthy children or adults, but it is the most common congenital infection that causes birth defects and one of the most common opportunistic infections associated with serious illness and death in immunocompromised patients. CMV persists in a latent state in patients who have recovered from the primary infection. Transmission is usually blood-borne, sexual or vertical (from parents to children or vice versa), or related to attendance at day care centers. The virus may be shed in saliva, tears, urine, breast milk and cervical secretions.
Infection with CMV is common in children who attend group day care, via close contact with infectious virus in urine or saliva. Several studies have documented a substantial risk of infection for adult contacts and day care providers of infected children.
CMV is one of the most common causes of life-threatening opportunistic infection in patients with acquired immunodeficiency syndrome and in patients who have had renal, hepatic, cardiac or bone marrow transplantations. Progressive T-cell depletion can lead to reactivation of latent CMV. Symptomatic, progressive CMV infection develops in 79 percent of AIDS patients and is the primary cause of death in 39 percent, second only to pneumocystis pneumonia. In immunocompromised patients, CMV can cause pneumonia, adrenal insufficiency and intractable diarrhea. CMV has also been suggested as a possible cofactor in the pathogenesis of AIDS.
Prevention strategies for CMV infections include (1) immunoprophylaxis with CMV-immune globulin or CMV-specific monoclonal antibodies; (2) administration of have attenuated vaccines or subunit vaccines; (3) administration of anti-idiotypic monoclonal antibodies; (4) use of good personal and environmental hygiene, and (5) limitation of contact with children in day care. Ganciclovir (Cytovene), foscarnet (Foscavir) or acyclovir and CMV-immune globulin may be useful in the treatment of chorioretinitis, but these agents have been disappointing in the treatment of other clinical manifestations. Immunotherapy with alpha interferon has also had limited success. The efficacy of CMV-immune globulin in the treatment of patients who have had renal or bone marrow transplantations is still being studied.
Current recommendations for prevention of CMV infection in the day care setting include frequent handwashing, proper disposal of contaminated objects such as diapers or tissues, cleaning and disinfecting mouthing toys after each use and careful food preparation. Intrafamilial transmission can be decreased by not kissing children on or around the mouth, not sharing food, utensils or drinking glasses, and wearing gloves during or washing hands after diaper changes.
Epstein-Barr virus (EBV) is the cause of heterophile-positive mononucleosis. It is spread primarily by oral secretions. Diagnostic tests include the Monospot test and specific EBV antibody titers. In the past, EBV had been associated with chronic fatigue syndrome, but recent research has disproved this association.[10,11]
In one study, therapy with oral acyclovir was evaluated for effectiveness in the treatment of acute infectious mononucleosis. Although oropharyngeal excretion of EBV was lower in study subjects treated with oral acyclovir, there was no evidence that treatment affected the course of the disease.
Human papillomavirus (HPV) can infect several body sites, including the anogenital tract, urethra, skin, larynx, tracheobronchial mucosa, nasal cavity, paranasal sinus, mouth and esophagus. HPV produces epithelial tumors of the skin and mucous membranes and is transmitted person-to-person by close contact.
Nongenital warts are acquired through minor skin trauma. Anogenital warts (condylomata acuminata) are acquired primarily through sexual contact. Common warts occur frequently in school-aged children. The incubation period appears to be three to four months. All types of squamous epithelium may be infected by HPV
It is believed that the virus life cycle begins with the entry of the virus into the stratum germinativum. As basal cells differentiate and progress to the surface epithelium, the virus replicates. This causes excessive proliferation in all of the epidermal layers except the basal layer.
A relationship seems to exist between condylomata of the genital tract in pregnant women and laryngeal papillomatosis in their newborn children. The risk of vertical transmission is thought to be low. Cesarean section for women with condylomata of the genital tract is not required, since cases of laryngeal papillomatosis have been documented in newborns delivered by cesarean section. Treatment of laryngeal papillomatosis remains experimental. Preventive strategies are similar to those for other sexually transmitted diseases.
Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract disease in young children. Essentially all persons are infected with RSV during the first few years of life. Transmission is by direct or close contact, usually from respiratory secretions or droplets. Immunity is incomplete and reinfection is common.
RSV causes upper respiratory tract infections and tracheobronchitis in older children and adults. It causes bronchiolitis and pneumonia in younger children and in the first few years of life may lead to life-threatening disease. RSV bronchiolitis and pneumonia in infancy may lead to chronic lung disease later in life, or it may be that the severity of the bronchiolitis simply identifies those who are more prone to chronic lung problems later.
Outbreaks of RSV occur annually, usually from December through April. The average incubation period appears to be two to eight days, and inoculation may occur by the nasal or ocular route. Peribronchiolar lymphocytic infiltration and edema of tissues leads to proliferation and necrosis of bronchiolar epithelium and obstruction of small airways.
Ribavirin (Virazole) is a virastatic agent that is effective against RSV. It is rapidly absorbed across the plasma membranes and is not significantly incorporated into host DNA or RNA. For the treatment of RSV infection, ribavirin is administered as an aerosol with 1- to 2-mm particles via oxygen tent, mask or hood for 12 to 20 hours per day, for a total of three to seven days. Ribavirin is absorbed systemically and excreted by the kidneys.
Administration of ribavirin seems to be beneficial, although reports are conflicting.[15,16] In a recent study, infants treated with ribavirin required fewer days of mechanical ventilation and supplemental oxygen than infants in the control group. A study of early ribavirin treatment of RSV infection in children with bronchopulmonary dysplasia or congenital heart disease showed that oxygen requirements were lower and oxygen saturation was higher after three days of therapy in those receiving the drug. The American Academy of Pediatrics has recommended consideration of the use of ribavirin in infants hospitalized with RSV (Table 2).
In another study, the most common side effects attributed to ribavirin in infants were rash, initial mild bronchospasm and reversible skin irritation. Among health care personnel, the most frequent complaints were eye irritation and headaches.
Ribavirin has been shown to be teratogenic, carcinogenic and embryocidal in laboratory animals and is contraindicated during pregnancy. Pregnant health care workers should not directly care for patients receiving ribavirin aerosol. Prevention of RSV is limited to controlling nosocomial spread, with careful handwashing and isolation in the hospital to prevent contact with respiratory tract secretions.
Rotavirus is a double-stranded RNA virus that is the most common etiologic agent of diarrheal and gastrointestinal illness in infants and children worldwide. In temperate zones, infection primarily occurs during the winter months. Transmission is by the fecal-oral route, and the incubation period is two to four days. Maximal shedding of the virus in stool occurs at two to five days after the onset of diarrhea. Infection in adults is usually asymptomatic.
Infants with acute rotavirus infection have excessive, watery stools. This seems to be due to the limited capacity for intestinal absorptive function, particularly sodium-glucose and sodium-alanine cotransport, as well as sodium chloride absorption. Recovery depends on the restoration of a normal mucosal surface dominated by villus cells. When infected, villus cell invasion triggers crypt cell proliferation. This rapid epithelial turnover allows cells migrating from the crypt to reach the mucosa without fully differentiating, leading to decreased absorption and consequent diarrhea.
Cross-reactivity has been noted among animals infected with different strains of animal and human rotaviruses. Thus, animal strains of rotavirus have been tested for a human vaccine, particularly Rhesus rotavirus vaccine. These vaccines have been administered in human trials for determining safety and immunogenicity. The vaccines were found to be immunogenic in 70 percent or more of the recipients without a high preexisting antibody titer. A low-grade fever occurred in a small percentage of patients. Field trials of a quadrivalent preparation of four serotypes are currently in progress.
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