HERPES SIMPLEX INFECTIONS
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Grouped vesicles on an erythematous base, typically in or around the mouth or genitals.
Fever, malaise, and tender regional adenopathy common with primary infection.
There are two types of herpes simplex virus (HSV). Type 1 (HSV-1) causes most cases of oral, perioral, skin, and cerebral disease in children, while type 2 (HSV-2) is now equally as common as HSV-1 as cause of genital and congenital HSV infections. Latent infection is routinely established in sensory ganglia during primary infection. Recurrences, due to reactivation of latent HSV, may be spontaneous or induced by external events (eg, fever, menstruation, or sunlight) or immunosuppression. Transmission is by direct contact with infected secretions.
Primary infection with HSV-1 often occurs early in childhood by contact with infected oral secretions of playmates or caretakers, with a second peak of infection later in life as a sexually transmitted disease. Primary infection with HSV-1 is subclinical in 80% of cases and causes gingivostomatitis or genital disease in the remainder. HSV-2, which is transmitted sexually, is also subclinical (65%) or produces mild, nonspecific symptoms. The source of primary infection is usually an asymptomatic excreter. Most previously infected individuals shed HSV at irregular intervals. At any one time (point prevalence), more than 5% of seropositive adults excrete HSV-1 in the saliva; the percentage is higher in recently infected children, and detection of viral DNA exceeds 12%. HSV-2 shedding in genital secretions occurs with a similar or higher point prevalence exceeding 15%, depending on the method of detection (viral isolation vs PCR) and the interval since the initial infection. A history of contact with clinically apparent HSV lesions is unusual. Infection with one type of HSV may prevent or attenuate clinically apparent infection with the other type, but individuals can be infected at different times with both HSV-1 and HSV-2.
High fever, irritability, and drooling occur in infants. Multiple oral ulcers are seen on the tongue and on the buccal and gingival mucosa, occasionally extending to the pharynx. Pharyngeal ulcers may predominate in older children and adolescents. Diffusely swollen red gums that are friable and bleed easily are typical. Cervical nodes are swollen and tender. Duration is 7–14 days. Herpangina, aphthous stomatitis, thrush, and Vincent angina should be excluded.
2. Vulvovaginitis or urethritis
Genital herpes (especially HSV-2) in a prepubertal child should suggest sexual abuse (See Chapter 44). In sexually adolescents, active vesicles or painful ulcers on the vulva, vagina, or penis and tender adenopathy are typical. Systemic symptoms (fever, flu-like illness, myalgia) are common with the initial episode. Painful urination is frequent, especially in females. Primary infection lasts 10–14 days before healing. Lesions may resemble trauma, syphilis (ulcers are painless), or chancroid (ulcers are painful and nodes are erythematous and fluctuant) in the adolescent, and bullous impetigo or severe chemical irritation in younger children.
Direct inoculation onto cuts or abrasions may produce localized vesicles or ulcers. A deep HSV infection on the finger (called herpetic whitlow) may be mistaken for a bacterial felon or paronychia; surgical drainage is of no value and is contraindicated. HSV infection of eczematous skin may result in extensive areas of vesicles and shallow ulcers (eczema herpeticum), which may be mistaken for impetigo or varicella.
4. Recurrent mucocutaneous infection
Recurrent oral shedding is asymptomatic. Recurrent perioral lesions (sometimes perinasal) often begin with a prodrome of tingling or burning limited to the vermillion border, followed by vesiculation, scabbing, and crusting around the lips over 3–5 days. Recurrent intraoral lesions are rare. Fever, adenopathy, and other symptoms are absent. Recurrent cutaneous herpes most closely resembles impetigo, but the latter is often outside the perinasal and perioral region, recurs infrequently in the same area of skin, responds to antibiotics, yields a positive result on Gram stain, and Streptococcus pyogenes or Staphylococcus aureus can be isolated. Recurrent genital disease is common after the initial infection with HSV-2. Recurrent infection is shorter (5–7 days) and milder (mean, four lesions) than primary infection and is not associated with systemic symptoms. Recurrent genital disease, which may also recur on the thighs and buttocks, is also preceded by a cutaneous sensory prodrome. Recurrence of HSV-1 in the genital region is much less frequent than are HSV-2 recurrences.
Keratoconjunctivitis may be part of a primary infection due to spread from infected saliva. Most cases are caused by reactivation of virus latent in the ciliary ganglion. Keratoconjunctivitis produces photophobia, pain, and conjunctival irritation. Dendritic corneal ulcers may be demonstrable with fluorescein staining. Stromal invasion may occur. Corticosteroids should never be used for unilateral keratitis without ophthalmologic consultation. Other causes of these symptoms include trauma, bacterial infections, and other viral infections (especially adenovirus if pharyngitis is present; bilateral involvement makes HSV unlikely) (see Chapter 16).
Although unusual in infants outside the neonatal period, encephalitis may occur at any age, usually without cutaneous herpes lesions. In older children, HSV encephalitis can follow a primary infection, but usually represents reactivation of latent virus. HSV is the most common identifiable cause of sporadic severe encephalitis. Diagnosis of HSV encephalitis is very important because it can be treated with specific antiviral therapy. Acute onset is associated with fever, headache, behavioral changes, and focal neurologic deficits and/or focal seizures. Mononuclear pleocytosis is typically present along with an elevated protein concentration. In older children, hypodense areas with a medial and inferior temporal lobe predilection are seen on CT scan, especially after 3–5 days, but the findings in infants may be more diffuse. Magnetic resonance imaging (MRI) is more sensitive and is positive sooner. Periodic focal epileptiform discharges are seen on electroencephalograms, but are not diagnostic of HSV infection. Viral cultures of CSF are rarely positive. The PCR assay to detect HSV DNA in CSF is a sensitive and specific rapid test. Without early antiviral therapy, the prognosis is poor. The differential diagnosis includes mosquito-borne and other viral encephalitides, parainfectious and postinfectious encephalopathy, brain abscess, acute demyelinating syndromes, and bacterial meningoencephalitis.
Infection is occasionally acquired by ascending spread prior to delivery (< 5% of cases), but most often occurs at the time of vaginal delivery from a mother with genital infection. Eight to fifteen percent of HSV-2–seropositive pregnant women at delivery have HSV-2 detected by PCR in the genital tract. However, in most cases this represents reactivation of infection acquired in the distant past. HSV-1 has now become a common cause of neonatal HSV infection. Neonatal infection is rarely acquired from mothers with reactivation disease, whereas it is frequently acquired during delivery of mothers with current or recent primary infection. This is because transplacentally acquired antibody is usually protective. Occasionally, the infection is acquired in the postpartum period from oral secretions of family members or hospital personnel. A history of genital herpes in the mother is often absent. Within a few days and up to 6 weeks (most often within 4 weeks), skin vesicles appear (especially at sites of trauma, such as where scalp monitors were placed). Some infants (45%) have infection limited to the skin, eye, or mouth. Other infants are acutely ill, presenting with jaundice, shock, bleeding, or respiratory distress (25%). Some infants appear well initially, but dissemination of the infection to the brain or other organs becomes evident during the ensuing week. HSV infection (and empiric therapy) should be strongly considered in newborns with the sepsis syndrome that is unresponsive to antibiotic therapy and has negative bacterial cultures. A mononuclear pleocytosis in the CSF and suggestive skin lesions support this, although skin lesions may be absent at the time of presentation or may never develop. Some infected infants exhibit only neurologic symptoms at 2–3 weeks after delivery: apnea, lethargy, fever, poor feeding, or persistent seizures. The brain infection in these children is often diffuse and is best diagnosed by MRI. The skin lesions may resemble impetigo, bacterial scalp abscesses, or miliaria. Skin lesions may recur over weeks or months after recovery from the acute illness. Progressive culture-negative pneumonitis is another manifestation of neonatal HSV. Most cases of neonatal HSV infection are acquired from mothers with undiagnosed genital herpes, most of whom acquired the infection during the pregnancy—especially near term.
Abnormalities in platelets, clotting factors, and liver function tests are often present in infants with multisystem disease. Lymphocytic pleocytosis and elevated CSF protein indicates viral meningitis or encephalitis. Virus may be cultured from infected epithelial sites (vesicles, ulcers, or conjunctival scrapings). Viral cultures of CSF yield positive results in about 50% of neonatal cases, but are uncommon in older children. HSV will be detected within 2 days by rapid tissue culture methods, but PCR is the preferred diagnostic method for all specimens. A positive test from skin, throat, eye, or stool of a newborn is diagnostic. Vaginal culture of the mother may offer circumstantial evidence for the diagnosis, but may be negative.
Rapid diagnostic tests include immunofluorescent stains or ELISA to detect viral antigen in skin or mucosal scrapings. The PCR assay for HSV DNA is positive (> 95%) in the CSF when there is brain involvement. HSV DNA is often present in the blood of patients with multisystem disease. Typing of genital HSV isolates from adolescents has prognostic value, since HSV-1 genital infection recurs much less frequently than genital HSV-2 infection.
Complications, Sequelae, & Prognosis
Gingivostomatitis may result in dehydration due to dysphagia; severe chronic oral disease and esophageal involvement may occur in immunosuppressed patients. Primary vulvovaginitis may be associated with aseptic meningitis, paresthesias, autonomic dysfunction due to neuritis (urinary retention, constipation), and secondary candidal infection. HIV transmission is facilitated from individuals who are also seropositive for HSV infection, and HIV acquisition is enhanced in HSV-infected contacts. Extensive cutaneous disease (as in eczema) may be associated with dissemination and bacterial superinfection. Keratitis may result in corneal opacification. Untreated encephalitis is fatal in 70% of patients and causes severe damage in most of the remainder. Even with early acyclovir treatment, 20% of patients die and 40% are neurologically impaired.
Disseminated neonatal infection is fatal for 30% of neonates in spite of therapy, and 20% of survivors are often impaired. Treated infants with CNS infection (30% of cases) have a 5% mortality and 70% of survivors are impaired; treated neonates with infection limited to skin, eye, and mouth survive without sequelae.
HSV is sensitive to antiviral therapy.
Antiviral agents are effective for corneal disease and include 1% trifluridine and 0.15% ganciclovir (1–2 drops five times daily). These agents should be used with the guidance of an ophthalmologist and concurrently with oral antiviral therapy.
2. Mucocutaneous HSV infections
These infections respond to administration of oral nucleoside analogues (acyclovir, valacyclovir, or famciclovir). The main indications are severe genital HSV infection in adolescents (see Chapter 44; acyclovir, 400 mg three times daily for 7–10 days) and severe gingivostomatitis in young children. Antiviral therapy is beneficial for primary disease when begun early. Recurrent disease rarely requires therapy. Frequent genital recurrences may be suppressed by oral administration of nucleoside analogues (acyclovir, 400 mg twice daily), but this approach should be used sparingly. Other forms of severe cutaneous disease, such as eczema herpeticum, respond to antivirals. Intravenous acyclovir may be required when disease is extensive in immunocompromised children (10–15 mg/kg or 500 mg/m2 every 8 hours for 14–21 days). Oral acyclovir, which is available in suspension, is also used within 72–96 hours for severe primary gingivostomatitis in immunocompetent young children (20 mg/kg per dose [maximum of 400 mg per dose] four times a day for 7 days). Antiviral therapy does not alter the incidence or severity of subsequent recurrences of oral or genital infection. Development of resistance to antivirals, which is very rare after treating immunocompetent patients, occurs in immunocompromised patients who receive frequent and prolonged therapy.
Treatment consists of intravenous acyclovir, 20 mg/kg (500 mg/m2) every 8 hours for 21 days.
Newborns receive intravenous acyclovir, 20 mg/kg every 8 hours for 21 days (14 days if infection is limited to skin, eye, or mouth). Therapy should not be discontinued unless a repeat CSF HSV PCR assay is negative near the end of treatment. The outcome at 1 year is improved in infants that receive oral acyclovir (300 mg/m2/dose three times daily) for 6 months after completion of IV therapy.
Gingivostomatitis is treated with pain relief and temperature control measures. Maintaining hydration is important because of the long duration of illness (7–14 days). Topical anesthetic agents (eg, viscous lidocaine or an equal mixture of kaolin–attapulgite [Kaopectate], diphenhydramine, and viscous lidocaine) may be used as a mouthwash for older children who will not swallow it; ingested lidocaine may be toxic to infants or may lead to aspiration. Antiviral therapy is indicated in normal hosts with severe disease.
Genital infections may require pain relief, assistance with voiding (warm baths, topical anesthetics, rarely catheterization), and psychological support. Lesions should be kept clean; drying may shorten the duration of symptoms. Sexual contact should be avoided during the interval from prodrome to crusting stages. Because of the frequency of asymptomatic shedding, the only effective way to prevent sexual transmission is the use of condoms. Candidal superinfection occurs in 10% of women with primary genital infections.
Skin lesions should be kept clean, dry, and covered if possible to prevent spread. Systemic analgesics may be helpful. Secondary bacterial infection is uncommon in patients with lesions on the mucosa or involving small areas, and with recurrences. Secondary infection should be considered and treated if necessary in patients with more extensive lesions.
4. Recurrent cutaneous disease
Recurrent disease is usually the cause of lesions. Sun block lip balm helps prevent labial recurrences that follow intense sun exposure. There is no evidence that the many popular topical or vitamin therapies are efficacious.
An ophthalmologist should be consulted regarding the use of cycloplegics, anti-inflammatory agents, local debridement, and other therapies.
Extensive support will be required for obtunded or comatose patients. Rehabilitation and psychological support are often needed for survivors.
Infected infants should be isolated and given acyclovir. Cesarean delivery is indicated if the mother has obvious cervical or vaginal lesions, especially if these represent primary infection (35%–50% transmission rate). With infants born vaginally to mothers who have active lesions of recurrent genital herpes, appropriate cultures and PCR should be obtained at 24 hours after birth, and the infant evaluated thoroughly for possible HSV infection. If the results are positive or the infant has suggestive signs or symptoms preemptive therapy should be started. Treatment is given to infants whose culture results are positive or who appear ill. Infants born to mothers with obvious primary genital herpes should also be evaluated, but should then receive therapy before the culture or PCR results are known. For women with a history of genital herpes infection, but no genital lesions, vaginal delivery with peripartum cultures of maternal cervix is the standard. Clinical follow-up of the newborn is recommended when maternal culture results are positive. Repeated cervical cultures during pregnancy are not useful.
A challenging problem is the newborn, especially in the first 3 weeks of life, that presents with fever (or hypothermia) and a sepsis-like picture. This is further confounded in the late summer by the existence of circulating enteroviruses. These infants should be considered for empiric acyclovir therapy, pending results of PCR studies, given the poor outcome of disseminated herpes in the newborn. The index of suspicion is increased when there is a CSF pleocytosis, elevated hepatic transaminase levels, a very ill-appearing infant, rash, or respiratory distress.
DW: Neonatal herpes simplex virus infection: epidemiology and treatment. Clin Perinatol 2015;427:4
VARICELLA & HERPES ZOSTER
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Primary infection with varicella-zoster virus results in varicella, which generally confers lifelong immunity, but the virus remains latent lifelong in sensory ganglia. Herpes zoster, which represents reactivation of this latent virus, occurs in 30% of individuals at some time in their life. The incidence of herpes zoster is highest in elderly individuals and in immunosuppressed patients, but herpes zoster occurs in immunocompetent children. Spread of varicella from a close contact is mainly by respiratory droplets or aerosols (occasionally direct contact) from vesicles or pustules, with an 85% infection rate in susceptible persons. Over 95% of young adults with a history of varicella are immune, as is 90% of native-born Americans who are unaware of having had varicella. Many individuals from tropical or subtropical regions fail to develop varicella in their childhood and remain susceptible through early adulthood. Humans are the only reservoir.
Exposure to varicella or herpes zoster has usually occurred 14–16 days previously (range, 10–21 days). Contact may not be recognized, since the index case of varicella is infectious 1–2 days before rash appears. A 1- to 3-day prodrome of fever, malaise, respiratory symptoms, and headache may occur, especially in older children. The unilateral, dermatomal vesicular rash and pain of herpes zoster is very distinctive. The preeruptive pain of herpes zoster may last several days and be mistaken for other illnesses.
The usual case consists of mild systemic symptoms followed by crops of red macules that rapidly become small vesicles with surrounding erythema (described as a “dew drop on a rose petal”), form pustules, become crusted, and then scab. Pruritus may be intense; scarring occurs, but it is not common. The rash appears predominantly on the trunk and face. Lesions occur in the scalp, and sometimes in the nose, mouth (where they are nonspecific ulcers), conjunctiva, and vagina. The magnitude of systemic symptoms usually parallels skin involvement. Up to five crops of lesions may be seen. New crops stop forming after 5–7 days. Pruritus is often intense. If varicella occurs in the first few months of life (except for the early postpartum period), it is often mild as a result of transplacentally acquired maternal antibody. Once crusting begins, the patient is no longer contagious. A modified form of varicella occurs in about 15% of vaccinated children exposed to varicella, in spite of receiving a single dose of varicella vaccine. This is usually much milder than typical varicella, with fewer lesions that heal rapidly. Cases of modified varicella are contagious.
2. Herpes zoster (shingles)
This eruption involves a single dermatome (thus unilateral and does not cross the midline), usually truncal or cranial; occasionally a contiguous dermatome is involved. Especially in older children this is preceded by neuropathic pain or itching in the same area (designated the “prodrome”). Ophthalmic zoster may be associated with corneal involvement. The closely grouped vesicles, which resemble a localized version of varicella or herpes simplex, often coalesce. Crusting occurs in 7–10 days. Postherpetic neuralgia is rare in children. Herpes zoster is a common problem in HIV-infected or other immunocompromised children, and is also common in children who had varicella in early infancy (< 1–2 years old) or whose mothers had varicella during pregnancy. Herpes zoster can occur infrequently in children who received the varicella vaccine.
Leukocyte counts are normal or low. Leukocytosis suggests secondary bacterial infection. Vesicular fluid or a scab can be used to identify the virus using PCR as the method of choice. DFA assay is less sensitive. Serum aminotransferase levels may be modestly elevated during typical varicella.
Varicella pneumonia classically produces numerous bilateral nodular densities and hyperinflation. This is very rare in immunocompetent children, but is seen more frequently in adults and immunocompromised children.
Varicella is usually distinctive. Similar rashes include those of coxsackievirus infection (fewer lesions, lack of crusting), impetigo (fewer lesions, smaller area, no classic vesicles, positive Gram stain, perioral or peripheral lesions), papular urticaria (insect bite history, nonvesicular rash), scabies (burrows, no typical vesicles, failure to resolve), parapsoriasis (rare in children < 10 years, chronic or recurrent, often a history of prior varicella), rickettsial pox (eschar where the mite bites, smaller lesions, no crusting), dermatitis herpetiformis (chronic, urticaria, residual pigmentation), and folliculitis. Herpes zoster is sometimes confused with a linear eruption of herpes simplex or a contact dermatitis.
Secondary bacterial infection with staphylococci or group A streptococci is most common, presenting as impetigo, cellulitis or fasciitis, abscesses, scarlet fever, or sepsis. Bacterial superinfection occurs in 2%–3% of children with varicella. Before a vaccine became available, hospitalization rates associated with varicella were 1:750–1:1000 cases in children and 10-fold higher in adults.
Protracted vomiting or a change in sensorium suggests Reye syndrome or encephalitis. Because Reye syndrome usually occurs in patients who are also receiving salicylates, these should be avoided in patients with varicella. Encephalitis occurs in less than 0.1% of cases, usually in the first week of illness, and is usually limited to cerebellitis with ataxia, which resolves completely. Diffuse encephalitis can be severe.
Varicella pneumonia usually afflicts immunocompromised children (especially those receiving high doses of corticosteroids or chemotherapy) and adults. Cough, dyspnea, tachypnea, rales, and cyanosis occur several days after onset of rash. New lesions may erupt for an extended period, and varicella may be life-threatening in immunosuppressed patients. In addition to pneumonitis, their disease may be complicated by hepatitis and encephalitis. The acute illness in these children often begins with unexplained severe abdominal pain. Varicella exposure in varicella-naïve severely immunocompromised children must be evaluated immediately for postexposure prophylaxis (see Chapter 10).
Hemorrhagic varicella lesions may be seen without other complications. This is most often caused by autoimmune thrombocytopenia, but hemorrhagic lesions can occasionally represent idiopathic disseminated intravascular coagulation (purpura fulminans).
Neonates born to mothers who develop varicella from 5 days before to 2 days after delivery are at high risk for severe or fatal (5%) disease and must be given varicella-zoster immunoglobulin (VariZIG) and followed closely (see Chapter 10).
Varicella occurring during the first 20 weeks of pregnancy may cause (2% incidence) congenital infection associated with cicatricial skin lesions, associated limb anomalies, eye abnormalities, and cortical atrophy.
Unusual complications of varicella include optic neuritis, myocarditis, transverse myelitis, orchitis, and arthritis.
Complications of herpes zoster include secondary bacterial infection, motor or cranial nerve paralysis, meningitis, encephalitis, keratitis and other ocular complications, and dissemination in immunosuppressed patients. These complications are rare in immunocompetent children. Postherpetic neuralgia occurs in immunocompromised children, but is rare in immunocompetent children.
Varicella-specific hyperimmune globulin is available for postexposure prevention of varicella in high-risk susceptible persons (see Chapter 10). In immunocompetent children, postexposure prophylaxis with acyclovir is effective when it is started at 7–9 days after exposure and is continued for 7 days, as is varicella vaccine when given within 3–5 days of the exposure.
Two doses of the live attenuated varicella vaccine provide close to 92% protection and are now part of routine childhood immunization. Catch-up immunization is recommended for all other susceptible children and adults.
Supportive measures include maintenance of hydration, administration of acetaminophen for discomfort, cool soaks or antipruritics for itching (diphenhydramine, 1.25 mg/kg every 6 hours, or hydroxyzine, 0.5 mg/kg every 6 hours), and observance of general hygiene measures (keep nails trimmed and skin clean). Care must be taken to avoid overdosage with antihistaminic agents. Topical or systemic antibiotics may be needed for bacterial superinfection.
Acyclovir is the preferred drug for varicella and herpes zoster infections. Recommended parenteral acyclovir dosage for severe disease is 10 mg/kg (500 mg/m2) intravenously every 8 hours, each dose infused over 1 hour, for 7–10 days. Parenteral therapy should be started early in immunocompromised patients or high-risk infected neonates. Hyperimmune globulin is of no value for established disease. The effect of oral acyclovir (80 mg/kg/day, divided in four doses) on varicella in immunocompetent children is modestly beneficial and nontoxic, but only when administered within 24 hours after the onset of varicella. Valacyclovir (20 mg/kg [maximum 1 g] PO TID) may be preferable (≥ 2 years). Oral acyclovir should be used selectively in immunocompetent children. For example, when a significant concomitant or underlying illness is present or possibly when the index case is a sibling or when the patient is an adolescent, both of which are associated with more severe disease, and in children with a significant underlying chronic illness. Valacyclovir and famciclovir are superior antiviral agents because of better absorption; only acyclovir is available as a pediatric suspension. Herpes zoster in an immunocompromised child should be treated with intravenous acyclovir when it is severe, but oral valacyclovir or famciclovir can be used in immunocompromised children when the nature of the underlying illness and the immune status support this decision.
Except for secondary bacterial infections, serious complications are rare and recovery complete in immunocompetent hosts. Complications are common in severely immune compromised children unless treated promptly.
R: Impact of the maturing varicella vaccination program on varicella and related outcomes in the United States: 1994–2012. J Ped Infect Dis Soc 2016;5:395
M: Epidemiology of varicella during the 2-dose vaccination program—United States, 2005–2014. MMWR Morb Mortal Wkly Rep 2016;65:902
ROSEOLA INFANTUM (EXANTHEM SUBITUM)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Roseola infantum (also called exanthem subitum) is a benign illness caused by HHV-6 or HHV-7. HHV-6 is a major cause of acute febrile illness in young children. Its significance is that it may be confused with more serious causes of high fever and its role in inciting febrile seizures.
The most prominent historical feature is the abrupt onset of fever, often reaching greater than 39.5°C, and lasting for 3–7 days (mean, 4 days; 15% ≥ 6 days) in an otherwise mildly ill child. The fever then ceases abruptly, and a characteristic rash may appear. Roseola occurs predominantly in children aged 6 months to 3 years, with 90% of cases occurring before the second year. HHV-7 infection tends to occur somewhat later in childhood. These viruses are the most common recognized cause of fever and rash in this age group and are responsible for 20% of emergency department visits by children aged 6–12 months.
Mild lethargy and irritability may be present, but generally there is dissociation between other systemic symptoms and the febrile course. The pharynx, tonsils, and tympanic membranes may be injected. Conjunctivitis and pharyngeal exudate are notably absent. Diarrhea and vomiting occur in one-third of patients. Adenopathy of the head (especially postoccipital) and neck often occurs. The anterior fontanelle is bulging in one-quarter of HHV-6–infected infants. If rash appears (20%–30% incidence), it coincides with lysis of fever and begins on the trunk and spreads to the face, neck, and extremities. Rose-pink macules or maculopapules, 2–3 mm in diameter, are nonpruritic, tend to coalesce, and disappear in 1–2 days without pigmentation or desquamation. Rash may occur without fever.
Leukopenia and lymphocytopenia are present early. Laboratory evidence of hepatitis occurs in some patients, especially adults. Detection of HHV-6 and HHV-7 by PCR is available but rarely influences clinical management except in immunocompromised children. Some newly available multiplex CSF PCR includes HHV-6, but given the chromosomal integration of the virus, a positive result should be interpreted with caution in the presence of pleocytosis.
The initial high fever may require exclusion of serious bacterial infection. The relative well-being of most children and the typical course and rash soon clarify the diagnosis. These distinguish roseola from measles, rubella, adenoviruses, enteroviruses, drug reactions, and scarlet fever. In a child with febrile seizures, exclusion of bacterial meningitis is important. The CSF is normal in children with roseola. In children who receive antibiotics or other medication at the beginning of the fever, the rash may be attributed incorrectly to drug allergy.
Febrile seizures occur in up to 10% of patients (even higher percentages in those with HHV-7 infections); especially if less than 24 months old. There is evidence that HHV-6 can directly infect the CNS, causing meningoencephalitis. Multiorgan disease (pneumonia, hepatitis, bone marrow suppression, encephalitis) may occur in immunocompromised patients.
Fever is managed readily with acetaminophen and sponge baths. Fever control should be a major consideration in children with a history of febrile seizures. Roseola infantum is otherwise entirely benign. Systemic infection in immunocompromised children is treated with antiviral agents.
T: HHV-6 and seizure: a systematic review and meta-analysis. J Med Virol 2017;89(1):161–169
TM: Clinical impact of primary infection with roseola viruses. Curr Opin Virol 2014;9:91
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Intrauterine growth retardation.
Microcephaly with intracerebral calcifications and seizures.
Retinitis and encephalitis.
Hepatosplenomegaly with thrombocytopenia.
“Blueberry muffin” small purpuric spots rash.
Retinitis and encephalitis.
Pneumonitis, enteritis, and hepatitis.
Bone marrow suppression.
Cytomegalovirus (CMV) is a ubiquitous herpesvirus transmitted by many routes. It can be acquired in utero following maternal viremia or postpartum from birth canal secretions or maternal milk. Young children are infected by the saliva of playmates; older individuals are infected by sexual partners (eg, from saliva, vaginal secretions, or semen). Transfused blood products and transplanted organs can be a source of CMV infection. Clinical illness is determined largely by the patient’s immune competence. Immunocompetent individuals usually develop a mild self-limited illness, whereas immunocompromised children can develop severe, progressive, often multiorgan disease. In utero infection can be teratogenic.
1. In Utero Cytomegalovirus Infection
Approximately 0.5%–1.5% of children are born with CMV infections acquired during maternal viremia. CMV infection is asymptomatic in over 90% of these children, who are usually born to mothers who had experienced reactivation of latent CMV infection during the pregnancy. Symptomatic infection occurs predominantly in infants born to mothers with primary CMV infection, but can also result from reinfection during pregnancy. Even when exposed to a primary maternal infection, less than 50% of fetuses are infected, and in only 10% of those infants is the infection symptomatic at birth. Primary infection in the first half of pregnancy poses the greatest risk for severe fetal damage.
Severely affected infants are born ill; they are often small for gestational age, floppy, and lethargic. They feed poorly and have poor temperature control. Hepatosplenomegaly, jaundice, petechiae, seizures, and microcephaly are common. Characteristic signs are a distinctive chorioretinitis and periventricular calcification. A purpuric rash (so-called “blueberry muffin”) similar to that seen with congenital rubella may be present, secondary to extramedullary hematopoiesis. The mortality rate is 10%–20%. Survivors usually have significant sequelae, especially mental retardation, neurologic deficits, retinopathy, and hearing loss. Isolated hepatosplenomegaly or thrombocytopenia may occur. Even mildly affected children may subsequently manifest mental retardation and psychomotor delay. Most infected infants (90%) are born to mothers with preexisting immunity who experienced a reactivation of latent CMV or reinfection during pregnancy. These children have no clinical manifestations at birth. Of these, 10%–15% develop sensorineural hearing loss, which is often bilateral and may appear several years after birth.
In severely ill infants, anemia, thrombocytopenia, hyperbilirubinemia, and elevated aminotransferase levels are common. Lymphocytosis occurs occasionally. Pleocytosis and an elevated protein concentration are found in CSF. The diagnosis is readily confirmed by PCR or isolation of CMV from urine or saliva within 48 hours, using rapid culture methods combined with immunoassay. The presence in the infant of IgM-specific CMV antibodies suggests the diagnosis. Some commercial ELISA kits are 90% sensitive and specific for these antibodies. Universal screening of asymptomatic children using blood or saliva CMV PCR during the first weeks of life is useful for early detection of children at high risk of developing hearing loss. Retrospective diagnosis of congenital CMV following hearing loss identified later in infancy is difficult.
Head radiologic examinations may show microcephaly, periventricular calcifications, and ventricular dilation. These findings strongly correlate with neurologic sequelae and retardation. Long bone radiographs may show the “celery stalk” pattern characteristic of congenital viral infections. Interstitial pneumonia may be present.
CMV infection should be considered in any newborn that is seriously ill shortly after birth, especially once bacterial sepsis, metabolic disease, intracranial bleeding, and cardiac disease have been excluded. Other congenital infections to be considered in the differential diagnosis include toxoplasmosis (more diffuse calcification of the CNS, specific type of retinitis, macrocephaly, serology), rubella (specific type of retinitis, cardiac lesions, eye abnormalities, serology), enteroviral infections (time of year, maternal illness, severe hepatitis, PCR), herpes simplex (skin lesions, cultures, severe hepatitis, PCR), Zika virus (exposure, microcephaly, PCR, serology), and syphilis (skin lesions, bone involvement, serology of both infant and mother).
Support is rarely required for anemia and thrombocytopenia. Most children with symptoms at birth have significant neurologic, intellectual, visual, or auditory impairment. Ganciclovir (6 mg/kg every 12 hours, for 6 weeks) has been recommended for children with severe, life- or sight-threatening disease, or if end-organ disease recurs or progresses. A recent randomized placebo-controlled study showed efficacy in reducing hearing loss using oral valganciclovir at 16 mg/kg twice daily for 6 months in children symptomatic at birth. Patients undergoing treatment should be monitored for neutropenia.
Recent developments in the diagnosis of primary CMV infection during pregnancy using anti-CMV IgM and low-avidity IgG assays followed by quantitative CMV PCR testing of the amniotic fluid at 20–24 weeks gestation have made possible the diagnosis of congenital CMV infection before birth. Many pregnant women elect to terminate gestation under these circumstances. Passive immunoprophylaxis with hyperimmune CMV IgG did not prevent development of congenital disease in a randomized placebo-controlled trial.
2. Perinatal Cytomegalovirus Infection
CMV infection can be acquired from birth canal secretions or shortly after birth from breast milk. In some socioeconomic groups, 10%–20% of infants are infected at birth and excrete CMV for many months. Infection can also be acquired in the postnatal period from unscreened transfused blood products.
Ninety percent of immunocompetent infants infected by their mothers at birth develop subclinical illness (ie, virus excretion only) or a minor illness within 1–3 months. The remainder develops an illness lasting several weeks characterized by hepatosplenomegaly, lymphadenopathy, and interstitial pneumonitis in various combinations. Very low birth weight and premature infants are at greater risk for severe disease. If they are born to CMV-negative mothers and subsequently receive CMV-containing blood or breast milk, they may develop severe infection and pneumonia after a 2- to 6-week incubation period.
Lymphocytosis, atypical lymphocytes, anemia, and thrombocytopenia may be present, especially in premature infants. Liver function is abnormal. CMV is readily isolated from urine and saliva. Secretions obtained at bronchoscopy contain CMV and epithelial cells bearing CMV antigens. Serum levels of CMV antibody rise significantly.
Chest radiographs may show a diffuse interstitial pneumonitis in severely affected infants.
CMV infection should be considered as a cause of any prolonged illness in early infancy, especially if hepatosplenomegaly, lymphadenopathy, or atypical lymphocytosis is present. This must be distinguished from granulomatous or malignant diseases and from congenital infections (syphilis, toxoplasmosis, hepatitis B, HIV) not previously diagnosed. Other viruses (Epstein-Barr virus [EBV], HIV, adenovirus) can cause this syndrome. CMV is a recognized cause of viral pneumonia in this age group. Because asymptomatic CMV excretion is common in early infancy, care must be taken to establish the diagnosis and to rule out concomitant pathogens such as Chlamydia and RSV. Severe CMV infection in early infancy may indicate that the child has a congenital or acquired immune deficiency.
The self-limited disease of normal infants requires no therapy. Severe pneumonitis in premature infants requires oxygen administration and often intubation. Very ill infants should receive ganciclovir (6 mg/kg every 12 hours). CMV infection acquired by transfusion can be prevented by excluding CMV-seropositive blood donors. Milk donors should also be screened for prior CMV infection. A common practice of freezing the milk prior to administration was shown to lack preventive effectiveness. It is likely that high-risk infants receiving large doses of IVIG for other reasons will be protected against severe CMV disease.
3. Cytomegalovirus Infection Acquired in Childhood & Adolescence
Young children are readily infected by playmates, especially because CMV continues to be excreted in saliva and urine for many months after infection. The cumulative annual incidence of CMV excretion by children in day care centers exceeds 75%. In fact, young children in a family are often the source of primary CMV infection of their mothers during subsequent pregnancies. An additional peak of CMV infection takes place when adolescents become sexually active. Sporadic acquisition of CMV occurs after blood transfusion and transplantation.
Most young children who acquire CMV are asymptomatic or have a minor febrile illness, occasionally with adenopathy. They provide an important reservoir of virus shedders that facilitates spread of CMV. Occasionally a child may have prolonged fever with hepatosplenomegaly and adenopathy. Older children and adults, many of whom are infected during sexual activity, are more likely to be symptomatic and can present with a syndrome that mimics the infectious mononucleosis syndrome that follows EBV infection (1–2 weeks of fever, malaise, anorexia, splenomegaly, mild hepatitis, and some adenopathy; see the next section). This syndrome can also occur 2–4 weeks after transfusion of CMV-infected blood.
In the CMV mononucleosis syndrome, lymphocytosis and atypical lymphocytes are common, as is a mild rise in amino-transferase levels. CMV is present in saliva and urine; CMV DNA can be uniformly detected in plasma or blood.
In older children, CMV infection should be included as a possible cause of fever of unknown origin, especially when lymphocytosis and atypical lymphocytes are present. CMV infection is distinguished from EBV infection by the absence of pharyngitis, the relatively minor adenopathy, and the absence of serologic evidence of acute EBV infection. Mononucleosis syndromes also are caused by Toxoplasma gondii, rubella virus, adenovirus, hepatitis A virus, and HIV.
Screening of transfused blood or filtering blood (thus removing CMV-containing white blood cells) prevents cases related to this source.
4. Cytomegalovirus Infection in Immunocompromised Children
In addition to symptoms experienced during primary infection, immunocompromised hosts develop symptoms with reinfection or reactivation of latent CMV. This is clearly seen in children with acquired immunodeficiency syndrome (AIDS), after transplantation, or with congenital immunodeficiencies. However, in most immunocompromised patients, primary infection is more likely to cause severe symptoms than is reactivation or reinfection. The severity of the resulting disease is generally proportionate to the degree of immunosuppression.
A mild febrile illness with myalgia, malaise, and arthralgia may occur, especially with reactivation disease. Severe disease often includes subacute onset of dyspnea and cyanosis as manifestations of interstitial pneumonitis. Auscultation reveals only coarse breath sounds and scattered rales. A rapid respiratory rate may precede clinical or radiographic evidence of pneumonia. Hepatitis without jaundice and hepatomegaly are common. Diarrhea, which can be severe, occurs with CMV colitis, and CMV can cause esophagitis with symptoms of odynophagia or dysphagia. These enteropathies are most common in AIDS, as is the presence of a retinitis that often progresses to blindness, encephalitis, and polyradiculitis.
Neutropenia and thrombocytopenia are common. Atypical lymphocytosis is infrequent. Serum aminotransferase levels are often elevated. The stools may contain occult blood if enteropathy is present. CMV is readily isolated from saliva, urine, buffy coat, and bronchial secretions. Results are available in 48 hours. Interpretation of positive cultures is made difficult by asymptomatic shedding of CMV in saliva and urine in many immunocompromised patients. CMV disease correlates more closely with the presence of CMV in the blood or lung lavage fluid. Monitoring for the appearance of CMV DNA in plasma or CMV antigen in blood mononuclear cells is used as a guide to early antiviral (“preemptive”) therapy.
Bilateral interstitial pneumonitis may be present on chest radiographs.
The initial febrile illness must be distinguished from treatable bacterial or fungal infection. Similarly, the pulmonary disease must be distinguished from intrapulmonary hemorrhage; drug-induced or radiation pneumonitis; pulmonary edema; and bacterial, fungal, parasitic, or other viral infections. CMV infection causes bilateral and interstitial abnormalities on chest radiographs, cough is nonproductive, chest pain is absent, and the patient is not usually toxic. Pneumocystis jiroveci infection may have a similar presentation. These patients may have polymicrobial disease. It is suspected that bacterial and fungal infections are enhanced by the neutropenia that can accompany CMV infection. Infection of the gastrointestinal tract is diagnosed by endoscopy. This will exclude candidal, adenoviral, and herpes simplex infections and allows tissue confirmation of CMV-induced mucosal ulcerations.
Blood donors should be screened to exclude those with prior CMV infection, or blood should be filtered. Ideally, seronegative transplant recipients should receive organs from seronegative donors. Severe symptoms, most commonly pneumonitis, often respond to early therapy with intravenous ganciclovir (5 mg/kg every 12 hours for 14–21 days). Neutropenia is a frequent side effect of this therapy. Foscarnet and cidofovir are alternative therapeutic agents recommended for patients with ganciclovir-resistant virus. Prophylactic use of oral or intravenous ganciclovir or foscarnet may prevent CMV infections in organ transplant recipients. Preemptive therapy can be used in transplant recipients by monitoring CMV in blood by PCR and instituting therapy when the results reach a certain threshold regardless of clinical signs or symptoms.
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INFECTIOUS MONONUCLEOSIS (EPSTEIN-BARR VIRUS)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Mononucleosis is the most characteristic syndrome produced by Epstein-Barr virus (EBV) infection. Young children infected with EBV have either no symptoms or a mild nonspecific febrile illness. As the age of the host increases, EBV infection is more likely to produce the typical mononucleosis syndrome reaching 20%–25% of infected adolescents. EBV is acquired by close contact from asymptomatic carriers (15%–20% of whom excrete the virus in saliva on any given day) and from recently ill patients, who excrete virus for many months. Young children are infected from the saliva of playmates and family members. Adolescents contract the infection primarily by deep kissing. EBV can also be transmitted by blood transfusion and organ transplantation.
After an incubation period of 32–49 days, a 2- to 3-day prodrome of malaise and anorexia yields, abruptly or insidiously, to a febrile illness with temperatures exceeding 39°C. The major complaint is pharyngitis, which is often (50%) exudative with transient petechiae. Lymph nodes are enlarged, firm, and mildly tender. Any area may be affected, but posterior and anterior cervical nodes are almost always enlarged. Splenomegaly is present in 50%–75% of patients. Hepatomegaly is common (30%), and the liver is frequently tender. Five percent of patients have a rash, which can be macular, scarlatiniform, or urticarial. Rash is almost universal in patients taking penicillin or ampicillin. Soft palate petechiae and eyelid edema are also observed.
Leukopenia may occur early, but an atypical lymphocytosis (comprising over 10% of the total leukocytes at some time in the illness) is most notable. Lymphocyte count less than 4000 mm3 has a 99% negative predictive value for infectious mononucleosis. Hematologic changes may not be seen until the third week of illness and may be entirely absent in some EBV syndromes (eg, neurologic).
2. Heterophile antibodies
These nonspecific antibodies appear in over 90% of older patients with mononucleosis, but in fewer than 50% of children younger than age 5 years. They may not be detectable until the second week of illness and may persist for up to 12 months after recovery. Rapid screening tests (slide agglutination) are usually positive if the titer is significant; a positive result strongly suggests but does not prove EBV infection.
Specific antibody titers have a 97% sensitivity and 94% specificity for diagnosis and are especially useful in children younger than 5 years. Acute EBV infection is established by detecting IgM antibody to the viral capsid antigen (VCA) or by detecting a fourfold or greater change of IgG anti-VCA titers (in normal hosts, IgG antibody peaks by the time symptoms appear; in immunocompromised hosts, the tempo of antibody production may be delayed). The absence of anti-EBV nuclear antigen (EBNA) antibodies, which are typically first detected at least 4 weeks after the initiation of symptoms, may also be used to diagnose acute infection in immunocompetent hosts. However, immunocompromised hosts may fail to develop anti-EBNA antibodies.
Site-specific detection of EBV DNA is the method of choice for the diagnosis of CNS and ocular infections. Quantitative EBV PCR in peripheral blood mononuclear cells has been used to diagnose EBV-related lymphoproliferative disorders in transplant patients. EBV PCR is less useful than serology for diagnosis of acute EBV infection in immunocompetent hosts.
Severe pharyngitis may suggest group A streptococcal infection. Enlargement of only the anterior cervical lymph nodes, a neutrophilic leukocytosis, and the absence of splenomegaly suggest bacterial infection. Although a child with a positive throat culture result for Streptococcus usually requires therapy, up to 10% of children with mononucleosis are asymptomatic streptococcal carriers. In this group, penicillin therapy is unnecessary and often causes a rash. Severe primary herpes simplex pharyngitis, occurring in adolescence, may also mimic infectious mononucleosis. With herpes simplex pharyngitis, some anterior mouth ulcerations should suggest the correct diagnosis. Adenoviruses are another cause of severe, often exudative pharyngitis. EBV infection should be considered in the differential diagnosis of any perplexing prolonged febrile illness. Similar illnesses that produce atypical lymphocytosis include rubella (pharyngitis not prominent, shorter illness, less adenopathy and splenomegaly), adenovirus (upper respiratory symptoms and cough, conjunctivitis, less adenopathy, fewer atypical lymphocytes), hepatitis A or B (more severe liver function abnormalities, no pharyngitis, no lymphadenopathy), and toxoplasmosis (negative heterophil test, less pharyngitis). Serum sickness-like drug reactions and leukemia (smear morphology is important) may be confused with infectious mononucleosis. CMV mononucleosis is a close mimic except for minimal pharyngitis and less adenopathy; it is much less common. Serologic tests for EBV and CMV should clarify the correct diagnosis. The acute initial manifestation of HIV infection can be a mononucleosis-like syndrome.
Splenic rupture is a rare complication, which usually follows significant trauma. Hematologic complications, including hemolytic anemia, thrombocytopenia, and neutropenia, are more common. Neurologic involvement can include aseptic meningitis, encephalitis, isolated neuropathy such as Bell palsy, and Guillain-Barré syndrome. Any of these may appear prior to or in the absence of the more typical signs and symptoms of infectious mononucleosis. Rare complications include myocarditis, pericarditis, and atypical pneumonia. Recurrence or persistence of acute EBV-associated symptoms for 6 months or longer characterizes chronic active EBV. This uncommon presentation is due to continuous viral replication and warrants specific antiviral therapy. Rarely EBV infection becomes a progressive lymphoproliferative disorder characterized by persistent fever, multiple organ involvement, neutropenia or pancytopenia, and agammaglobulinemia. Hemocytophagia is often present in the bone marrow. An X-linked genetic defect in immune response has been inferred for some patients (Duncan syndrome, X-linked lymphoproliferative disorder). Children with other congenital immunodeficiencies or chemotherapy-induced immunosuppression can also develop progressive EBV infection, EBV-associated lymphoproliferative disorder, lymphoma, and other malignancies.
Bed rest may be necessary in severe cases. Acetaminophen controls high fever. Potential airway obstruction due to swollen pharyngeal lymphoid tissue responds rapidly to systemic corticosteroids. Corticosteroids may also be given for hematologic and neurologic complications, although no controlled trials have proven their efficacy in these conditions. Fever and pharyngitis disappear spontaneously by 10–14 days. Adenopathy and splenomegaly can persist several weeks longer. Some patients complain of fatigue, malaise, or lack of well-being for several months. Although corticosteroids may shorten the duration of illness by 12 hours, there is no evidence that its use decreases the course or severity of the disease. Patients may return to contact sports after 4 weeks if they have had resolution of symptoms and no splenomegaly. Acyclovir, valacyclovir, penciclovir, ganciclovir, and foscarnet are active against EBV and are indicated in the treatment of chronic active EBV. Antiviral therapy in the immunocompetent child has not proven efficacious.
Management of EBV-related lymphoproliferative disorders relies primarily on decreasing the immunosuppression whenever possible. Adjunctive therapy with acyclovir, ganciclovir, or another antiviral active against EBV as well as γ globulin has been used without scientific evidence of efficacy.
HH Jr, Dunmire
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