Chapter 40: Infections: Viral & Rickettsial

Viruses cause most pediatric infections. Mixed viral or viral-bacterial infections of the respiratory and intestinal tracts are common, as is prolonged asymptomatic shedding of many viruses in childhood, especially in young children. Thus, the detection of a virus is not always proof that it is the cause of a given illness. Viruses are often a predisposing factor for bacterial respiratory infections (eg, otitis, sinusitis, and pneumonia).

Many respiratory viruses and herpesviruses can now be detected within 24 through antigen or nucleic acid detection techniques. Polymerase chain reaction (PCR) amplification of viral genes has led to detection of previously unrecognized infections. It is now possible to detect multiple organisms causing the same syndrome (eg, respiratory, gastrointestinal, encephalitis/meningitis) within a single test system (multiplex assay). The available tests vary in format and turnaround time, and can include both viral and bacterial etiologies. New diagnostic tests have changed some basic concepts about viral diseases and made diagnosis of viral infections both more certain and more complex. Only laboratories with excellent quality-control procedures should be used. The availability of specific antiviral agents increases the value of early diagnosis for some serious viral infections. Table 40–1 lists diagnostic tests. The viral diagnostic laboratory should be contacted for details regarding specimen collection, handling, and shipping. Table 40–2 lists common causes of red rashes in children that should be considered in the differential diagnosis of certain viral illnesses.

Many viral infections can cause either upper or lower respiratory tract signs and symptoms, sometimes both in the same patient. Many so-called respiratory viruses can also produce distinct nonrespiratory disease (eg, enteritis, cystitis or myocarditis caused by adenoviruses; parotitis caused by parainfluenza viruses). Respiratory viruses can cause disease in any area of the respiratory tree, although certain viruses tend to be closely associated with one anatomic area (eg, parainfluenza with croup, respiratory syncytial virus [RSV] with bronchiolitis) or with discrete epidemics (eg, influenza, RSV, parainfluenza). Thus, it is usually impossible on clinical grounds alone to be certain of the specific viral cause of an infection in a given child. The information provided by the virology laboratory is often important for epidemiologic, therapeutic, and preventive reasons. In immunocompromised patients, otherwise benign viruses can cause severe pneumonia.

VIRUSES CAUSING THE COMMON COLD

The common cold syndrome (also called upper respiratory infection) is characterized by combinations of runny nose, nasal congestion, sore throat, conjunctivitis, cough, and sneezing. Low-grade fever may be present. Rhinoviruses, which are the most common cause (30%–40%), are present throughout the year, but are more prevalent in the colder months in temperate climates. Adenoviruses also cause colds in all seasons and epidemics are common. RSV, parainfluenza viruses, human metapneumovirus (hMPV), and influenza viruses cause the cold syndrome during epidemics from late fall through winter. Multiple strains of coronaviruses account for 5%–10% of cold syndromes in winter. Often (25%–50%) more than one virus is detected during a common cold. The precise role of newly identified respiratory viruses, such as the human bocavirus (a parvovirus) and several polyomaviruses, are under study. Enteroviruses cause the “summer cold.” The usual outcome of the common cold is morbidity continuing for 5–7 days. However, changes in the respiratory epithelium, local mucosal swelling, and altered local immunity may act as precursors to more severe bacterial illnesses, such as otitis media, pneumonia, and sinusitis. During and following a cold, the bacterial flora changes and bacteria are found in normally sterile areas of the upper airway. Asthma attacks are frequently provoked by any of the viruses that cause the common cold. These “cold viruses” are also a common cause of lower respiratory tract infection in young children. There is no evidence that antibiotics will prevent complications of the common cold, and they do not limit the duration of purulent rhinitis.

In 5%–10% of children, symptoms from these virus infections persist for more than 10 days. Overlap with the symptoms of bacterial sinusitis presents a difficult problem for clinicians, especially because colds can produce sinuses abnormalities on computed tomography (CT) scan. Viruses that cause a minor illness in immunocompetent children, such as rhinoviruses, influenza, RSV, and metapneumovirus, can cause severe lower respiratory disease in immunologically or anatomically compromised children.

There is conflicting evidence that symptomatic relief for children can be achieved with oral antihistamines, decongestants, or cough suppressants. The FDA has recommended that such over-the-counter medications not be used in children less than 2 years old. Topical decongestants do not provide clinically important improvement in nasal symptoms. Vitamin C has not been shown to have a significant preventative or therapeutic role. Zinc therapy for the common cold and prevention with zinc may be effective in adults, but there is great uncertainty about dosing and some adverse effects. Humidified air and garlic do not alter the course of colds.

INFECTIONS DUE TO ADENOVIRUSES

There are more than 50 types of adenoviruses, which account for 5%–15% of all respiratory illnesses in childhood, usually pharyngitis or tracheitis, but also including 5% of childhood lower respiratory tract infections. Adenoviral infections, which are common early in life (most < 2 years old), occur 3–10 days after exposure to respiratory droplets or fomites. Enteric adenoviruses are an important cause of childhood diarrhea, most often in children younger than 4 years. Epidemic respiratory disease from adenoviruses occurs in winter and spring, especially in closed environments such as day care centers and institutions. Because of latent infection in lymphoid tissue, asymptomatic shedding from the respiratory or intestinal tract is common.

Specific Adenoviral Syndromes

A. Pharyngitis

Pharyngitis is the most common adenoviral disease, and the most common viral cause of severe pharyngitis in children. Fever and adenopathy are common. Tonsillitis may be exudative. Rhinitis and an influenza-like systemic illness may be present. Laryngotracheitis or bronchitis may accompany pharyngitis.

B. Pharyngoconjunctival Fever

Conjunctivitis may occur alone and be prolonged, but most often is associated with preauricular adenopathy, fever, pharyngitis, and cervical adenopathy. Foreign body sensation in the eye and other symptoms last less than a week. Lower respiratory symptoms are uncommon.

C. Epidemic Keratoconjunctivitis

Symptoms include severe conjunctivitis with punctate keratitis and occasionally visual impairment. A foreign body sensation, photophobia, and swelling of conjunctiva and eyelids are characteristic. Preauricular adenopathy and subconjunctival hemorrhage are common.

D. Pneumonia

Severe pneumonia may occur at any age. It is especially common in young children (< 3 years). Chest radiographs show bilateral peribronchial and patchy ground-glass interstitial infiltrates in the lower lobes. Symptoms persist for 2–4 weeks. Adenoviral pneumonia can be necrotizing and cause permanent lung damage, such as bronchiectasis and bronchiolitis obliterans. A pertussis-like syndrome with typical cough and lymphocytosis can occur with lower respiratory tract infection. A new variant of adenovirus serotype 14 can cause unusually severe, sometimes fatal pneumonia in children and adults.

E. Rash

A diffuse morbilliform (rarely petechial) rash resembling measles, rubella, or roseola may occur alone or with respiratory symptoms. Koplik spots are absent.

F. Diarrhea

Enteric adenoviruses (types 40 and 41) cause 3%–5% of cases of short-lived diarrhea in afebrile children, especially in those younger than 4 years.

G. Mesenteric Lymphadenitis

Fever and abdominal pain may mimic appendicitis. Pharyngitis is often associated. Adenovirus-induced adenopathy may be a factor in appendicitis and intussusception.

H. Other Syndromes

Immunosuppressed patients, including neonates, may develop severe or fatal pulmonary or gastrointestinal infections or multisystem disease. Hemorrhagic cystitis can be a serious problem in immunocompromised children. Other rare complications that can occur in the immunocompetent child include encephalitis, hepatitis, and myocarditis. Adenoviruses have been implicated in the syndrome of idiopathic myocardiopathy.

Laboratory & Diagnostic Studies

PCR of respiratory specimens, conjunctival, or stool specimens is rapid, sensitive, and the preferred diagnostic method for adenovirus infections. Diagnosis can also be made by conventional culture, but several days to weeks are required. Viral culture using the rapid culture technique with immunodiagnostic reagents detects adenovirus in 48 hours. Adenovirus infection can also be diagnosed using these reagents directly on respiratory secretions. This is quicker, but less sensitive, than the culture methods. ELISA (enzyme-linked immunosorbent assay) tests rapidly detect enteric adenoviruses in diarrheal specimens. Respiratory adenovirus infections can be detected retrospectively by comparing acute and convalescent sera, but this is not helpful during an acute illness.

Treatment

There is no specific treatment for adenovirus infections. Intravenous immunoglobulin (IVIG) may be tried in immunocompromised patients with severe pneumonia. Adoptive T-cell transfer has shown promising results in hematopoietic stem cell transplant recipients. There is some evidence of successful treatment of immunocompromised patients with cidofovir and, more recently, with brincidofovir, a cidofovir derivative with good oral bioavailability and less nephrotoxicity than the parent drug.

INFLUENZA

Symptomatic infections are common in children because they lack immunologic experience with influenza viruses. Infection rates in children are greater than in adults and are instrumental in initiating community outbreaks. Epidemics occur in fall and winter. Three main types of influenza viruses (A/H1N1, A/H3N2, B) cause most human epidemics, with antigenic drift ensuring a supply of susceptible hosts of all ages. In recent years, avian influenza A/H5N1 and A/H7N9 caused isolated human outbreaks in Asia that were associated with high rates of hospitalization and death. A swine-origin influenza A/H1N1 caused a human pandemic in 2009 and 2010 and has since circulated with seasonal periodicity.

Clinical Findings

Spread of influenza occurs by way of airborne respiratory secretions. The incubation period is 2–7 days.

A. Symptoms and Signs

Influenza infection in older children and adults produces a characteristic syndrome of sudden onset of high fever, severe myalgia, headache, and chills. These symptoms overshadow the associated coryza, pharyngitis, and cough. Usually absent are rash, marked conjunctivitis, adenopathy, exudative pharyngitis, and dehydrating enteritis. Fever, diarrhea, vomiting, and abdominal pain are common in young children. Infants may develop a sepsis-like illness and apnea. Chest examination is usually unremarkable. Less frequent clinical findings include croup (most severe with type A influenza), exacerbation of asthma, myositis (especially calf muscles), myocarditis, parotitis, encephalopathy, nephritis, and a transient maculopapular rash. Acute illness lasts 2–5 days. Cough and fatigue may last several weeks. Viral shedding may persist for several weeks in young children.

B. Laboratory Findings

The leukocyte count is normal to low, with variable shift. Influenza infections may be more difficult to recognize in children than in adults even during epidemics, and therefore a specific laboratory test is highly recommended. The virus can be found in respiratory secretions by direct fluorescent antibody (DFA) staining of nasopharyngeal epithelial cells, ELISA, optic immunoassay (OIA), and PCR. PCR has the highest sensitivity and specificity (close to 100%) and has become the preferred test as the results can be available within several hours. Influenza virus can be cultured within 3–7 days from pharyngeal swabs or throat washings, but this is mainly of value for epidemiology and antiviral sensitivity testing. Some laboratories use the rapid culture technique by centrifuging specimens onto cultured cell layers and detecting viral antigen after 48 hours. Other body fluids or tissues (except lung) rarely yield the virus in culture and are more appropriately tested by PCR. A late diagnosis may be made with paired serology, using hemagglutination inhibition assays.

C. Imaging

The chest radiograph is nonspecific; it may show hyperaeration, peribronchial thickening, diffuse interstitial infiltrates, or bronchopneumonia in severe cases. Hilar nodes are not enlarged. Pleural effusion is rare in uncomplicated influenza.

Differential Diagnosis

The following may be considered: all other respiratory viruses, Mycoplasma pneumoniae or Chlamydia pneumoniae (longer incubation period, prolonged illness), streptococcal pharyngitis (pharyngeal exudate or petechiae, adenitis, no cough), bacterial sepsis (petechial or purpuric rash may occur), toxic shock syndrome (rash, hypotension), and rickettsial infections (rash, different season, insect exposure). High fever, the nature of preceding or concurrent illness in family members, and the presence of influenza in the community are distinguishing features from parainfluenza or RSV infections.

Complications & Sequelae

Lower respiratory tract symptoms are most common in children younger than 5 years. Hospitalization rates are highest in children younger than 2 years. Influenza can cause croup in these children. Secondary bacterial infections (classically staphylococcal) of the middle ear, sinuses, or lungs are common. Children with influenza who develop protracted vomiting or irrational behavior while on aspirin should be evaluated for Reye syndrome. Influenza can also cause viral or postviral encephalitis, with cerebral symptoms much more prominent than those of the accompanying respiratory infection. Although the myositis is usually mild and resolves promptly, severe rhabdomyolysis and renal failure have been reported.

Children with underlying obesity, cardiopulmonary, metabolic, neuromuscular, or immunosuppressive disease are at risk for severe disease.

Prevention

The trivalent and quadrivalent influenza vaccines are licensed as inactivated (IIV) or live attenuated (LAIV) and are moderately protective (see Chapter 10). Influenza vaccination should occur before onset of influenza activity in the community, though immunity may wane during a single season. For egg-allergic children, observation for 30 minutes postvaccination is now the only precaution, and those with a history of severe allergic reaction to egg (eg, any symptom other than hives) should be vaccinated in an inpatient or outpatient medical setting under the supervision of a health care provider. Prophylaxis with oseltamivir can be used in select cases for children older than 3 months (children < 15 kg, 30 mg daily; those 15–23 kg, 45 mg daily; those 23–40 kg, 60 mg daily; and those > 40 kg, 75 mg daily). Inhaled zanamivir can also be used in children older than 5 years, but avoid use in children with asthma or chronic pulmonary disease. Chemoprophylaxis may be considered during an epidemic for high-risk children who cannot be immunized or who have not yet developed immunity (about 6 weeks after primary vaccination or 2 weeks after a booster dose). For outbreak prophylaxis, therapy should be maintained for 2 weeks or more and for 1 week after the last case of influenza is diagnosed.

Treatment & Prognosis

Treatment consists of general support and management of pulmonary complications, especially bacterial superinfections. Antivirals are of benefit against seasonal influenza in immunocompetent hosts if begun within 48 hours after symptom onset. In hospitalized children, early antiviral treatment shortens the duration of hospitalization. Treatment duration is 5 days and the doses are twice those used for prophylaxis (see earlier). Studies in immunocompromised patients during the 2009/2010 pandemic showed that oseltamivir was useful even when initiated later than 2 days after the onset of disease. Peramivir, a neuraminidase inhibitor that is available for IV administration, is approved for treatment.

Recovery is usually complete unless severe cardiopulmonary or neurologic damage has occurred. Fatal cases occur in very young infants, immunodeficient and anatomically compromised children, pregnant women, including the first 2 weeks postpartum, and obese individuals. Effective treatment or prophylaxis of influenza in children markedly reduces the incidence of acute otitis media and antibiotic usage during the flu season.

PARAINFLUENZA (CROUP)

Human parainfluenza viruses (HPIV) are the most important cause of croup in children. Four types of HPIV (1–4) are known. HPIV 1 and 2 cause most cases of croup, and infections occur during the first 5 years of life, usually during outbreaks in the fall. Most infants are infected with type 3 within the first 3 years of life, most often in the first year. HPIV 4 has year-round circulation and may be less pathogenic than other types.

Clinical Findings

A. Symptoms and Signs

The incubation period is 2–7 days. Clinical disease has an acute onset that includes febrile upper respiratory infection (especially in older children with re-exposure), laryngitis, tracheobronchitis, croup, and bronchiolitis (second most common cause after RSV). The relative incidence of these manifestations is type-specific. HPIVs (especially type 1) cause 65% of cases of croup in young children, 25% of tracheobronchitis, and 50% of laryngitis. Croup is characterized by a barking cough, inspiratory stridor, and hoarseness. HPIV can cause pneumonia in infants and immunodeficient children, and causes particularly high mortality among stem cell recipients.

B. Laboratory Findings

Diagnosis is often based on clinical findings. These viruses can be identified by PCR (< 24 hours), conventional or rapid culture techniques (48 hours), or by direct immunofluorescence on nasopharyngeal epithelial cells in respiratory secretions (< 3 hours).

Differential Diagnosis

HPIV-induced respiratory syndromes are difficult to distinguish from those caused by other respiratory viruses. Viral croup must be distinguished from epiglottitis caused by Haemophilus influenzae type b (if unimmunized) or other bacterial infections causing upper airway obstruction (eg, peritonsillar abscess).

Treatment

No specific therapy or vaccine is available. Croup management is discussed in Chapter 19. Ribavirin is active in vitro and has been used in immunocompromised children, but its efficacy is unproven.

RESPIRATORY SYNCYTIAL VIRUS DISEASE

General Considerations

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract illness in young children, accounting for more than 70% of cases of bronchiolitis and 40% of cases of pneumonia. RSV is very common in early childhood. Almost all children develop upper respiratory symptoms, and 20%–30% will manifest as lower respiratory infection. Outbreaks occur annually, and attack rates are high; 60% of children are infected in the first year of life, and 90% by age 2 years. During peak season (cold weather in temperate climates), the clinical diagnosis of RSV infection in infants with bronchiolitis is as accurate as most laboratory tests. Despite the presence of serum antibody, reinfection is common. Two distinct genotypes can cocirculate or one may predominate in a community. Yearly shift in prevalence of these genotypes is a partial explanation for reinfection. However, reinfection generally causes only upper respiratory symptoms in anatomically normal children. Immunosuppressed patients may develop progressive severe pneumonia. Children with congenital heart disease with increased pulmonary blood flow, children with chronic lung disease (eg, cystic fibrosis), and premature infants younger than 6 months (especially when they have chronic lung disease of prematurity) are also at higher risk for severe illness. No vaccine is available.

Clinical Findings

A. Symptoms and Signs

Initial symptoms are those of upper respiratory infection. Low-grade fever may be present. The classic disease is bronchiolitis, characterized by diffuse wheezing, variable fever, cough, tachypnea, difficulty feeding, and in severe cases, cyanosis. Hyperinflation, crackles, prolonged expiration, wheezing, hypoxia, and retractions may be present. The liver and spleen may be palpable because of lung hyperinflation, but are not enlarged. The disease usually lasts 3–7 days in previously healthy children. Fever is present for 2–4 days; it does not correlate with pulmonary symptoms and may be absent during the height of lung involvement.

Apnea, poor feeding, and lethargy may be presenting manifestations, especially in premature infants, in the first few months of life. Apnea usually resolves after a few days, often being replaced by obvious signs of bronchiolitis.

RSV infection in older children is more likely to cause tracheobronchitis or upper respiratory tract infection. Exceptions are immunocompromised children and those with severe chronic lung or heart disease, who may have especially severe or prolonged primary infections and are subject to additional attacks of severe pneumonitis.

B. Laboratory Findings

Rapid detection of RSV antigen in nasal or pulmonary secretions by fluorescent antibody staining or ELISA requires only several hours and is more than 90% sensitive and specific. Real-time PCR is more sensitive and expensive than antigen testing and is often multiplexed to detect additional respiratory pathogens in the same assay. Rapid tissue culture methods take 48 hours and have comparable sensitivity, but require a carefully collected and handled specimen.

C. Imaging

Diffuse hyperinflation and peribronchiolar thickening are most common; atelectasis and patchy infiltrates also occur in uncomplicated infection, but pleural effusions are rare. Consolidation (usually subsegmental) occurs in 25% of children with lower respiratory tract disease.

Differential Diagnosis

Although almost all cases of bronchiolitis are due to RSV during an epidemic, parainfluenza, rhinovirus, and especially hMPV cannot be excluded. Mixed infections with other viruses or bacteria can occur. Wheezing may be due to asthma, a foreign body, or other airway obstruction. RSV infection may closely resemble Mycoplasma or chlamydial pneumonitis when fine crackles are present and fever and wheezing are not prominent. The two may also coexist. Cystic fibrosis may present with respiratory symptoms resembling RSV infection; a positive family history or failure to thrive associated with GI symptoms, hyponatremia or hypoalbuminemia should prompt a sweat chloride test. Pertussis should also be considered in this age group, especially if cough is prominent and the infant is younger than 6 months. A markedly elevated leukocyte count should suggest bacterial superinfection (neutrophilia) or pertussis (lymphocytosis).

Complications

RSV commonly infects the middle ear. Symptomatic otitis media is more likely when secondary bacterial infection is present (usually due to pneumococci or nontypable H influenzae). This is the most common complication (10%–20%) of RSV infection. Bacterial pneumonia complicates only 0.5%–1% of hospitalized patients. Sudden exacerbations of fever and leukocytosis should suggest bacterial infection. Respiratory failure or apnea may require mechanical ventilation, but occurs in less than 2% of hospitalized previously healthy full-term infants. Cardiac failure may occur as a complication of pulmonary disease or myocarditis. RSV commonly causes exacerbations of asthma. Nosocomial RSV infection is so common during outbreaks that elective hospitalization or surgery, especially for those with underlying illness, may be postponed. Well-designed hospital programs to prevent nosocomial spread are imperative (see the next section).

Prevention & Treatment

Oxygen therapy is only indicated in infants and children with oxyhemoglobin saturation less than 90%. Children who are very hypoxic or cannot feed because of respiratory distress must be hospitalized and given humidified oxygen as directed by oxygen saturation, and given tube or intravenous feedings. Antibiotics, decongestants, and expectorants are of no value in routine infections. RSV-infected children should be kept in respiratory isolation. Cohorting ill infants in respiratory isolation during peak season (with or without rapid diagnostic attempts) and emphasizing good hand washing should decrease nosocomial transmission.

Clinicians should not administer albuterol (or salbutamol) or epinephrine to infants and children with a diagnosis of bronchiolitis since this does not impact disease resolution, need for hospitalization, or length of stay. The use of systemic corticosteroids is also discouraged in RSV bronchiolitis, unless there are complicating features such as asthma and chronic lung disease of prematurity. A meta-analysis of numerous studies of corticosteroid therapy indicated a significant effect on hospital stay, especially in those most ill at the time of treatment, but use of a single dose of corticosteroids in an outpatient setting had no lasting effect on respiratory status and did not prevent hospitalization.

Ribavirin is the only licensed antiviral therapy used for RSV infection. It is given by continuous aerosolization. It is rarely used in infants without significant anatomic or immunologic defects. At best, there is a very modest effect on disease severity in immunocompetent infants with no underlying anatomic abnormality. Even in high-risk infants, a favorable clinical response to ribavirin therapy was not demonstrated in several studies, although some data suggest that it might be more efficacious if initiated early in the illness. Thus, ribavirin is only used in severely ill children who are immunologically or anatomically compromised and in those with severe cardiac disease.

Monthly intramuscular administration of humanized RSV monoclonal antibody is now recommended to prevent severe disease in selected high-risk patients during epidemic periods. Monthly administration should be considered during the RSV season for high-risk children (described in Chapter 10). Long-acting monoclonal antibodies are also under development. Use of passive immunization for immunocompromised children is logical but not established. RSV antibody is not effective for treatment of established infection.

Prognosis

Although mild bronchiolitis does not produce long-term problems, 30%–40% of patients hospitalized with this infection will wheeze later in childhood, and RSV infection in infancy may be an important precursor to asthma. Chronic restrictive lung disease and bronchiolitis obliterans are rare sequelae.

HUMAN METAPNEUMOVIRUS INFECTION

General Considerations

Human metapneumovirus (hMPV) is a common agent of respiratory tract infections that is very similar to RSV in epidemiologic and clinical characteristics. Like RSV, parainfluenza, mumps, and measles, hMPV belongs to the paramyxovirus family. Humans are its only known reservoir. Seroepidemiologic surveys indicate that the virus has worldwide distribution. More than 90% of children contract hMPV infection by age 5 years, typically during late autumn through early spring outbreaks. hMPV accounts for 15%–25% of the cases of bronchiolitis and pneumonia in children younger than 2 years. Older children and adults can also develop symptomatic infection.

Clinical Findings

A. Symptoms and Signs

The most common symptoms are fever, cough, rhinorrhea, and sore throat. Bronchiolitis and pneumonia occur in 40%–70% of the children who acquire hMPV before the age of 2 years. Asymptomatic infection is uncommon. Other manifestations include otitis, conjunctivitis, diarrhea, and myalgia. Acute wheezing has been associated with hMPV in children of all ages, raising the possibility that this virus, like RSV, might trigger reactive airway disease. Dual infection with hMPV and RSV or other respiratory viruses seems to be a common occurrence and may increase morbidity and mortality.

B. Laboratory Findings

The preferred method of diagnosis is PCR performed on respiratory specimens. Rapid shell vial culture is an acceptable, albeit less sensitive. Antibody tests are most appropriately used for epidemiologic studies.

C. Imaging

Lower respiratory tract infection frequently shows hyperinflation and patchy pneumonitis on chest radiographs.

Treatment & Prognosis

No antiviral therapy is available to treat hMPV. Ribavirin has in vitro activity against hMPV, but there are no data to support its therapeutic value. Children with lower respiratory tract disease may require hospitalization and ventilatory support, but less frequently than with RSV-associated bronchiolitis. Duration of hospitalization in hMPV is typically shorter than in RSV. Infection of immune compromised children can lead to severe or fatal disease.

INFECTIONS DUE TO HUMAN CORONAVIRUSES

Human coronaviruses (HCoVs) are RNA viruses that can infect humans and various animals. They are transmitted via inoculation of the respiratory tract by droplets from the respiratory tract of infected individuals. The incubation period is 2-5 days for the non-severe infections and likely longer for severe acute respiratory syndromes. Infections from HCoVs, including strains OC43, NL63, HKU1, and 229E, manifest each year as the common cold and lower respiratory tract disease (LRTD). However, LRTD is more frequent and severe in immunocompromised children. Co-infections with other viruses occur in 10–40% of HCoV infections.

HCoV Clinical Syndromes

A. Upper and Lower Respiratory Tract Infection

HCoVs 229E, OC43, NL63 and HKU1 are the second most common cause of the common cold after rhinoviruses and manifest with rhinorrhea, sore throat, cough, and occasionally fever. HCoVs may also present as acute otitis media or trigger asthma exacerbations. HCoV NL63 is the second most common cause of croup after parainfluenza 1. HCoV HKU1 also can present as acute gastroenteritis.

B. Severe Acute Respiratory Syndromes (SARS)

The three novel HCoVs causing severe symptoms are SARS-CoV, which emerged in 2002 in China. This had moderate infectivity, caused epidemics in several countries, and had a case fatality rate of ~10%. The Middle Eastern Respiratory Syndrome (MERS)-CoV appeared in 2012 in Saudi Arabia, was less infectious, but more severe clinically with a case fatality rate of ~30%. It is endemic in the Middle East and acquired by close contact with camels, although human-to-human spread also occurs. The SARS-CoV-2 virus originated in China in 2019 and resulted in worldwide spread. This virus appears to spread somewhat more readily than influenza virus. HCoVs that cause severe disease disproportionally affect immune- or anatomically-compromised adults and the elderly. Infected children are either asymptomatic or have typically milder symptoms that include fever, cough, myalgia, mild diarrhea, and abdominal pain. Complications including multiorgan dysfunction and death can occur in children with co-morbidities.

The recently emerged SARS-CoV-2 manifests as fever, cough, and less commonly with shortness of breath (COVID-19). Most children with pulmonary symptoms may have radiographic evidence of bilateral disease, including ground-glass opacities with surrounding halo sign and occasional small nodules. Young children shed SARS-CoV-2 for prolonged periods.

Laboratory and Diagnostic Studies

Children infected with the novel SARS-CoV-2 have elevated procalcitonin in 80% of the symptomatic cases. The new multiple rt-PCR test for respiratory viruses may include detection of HCoVs 229E, OC43, NL54, and HKU1. Public health laboratories have added the capacity to diagnose novel coronaviruses causing severe disease, including the current pandemic SARS-CoV-2, by rt-PCR.

Treatment and Prevention

Most common HCoVs cause mild, self-limited disease. For the novel coronavirus infections associated with severe disease, especially in immunocompromised children, type 1 interferon, ribavirin, and convalescent plasma have been used with anecdotal benefit. Antiviral drugs that are effective against HCoVs in vitro are in phase III trials and vaccines are rapidly under development in the SARS-CoV-2 pandemic. Appropriate hand hygiene, social distancing, and isolation precautions, including personal protective equipment for health care workers, are considered useful for limiting transmission. Contact tracing and quarantine were effective for SARS-CoV, but failed to stop the pandemic of SARS-CoV-2 in 2020.

Enteroviruses (EV) are a major cause of acute febrile illness in young children. From the family of picornaviruses (“small”), antigenically they are divided into four groups: polioviruses (PV), coxsackieviruses A and B, and echoviruses. Their common RNA sequences and group antigens are the basis for diagnostic tests for enterovirus-specific nucleic acid and proteins. A PCR assay is available in many medical centers as a one-step test with results in a few hours. Cross-reactivity with rhinoviruses is common on the PCR respiratory panel. Viral cultures are more specific but take 2–5 days. PCR is now the diagnostic method of choice for meningoencephalitis and severe unexplained illness in neonates.

Parechoviruses (HPeV), also picornaviruses, are responsible for severe infections in young children including sepsis and meningitis. Some of the 15 types of parechoviruses infect almost every child before the age of 2 years; others before age 5 years.

Transmission of EV and HPeV is fecal-oral or from upper respiratory secretions. Multiple enteroviruses circulate in the community at any one time; summer-fall outbreaks are common in temperate climates, but infections are seen year-round. After poliovirus, coxsackie B virus is most virulent, followed by echovirus. Neurologic, cardiac, and overwhelming neonatal infections are the most severe forms of illness.

ACUTE FEBRILE ILLNESS

Accompanied by nonspecific upper respiratory or enteric symptoms, the sudden onset of fever and irritability in infants or young children is often enteroviral, especially in late summer and fall. More than 90% of enteroviral infections are not distinctive. Occasionally a petechial rash is seen; more often a diffuse maculopapular or morbilliform eruption (often prominent on palms and soles) occurs on the second to fourth day of fever. Rapid recovery is the rule. More than one febrile enteroviral illness can occur in a patient in one season. The leukocyte count is usually normal. Infants, because of fever and irritability, may undergo an evaluation for sepsis or meningitis and be hospitalized. Approximately half of these infants have aseptic meningitis. Duration of illness is 4–5 days.

RESPIRATORY TRACT ILLNESSES

1. Acute Febrile Pharyngitis

Sore throat, headache, myalgia, and abdominal discomfort lasting 3–4 days are common in older children. Vesicles or papules may be seen in the pharynx without exudate. Occasionally, enteroviruses are the cause of croup, bronchitis, or pneumonia. They may also exacerbate asthma as seen with the recent outbreaks of EV68.

2. Herpangina

Herpangina manifests as acute onset fever and posterior pharyngeal grayish white vesicles that quickly form ulcers (< 20 in number), linearly along the posterior palate, uvula, and tonsillar pillars. Bilateral facial ulcers may also be seen. Dysphagia, drooling, vomiting, abdominal pain, and anorexia also occur and, rarely, parotitis or vaginal ulcers. Symptoms disappear in 4–5 days. Coxsackievirus A10 has been associated with a sporadic febrile pharyngitis, called acute lymphonodular pharyngitis, which is characterized by nonulcerative yellow-white posterior pharyngeal papules in the same distribution as herpangina. The duration is 1–2 weeks. Therapy is supportive.

Primary herpes simplex gingivostomatitis (ulcers are more prominent anteriorly, and gingivitis is present), aphthous stomatitis (fever absent, recurrent episodes, anterior lesions), trauma, hand-foot-and-mouth disease (see discussion in section Rashes [Including Hand-Foot-&-Mouth Disease]), and Vincent angina (painful gingivitis spreading from the gum line; older child; underlying dental disease) should be in the differential diagnosis.

3. Pleurodynia (Bornholm Disease, Epidemic Myalgia)

Caused by coxsackie B virus (epidemic form) or many nonpolio enteroviruses (sporadic form), pleurodynia is associated with an abrupt onset of unilateral or bilateral spasmodic pain over the lower ribs or upper abdomen. Associated symptoms include headache, fever, vomiting, myalgias, and abdominal and neck pain. Physical findings include fever, chest muscle tenderness, decreased thoracic excursion, and occasionally a friction rub. The chest radiograph is normal. Hematologic tests are not diagnostic. The illness generally lasts less than 1 week.

This is a disease of muscles, but the differential diagnosis includes bacterial pneumonia, bacterial and tuberculous effusion, and endemic fungal infections (all excluded radiographically and by auscultation), costochondritis (no fever or other symptoms), and a variety of abdominal problems, especially those causing diaphragmatic irritation. Epidemics of acute myalgia have also been reported due to HPeV type 3 in Japan in children and adults. Potent analgesic agents and chest splinting alleviate the pain.

RASHES (INCLUDING HAND-FOOT-&-MOUTH DISEASE)

The EV rash can be macular, maculopapular, urticarial, scarlatiniform, petechial, or vesicular. One of the most characteristic is that of hand-foot-and-mouth disease (caused by coxsackieviruses, especially types A5, A10, and A16), in which vesicles or red papules are found on the tongue, oral mucosa, hands, and feet. Often, they appear near the nails and on the heels and may last up to 1–2 weeks. Associated fever, sore throat, and malaise are mild. The rash may appear when fever abates, simulating roseola.

Cardiac Involvement

Myocarditis and pericarditis can be caused by a number of nonpolio enteroviruses, particularly type B coxsackieviruses. Most commonly, upper respiratory symptoms are followed by substernal pain, dyspnea, and exercise intolerance. A friction rub or gallop may be detected. Ultrasound will define ventricular dysfunction or pericardial effusion, and electrocardiography may show pericarditis or ventricular irritability. Creatine phosphokinase may be elevated and troponin (hs-TnT) is highly sensitive for acute myocarditis. The disease may be mild or fatal; most children recover completely. In infants, other organs may be involved at the same time; in older patients, cardiac disease is usually the sole manifestation (see Chapter 20 for therapy). Enteroviral RNA is present in cardiac tissue in some cases of dilated cardiomyopathy or myocarditis; the significance of this finding is unknown. Epidemics of EV 71 in Asia, as well as sporadic cases in the United States, are associated with severe left ventricular dysfunction and pulmonary edema following typical mucocutaneous manifestations of enterovirus infection. Enterovirus 71 also can cause isolated severe neurologic disease or neurologic disease in combination with myocardial disease.

Severe Neonatal Infection

Neonatal EV infection is usually systemic and severe in otherwise normal newborns. Clinical manifestations include fever, rash, pneumonitis, meningo-encephalitis, hepatitis, gastroenteritis, myocarditis, pancreatitis, and myositis. Transplacental infections present within 1 week of birth as sepsis with cyanosis, dyspnea, and seizures. Nosocomial outbreaks are less common. The differential diagnosis includes bacterial and herpes simplex infections, necrotizing enterocolitis, other causes of heart or liver failure, and metabolic diseases. Diagnosis is suggested by the finding of cerebrospinal fluid (CSF) mononuclear pleocytosis and detection of EV RNA in stool or pharynx, and confirmed by PCR in CSF, blood, or urine. IVIG is often administered, but its value is still uncertain. Some investigational antivirals (eg, pleconaril, pocapavir) have shown promise. Passively acquired maternal antibody may protect newborns from severe disease. Parechovirus infection of neonates is similar to EV but occurs in older neonates, with almost half of infected newborns requiring ICU management.

CENTRAL NERVOUS SYSTEM ILLNESSES

1. Poliomyelitis, Acute Flaccid Myelitis, & Acute Flaccid Paralysis

General Considerations

Poliovirus infection is asymptomatic in 90%–95% of cases; presents as acute febrile illness in about 5% of cases or as aseptic meningitis, with or without paralysis, in 1%–3%. Polio has been eliminated from more than 99% of the world’s population with the only endemic areas now in Nigeria, Pakistan, and Afghanistan. Most older children and adults are now protected due to vaccination or previous silent infection. Occasional cases in the United States have occurred in unvaccinated travelers to foreign countries or in populations with low polio vaccine coverage who come in contact with visitors from endemic areas. Vaccine-associated paralytic polio (VAPP) and vaccine-derived polio viruses (VDPV) are a consequence of oral polio vaccine (OPV) that has mutated and reverted to neurovirulent. The later has caused outbreaks of acute flaccid paralysis (AFP) similar to wild-type polio. Since 2000, inactivated poliovirus vaccine (IPV) has been the only polio vaccine in use in the United States, and since 2016, at least one dose of IPV along with bivalent OPV (types 1 and 3) is being given to children worldwide to prevent cVDPV (see Chapter 10). Other nonpolio EV can present as AFP, including EV71 in Asia and since 2014, EV-68 in Europe and the United States as acute flaccid myelitis (AFM).

Clinical Findings

A. Symptoms and Signs

The initial symptoms of polioviruses as well as other neurotropic enteroviruses (EV71 and EV68) are fever, myalgia, sore throat, and headache for 2–6 days. In less than 5% of infected children, symptom-free days are followed by recurrent fever and signs of aseptic meningitis: headache, nuchal rigidity, and nausea. Mild cases resolve completely. In 1%–2% of those infected, high fever, severe myalgia, and anxiety herald progression to loss of reflexes and subsequent acute flaccid asymmetrical paralysis. Proximal limb muscles are more often involved than distal, and lower limb involvement is more common than upper. Sensation remains intact, although hyperesthesia of skin overlying paralyzed muscles is common and pathognomonic.

Bulbar involvement affects swallowing, speech, and cardiorespiratory function and accounts for most deaths. Bladder distention and marked constipation characteristically accompany lower limb paralysis. Paralysis is usually complete by the time the temperature normalizes. Atrophy is usually apparent by 4–8 weeks. Most improvement of muscle paralysis occurs within 6 months.

B. Laboratory Findings

In patients with meningeal symptoms, the CSF shows a lymphocytic pleocytosis and a normal glucose with mildly elevated protein concentration. Poliovirus is easy to grow in cell culture and can be readily differentiated from other enteroviruses. It is rarely isolated from spinal fluid but is often present in the throat and stool for several weeks following infection. PCR is the method of choice for detection of polioviruses as well as other neurotropic enteroviruses.

Differential Diagnosis

Aseptic meningitis due to poliovirus is indistinguishable from that due to other viruses. Paralytic disease in the United States is usually due to nonpolio enteroviruses (recently EV68). Polio and neurotropic EVs may resemble Guillain-Barré syndrome (minimal sensory loss, ascending symmetrical loss of function; minimal pleocytosis, high protein concentration in spinal fluid), polyneuritis (sensory loss), pseudoparalysis due to bone or joint problems (eg, trauma, infection), botulism, or tick paralysis. West Nile virus infection can present like AFP in children.

Complications

Complications are the result of permanent destruction of anterior horn cells and paralysis. Respiratory, pharyngeal, bladder, and bowel malfunction are most critical. Death is usually the consequence of respiratory dysfunction. Limbs injured near the time of infection (by intramuscular injections, prior excessive prior, or trauma) tend to be most severely involved and have the worst prognosis for recovery (provocation paralysis).

Treatment & Prognosis

Therapy is supportive and although some antivirals are under investigation (eg, pocapavir), none are available for the treatment of enterovirus infections. Several potent antivirals are available to inhibit other positive-strand RNA viruses with a similar replication strategy. Bed rest, fever and pain control (heat therapy is helpful), and careful attention to progression of weakness (particularly of respiratory muscles) are important. Early or late corticosteroid treatment has been associated with increased mortality in children infected with EV-7, so they are not recommended. No intramuscular injections should be given during the acute phase. Intubation or tracheostomy for secretion control and ventilation, enteral feeding and catheter drainage of the bladder may be needed. Disease is worse in adults and pregnant women. Postpolio muscular atrophy occurs in 30%–40% of paralyzed limbs 20–30 years later, characterized by increasing weakness and fasciculations in previously affected, partially recovered limbs.

2. Nonpolio Viral Meningitis

Nonpolio enteroviruses cause over 80% of cases of aseptic meningitis at all ages, especially in the summer and fall. Nosocomial outbreaks also occur.

Clinical Findings

The usual EV incubation period is 4–6 days. Most EV infections are subclinical or not associated with central nervous system (CNS) symptoms; therefore, a history of a sick contact is unusual. Neonates may acquire infection from maternal blood, vaginal secretions, or feces at birth; occasionally the mother has had a febrile illness just prior to delivery.

A. Symptoms and Signs

Incidence is much greater in children younger than 1 year, and CSF pleocytosis is more frequent in very young children undergoing a septic work up during the summer and fall. Onset is usually acute with fever, marked irritability, and lethargy in infants. Older children also describe frontal headache, photophobia, and myalgia. Abdominal pain, diarrhea, and projectile vomiting may occur. The incidence of rash varies with the infecting strain. If rash occurs, it is usually seen after several days of illness and is diffuse, macular or maculopapular, occasionally petechial, but not purpuric. Oropharyngeal vesicles and rash on the palms and soles suggest an enterovirus. The anterior fontanel may be full and meningismus present. The illness may be biphasic, with nonspecific symptoms and signs preceding those related to the CNS. In older children, meningeal signs are more frequent, but seizures are unusual. Focal neurologic findings, which are rare, should lead to a search for an alternative cause. Frank encephalitis, which is uncommon at any age, occurs most often in neonates. Because of the overall frequency of enteroviral disease in children, 5%–10% of all cases of encephalitis of proved viral origin are caused by enteroviruses. Enteroviruses tend to cause less severe encephalitis than other viruses. However, parechoviruses, which have recently been demonstrated to be a significant cause of aseptic meningitis, sometimes cause white matter changes.

Enterovirus 71 infections that begin with typical mucocutaneous manifestations of enteroviruses can be complicated by severe brainstem encephalitis. Outbreaks of respiratory disease with meningitis and acute paralysis due to EV68 have occurred in western United States and Europe. Enterovirus 70 outbreaks are characterized by hemorrhagic conjunctivitis together with paralytic poliomyelitis.

B. Laboratory Findings

Blood leukocyte counts are often normal. The spinal fluid leukocyte count is 100–1000/μL with polymorphonuclear cells predominating early and shifting to mononuclear cells within 8–36 hours. In about 95% of cases, spinal fluid parameters include a total leukocyte count less than 3000/μL, protein less than 80 mg/dL, and glucose more than 60% of serum values. Marked deviation from any of these findings should prompt consideration of another diagnosis (see following section).

Culture of CSF may yield an enterovirus within a few days (< 70%), but EV PCR is the most useful diagnostic method in many centers (sensitivity > 90%) and can give an answer within few hours. Parechoviruses will be detected by most PCR methods, but will be identified as “enterovirus.” Virus may be detected even with no CSF pleocytosis. Detection of an enterovirus from throat or stool suggests, but does not prove, enteroviral meningitis. Vaccine-derived poliovirus present in feces in infants being evaluated for aseptic meningitis may confuse the diagnosis, but history of travel or exposure to OPV should help.

C. Imaging

Cerebral imaging is not often indicated; if done, it is usually normal. Subdural effusions, infarcts, edema, or focal abnormalities seen in bacterial meningitis are absent except for the rare case of focal encephalitis.

Differential Diagnosis

Enteroviral infections account for up to 90% of the cases of aseptic meningitis in which an etiologic agent is identified, especially in the summer and fall. Other causative viruses are mosquito-borne (flavivirus, bunyavirus) and are part of the investigation of encephalitis, but many of them are more likely to cause isolated meningitis. Primary herpes simplex infection can cause aseptic meningitis in adolescents who have a genital herpes infection. In neonates, early herpes simplex meningoencephalitis may mimic enteroviral disease (see section Infections Due to Herpesviruses) and if suspected urgent antiviral therapy is recommended. Lymphocytic choriomeningitis virus causes meningitis in children in contact with rodents (pet or environmental exposure). Meningitis occurs in some patients at the time of infection with human immunodeficiency virus (HIV).

Other causes of aseptic meningitis that may resemble enteroviral infection include partially treated bacterial meningitis (recent antibiotic treatment, CSF parameters resembling those seen in bacterial disease and bacterial antigen sometimes present); bacterial parameningeal foci such as brain abscess, subdural empyema, mastoiditis (predisposing factors, lower CSF glucose level, focal neurologic signs, and characteristic imaging); tumors or cysts (malignant cells on cytologic examination, higher protein or lower glucose levels in CSF); trauma (presence, without exception, of crenated red blood cells and fail to clear); tuberculous or fungal meningitis (see Chapters 42 and 43); cysticercosis; para and postinfectious encephalopathies (M pneumoniae, cat-scratch disease, influenza; leptospirosis; rickettsial diseases including Lyme; and acute demyelinating encephalomyelitis.

Prevention & Treatment

No specific antiviral therapy exists. Infants are usually hospitalized, isolated, and treated with fluids and antipyretics. Moderately to severely ill infants are given empiric antibiotics for bacterial pathogens until cultures, or PCR, are negative. In children and infants at low risk of serious bacterial infection, antibiotics may be withheld and the child observed until PCR results are available. The illness usually lasts less than 1 week. Strong analgesics may be needed. With clinical deterioration, repeat lumbar puncture, cerebral imaging, neurologic consultation, and more aggressive diagnostic tests should be considered. Herpesvirus encephalitis is an important consideration in such cases, particularly in infants younger than 1 month, and often warrants empiric acyclovir until HSV infection can be ruled out.

Prognosis

In general, enteroviral meningitis has no significant short-term neurologic or developmental sequelae. Developmental delay may follow severe neonatal infections. Unlike mumps, enterovirus infections rarely cause hearing loss.

HERPES SIMPLEX INFECTIONS

General Considerations

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.

Clinical Findings

A. Symptoms and Signs

1. Gingivostomatitis

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.

3. Cutaneous infections

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.

5. Keratoconjunctivitis

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).

6. Encephalitis

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.

7. Neonatal infections

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.

B. Laboratory Findings

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.

Treatment

A. Specific Measures

HSV is sensitive to antiviral therapy.

1. Topical antivirals

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.

3. Encephalitis

Treatment consists of intravenous acyclovir, 20 mg/kg (500 mg/m²) every 8 hours for 21 days.

4. Neonatal infection

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.

B. General Measures

1. Gingivostomatitis

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.

2. Genital infections

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.

3. Cutaneous lesions

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.

5. Keratoconjunctivitis

An ophthalmologist should be consulted regarding the use of cycloplegics, anti-inflammatory agents, local debridement, and other therapies.

6. Encephalitis

Extensive support will be required for obtunded or comatose patients. Rehabilitation and psychological support are often needed for survivors.

7. Neonatal infection

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.

VARICELLA & HERPES ZOSTER

General Considerations

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.

Clinical Findings

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.

A. Symptoms and Signs

1. Varicella

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.

B. Laboratory Findings

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.

C. Imaging

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.

Differential Diagnosis

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.

Complications & Sequelae

A. Varicella

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.

B. Herpes Zoster

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.

Prevention

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.

Treatment

A. General Measures

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.

B. Specific Measures

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.

Prognosis

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.

ROSEOLA INFANTUM (EXANTHEM SUBITUM)

General Considerations

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.

Clinical Findings

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.

A. Symptoms and Signs

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.

B. Laboratory Findings

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.

Differential Diagnosis

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.

Complications & Sequelae

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.

Treatment & Prognosis

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.

CYTOMEGALOVIRUS INFECTIONS

General Considerations

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.

Clinical Findings

A. Symptoms and Signs

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.

B. Laboratory Findings

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.

C. Imaging

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.

Differential Diagnosis

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).

Prevention & Treatment

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.

Clinical Findings

A. Symptoms and Signs

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.

B. Laboratory Findings

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.

C. Imaging

Chest radiographs may show a diffuse interstitial pneumonitis in severely affected infants.

Differential Diagnosis

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.

Prevention & Treatment

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.

Clinical Findings

A. Symptoms and Signs

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.

B. Laboratory Findings

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.

Differential Diagnosis

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.

Prevention

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.

Clinical Findings

A. Symptoms and Signs

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.

B. Laboratory Findings

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.

C. Imaging

Bilateral interstitial pneumonitis may be present on chest radiographs.

Differential Diagnosis

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.

Prevention & Treatment

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.

INFECTIOUS MONONUCLEOSIS (EPSTEIN-BARR VIRUS)

General Considerations

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.

Clinical Findings

A. Symptoms and Signs

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.

B. Laboratory Findings

1. Peripheral blood

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.

3. Anti-EBV antibodies

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.

4. EBV PCR

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.

Differential Diagnosis

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.

Complications

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.

Treatment & Prognosis

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.

In the United States, mosquitoes are the most common insect vectors that spread viral infections (Table 40–3). As a consequence, these infections—and others that are spread by ticks—tend to occur as summer-fall epidemics that coincide with the seasonal breeding and feeding habits of the vector, and the etiologic agent varies by region. Other insect-borne viral infections are seen in international travelers. Thus, a careful travel and exposure history is critical for correct diagnostic workup.

ENCEPHALITIS

Encephalitis is a common severe manifestation of many infections spread by insects (see Table 40–3). With many viral pathogens, the infection is often subclinical, or includes mild CNS disease such as meningitis. These infections have some distinguishing features in terms of subclinical infection rate, unique neurologic syndromes, associated systemic symptoms, and prognosis. The diagnosis is generally made clinically during recognized outbreaks and is confirmed by virus-specific serology or PCR. Prevention consists of control of mosquito vectors and precautions with proper clothing and insect repellents to minimize mosquito and tick bites. It is essential before making the diagnosis of arboviral encephalitis, which is not treatable, to exclude herpes encephalitis, which warrants specific antiviral therapy. Delay in administering this therapy may have dire consequences.

West Nile Virus Encephalitis

This flavivirus, primarily transmitted by Culex mosquitos, is the most important arbovirus infection in the United States. In 2003, there were more than 10,000 clinically apparent infections, more than 2900 nervous system infections, and 265 deaths in 47 states. In 2012, there was a resurgence to more than 5000 reported cases, of which approximately half were neuroinvasive; 240 were fatal. Other years typically have 1500–3000 reported cases. The reservoir of West Nile virus includes more than 160 species of birds whose migration explains the extent of endemic disease. Epidemics occur in summer-fall. Approximately 20% of infected individuals develop West Nile fever, characterized by fever, headache, retro-orbital pain, nausea, vomiting, lymphadenopathy, and a maculopapular rash (20%–50%). Less than 1% of infected patients develop meningitis or encephalitis, but 10% of these cases are fatal. The major risk factors for severe disease are age > 50 years and immune compromise. Symptomatic children usually manifest with West Nile fever and less than one-third will develop neuroinvasive disease, most likely limited to meningitis. Neurologic manifestations are most often those found with other meningoencephalitides, but some distinguishing features include polio-like acute flaccid paralysis, movement disorders (Parkinsonism, tremor, and myoclonus), brainstem symptoms, polyneuropathy, and optic neuritis. Muscle weakness, facial palsy, and hyporeflexia are common (20%). Recovery is slow and significant sequelae may persist in some severely affected patients. Diagnosis is best made by detecting IgM antibody (enzyme immunoassay) to the virus in CSF. This will be present by 5–6 days (95%) after onset. PCR is a specific diagnostic tool, but is less sensitive than antibody detection. Antibody rise in serum can also be used for diagnosis.

Treatment is supportive, although various antivirals and specific immunoglobulins are being studied. The infection is not spread between contacts, but can be spread by donated organs, blood, breast milk, and transplacentally.

DENGUE

Dengue virus is responsible for an estimated 400 million infections and 100 million episodes of symptomatic dengue fever annually. Dengue is one of the most common cause of fever in returning travelers and occurs throughout Latin America, the Caribbean, Southeast Asia, Oceania, and Africa; sporadic outbreaks occur occasionally in the southern United States, and dengue is hyperendemic (≥ 2 serotypes) in Puerto Rico. The spread of dengue requires the Aedes mosquito (present in the southern United States), which transmits virus from a reservoir of viremic humans in endemic areas. Most symptomatic patients have mild disease, especially young children, who may have a nonspecific fever and rash. Severity is a function of age, and prior infection with other serotypes of dengue virus significantly increases the risk for severe complications.

Clinical Findings

A. Symptoms and Signs

Dengue fever begins abruptly 4–7 days after transmission (range, 3–14 days) with fever, chills, severe retro-orbital pain, severe muscle and joint pain (“breakbone fever”), nausea, and vomiting. Erythema of the face and torso may occur early. After 3–4 days, a centrifugal maculopapular rash appears in half of the patients described as “islands of white in a sea of red.” The rash can become petechial, and mild hemorrhagic signs (epistaxis, gingival bleeding, microscopic blood in stool or urine) may be noted. The illness lasts 3–7 days, although rarely fever may reappear for several additional days. Fever may become relatively lower on the third day, only to become higher until defervescence. Since there are four serotypes of dengue virus, multiple sequential infections can occur.

B. Laboratory Findings

In most symptomatic cases, mild leukopenia and thrombocytopenia are common. Liver transaminases are usually normal. Diagnosis during acute infection (≤ 5 days of symptoms) is usually made by detection of viral antigenemia (NS1 antigen) or dengue virus reverse transcription polymerase chain reaction (RT-PCR) (80%–90% sensitive, 95% specific). After 5 days, dengue may be diagnosed by detection of IgM-specific antibodies (70%–80% sensitive by day 6, and increases thereafter) or a rise in type-specific antibody during convalescent testing (10–14 days later). Neutralizing antibodies against dengue virus are the most accurate serologic method, but they may cross-react with other flaviviruses (eg, Zika), especially with multiple prior dengue infections. Therefore, early testing by RT-PCR or NS1 antigen is preferable.

Differential Diagnosis

This diagnosis should be considered for any traveler to an endemic area who has symptoms suggestive of a systemic viral illness, although less than 1 in 1000 travelers to these areas develops dengue. Often the areas visited have other endogenous pathogens circulating (eg, malaria, typhoid fever, leptospirosis, rickettsial diseases, other endemic alphaviruses and flaviviruses, and measles). Chikungunya has a similar geographic distribution and also presents with fever and rash, but is more strongly associated with arthralgia/arthritis, which may persist for weeks to months. Zika is also clinically indistinguishable from dengue, though conjunctivitis may be more common with Zika. EBV, influenza, enteroviruses, and acute HIV infection may produce a similar illness. Dengue is not associated with sore throat or cough. An illness that starts 2 weeks after the trip ends or that lasts longer than 2 weeks is probably not dengue.

Complications

More common in endemic areas is the appearance of severe dengue, which typically occurs at the time of defervescence (day 3–7) and may include respiratory distress, circulatory shock (dengue septic shock), severe bleeding (dengue hemorrhagic fever), and end-organ damage. Severe dengue typically occurs during a second dengue episode as a consequence of pre-existing, non-neutralizing antibodies enhancing virus uptake into cells and leading to increased viremia and cytokine response (antibody-dependent enhancement). Warning signs for severe dengue that may be seen during the acute febrile phase of illness include abdominal pain, persistent vomiting, clinical fluid accumulation (eg, pleural effusion, ascites), mucosal bleeding, altered mental status, hepatomegaly, and hemoconcentration (hematocrit > 20% higher than baseline) with concurrent thrombocytopenia (< 100,000 cells/μL).

Prevention

Prevention of dengue fever involves avoiding high-risk areas and using conventional mosquito avoidance measures. The Aedes mosquito vector is a daytime feeder. Several dengue vaccines are under development, and one licensed vaccine demonstrated 60% efficacy in clinical trials, though it was associated with increased risk of subsequent severe dengue disease in children without prior immunity. No vaccines are currently recommended for travelers.

Treatment

Dengue fever is treated by oral rehydration and antipyretics, avoiding nonsteroidal anti-inflammatory agents that affect platelet function. Recovery is complete without sequelae. The hemorrhagic syndrome and shock require prompt fluid therapy with plasma expanders and isotonic saline along with close ICU monitoring.

CHIKUNGUNYA

Chikungunya has been endemic in Africa and Asia for decades, but emerged in the Americas for the first time in 2013, leading to a widespread epidemic that included transmission within the southern United States. Chikungunya is transmitted by Aedes mosquitos and has a similar geographic distribution and acute clinical presentation to dengue and Zika. The name “chikungunya” means “that which bends up” in the Makonde language from where it was first described in Tanzania, referring to the debilitating musculoskeletal symptoms (eg, arthralgia, arthritis) associated with the disease.

Clinical Findings

A. Symptoms and Signs

After a 3–7 day incubation period (maximum 14 days), high-grade fever appears suddenly and lasts 3–5 days. Symptoms may include headache (15%) and a diffuse maculopapular rash (30%–60%). Myalgia, arthralgia, and arthritis are more common in adults (87%–99%) than in children (30%–50%), and can be debilitating. Young children and infants, especially those perinatally infected, are more likely to have neurologic symptoms (seizure, encephalitis), bleeding, and multiorgan failure.

B. Laboratory Findings

Leukopenia, thrombocytopenia, and elevated transaminases may be seen, especially in young infants. Elevated creatinine is also observed. In the first 5–7 days of infection, RT-PCR is the preferred diagnostic test. Chikungunya IgM antibodies appear around day 5, lasting for 1–3 months and sometimes longer in individuals with persistent joint disease; IgG antibodies appear by 2 weeks and persist for years. They do not cross-react with flaviviruses.

Differential Diagnosis

Chikungunya is clinically indistinguishable from dengue and Zika, which all demonstrate similar geographic distribution. Chikungunya is less likely than dengue to result in bleeding and shock (except in young infants), and Zika may be more likely to produce conjunctivitis. Other infections with similar clinical presentations include parvovirus, rubella, measles, leptospirosis, malaria, typhoid, Rickettsia, and influenza. A febrile illness that starts 2 weeks after the trip ends or that lasts longer than 2 weeks is probably not chikungunya.

Complications

Chronic musculoskeletal symptoms (arthritis, arthralgia, and tenosynovitis), though less common in children, may persist or relapse for months or even years following infection and can be severely debilitating. Affected individuals, especially young infants, may have long-term neurodevelopmental sequelae including hearing and vision impairment as well as cerebral disorders (eg, attention deficit hyperactivity disorder).

Prevention & Treatment

Prevention includes avoiding high-risk areas and using conventional mosquito avoidance measures. Treatment involves supportive care, including fluids and acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) for fever and pain, though NSAIDS should be avoided if dengue is a possibility or if the patient has thrombocytopenia or bleeding. Chronic symptoms may be treated with NSAIDs and physical therapy. Vaccines are under development.

ZIKA

Zika virus has been endemic in Africa and Asia for decades but recently emerged in the Americas and resulted in a widespread epidemic, including endemic cases in the southern United States. Zika can be transmitted by Aedes mosquitos and sexually. Though most Zika infections are asymptomatic or benign, infection during pregnancy can result in vertical transmission and lead to severe neurodevelopmental sequelae in the infant, known as congenital Zika syndrome. Diagnosis is made difficult by similar geographic distribution and clinical presentation to dengue and chikungunya, as well as cross-reactivity of serologic testing with other flaviviruses such as dengue.

Clinical Findings

A. Symptoms and Signs

After a 3- to 7-day incubation period, most acute Zika infections are asymptomatic (up to 80%) or mild. Symptoms are similar to dengue and chikungunya and include maculopapular rash, low-grade fever, nonpurulent conjunctivitis, and arthralgia. The vast majority of infections resolve within 2–7 days.

Maternal infection during pregnancy, which may be symptomatic or subclinical, can result in vertical transmission and lead to congenital Zika syndrome (see Complications).

B. Laboratory Findings

Leukopenia, thrombocytopenia, and elevated liver transaminases may be seen during acute infection. In the first 14 days of infection, RT-PCR of blood or urine is usually obtained first, but a negative result does not rule out infection. IgM antibodies against Zika appear around day 4 and usually last around 3 months. Early testing by RT-PCR is preferable as Zika antibodies may cross-react with other flaviviruses (eg, dengue), making serologic diagnosis more difficult. Infants exposed in utero should undergo extensive diagnostic evaluation for infection according to the latest guidelines, which may include placental and umbilical cord tissue assessment by RT-PCR. Congenitally exposed infants should also undergo neurodevelopment, ophthalmologic, and audiometric evaluation.

C. Radiologic Findings

Radiologic imaging of the fetus or neonate with congenital Zika syndrome may demonstrate growth restriction, intracranial calcifications, ventriculomegaly, reduced brain volume, and other abnormalities.

Differential Diagnosis

Zika is clinically indistinguishable from dengue and chikungunya, which are both transmitted by the same Aedes mosquito vectors. Unlike dengue, Zika does not lead to hemorrhage or shock. Unlike chikungunya, Zika does not lead to severe or persistent musculoskeletal symptoms. Other infections with similar acute presentations include parvovirus, rubella, measles, leptospirosis, malaria, typhoid, rickettsia, and influenza. Rubella, cytomegalovirus, toxoplasmosis, and other congenital infections should be considered in infants undergoing evaluation for congenital Zika syndrome. A febrile illness that starts 2 weeks after the trip ends or that lasts longer than 2 weeks is probably not Zika.

Complications

Infants affected with congenital Zika syndrome may be small for gestational age and demonstrate neurodevelopmental sequelae, including microcephaly, seizures, irritability, spasticity, feeding difficulty, arthrogryposis, ocular findings, and sensorineural hearing loss. Additional sequelae may be described as more data become available and affected infants are followed into childhood, but preliminary data suggests 1%–13% of congenital infections result in congenital Zika syndrome, with higher risk in the first trimester (but risk persists into the third trimester). There is an increased risk of Guillain-Barré syndrome following Zika infection.

Prevention and Treatment

Prevention, which is particularly important for pregnant women and those intending to conceive, involves avoiding high-risk areas, using conventional mosquito avoidance measures, and using a barrier method for sex with potentially infected individuals (Zika virus persists in the genital tract for weeks to months). Acute disease is treated with supportive care. Multiple vaccines are in clinical trials.

COLORADO TICK FEVER

Colorado tick fever is endemic in the high plains and mountains of the central and northern Rocky Mountains and northern Pacific coast of the United States. The reservoir of the virus consists of squirrels and chipmunks. Many hundreds of cases of Colorado tick fever occur each year in visitors or laborers entering this region, primarily from May through July.

Clinical Findings

A. Symptoms and Signs

After a 3- to 4-day incubation period (maximum, 14 days), fever begins suddenly together with chills, lethargy, headache, ocular pain, myalgia, abdominal pain, nausea, and vomiting. Conjunctivitis may be present. A nondistinctive maculopapular rash occurs in 5%–10% of patients. The illness lasts 7–10 days, and half of patients have a biphasic fever curve with several afebrile days in the midst of the illness.

B. Laboratory Findings

Leukopenia is characteristic early in the illness. Platelets are modestly decreased. Specific ELISA testing is available, but 2–3 weeks may elapse before seroconversion. Fluorescent antibody staining will detect virus-infected erythrocytes during the illness and for weeks after recovery. RT-PCR is available in some areas and will be positive within the first week of illness.

Differential Diagnosis

Early findings, especially if rash is present, may suggest enterovirus, measles, or rubella infection. Enteric fever may be an early consideration because of the presence of leukopenia and thrombocytopenia. A history of tick bite, information about local risk, and the biphasic fever pattern will help with the diagnosis. Because of the wilderness exposure, diseases such as leptospirosis, borreliosis, tularemia, ehrlichiosis, and Rocky Mountain spotted fever will be considerations.

Complications

Meningoencephalitis occurs in 3%–7% of patients. Cardiac and pulmonary complications are rare.

Prevention & Treatment

Prevention involves avoiding endemic areas and using conventional means to avoid tick bite. Therapy is supportive. Do not use analgesics that modify platelet function.

See section Infections Due to Herpesviruses for a discussion of varicella and roseola, the two other major childhood exanthems.

ERYTHEMA INFECTIOSUM

General Considerations

This benign exanthematous illness of school-aged children is caused by the human parvovirus B19. Spread is respiratory, occurring in winter-spring epidemics. A nonspecific mild flu-like illness may occur during the viremia at 7–10 days; the characteristic rash occurring at 10–17 days represents an immune response. The patient is viremic and contagious prior to—but not after—the onset of rash.

Approximately half of infected individuals have a subclinical illness. Most cases (60%) occur in children between ages 5 and 15 years, with an additional 40% occurring later in life. Forty percent of adults are seronegative. The secondary attack rate in a school or household setting is 50% among susceptible children and 20%–30% among susceptible adults.

Clinical Findings

Owing to the nonspecific nature of the exanthem and the many subclinical cases, a history of contact with an infected individual is often absent or unreliable. Recognition of the illness is easier during outbreaks.

A. Symptoms and Signs

Typically, the first sign of illness is the rash, which begins as raised, fiery red maculopapular lesions on the cheeks that coalesce to give a “slapped-cheek” appearance. The lesions are warm, nontender, and sometimes pruritic. They may be scattered on the forehead, chin, and postauricular areas, but the circumoral region is spared. Within 1–2 days, similar lesions appear on the proximal extensor surfaces of the extremities and spread distally in a symmetrical fashion. Palms and soles are usually spared. The trunk, neck, and buttocks are also commonly involved. Central clearing of confluent lesions produces a characteristic lace-like pattern. The rash fades in days to several weeks, but frequently reappears in response to local irritation, heat (bathing), sunlight, and stress. Nearly 50% of infected children have some rash remaining (or recurring) for 10 days. Fine desquamation may be present. Mild low-grade fever, malaise, myalgia, sore throat, and coryza occur in up to 50% of children. These symptoms appear for 2–3 days followed by a week-long asymptomatic phase before the rashes appear.

Purpuric stocking-glove rashes, neurologic disease, and severe disorders resembling hemolytic-uremic syndrome have also been described in association with parvovirus B19.

B. Laboratory Findings

A mild leukopenia occurs early in some patients, followed by leukocytosis and lymphocytosis. Specific IgM and IgG serum antibody tests are available, but care must be used in choosing a reliable laboratory. IgM antibody is present in 90% of patients at the time of the rash. Nucleic acid detection tests are often definitive, but parvovirus DNA may be detectable in blood for prolonged periods. The disease is not diagnosed by routine viral culture.

Differential Diagnosis

In children immunized against measles and rubella, parvovirus B19 is the most frequent agent of morbilliform and rubelliform rashes. The characteristic rash and the mild nature of the illness distinguish erythema infectiosum from other childhood exanthems. It lacks the prodromal symptoms of measles and the lymphadenopathy of rubella. Systemic symptoms and pharyngitis are more prominent with enteroviral infections and scarlet fever.

Complications & Sequelae

A. Arthritis

Arthritis is more common in older patients, beginning with late adolescence. Approximately 10% of older children have severe joint symptoms. Girls are affected more commonly than boys. Pain and stiffness occur symmetrically in the peripheral joints. Arthritis usually follows the rash and may persist for 2–6 weeks, but resolves without permanent damage.

B. Aplastic Crisis and Other Hematologic Abnormalities

Parvovirus B19 may cause reticulocytopenia for approximately 1 week during the illness. This goes unnoticed in individuals with a normal erythrocyte half-life, but results in severe anemia in patients with chronic hemolytic anemia.

Pure red cell aplasia, leukopenia, pancytopenia, idiopathic thrombocytopenic purpura, and a hemophagocytic syndrome have been described. Patients with HIV infection and other immunosuppressive illnesses may develop prolonged anemia or pancytopenia. Patients with hemolytic anemia and aplastic crisis, or with immunosuppression, may be contagious and should be isolated while in the hospital.

C. Other End-Organ Infections

Parvovirus has been associated with neurologic syndromes, hepatitis, and suppression of bone marrow lineages. It is implicated as a cause of myocarditis.

D. In Utero Infections

Infection of susceptible pregnant women may produce fetal infection with hydrops fetalis. Fetal death occurs in about 6% of cases, most often in the first 20 weeks. This rate of fetal loss is higher than expected in typical pregnancies. Congenital anomalies have not been associated with parvovirus B19 infection during pregnancy.

Treatment & Prognosis

Erythema infectiosum is a benign illness for immunocompetent individuals. Patients with aplastic crisis may require blood transfusions. It is unlikely that this complication can be prevented by quarantine measures because acute parvovirus infection in contacts is often unrecognized and is most contagious prior to the rash. Pregnant women who are exposed to erythema infectiosum or who work in a setting in which an epidemic occurs should be tested for evidence of prior infection. Susceptible pregnant women should then be followed up for evidence of parvovirus infection. Approximately 1.5% of women of childbearing age are infected during pregnancy. If maternal infection occurs, the fetus should be followed by ultrasonography for evidence of hydrops and distress. In utero transfusion or early delivery may salvage some fetuses. Pregnancies are typically not terminated because of parvovirus infection. The risk of fetal death among exposed pregnant women of unknown serologic status is less than 2.5%.

Intramuscular immunoglobulin is not protective. High-dose IVIG has stopped viremia and led to marrow recovery in some cases of prolonged aplasia. Its role in immunocompetent patients and pregnant women is unknown.

MEASLES (RUBEOLA)

General Considerations

Measles is one of the most contagious infectious diseases of childhood that presents as a febrile exanthema. The attack rate in susceptible individuals is extremely high; spread is via respiratory droplets. Considered eliminated from the United States in 2000, frequent outbreaks have occurred recently (including 1000 cases in the first half of 2019), mainly due to accumulation of susceptible individuals, low vaccination coverage, increasing vaccine hesitancy, and importation. It is recommended that all children receive two doses of measles vaccine prior to primary or secondary school entry (see Chapter 10). Morbidity and mortality rates in the developing world are substantial because of underlying malnutrition and secondary infections. Because humans are the sole reservoir of measles, there is the potential to eliminate this disease worldwide.

Clinical Findings

A history of contact with a suspected case may be absent because airborne spread is efficient and patients are contagious during the prodrome. Contact with an imported case may not be recognized. In temperate climates, epidemic measles is a winter-spring disease. Because measles is uncommon in the United States, a high index of suspicion is required during outbreaks.

A. Symptoms and Signs

After 2–3 days of a prodrome of sneezing, eyelid edema, tearing, copious coryza, photophobia, and harsh cough, high fever and lethargy become prominent. Koplik spots are white macular lesions on the buccal mucosa, typically opposite the lower molars that appear in the first 2–4 days of the illness. A discrete maculopapular rash begins when the respiratory symptoms and fever are maximal and spreads quickly from the face to the trunk, coalescing to a bright red. As it spreads to the extremities, the rash fades turning coppery from the face and is completely gone within 6 days; fine desquamation may occur. Diarrhea can occur in young children and lead to hospitalization; persistent fever and cough may signal pneumonia. Measles should be considered in any child with febrile rash illness, especially if recently traveled internationally or exposed to a person with febrile rash illness. Suspected measles cases should be reported to local health department within 24 hours.

B. Laboratory Findings

Lymphopenia is characteristic. The diagnosis is usually made by PCR testing of oropharyngeal secretions (or urine), which is extremely sensitive and specific and can detect infection up to 5 days before symptoms. Measles may be diagnosed serologically by IgM detection in serum at ≥3 days after the onset of rash (false negative may occur early in infection), or significant rise in IgG antibody between acute and convalescent samples.

C. Imaging

Chest radiographs often show hyperinflation, perihilar infiltrates, or parenchymal patchy, fluffy densities. Secondary consolidation or effusion may be visible.

Differential Diagnosis

Table 40–2 lists other illnesses that may resemble measles.

Complications & Sequelae

A. Respiratory Complications

These occur in up to 15% of patients. Bacterial superinfection of the lungs, middle ear, sinus, and cervical nodes are most common. Fever that persists after the third or fourth day of rash and/or leukocytosis suggests such a complication. Bronchospasm, severe croup, and progressive viral pneumonia or bronchiolitis (in infants) also occur. Immunosuppressed patients are at much greater risk for fatal pneumonia than are immunocompetent patients.

B. Cerebral Complications

Encephalitis occurs in 1 in 2000 cases. Onset is usually within a week after appearance of rash. Symptoms include combativeness, ataxia, vomiting, seizures, and coma. Lymphocytic pleocytosis and a mildly elevated protein concentration are usual CSF findings, but the fluid may be normal. Forty percent of patients so affected die or have severe neurologic sequelae.

Subacute sclerosing panencephalitis (SSPE) is a slow measles virus infection of the brain that becomes symptomatic years later in about 1 in 100,000 previously infected children. This progressive cerebral deterioration is associated with myoclonic jerks and a typical electroencephalographic pattern. It is fatal in 6–12 months. High titers of measles antibody are present in serum and CSF.

C. Other Complications

These include hemorrhagic measles (severe disease with multiorgan bleeding, fever, and cerebral symptoms), thrombocytopenia, appendicitis, keratitis, myocarditis, and premature delivery or stillbirth. Mild liver function test elevation is detected in up to 50% of cases in young adults; jaundice may also occur. Measles causes transient immunosuppression; thus, reactivation or progression of tuberculosis (including transient cutaneous anergy) can occur in children.

Prevention

The current two-dose active vaccination strategy provides more than 97% protection. Vaccine should not be withheld for concurrent mild acute illness, tuberculosis or positive tuberculin skin test, breast-feeding, or exposure to an immunodeficient contact. The vaccine is recommended for HIV-infected children without severe HIV complications, with CD4 cells ≥ 15%, and preferably receiving antiretroviral therapy.

Treatment & Prognosis

Vaccination prevents the disease in susceptible exposed individuals if given within 72 hours (see Chapter 10). Immunoglobulin (0.25 mL/kg intramuscularly; 0.5 mL/kg if immunocompromised) will prevent or modify measles if given within 6 days. Suspected cases should be diagnosed promptly and reported to the local health department.

Recovery generally occurs 7–10 days after onset of symptoms. Therapy is supportive: eye care, cough relief (avoid opioid suppressants in infants), and fever reduction (acetaminophen, lukewarm baths; avoid salicylates). Secondary bacterial infections should be treated promptly; antimicrobial prophylaxis is not indicated. Ribavirin is active in vitro and may be useful in infected immunocompromised children. In malnourished children, vitamin A supplementation should be given to avoid blindness and decrease mortality.

RUBELLA

General Considerations

Rubella is a togavirus that causes a mild, self-limited exanthema (> 80% of infections are subclinical), but infection during pregnancy leads to teratogenicity and miscarriage. Rubella is transmitted by aerosolized respiratory secretions. Patients are infectious 5 days before until 5 days after the rash. Endemic rubella is absent in the United States and the Americas, and congenital rubella in infants born to unimmunized women and the occasional woman who is reinfected in pregnancy, is now very rare. Sporadic cases occur in migrants to the United States from Asia and Africa.

Clinical Findings

The incubation period is 14–21 days. The nondistinctive signs may make exposure history unreliable. A history of immunization makes rubella unlikely but still possible. Congenital rubella usually follows maternal infection in the first trimester.

A. Symptoms and Signs

1. Infection in children

Young children may only have rash. Older patients often have a nonspecific prodrome of low-grade fever, ocular pain, sore throat, and myalgia. Postauricular and suboccipital adenopathy (sometimes generalized) is characteristic. The rash consists of erythematous discrete maculopapules beginning on the face and spreading to the trunk and extremities within 24 hours. Scarlatiniform, morbilliform, and erythema infectiosum-like rash variants may occur. The rash fades from the face to extremities by the third day. Enanthema is usually absent.

2. Congenital infection

More than 80% of women infected in the first 4 months of pregnancy (25% near the end of the second trimester) deliver an affected infant; congenital disease occurs in less than 5% of women infected later in pregnancy. Later infections can result in isolated defects, such as deafness. The main manifestations include the following: growth retardation (50%–85%), cardiac anomalies (pulmonary artery stenosis, patent ductus arteriosus, ventricular septal defects), ocular anomalies (cataracts, microphthalmia, glaucoma, retinitis), sensorineural hearing loss (> 50%), cerebral disorders (chronic encephalitis, developmental delay), hematologic disorders (thrombocytopenia, extramedullary “blueberry muffin” hematopoiesis, lymphopenia), and others (hepatitis, osteomyelitis, immune disorders, malabsorption, diabetes).

B. Laboratory Findings

Leukopenia is common, and platelet counts may be low. Congenital infection is associated with low platelet counts, abnormal liver function tests, hemolytic anemia, and CSF pleocytosis in the newborn period. Virus may be isolated from oral secretions or urine from 1 week before to 2 weeks after onset of rash. Children with congenital infection are infectious for months. PCR is very sensitive. Serologic immunoassay diagnosis is best made by demonstrating a fourfold rise in antibody titer between specimens drawn 1–2 weeks apart. The first should be drawn promptly, because titers increase rapidly after onset of rash; both specimens must be tested simultaneously by a single laboratory. Rubella IgM is present in 50% of patients at the onset of the rash, but in almost all by 5 days. Because the decision to terminate a pregnancy is usually based on serologic results, testing must be done carefully.

C. Imaging

Pneumonitis and bone metaphyseal longitudinal lucencies may be present in radiographs of children with congenital infection.

Differential Diagnosis

Rubella may resemble infections due to measles, enterovirus, adenovirus, EBV, roseola, parvovirus, and T gondii. Drug reactions may also mimic rubella. Because public health implications are great, sporadic suspected cases should be confirmed serologically or virologically. Congenital rubella must be differentiated from congenital CMV infection, toxoplasmosis, Zika, and syphilis.

Complications & Sequelae

A. Arthralgia and Arthritis

Both occur more often in adult women. Polyarticular involvement (fingers, knees, wrists) lasting a few days to weeks is typical. Frank arthritis occurs in a small percentage of patients. It may resemble acute rheumatoid arthritis.

B. Encephalitis

With an incidence of about 1:6000, this is a parainfectious encephalitis associated with a low mortality rate. A syndrome resembling SSPE (see section on Measles) has also been described in congenital rubella.

C. Rubella in Pregnancy

Infection in the mother as in older children is self-limited and not severe.

Prevention

Rubella is one of the infections that could be eradicated through vaccination (see Chapter 10). Standard prenatal care should include rubella antibody testing. Seropositive mothers are at no risk; seronegative mothers are vaccinated after delivery.

A pregnant woman possibly exposed to rubella should be tested immediately; if seropositive, she is considered protected and without risk to the fetus. If she is seronegative, a second specimen should be drawn in 4 weeks, and both specimens should be tested simultaneously. Seroconversion in the first trimester is associated with high fetal risk; such women require counseling regarding therapeutic abortion.

When pregnancy termination is not an option, some experts recommend intramuscular administration of immunoglobulin (up to 0.55 mL/kg IM) within 72 hours after exposure in an attempt to prevent infection. Only very small fractions of IgG are transferred to the fetus in early pregnancy and the efficacy of this practice is unknown.

Treatment & Prognosis

Symptomatic therapy is sufficient. Arthritis may improve with administration of anti-inflammatory agents. The prognosis is poor in congenitally infected infants, in whom most defects are irreversible or progressive. The severe cognitive defects in these infants seem to correlate closely with the degree of growth failure.

HANTAVIRUS CARDIOPULMONARY SYNDROME

General Considerations

Hantavirus cardiopulmonary syndrome is the first native bunyavirus infection endemic in the United States. This syndrome is distinctly different in mode of spread (no arthropod vector) and clinical picture from other bunyavirus diseases.

Clinical Findings

Hantavirus cardiopulmonary syndrome has been confirmed in more than 34 states and Canada that have the appropriate rodent reservoirs. Epidemics occur when environmental conditions favor large increases in the rodent population and increased prevalence of virus.

A. Symptoms and Signs

After an incubation period of 1–3 weeks, onset is sudden, with a nonspecific virus-like prodrome: fever; back, hip, and leg pain; chills; headache; and nausea and vomiting. Abdominal pain may be present. Sore throat, conjunctivitis, rash, and adenopathy are absent, and respiratory symptoms are absent or limited to a dry cough. After 3–7 days, dyspnea, tachypnea, and evidence of a pulmonary capillary leak syndrome appear. This often progresses rapidly over hours. Hypotension is common, not only from hypoxemia but also from myocardial dysfunction, which is different from septic shock. Copious, amber-colored, nonpurulent secretions are common. Decreased cardiac output due to myocardiopathy and elevated systemic vascular resistance distinguish this disease from early bacterial sepsis.

B. Laboratory Findings

The hemogram shows leukocytosis with a prominent left shift and immunoblasts, thrombocytopenia, and hemoconcentration. Lactate dehydrogenase (LDH) is elevated, as are liver function tests; serum albumin is low. Creatinine is elevated in some patients, and proteinuria is common. Lactic acidosis and low venous bicarbonate are poor prognostic signs. A serum IgM ELISA test is positive early in the illness. Otherwise, the diagnosis is made by PCR or specific staining of tissue at autopsy.

C. Imaging

Initial chest radiographs are normal. Subsequent radiographs show bilateral interstitial infiltrates with the typical butterfly pattern of acute pulmonary edema, bibasilar airspace disease, or both. Significant pleural effusions are often present. These findings contrast with those of other causes of acute respiratory distress syndrome.

D. Differential Diagnosis

In some geographic areas, plague and tularemia may be possibilities. Infections with viral respiratory pathogens and Mycoplasma have a slower progression, do not elevate the LDH, and do not cause the hematologic changes seen in this syndrome. Q fever, psittacosis, toxin exposure, legionellosis, and fungal infections are possibilities, but the history, tempo of the illness, and blood findings, as well as the exposure history, should be distinguishing features. Hantavirus cardiopulmonary syndrome is a consideration in previously healthy persons from a rural area or potential exposure to wild rodents, who have a febrile illness associated with unexplained pulmonary edema.

E. Treatment and Prognosis

There is no established antiviral therapy. Management should concentrate on oxygen therapy and mechanical ventilation as required. Because of capillary leakage, Swan-Ganz catheterization to monitor cardiac output and inotropic support—rather than fluid therapy—should be used to maintain perfusion. Venoarterial extracorporeal membrane oxygenation can provide short-term support for selected patients. The strains of virus present in North America are not spread by person-to-person contact. No isolation is required. The case fatality rate is 30%–40%. Guidelines are available for reduction of exposure to the infectious agent.

MUMPS

General Considerations

Mumps virus, a paramyxovirus, is spread by the respiratory route and attacks almost all nonprotected children (asymptomatically in 30%–40% of cases). As a result of prior clinical or subclinical infection, or childhood immunization, 95% of adults are immune, although immunity can wane in late adolescence. When the number of unprotected rises, epidemics (5833 cases in 2016 and 3176 at mid-2017) can occur, which are aborted by reimmunization of the at-risk population, especially college students. Infected patients are infectious from 2 days prior to 5 days after the onset of parotitis. The incubation period is 14–21 days. In an adequately immunized individual, parotitis is usually due to another cause. Two doses of the vaccine are 88% (range: 66%–95%) effective at protecting against mumps; one dose is 78% effective (range: 49%–92%). However, an outbreak in Guam occurred even when most children had two doses of vaccine, likely spread by crowding.

Clinical Findings

A. Symptoms and Signs

1. Salivary gland disease

After a prodrome of fever, severe headache, arthralgia, and anorexia, tender swelling of parotid glands occurs (70%–80% bilateral). The ear is displaced upward and outward; the mandibular angle is obliterated. Parotid stimulation with sour foods may be quite painful. The orifice of the Stensen duct may be red and swollen; yellow secretions may be expressed, but pus is absent. Parotid swelling dissipates after 1 week.

2. Meningoencephalitis

Once the most common cause of aseptic meningitis, mumps meningitis was manifested by severe headache, vomiting, and/or asymptomatic mononuclear pleocytosis. Fewer than 10% of patients had clinical meningitis or encephalitis. Parotitis is present in only half of the cases of mumps meningoencephalitis. Although neck stiffness, nausea, and vomiting can occur, encephalitic symptoms are rare (1:4000 cases of mumps); recovery in 3–10 days is the rule.

3. Pancreatitis

Epigastric abdominal pain may represent transient pancreatitis. Because salivary gland disease may elevate serum amylase, specific markers of pancreatic function (lipase, amylase isoenzymes) are required for assessing pancreatic involvement.

4. Orchitis, oophoritis

Involvement of the gonads is associated with fever, local tenderness, and swelling and is second to parotitis as presentation of mumps in adolescents. Epididymitis is usually present. Most often unilateral, it resolves in 1–2 weeks. Although one-third of infected testes atrophy, bilateral involvement and sterility are rare.

5. Other

Thyroiditis, mastitis (especially in adolescent females), arthritis, and presternal edema (occasionally with dysphagia or hoarseness) may be seen.

B. Laboratory Findings

Peripheral blood leukocyte count is usually normal. CSF may contain a modest number of cells (∼ 250 cells/μL, predominantly lymphocytes), with mildly elevated protein and normal to slightly decreased glucose. Viral PCR or culture of saliva, throat, urine, or spinal fluid may be positive for at least 1 week after onset. Paired sera assayed by ELISA or a single positive IgM antibody test may be used for diagnosis.

Differential Diagnosis

A history of contact with a child with parotitis is not proof of mumps exposure. Mumps parotitis may resemble cervical adenitis (the jaw angle may be obliterated, but the ear does not usually protrude; the Stensen duct orifice is normal; leukocytosis and neutrophilia are observed), bacterial parotitis (pus in the Stensen duct, toxicity, exquisite tenderness), recurrent parotitis (idiopathic or associated with calculi), tumors or leukemia, and tooth infections. Many viruses, including parainfluenza, enteroviruses, EBV, CMV, and influenza, can cause parotitis. Parotid swelling in HIV infection is less painful and tends to be bilateral and chronic, but may occur.

Unless parotitis is present, mumps meningitis resembles that caused by enteroviruses or early bacterial infection. An elevated amylase level may be useful clue in this situation. Isolated pancreatitis is not distinguishable from many other causes of epigastric pain and vomiting. Mumps is a classic cause of orchitis, but torsion, bacterial or chlamydial epididymitis, Mycoplasma infection, other viral infections, hematomas, hernias, and tumors must also be considered.

Complications

The major neurologic complication is nerve deafness (usually unilateral) which can result in inability to hear high tones. Although rare, occurring in less than 0.1% of cases of mumps, it may occur without meningitis. Aqueductal stenosis and hydrocephalus (especially following congenital infection), myocarditis, transverse myelitis, and facial paralysis are other rare complications.

Treatment & Prognosis

Treatment is supportive and includes provision of fluids, analgesics, and scrotal support for orchitis. Systemic corticosteroids have been used for orchitis, but their value is anecdotal.

RABIES

General Considerations

Rabies is an acute progressive CNS viral zoonotic infection. It remains a serious public health problem wherever animal immunization is not widely practiced or when humans play or work in areas with sylvan rabies. Infection is almost invariably fatal and will occur in 40% after rabid animal bites. Any warm-blooded animal may be infected, but susceptibility and transmissibility vary with different species. Bats often carry and excrete the virus in saliva or feces for prolonged periods; they are the major cause of rabies in the United States. Dogs and cats, responsible for most rabies in the world, are usually clinically ill within 10 days after becoming contagious (the standard quarantine period for suspect animals). Valid quarantine periods or signs of illness are not fully known for many species. Rodents rarely transmit infection. Animal vaccines are very effective when properly administered, but a single inoculation may fail to produce immunity in up to 20% of dogs.

The risk is assessed according to the type of animal (high-risk animals include bats, raccoons, skunks, and foxes), wound extent and location (infection more common after head or hand bites, or if wounds have extensive salivary contamination and are not quickly and thoroughly cleaned), geographic area (urban rabies is rare to nonexistent in the United States; rural rabies is possible, especially outside the United States), and animal vaccination history (risk low if documented). Most rabies in the United States is caused by bat genotypes, yet a history of bat bite is often not obtained especially in young children. Aerosolized virus in caves inhabited by bats has caused infection.

Clinical Findings

A. Symptoms and Signs

Most cases occur within 3–12 weeks of exposure and may present with vague symptoms. Paresthesia at the bite site is usually the first symptom. Nonspecific anxiety, excitability, or depression follows, then muscle spasms, drooling, hydrophobia, delirium, and lethargy. Swallowing or even the sensation of air blown on the face may cause pharyngeal spasms. Seizures, fever, cranial nerve palsies, coma, and death follow within 7–14 days after onset. In a minority of patients, the spastic components are initially absent and the symptoms are primarily flaccid paralysis and cranial nerve defects. The furious components appear subsequently.

B. Laboratory Findings

Leukocytosis is common. CSF is usually normal, but may show elevation of protein and mononuclear cell pleocytosis. Cerebral imaging and electroencephalography are not diagnostic. Infection in an animal may be determined by PCR or fluorescent antibody test to examine brain tissue for antigen. Rabies virus is excreted in the saliva of infected humans, but the diagnosis is usually made by nucleic acid (RT-PCR) or antigen detection in scrapings or tissue samples of richly innervated epithelium, such as the cornea or the hairline of the neck. Classic Negri cytoplasmic inclusion bodies in brain tissue are not always present. Seroconversion measured by neutralizing antibody occurs after 7–10 days. Clinical recovery has been associated with detection of neutralizing antibody and clearance of infectious rabies virus in the CNS.

Differential Diagnosis

Failure to elicit the bite history in areas where rabies is rare may delay diagnosis. Other disorders to be considered include parainfectious encephalopathy; encephalitis due to herpes simplex, mosquito-borne viruses, or other causes of viral encephalitis or acute paralysis. However, classic furious rabies is not readily confused with these alternative diagnoses.

Prevention

See Chapter 10 for information regarding vaccination and postexposure prophylaxis. Rabies immunoglobulin and diploid cell vaccine have made prophylaxis more effective and minimally toxic. Because rabies is almost always fatal, presumed exposures must be managed carefully.

Treatment & Prognosis

Survival is very rare, but it has been reported in a very small number of patients receiving meticulous intensive care and protocols that focus on the altered CNS metabolic state (eg, Milwaukee protocol). Early diagnosis is important for the protection and postexposure prophylaxis of patient contacts.

Rickettsiae are pleomorphic, gram-negative coccobacilli that are obligate intracellular parasites. Rickettsial diseases are often included in the differential diagnosis of febrile rashes. Severe headache, myalgia, and pulmonary symptoms are prominent manifestations. The endothelium is the primary target tissue, and the ensuing vasculitis is responsible for severe illness.

All rickettsioses are transmitted by arthropod contact (ticks, fleas, lice—depending on the disease), either by bite or by contamination of skin breaks with vector feces. Except Rocky Mountain spotted fever and murine typhus, all other rickettsial diseases have a characteristic eschar at the bite site, called the tache noire. Evidence of arthropod contact by history or physical examination may be lacking, especially in young children. The geographic distribution of the vector is often the primary determinant for suspicion of these infections. Therapy often must be empiric. Many new broad-spectrum antimicrobials are inactive against these cell wall-deficient organisms; tetracyclines are usually effective.

Q fever, which is not a rickettsiae, is included here because it was long classified as such and, like rickettsiae, is an obligate intracellular bacterium. It is not transmitted by an insect vector and is not characterized by rash.

HUMAN EHRLICHIOSIS & ANAPLASMOSIS

In children, the major agent of North American human ehrlichiosis is Ehrlichia chaffeensis. The reservoir hosts are probably wild rodents, deer, and sheep; ticks are the vectors. Most cases caused by this agent are reported in the south-central, southeastern, and middle Atlantic states (Arkansas, Missouri, Oklahoma, Kentucky, Tennessee, and North Carolina are high-prevalence areas). Almost all cases occur between March and October, when ticks are active.

A second ehrlichiosis syndrome, seen in the upper Midwest and Northeast (Rhode Island, Connecticut, Wisconsin, Minnesota, and New York are high-prevalence areas), is caused by Anaplasma phagocytophilum and Ehrlichia ewingii. Anaplasmosis also occurs in the western United States.

E chaffeensis has a predilection for mononuclear cells, whereas A phagocytophilum and E ewingii infect and produce intracytoplasmic inclusions in granulocytes. Hence, diseases caused by these agents are referred to as human monocytic ehrlichiosis or human granulocytic ehrlichiosis, respectively. Ehrlichiosis, Lyme disease, and babesiosis share some tick vectors; thus, dual infections can occur and should be considered in patients who fail to respond to therapy.

Clinical Findings

In approximately 75% of patients, a history of tick bite can be elicited. The majority of the remaining patients report having been in a tick-infested area. The usual incubation period is 5–21 days.

A. Symptoms and Signs

Fever is universally present and headache is common (less so in children). Gastrointestinal symptoms (abdominal pain, anorexia, nausea, and vomiting) are reported in most pediatric patients. Distal limb edema may occur. Chills, photophobia, conjunctivitis, and myalgia occur in more than half of patients. Rash occurs in ∼ 50% of children with monocytic ehrlichiosis and is much less common in granulocytic ehrlichiosis. Rash may be erythematous, macular, papular, petechial, scarlatiniform, or vasculitic. Meningitis occurs, and altered mental status is common. Interstitial pneumonitis, acute respiratory distress syndrome, and renal failure occur in severe cases. Physical examination reveals rash (not usually palms and soles), mild adenopathy, and hepatomegaly. In children without a rash, infection may present as a fever of unknown origin.

B. Laboratory Findings

Laboratory abnormalities include leukopenia with left shift, lymphopenia, thrombocytopenia, elevated aminotransferase and LDH levels. Hypoalbuminemia and hyponatremia are common. Disseminated intravascular coagulation can occur. Anemia occurs in one-third of patients. CSF pleocytosis (mononuclear cells and increased protein) is common. The definitive diagnosis can be made by PCR or serologically, either by a single high titer or a fourfold rise in titer during acute and convalescent samples. The CDC uses an immunofluorescent antibody test to distinguish between the etiologic agents. Intracytoplasmic inclusions (morulae) may occasionally be observed in mononuclear cells in monocytic ehrlichiosis, and are usually observed in polymorphonuclear cells from the peripheral blood or bone marrow in granulocytic ehrlichiosis. PCR may be negative after 48 hours if patient is on appropriate antibiotics.

Differential Diagnosis

In regions where these infections exist, ehrlichiosis should be included in the differential diagnosis of children who present during tick season with fever, leukopenia or thrombocytopenia (or both), increased serum transaminase levels, and rash. The differential diagnosis includes septic or toxic shock, other rickettsial infections (especially Rocky Mountain spotted fever), Colorado tick fever, leptospirosis, Lyme borreliosis, relapsing fever, EBV, CMV, viral hepatitis and other viral infections, Kawasaki disease, systemic lupus erythematosus, and leukemia.

Treatment & Prognosis

Asymptomatic or clinically mild and undiagnosed infections are common in some endemic areas. The disease may last several weeks if untreated. One-quarter of hospitalized children require intensive care. Meningoencephalitis and persisting neurologic deficits occur in 5%–10% of patients. Doxycycline for 7–10 days is the treatment of choice. Patients with suspected disease must be treated preemptively concurrently with attempts to establish the diagnosis. Response to therapy should be evident in 24–48 hours. Deaths are uncommon in children. Immune compromise and asplenia are risk factors for severe disease.

ROCKY MOUNTAIN SPOTTED FEVER

Rickettsia rickettsii causes one of many similar tick-borne illnesses characterized by fever and rash that occur worldwide. Most are named after their geographic area. Dogs and rodents, as well as large mammals, are reservoirs of R rickettsii.

Rocky Mountain spotted fever is the most severe rickettsial infection and the most important (∼ 2000 cases per year) in the United States. It occurs predominantly along the eastern seaboard; in the southeastern states; and in Arkansas, Missouri, and Oklahoma. It is much less common in the west. Most cases occur in children exposed in rural areas from April to September. Infection can be acquired from dog ticks.

Clinical Findings

A. Symptoms and Signs

After the incubation period of 3–12 days (mean, 7 days), there is high fever (> 40°C), usually of abrupt onset, myalgia, severe and persistent headache (retro-orbital), toxicity, photophobia, vomiting, abdominal pain, and diarrhea. A rash occurs in more than 95% of patients and appears 2–6 days after fever onset as macules and papules; most characteristic (65%) is involvement of the palms, soles, and extremities; the face is spared. The rash becomes petechial and spreads centrally from the extremities. The rash reflects infection of endothelial cells, which also causes vascular leak and resulting edema, hypovolemia, and hypotension. Conjunctivitis, splenomegaly, pneumonitis, meningismus, and confusion may occur.

B. Laboratory Findings

Laboratory findings reflect diffuse vasculitis: thrombocytopenia, hyponatremia, early mild leukopenia, proteinuria, mildly abnormal liver function tests, hypoalbuminemia, and hematuria. CSF pleocytosis is common. Serologic diagnosis is achieved with indirect fluorescent or latex agglutination antibody methods, but generally is informative only 7–10 days after onset of the illness. Skin biopsy with specific fluorescent staining is a specific and moderately sensitive diagnostic method available during the first week of the illness.

Differential Diagnosis

The differential diagnosis includes meningococcemia, measles, meningococcal meningitis, staphylococcal sepsis, EBV infection, enteroviral infection, leptospirosis, Colorado tick fever, scarlet fever, murine typhus, Kawasaki disease, and ehrlichiosis.

Treatment & Prognosis

To be effective, therapy for Rocky Mountain spotted fever must be started early, most often on the basis of a high clinical suspicion prior to rash onset in endemic areas. Atypical presentations, such as the absence of pathognomonic rash, can lead to delay in appropriate therapy. Rash is rarely present during the first day of diagnosis and in 50% within 3 days of onset of fever. Doxycycline is the treatment of choice for children, regardless of age, and should be continued for 10 days and at least 2–3 days after resolution of fever for a full day.

Complications and death result from severe vasculitis, especially in the brain, heart, and lungs. The mortality rate is 5%–7%. Persistent neurologic deficits occur in 10%–15% of children who recover. Delay in therapy is an important determinant of sequelae and mortality.

Because tick attachment lasting 6 hours or longer is associated with transmission of the pathogen, frequent tick removal is a preventive measure.

ENDEMIC TYPHUS (MURINE TYPHUS)

Endemic typhus is present in the southern United States, mainly in southern Texas, southern California, and Hawaii. The disease is transmitted by fleas from infected rodents or inhalation of rodent feces. Domestic cats, dogs, and opossums may play a role in the transmission of suburban cases. The incubation period is 6–14 days. Headache, myalgia and arthralgia, and chills slowly worsen. Fever may last 10–14 days. After 3–7 days, a rash appears. Truncal macules and papules spread to the extremities; the rash is rarely petechial and resolves in < 5 days. The location of the rash in typhus, with sparing of the palms and soles, helps distinguish the disease from Rocky Mountain spotted fever. Rash may be absent in 20%–40% of patients. Hepatomegaly may be present. Intestinal and respiratory symptoms may occur. Mild thrombocytopenia and elevated liver enzymes may be present. Prolonged neurologic symptoms can occur. Clinicians in endemic areas should consider early treatment when presented with a child with protracted fever, rash, and headache. Doxycycline is the drug of choice, which should be continued for 3 days after evidence of clinical improvement. Fluorescent antibody and ELISA tests are available.

Q FEVER

Coxiella burnetii is transmitted by inhalation rather than by an arthropod bite. Q fever is also distinguished from rickettsial diseases by the infrequent occurrence of cutaneous manifestations and by the prominence of pulmonary disease. The birth tissues and excreta of domestic animals and of some rodents are major infectious sources. The organisms may be carried long distances in fine particle aerosols. Unpasteurized milk from infected animals may also transmit disease.

Clinical Findings

A. Symptoms and Signs

Most patients have a self-limited flu-like syndrome of chills, fever, severe headache, and myalgia of abrupt onset occurring 10–25 days after exposure. Abdominal pain, vomiting, chest pain, and dry cough are prominent in children. Examination of the chest may yield few findings, as in other atypical pneumonias. Hepatosplenomegaly is common. The illness lasts 1–4 weeks and frequently is associated with weight loss. Only about 50% of infected patients develop significant symptoms.

B. Laboratory Findings

Leukopenia with left shift is characteristic. Thrombocytopenia is unusual, which is another distinction from rickettsial diseases. Aminotransferase and γ-glutamyl transferase levels are elevated, but significant bilirubin elevation is unusual. Diagnosis is made by positive PCR or serologic response (fourfold rise or single high titer in ELISA, IFA, or CF antibody assay) to the phase II organism. Chronic infection is indicated by antibody against the phase I organism. IgM ELISA tests are available.

C. Imaging

Pneumonitis occurs in 50% of patients. Multiple segmental infiltrates are common, but the radiographic appearance is not pathognomonic. Consolidation and pleural effusion are rare.

Differential Diagnosis

In the appropriate epidemiologic setting, Q fever should be considered in evaluating causes of atypical pneumonias, such as M pneumoniae, viruses, Legionella, and C pneumoniae. It should also be included among the causes of mild to moderate hepatitis without rash or adenopathy in children with exposure to farm animals.

Treatment & Prognosis

Typically the illness lasts 1–2 weeks without therapy. The course of the uncomplicated illness is shortened with doxycycline. Therapy is continued for several days after the patient becomes afebrile (usually 10–14 days). Quinolones are also effective.

One complication is chronic disease, which often implies myocarditis or granulomatous hepatitis. Meningoencephalitis is a rare complication. C burnetii is also one of the causes of “culture-negative” endocarditis. Coxiella endocarditis often occurs in the setting of valve abnormalities and is difficult to treat; mortality approaches 50%.