Exanthematous diseases of childhood

Varicella (chickenpox)

Varicella zoster virus (VZV) is a member of the herpesvirus family and the causative agent of both varicella (chickenpox) and herpes zoster (shingles, see Chapter 15 ). Varicella results from primary infection with VZV and is a highly communicable human disease. Once acquired, VZV becomes permanently established in the sensory ganglia in a latent form with intermittent reactivation in a dermatomal distribution, resulting in herpes zoster. Although acute varicella is usually a self-limited infection, before extensive use of the varicella vaccine, most children had upward of 250 to 500 skin lesions, approximately 9000 to 11,000 children were hospitalized annually, and up to 100 individuals per year died of the disease or its complications. ^,

VZV is found worldwide, and annual epidemics occur most often during late winter and spring. Varicella is highly contagious and is usually spread between the prodrome and the first 3 days of the skin eruption. VZV is transmitted via respiratory droplets, then enters regional lymph nodes, and eventually a viremia ensues with more widespread dissemination. Primary infection elicits a humoral immune response with production of immunoglobulin (Ig) A, IgM, and IgG anti-VZV antibodies, the latter of which help protect against reinfection. Patients are considered contagious until at least 5 days after onset of the rash or until all existing lesions are dry and crusted.

A live attenuated varicella vaccine (Oka strain) was introduced in 1995, and in 1996 the Advisory Committee on Immunization Practices (ACIP) recommended universal one-dose vaccination of all children at age 12 to 18 months, with catch-up vaccination of all susceptible children before age 13 years. The ACIP and the American Academy of Pediatrics (AAP) expanded their recommendations to include use of the vaccine for postexposure prophylaxis and for some immunocompromised children. The vaccine is also indicated in adults who are susceptible to varicella.

The varicella vaccine has been quite effective in decreasing the overall incidence of varicella, and in vaccinees who develop breakthrough disease (“breakthrough varicella”), the disease tends to be milder with fewer lesions that may remain papular rather than becoming vesicular. In a 6-year case-control study of the effectiveness of the varicella vaccine over time, the effectiveness in the year after vaccination (97%) was greater than in years 2 through 8 after vaccination (84%), although most cases of breakthrough disease in vaccinees were mild. Another study of the effectiveness of a one- versus two-vaccination regimen revealed high vaccine efficacy over 10 years for both groups (94.4% and 98.3%, respectively), and again, breakthrough disease was mild. Despite these reports, severe breakthrough varicella has rarely been described and may occasionally be associated with other organ (pulmonary, central nervous system, hematologic, renal, hepatic, and ocular) involvement.

A decline in varicella-related hospitalizations for invasive group A β-hemolytic streptococcus (GABHS) infections was documented between the period of the prevaccine era and that of widespread vaccine use. Although some studies have demonstrated lower effectiveness of the varicella vaccine than expected, overall, the data support its universal use. In 2006, because of insufficient population immunity to prevent community transmission, the ACIP and AAP changed the varicella vaccine policy, recommending a universal two-dose vaccination program. This two-dose vaccination regimen has been demonstrated highly effective against varicella outbreaks in public school students.

The varicella vaccine is available as a monovalent vaccine (Varivax, Merck & Co, Kenilworth, NJ) and as part of a quadrivalent measles, mumps, rubella, varicella vaccine (MMRV; ProQuad, Merck & Co). Postlicensure studies have suggested a slightly increased risk of febrile seizures among children aged 12 to 23 months who received MMRV for their initial dose (versus separate MMR and varicella vaccines). A personal or family history of seizures is considered a precaution for use of MMRV, and unless a parent expresses strong preference for this vaccine, it is recommended that the first dose be administered as separate MMR and varicella vaccines. For the second dose at any age or the first dose at ages 48 months and older, the combination MMRV vaccine is recommended.

Primary varicella begins with a prodrome of fever, chills, malaise, headache, arthralgia, and myalgia. After 24 to 48 hours, the earliest skin lesions become evident, initially as red macules or papules ( Fig. 16.1 ) that progress rapidly to a vesicular phase. The fully developed lesion has been likened to a “dewdrop on a rose petal” ( Fig. 16.2 ). Varicella lesions present initially on the scalp, face, or trunk and then spread to the extremities. Older lesions crust over, and new lesions continue to develop, resulting in the pathognomonic finding of lesions in various stages being present at the same time ( Fig. 16.3 ). New lesions continue to develop for 3 to 4 days, and by day 6, most lesions have crusted over. Patients with sunburn or dermatitis may develop a more severe exanthem. An associated enanthem may be present and consists of painful erosions in the oropharynx, conjunctivae, or vaginal mucosae. The lesions of varicella heal with hypopigmentation ( Fig. 16.4 ) and scarring ( Fig. 16.5 ), especially at sites of the initial lesions.

Varicella tends to be a mild, self-limited disease in most immunocompetent hosts. Complications, however, may occur. The most common complication is secondary bacterial superinfection, usually the result of Staphylococcus aureus or GABHS. Invasive GABHS infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, may rarely occur. Secondary bacterial infection usually presents as isolated secondary fever or localized symptoms, such as bulla (large blister) formation or cellulitis. Varicella gangrenosa is diagnosed when an area reveals rapidly progressing erythema, induration, and pain. Peripheral gangrene may occur in the distal extremities. Other skin-related complications include deep ulcerative lesions ( Fig. 16.6 ), subcutaneous abscesses, and regional lymphadenitis. Patients under the age of 5 years who live in a household with older children seem to be at greatest risk for bacterial complications. In patients who develop secondary bacterial infection, bacteremia may occur, as may pneumonia, arthritis, or osteomyelitis.

Second to bacterial superinfection, the most common complication in patients with primary varicella is neurologic involvement. This may present as encephalitis, meningoencephalitis, cerebellar ataxia, transverse myelitis, or Guillain–Barré syndrome. Reye syndrome was a fairly common complication of varicella before the association with salicylates was identified. Reye syndrome (acute encephalopathy and fatty degeneration of the viscera) presents with decreased level of consciousness, vomiting, and abnormalities in liver function. The incidence of this complication has fallen dramatically following implementation of universal vaccination. Varicella pneumonia is the most common serious complication in adults but is rare in healthy children. ^, When it occurs during the course of childhood varicella, it is usually bacterial in origin. Severe pulmonary deterioration may occur, and it may occasionally be fatal. Thrombocytopenia, arthritis, uveitis, nephritis, myocarditis, pancreatitis, and hepatitis may also occasionally occur. When arthritis occurs in this setting, it may be bacterial ( Streptococcus pyogenes or S. aureus ) or aseptic (“varicella arthritis”) in origin. The latter is typically confined to a single joint, most commonly the knee, ankle, shoulder, or foot. Purpura fulminans is a rare and life-threatening complication of varicella, and disseminated intravascular coagulopathy may occasionally occur.

Immunocompromised hosts with varicella, including those with leukemia, lymphoma, or human immunodeficiency virus (HIV) infection; those receiving corticosteroids (>2 mg/kg per day of prednisone or equivalent); and those with a history of organ or bone marrow transplantation may have more serious disease and a higher incidence of complications. These individuals have an increased risk of disseminated varicella, with high fever, pneumonia, hepatitis, and encephalitis. Bacterial superinfection may also occur with increased incidence, and hemorrhagic complications of the disease are more common. Varicella during pregnancy poses an increased risk of serious disease to both the mother and the fetus (see Chapter 2 ). Pregnant females have a higher incidence of varicella pneumonia, and mortality from the disease is increased.

The diagnosis of primary varicella is usually based on the history and clinical findings. Laboratory confirmation, when desired, can be performed by either virologic or serologic methods. The diagnostic method of choice is polymerase chain reaction (PCR) testing of vesicular fluid or crusts, although early in the illness, PCR testing can also be performed on buccal swab material or saliva. Direct fluorescent antibody testing, performed on cells scraped from the base of a fresh vesicle, is also useful, and although not as highly sensitive as PCR, is rapid and fairly sensitive. ^, Tzanck smears on skin scrapings identify multinucleated giant cells and confirm the diagnosis of herpesvirus infection but are not specific for VZV. Cell culture is unequivocally confirmatory but not ideal for VZV, given the prolonged time necessary for cytopathic effects to appear. Serologic studies looking for a fourfold or greater increase in IgG antibody between acute and convalescent samples can help in the diagnosis, but may not be reliable in immunocompromised individuals.

The treatment of varicella in otherwise-healthy children is usually symptomatic, with the goals being control of pain and pruritus and prevention of secondary superinfection. Supportive therapies include oral antihistamines for pruritus, acetaminophen for fever or pain, and topical care. Useful topical regimens may include cool compresses, oatmeal baths, and application of topical products such as bacitracin ointment, calamine lotion, pramoxine-containing preparations, or menthol-camphor (Sarna) lotion. Antibiotics should be given if secondary bacterial infection is present.

The decision regarding the use of antiviral therapy for primary varicella depends on several factors, including host immune status, the extent of the infection, and timing of the diagnosis. In general, routine use of antiviral agents for varicella in otherwise-healthy children is not recommended. Acyclovir, famciclovir, and valacyclovir are antiviral agents licensed for treatment of VZV infections, although famciclovir is not approved for primary varicella. Oral acyclovir has been suggested in some studies to decrease the severity of primary VZV infection, including a decrease in the days of fever, number of days of new lesion formation, total number of lesions, and pruritus. In a review of published studies on acyclovir treatment of varicella in otherwise-healthy children and adolescents, a reduction in the number of days with fever was noted, but the results were inconsistent with respect to the number of days to no new lesions, maximum number of lesions, and number of days to relief of itching. In addition, no differences in the incidence of varicella complications between acyclovir and placebo groups were consistently noted. Oral antiviral therapy should be considered, however, for healthy individuals who are at risk for moderate or severe disease, such as those over 12 years of age (especially unvaccinated), those with chronic skin or lung disorders, and those receiving therapy with salicylates (long-term courses) or corticosteroids (short, intermittent, or aerosolized courses). When used in the treatment of varicella in otherwise-healthy patients, antiviral therapy should be started within 24 hours of the appearance of the rash. The use of oral antivirals for pregnant females with uncomplicated varicella remains controversial, although some experts recommend its use for those who develop it during the second or third trimester. Intravenous acyclovir is recommended for pregnant females with serious complications of varicella.

In immunocompromised children, intravenous antiviral therapy with acyclovir should be administered and is most effective when initiated early in the course of the disease (preferably within 24 hours of the onset of the rash). Some experts endorse high-dose oral acyclovir in selected immunocompromised individuals who are perceived to be at a lower risk for severe disseminated varicella. Valacyclovir is also approved for treatment of primary varicella in children 2 to under 18 years of age; some experts have used this agent for treating selected immunocompromised patients. In susceptible individuals with a known exposure to VZV, options include administration of varicella zoster immune globulin (VariZIG) or varicella vaccine. VariZIG is a high-titer preparation of VZV IgG that is given via the intramuscular route. It is recommended for susceptible individuals at high risk for infection and pregnant females who have been exposed to VZV ( Box 16.1 ). VariZIG is best given within 48 hours of the exposure, but the US Food and Drug Administration (FDA) extended the approved period for which it can be given to up to 10 days. ^{, ,}

Rubeola (measles)

In the prevaccine era, more than 500,000 cases of measles, or rubeola, were reported annually in the United States. After introduction of a live-virus vaccine in 1963, a significant reduction in the incidence of infection was noted. The MMR vaccine has been distributed in excess of 575 million doses and is one of the most widely used combination viral vaccines in the world. However, a dramatic resurgence occurred from 1989 to 1990, and during this period the highest mortality since 1977 was noted. ^, Those affected most during these measles resurgences were preschool-aged children from the inner-city areas, especially those who were unvaccinated and from low-income families. A majority of the deaths occurring from measles infection during this period occurred in children aged 5 years or younger. Other target populations during the measles resurgence included vaccinated school-aged children and college students, probably due to the insufficiency of a single vaccine dose and waning immunity.

In response to the measles resurgence of the 1980s, the Committee on Infectious Diseases of the AAP and the ACIP recommended an amendment to the previous vaccination schedule and suggested two doses of measles vaccination rather than one. ^, The current recommendation for measles vaccination calls for a two-dose schedule, with the first given at 12 to 15 months and the second at 4 to 6 years of age, and catch-up vaccination of children and adolescents as long as the two vaccinations are given at least 4 weeks apart. Changes in the measles vaccination strategy resulted in a markedly diminished incidence of the disease in the United States, with 100 cases reported in 1999. Although the incidence in the United States declined to extremely low levels compared with the prevaccine era, measles continues to be a major health problem worldwide, with an estimated 89,780 measles deaths in 2016. Of the 100 cases reported in the United States in 1999, 33% were imported from other countries. In developing countries, infants under 9 months of age who are too young to have received vaccination have a high incidence of measles, with more multisystem involvement and a greater risk of death. Importantly, epidemics of measles continue to occur in the United States, Europe, Africa, and other regions. During January through July 2008, 131 measles cases were reported to the Centers for Disease Control and Prevention (CDC), and these occurred primarily in unvaccinated school-aged children. The majority of these children were eligible for vaccination but had parents who chose not to have them vaccinated. In 2011, 222 measles cases were reported to the CDC, the majority of which were associated with importations from other countries, and more than 85% of cases occurring in individuals who were unvaccinated or had unknown vaccination status. In 2014, measles cases in the United States had risen to 644. In early 2015 the United States experienced a large, multistate outbreak of measles infection linked to an amusement park in California. Among 110 of the earliest patients in this outbreak, 45% were unvaccinated, 5% had received only one dose of the vaccine, and 43% had unknown or undocumented vaccination status. Of the unvaccinated patients, 67% were intentionally unvaccinated because of personal beliefs (65% of these were children under the age of 18 years). In 2017, 79 confirmed measles cases were reported to the Minnesota Department of Health, most of them Somali-American children, a community with declining vaccination coverage relating to concerns about an association with autism. ^, And as of April 2019, there were 704 reported cases of measles in the United States in 2019, representing the largest number reported in a single year since 1994. Of the 13 outbreaks between January 1 and April 26, six of them were associated with underimmunized close-knit communities (accounting for 88% of all cases), including the 2018–2019 outbreak that occurred in Rockland County, New York, and nearby counties, affecting primarily individuals in orthodox Jewish neighborhoods with low school immunization rates. Given these and other observations, maintaining high vaccination coverage and index of suspicion for measles and ensuring a rapid public health response at times of outbreaks are critical in the attempt to maintain measles elimination in the United States. ^, In response to the previously mentioned New York outbreak, the affected counties excluded unvaccinated students from school for 21 days after measles exposure and extended school exclusions to include all nonimmune students at schools with immunity rates <95%, as documented by two valid doses of MMR vaccine or serologic evidence of immunity.

Measles is caused by a single-stranded ribonucleic acid (RNA) virus in the family Paramyxoviridae . Infection begins in the nasopharyngeal epithelium and, less commonly, through the conjunctivae. Transmission of measles is primarily via respiratory droplets and, less commonly, by small-particle aerosols. The incubation period is around 10 to 14 days. From the initial site of infection, the virus enters the lymph nodes and lymphatics and multiplies within the reticuloendothelial system with a subsequent viremia. The virus is then disseminated to multiple lymphoid tissues and other organs, including the skin, liver, and gastrointestinal tract. Measles immunity includes cell-mediated, humoral, and mucosal responses. Measles antibodies are responsible for protection from future infection or reinfection.

Measles classically presents with fever and the three Cs: cough, coryza, and conjunctivitis. The pathognomonic enanthem, Koplik spots, usually occurs during this prodromal period and presents with punctuate, gray-white to erythematous papules distributed on the buccal mucosa ( Fig. 16.7 ). These lesions have been found to be highly predictive of confirmed measles, although they are not always present. The skin eruption of measles usually begins 2 to 4 days after the prodrome, which may intensify several days before the onset of rash. It begins on the face ( Fig. 16.8 ), especially the forehead, hairline, and behind the ears, and spreads downward onto the trunk ( Fig. 16.9 ) and extremities. The lesions are erythematous to purple-red macules and papules that may become confluent and fade in the same order as their appearance, leaving behind coppery macules and desquamation. The diagnosis of measles should be considered in any child presenting with fever and an erythematous rash, especially with the earlier concomitant findings.

Complications of measles include pneumonia, laryngotracheobronchitis, otitis media, stomatitis, gastroenteritis, myocarditis, and encephalitis. Pneumonia may be caused by the measles virus itself or be related to secondary bacterial or viral infection. Keratoconjunctivitis is common, especially in children with vitamin A deficiency, in which case it may result in blindness. Measles complications occur in up to 40% of patients and tend to be more severe in patients at the extremes of age and in malnourished patients.

Modified measles is measles occurring in a previously vaccinated individual. In this situation the prodrome is milder and of shorter duration, the exanthem is less prominent, and Koplik spots may be absent. This presentation of measles may pose a diagnostic challenge, given the nonpathognomonic presentation. Atypical measles occurs rarely in contemporary times and is seen in individuals exposed to natural measles after vaccination with the killed measles vaccines. These vaccines were utilized for a short period in the 1960s in the United States and for more variable periods of time in other countries, including Canada and Sweden. It has occasionally been reported in children who received the live attenuated vaccine. Atypical measles presents with high fever, headaches, and myalgias and eventually the measles rash and often pneumonia. Hemorrhagic features may be present, and the exanthem may be confused with Rocky Mountain spotted fever (RMSF).

Subacute sclerosing panencephalitis (SSPE) is a delayed neurodegenerative disease characterized by seizures, personality changes, cognitive decline, motor dysfunction, coma, and death within 5 to 15 years of the measles diagnosis. It classically occurs many years later in 1 in 100,000 patients with measles, but fortunately has been dramatically decreased in incidence with widespread vaccination strategies. ^,

The diagnosis of measles is traditionally based upon the clinical presentation with laboratory confirmation. Acute and convalescent serologic studies documenting a fourfold increase in titer confirm the diagnosis of measles. Culture can be performed on nasopharyngeal or conjunctival swabs, respiratory secretions, urine, or blood. PCR and semiquantitative real-time PCR assays have been developed, the latter being quite sensitive and specific and potentially useful in situations where early and rapid diagnosis is vital. Measles is a notifiable disease and should be reported to the local health department in a timely fashion.

The treatment of uncomplicated measles is largely supportive, because specific antiviral therapies do not exist. Ribavirin, a synthetic nucleoside analog useful in the treatment of other paramyxovirus (respiratory syncytial virus) infections, has been utilized in severely ill or immunocompromised patients. ^, Antibiotics are useful in patients with secondary bacterial infections such as otitis media or bacterial pneumonia. Vitamin A supplementation is currently recommended by the World Health Organization (WHO) for all children diagnosed with measles, despite their country of residence, administered once daily for 2 days. This recommendation is based on the observations that children in resource-limited countries appear to have decreased morbidity and mortality when treated with vitamin A and that some children diagnosed with measles in the United States have decreased levels; vitamin A appears to ameliorate the severity of diarrhea, possibly through a protective action on the epithelial lining of the gastrointestinal tract, increased mucous secretion, and enhanced local barriers to infection. ^, Hospitalized patients with measles should be kept in respiratory isolation for 4 days from the onset of the rash (and for the duration of the illness in immunocompromised hosts). Most patients will recover completely without sequelae and have lifelong immune protection against reinfection.

Scarlet fever

Scarlet fever (scarlatina) is a bacterial exanthem that may at times be confused with a variety of viral exanthematous diseases. It is caused by GABHS and is primarily a disease of children between the ages of 1 and 10 years. It is very rarely diagnosed in infants. Transmission of GABHS is usually via respiratory secretions. The organism produces a variety of toxins referred to as streptococcal pyrogenic exotoxins (SPEs) (including serotypes A, C, and G to M) and can produce up to 11 serologically distinct superantigens, which include the SPEs, streptococcal superantigen, streptococcal M protein, and streptococcal mitogenic exotoxin Z _n . SPE B is another toxin that appears to have some superantigen properties, but also appears to be a cysteine protease. The majority of the SPEs are encoded by bacteriophages. Epidemiologic changes over time in the types of SPEs produced appeared to correlate with changes in the severity of this disease. The shift from SPE-A– to SPE-B– and SPE-C–producing strains, which was seen early in the twentieth century, paralleled the decrease in morbidity and mortality from scarlet fever, as well as the decline in incidence and severity of acute rheumatic fever (ARF) in the United States. However, ARF (a systemic inflammatory autoimmune reaction appearing 2 to 4 weeks after GABHS pharyngitis) and rheumatic heart disease (RHD; progressive valve damage) continue to burden many low- and middle-income countries, as well as some populations in higher-income countries. Immigration from countries where ARF and RHD are endemic to higher-income areas have resulted in an increased prevalence in some regions where they were once believed to be eliminated. In the United States, the incidence of ARF is generally lower than in developing countries, but there have been some regional outbreaks, including an outbreak in Utah in the 1980s in which the incidence in children aged 3 to 17 years approached 12 per 100,000. The incidence of ARF peaks between 5 and 15 years, and the risk of subsequent RHD is greater in women; the global health burden of these disorders continues to be significant, with a high prevalence in Africa, the Pacific region, Latin America, the Middle East, and Asia. The revised Jones criteria for ARF are listed in Table 16.2 .

Scarlet fever presents with fever, throat pain, headache, and chills along with cutaneous findings. It is less commonly associated with streptococcal skin infection rather than pharyngitis. The primary distinction between GABHS pharyngitis and scarlet fever is the accompanying exanthem present in the latter. Oropharyngeal inspection reveals tonsillopharyngeal erythema, exudates, and petechial macules of the palate. During the first few days of illness, the tongue may reveal a white coating with red and edematous papillae projecting through (white strawberry tongue). By the fourth or fifth day, the coating peels off, leaving behind a red, glistening tongue studded with prominent papillae (red strawberry tongue).

The differential diagnosis of GABHS pharyngitis includes infection with viral agents (especially Epstein–Barr virus [EBV], mononucleosis), Mycoplasma , Chlamydia , and Arcanobacterium haemolyticum . In adolescents the differential diagnosis should include groups C and G Streptococcus species and Neisseria gonorrhoeae , and in developing countries Corynebacterium diphtheriae may be implicated. A. haemolyticum , formerly known as Corynebacterium haemolyticum , is a Gram-positive bacillus that most often infects adolescents and young adults and may result in a syndrome of pharyngitis and a scarlatiniform exanthem. The pharyngitis in these patients is usually severe (occasionally mistaken for diphtheria), and the exanthem may also occasionally mimic toxic shock syndrome, measles, urticaria, or erythema multiforme. ^, Infection with A. haemolyticum can occasionally be associated with bacteremia, severe sepsis, and soft-tissue infections (especially in patients with concomitant diabetes mellitus). ^, Lemierre syndrome, a condition characterized by pharyngitis, bacteremia (usually with anaerobic organisms including Bacillus and Fusobacterium ), and thrombophlebitis of the internal jugular vein, has also been reported in association with this organism.

Tender anterior cervical adenopathy is commonly present in patients with scarlet fever, and rhinorrhea and cough are usually absent. Some experts argue that presence of the latter two findings is a negative factor for the diagnosis of GABHS infection. The exanthem of scarlet fever presents as a fine, erythematous, macular and papular eruption ( Fig. 16.10 ) that has been described as “sandpapery.” It involves the trunk and extremities and may be accentuated in flexural areas with a petechial component (Pastia lines). In darker-skinned individuals, the exanthem of scarlet fever may be more difficult to recognize and may consist only of punctate papules resembling cutis anserina (“goose flesh”) ( Fig. 16.11 ). Circumoral pallor may be a useful clinical sign and is visualized as a rim of pallor encircling the perioral area. The exanthem generally resolves over 4 to 5 days and often heals with desquamation ( Fig. 16.12 ), which can occasionally occur in thick sheets, especially over the hands, feet, toes, and fingers ( Fig. 16.13 ). An interesting observation is that the SPEs produced by GABHS contribute to the exanthem by their ability to stimulate a delayed-type hypersensitivity response that requires prior exposure of the host to the organism.

Scarlet fever is diagnosed based on the clinical presentation in conjunction with results of laboratory testing. The gold-standard laboratory examination is throat culture with growth of GABHS. Rapid antigen detection (rapid strep testing), when properly performed, has a high sensitivity and specificity. In addition, antistreptococcal serologies may occasionally be useful. Complications of scarlet fever include pneumonia, pericarditis, meningitis, hepatitis, glomerulonephritis, and ARF. In endemic regions, around 60% of patients with ARF go on to develop RHD. Although the symptoms of GABHS pharyngitis and scarlet fever will often improve spontaneously, treatment more rapidly alleviates symptoms and, more importantly, is the primary mode of prevention for the subsequent occurrence of ARF. The prevailing theory regarding ARF prevention is that antimicrobial therapy should be started within 9 days from the onset of symptoms of GABHS pharyngitis. ^, In a review of an ARF prevention program in New Zealand entailing a vigorous school-clinic sore throat management approach with free care, antibiotics, and monitoring, a marked decline in the diagnosis of ARF in 5- to 12-year-old children was demonstrated.

The drug of choice for the treatment of scarlet fever and GABHS pharyngitis is penicillin V, given for 10 days. Amoxicillin administered as a single daily dose has been demonstrated to be as effective as penicillin V or multiple daily doses of amoxicillin. In patients allergic to penicillin, erythromycin or another macrolide (e.g., clarithromycin or azithromycin) or clindamycin may be utilized. Other options include a first-generation cephalosporin (as long as the history of penicillin allergy is nonanaphylactic in origin) or intramuscular penicillin G benzathine, which has the advantage of not being adherence-dependent but the disadvantage of being painful during administration.

Rubella (German measles)

Rubella, or German measles, is a viral exanthematous disease with a worldwide distribution. The incidence of rubella has greatly decreased since widespread rubella vaccination began in the United States in 1969. Before that time, epidemics occurred every 6 to 9 years, and major epidemics or pandemics occurred every 10 to 20 years. The primary goal of the rubella vaccination program was to prevent fetal infection, which may have various effects, including miscarriage, stillbirth, and congenital rubella syndrome (CRS) (see Chapter 2 ). As of 2013, goals for rubella elimination had been established in two WHO regions, the Americas (by 2010) and the European region (by 2015), and accelerated control of rubella and prevention of CRS had been established for the Western Pacific region. ^, The African, Eastern Mediterranean, and Southeast Asia regions have not yet established goals for control or elimination of rubella. In Japan, rubella outbreaks significantly increased in 2012 and 2013 with a corresponding increase in CRS. The effects of such outbreaks can be far-reaching, given the possibility of disease importation into other countries, and serve as a reminder of the need to maintain high levels of vaccination coverage and infectious disease surveillance. In April 2015, the Pan American Health Organization announced the elimination of rubella and CRS from the WHO Americas region, making them the third and fourth diseases to be officially eliminated from the region, following smallpox in 1971 and polio in 1994. ^,

Rubella is caused by an RNA virus in the Togaviridae family. Humans are the only source of infection, and postnatal disease is spread through direct or droplet contact from nasopharyngeal secretions. Up to 50% of cases of rubella are asymptomatic, and mild, self-limited disease is common. The incubation period ranges from 14 to 23 days, and the mean age of rubella infection is 5 to 9 years.

Prodromal symptoms may occur, especially in adolescents and adults, and include low-grade fever, headache, malaise, eye pain, myalgias, sore throat, rhinorrhea, and cough. The prodrome usually presents 2 to 5 days before the exanthem appears. The skin eruption consists of erythematous to rose-pink macules and papules ( Fig. 16.14 ) that tend to become confluent and most commonly involve the face and trunk. The eruption spreads in a cephalocaudad manner and begins to involute after 1 to 3 days, fading in the same order in which it appeared. After severe rubella eruptions, a fine flaky desquamation may be observed in areas of maximum involvement.

Generalized lymphadenopathy often occurs, especially in the suboccipital, postauricular, and cervical regions. Although this pattern of lymph node enlargement is highly characteristic of rubella, it is not pathognomonic and may occur in other disorders, including measles, varicella, adenovirus infection, and mononucleosis. Arthralgias and arthritis are common, especially in females, in whom they occur up to 52% of the time. The most common joints affected are those of the fingers, wrists, and knees. Complete resolution of the joint symptoms may take up to several weeks, and chronic arthritis occasionally develops. A characteristic enanthem, Forschheimer spots, may be present in patients with rubella and presents with erythematous and petechial macules on the soft palate. Other complications of rubella include encephalitis (which occurs in 1 in 6000 patients), myocarditis, pericarditis, and hepatitis. Anemia, neutropenia, and thrombocytopenia may also occur, as may hemolytic uremic syndrome.

A clinical diagnosis of rubella is difficult to make, given the potential overlap with multiple other exanthematous diseases. Serologic tests are most useful in confirming the diagnosis of rubella. The presence of rubella-specific IgM antibody indicates recent infection, as does a fourfold or greater increase in titer between acute and convalescent serum taken 1 to 2 weeks apart. ^, The virus can be isolated from nasal specimens plated onto appropriate cell-culture media, and amplification of rubella virus RNA with PCR from throat or nasal swabs or urine can be useful for diagnosis, and although not currently FDA approved, is available in several laboratories. The treatment of postnatal rubella is generally supportive. Hospitalized patients require contact isolation for 7 days after onset of the rash, and nonhospitalized children should be excused from school or day care.

The live-virus rubella vaccine, typically given as a component of the combination MMR vaccine, is typically recommended in the United States at 12 to 15 months of age, with a second dose at 4 to 6 years of age. The ongoing efforts of global rubella eradication campaigns will hopefully result in eventual worldwide elimination of the disease. Continued efforts to ensure the immunity of women of childbearing age will help to decrease the incidence of vertical transmission and CRS.

Filatow–Dukes disease

In 1900, Dukes described what was believed to be a unique exanthem and contrasted it with rubella and scarlet fever. This disorder was termed fourth disease and subsequently became known as Filatow–Dukes disease, given a similar description by Filatow 15 years earlier. The exanthem was described as bright red papules with a diffuse distribution, skin tenderness, and fever, and there was significant overlap with other exanthematous diseases, including staphylococcal scalded skin syndrome, scarlet fever, and rubella. Significant controversy followed the initial descriptions of fourth disease, and some authors propose that a distinct disorder never existed. The possibility that epidermolytic toxin-producing staphylococci were the etiologic agent for the disorder described in the original reports has been suggested. In general, researchers and practitioners alike have abandoned the idea of Filatow–Dukes disease representing a distinct entity.

Erythema infectiosum

Erythema infectiosum (EI; fifth disease) is a common childhood exanthematous illness caused by parvovirus B19 (referred to as B19 ). Although parvoviruses are ubiquitous in nature and may cause significant disease in a wide range of animals, B19 is the only one resulting in human disease. Several disorders have been linked to B19 infection in humans ( Box 16.2 ), including EI, arthritis, aplastic crises, and fetal hydrops. B19 infection is common in most countries, and in the United States 60% of adults are seropositive for the virus. Infection is most common in school-aged children, with approximately 20% of susceptible contacts in the school setting becoming infected during an outbreak. The incubation period ranges from 4 to 21 days. In immunocompromised hosts, persistent bone marrow suppression may occur, resulting in severe cytopenias that may be misinterpreted as being related to malignancy relapse or drug reactions.

In patients with classic EI, B19 infection is transmitted via the respiratory tract and is followed by a viremia that ends after 5 to 7 days with the production of IgM anti-B19 antibody. Prodromal symptoms such as headaches, fever, and chills are common during the viremic phase. Respiratory symptoms may also be present. IgG antibody appears during the third week of illness and coincides with the appearance of the rash and arthralgias, and hence patients with the cutaneous findings of EI are not considered infectious. Outbreaks of EI occur primarily during the winter and spring.

EI is the most recognizable B19-associated manifestation. It is also known as “slapped cheek” disease, given the characteristic fiery-red facial erythema ( Fig. 16.15 ) that occurs 2 to 3 days after the prodromal symptoms. The cheeks are most prominently affected, with the nasal bridge and perioral areas usually being spared. This phase of the illness has been termed the first stage, and is subsequently followed by stages two and three. The differential diagnosis of the initial eruption of EI includes phototoxic reaction and systemic lupus erythematosus.

During stage two, the patient develops a lacy, reticulated eruption on the extremities and trunk 1 to 4 days after the facial rash. This eruption may be pruritic and is often evanescent. It often begins with a confluent pattern followed by central clearing, which results in the lacy and reticulated appearance ( Figs. 16.16 and 16.17 ). The palms and soles are usually spared. The rash of the second stage of EI tends to fade over 2 to 3 weeks but may intermittently recur in response to environmental stimuli, including sunlight, warm temperatures (e.g., a hot bath), or physical activity. This intermittent waxing and waning represents the third stage of EI, and the duration is variable, usually 1 to 3 weeks.

Joint symptoms occur in 8% to 10% of children with EI but in up to 60% of adults with primary B19 infection, especially females. ^{, ,} The most commonly involved joints include the metacarpophalangeal joints, proximal interphalangeal joints, knees, wrists, and ankles. For most patients, the joint symptoms are transient and self-limited. Occasionally, affected children develop a chronic arthritis. Some experts have suggested a potential association between B19 infection and rheumatic arthritis or other connective tissue diseases, although the strength of this association remains unclear.

B19 has a remarkable affinity for erythroid precursors, binding to a receptor known as P antigen (globoside) . Direct infection of the red blood cell precursors results in a transient arrest in red blood cell production and resultant transient anemia. Transient aplastic crises may occur in patients suffering from disorders of decreased red blood cell production or increased red blood cell destruction or loss. Predisposing disorders include iron-deficiency anemia, spherocytosis, sickle cell disease, thalassemia, glucose-6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency. Although these episodes may be asymptomatic with spontaneous recovery, severe involvement may result in chills, pallor, weakness, fatigue, vasoocclusive crises, or congestive heart failure. Treatment with red blood cell transfusions may be indicated and for some patients is lifesaving.

Because B19 can cross the placenta, fetal infection is possible in nonimmune females with acute infection. Fetal infection with B19 may result in a variety of effects, occasionally even in utero fetal death. This epidemiologic consideration is important in caring for pediatric patients with B19-associated disorders. Fetal effects of B19 infection may include anemia (ranging from mild and self-limited to severe), high-output congestive heart failure, hydrops fetalis (generalized edema with ascites, pleural effusions, and polyhydramnios), and intrauterine fetal demise. Neonatal encephalopathy, encephalitis, cerebral migratory abnormalities, and meningitis have rarely been reported. The majority of pregnant women with B19 infection are asymptomatic, which makes the true incidence of fetal involvement difficult to determine. ^, When infected gravid females are symptomatic, they typically experience a biphasic illness with fever, headache, and myalgia followed 1 to 3 weeks later by arthritis or an exanthem. It is estimated that 30% to 66% of adult females are immune to B19 infection, ^, and therefore their fetuses are not at risk. In the majority of fetuses who acquire acute infection in utero , the infection is self-limited and the infants are delivered asymptomatic and at term. The greatest risk appears to be when infection is acquired before 20 weeks’ gestation, and the majority of fetal losses occur between 9 and 28 weeks’ gestation, mostly between 20 and 24 weeks. ^{, ,} The overall risk of B19-related fetal loss in pregnancies complicated by B19 infection is estimated around 1% to 9%. ^{, ,} Surviving infants tend to be healthy with normal development and neurologic outcome. ^, In one retrospective series of fetuses with confirmed B19 infection with anemia and/or hydrops, survival was 70% overall and 76% in those fetuses that received one or more transfusions. B19-related teratogenicity has only rarely been reported. ^, The diagnosis of B19 infection during pregnancy can be confirmed by maternal B19 IgM and IgG antibodies or PCR assay (see later). These studies are usually corroborated with findings on prenatal ultrasonography, most often evidence of fetal anemia and hydrops. PCR assays on fetal cord blood or amniotic fluid samples have also been utilized for diagnosis. Management of severely afflicted fetuses with B19 infection includes fetal digitalization and in utero blood transfusions.

B19 may be associated with a variety of purpuric or petechial exanthems, including PPGSS (see later) and more generalized presentations. In one outbreak of petechial rashes, B19 was confirmed in 76% of 17 children, and the petechiae were widely distributed, often with accentuation in the axillary and inguinal regions as well as the distal extremities. A similar purpuric or petechial presentation, with periflexural accentuation and arthralgias, has been observed in adults. Some authors have suggested the terminology parvovirus B19–associated purpuric-petechial eruption for these polymorphous presentations that appear to correspond to the viremic phase of primary infection. A B19-associated bathing-trunk exanthem has been described in children and adults, and presents with erythema and petechiae, with a predilection for the groin and, in some, the axillae. A generalized exanthem with microvesicles has also been reported in a child.

Papular-purpuric gloves-and-socks syndrome

PPGSS is another viral exanthematous illness that in many (but not all) cases has been documented to be caused by B19. This rare disorder presents most often in young adults and less often in children and is usually diagnosed during the spring and summer months. ^, Patients with PPGSS present with the acute onset of rapidly progressive, symmetric swelling and erythema of the hands and feet, often with a petechial or purpuric component ( Figs. 16.18 and 16.19 ). Bullous lesions are rarely present. The eruption has a sharp demarcation at the wrists and ankles and is usually quite pruritic. A more diffuse, papular exanthem may occur elsewhere on the body. An associated enanthem consisting of hyperemia, petechiae, and erosions is often present and affects the soft and hard palate, pharynx, tongue, and inner lips. ^, The symptoms of PPGSS tend to be milder in children and adolescents compared with adults.

Associated symptoms include fever, arthralgias, malaise, and respiratory or gastrointestinal complaints. Hematologic complications, including leukopenia and thrombocytopenia, are rarely observed. ^{, , ,} Mononeuritis multiplex has been described in association with perineuritis noted on skin biopsy. PPGSS resolves spontaneously over 1 to 2 weeks, and recurrences are rare. Importantly, the antibody response to B19 seen in PPGSS may differ from that observed in patients with EI, such that patients with the exanthem of PPGSS may still be viremic and therefore infectious. ^, The B19 VP2 structural protein has been demonstrated in the endothelial lining of dermal blood vessels in skin biopsies from patients with PPGSS.

The diagnosis of B19 infections is often made clinically in patients presenting with classic EI. In immunocompetent children who are otherwise well, laboratory confirmation of B19 infection is usually unnecessary. Instances in which such confirmation may be indicated, however, include atypical presentations, immunocompromised hosts, individuals with hematologic diseases, and those who have been exposed to gravid females. Serologic studies, including enzyme immunoassays and radioimmunoassay, are useful in detecting anti-B19 IgM and IgG antibodies, and other useful tests include direct hybridization with deoxyribonucleic acid (DNA) probes, in situ hybridization, and PCR studies. ^{, ,} In immunocompetent children for whom diagnostic testing is preferred, detection of B19-specific IgM antibodies is the testing of choice; however, as serologic studies are not always reliable in those who are immunocompromised, PCR-based assays are recommended. In a pregnant female who has been exposed to B19, serologic testing for IgM and IgG antibodies should be performed, and if acute infection is documented, serial fetal ultrasonography is usually indicated. As mentioned, maternal and fetal serum PCR techniques may be useful, especially when serologic study results are unclear, and B19 antigen detection in amniotic fluid samples has also been described.