CHAPTER 139

Morbilliform Rashes

Houmin Li, MD, PhD; Delphine J. Lee, MD, PhD, FAAD; and Ki-Young Yoo, MD

Exanthems are skin findings resulting from an underlying disease, most often caused by a viral infection, although in a few cases, they may be due to bacteria or other rare pathogens. In children, these exanthems are most commonly macular, papular, or mixed. The rash of measles is described as morbilliform, and this adjective is used to describe similar-appearing eruptions of macules and papules. Frequently, these rashes present in conjunction with fever, and additional nonspecific symptoms include myalgia, rhinorrhea, conjunctivitis, headache, gastrointestinal (GI) symptoms, and lymphadenopathy. Rarely, other internal organs, such as the liver, spleen, lung, heart, and central nervous system (CNS), are also damaged in serious cases. The exanthems of various underlying pathogens can also be seasonal and have unique presentations. Although many of the common childhood illnesses of the past are now prevented by immunizations, not all segments of the population are adequately immunized. In addition, some children are not eligible for immunization because of their young age. Allergic reactions to medications, particularly antibiotics, may also result in similar eruptions and can be accompanied by symptoms of low-grade fever and pruritus. Differentiating viral exanthems from allergic reactions may be difficult in febrile children who have been empirically started on antimicrobial agents.

Epidemiology

In most children, viruses that cause exanthems produce mild disease without significant morbidity or long-term sequelae. Of greater concern to the public health is the risk of potential spread through the population. Morbilliform eruptions are a common presenting symptom, particularly in certain age groups and at certain times of the year.

Measles, also known as rubeola, is caused by an RNA virus and has markedly decreased in the United States since the live vaccine was introduced in 1963. It is transmitted by direct contact with infectious droplets or by airborne spread. In temperate climates, it is most frequently seen in the winter and spring. In the pre-vaccine era, measles was a significant cause of morbidity and mortality. Periodic resurgences have occurred, particularly among unimmunized preschoolers, older adolescents, and young adults. In addition, young infants are also at risk because of decreased levels of passively transferred maternal immunity related to lack of maternal natural infection or immunization. Vaccine-related immunity apparently wanes more rapidly in mothers than does naturally acquired immunity. Because of the increased number of cases in preschoolers and children with primary vaccine failure who received the vaccine appropriately, a 2-dose recommendation by the American Academy of Pediatrics was implemented in 1989, although there continue to be cases each year. Although no longer endemic in the United States, decreasing vaccination rates have resulted in an increased risk for outbreaks of previously eradicated infectious diseases, specifically measles. The incubation period of measles is about 10 days. Individuals are infectious from about 3 to 5 days before the onset of rash until 4 days following its appearance.

Rubella is also caused by an RNA virus and is no longer considered endemic in the United States, with rare cases reported annually. Sporadic outbreaks are reported, generally in foreign-born or under-immunized persons, and the last confirmed endemic case in the Americas was diagnosed in Argentina in 2009. However, about 5% to 10% of US individuals older than 5 years are considered to be susceptible. Peak incidence is in the late winter to spring, and it is likely transmitted via direct or droplet contact from nasopharyngeal secretions. Although generally a mild disease, its most serious manifestation is congenital rubella syndrome, which may develop in the offspring of infected pregnant women, with the greatest risk of congenital defects during the first trimester. The incubation period is 14 to 23 days.

Erythema infectiosum, also called fifth disease, is most commonly seen in school-age children during late winter to early spring. Most adults have antibodies indicating previous infection. The disease is caused by an acute infection with parvovirus B19, a DNA virus, and spread through respiratory secretions, percutaneous exposure to blood or blood products, and vertical transmission from mother to fetus. The incubation period is generally 4 to 14 days but may be up to 21 days.

Exanthem subitum, also known as roseola infantum, generally affects children from 6 months to 2 years of age, as maternal antibodies are protective until the age of 6 months. The illness is due to infection with human herpesvirus (HHV) 6 or 7, although HHV-6B, a DNA virus, is most commonly the etiologic agent. The virus is shed in the saliva, even among healthy, previously infected individuals. Almost all children are seropositive for HHV-6B by the age of 4 years. Reactivation is possible, although not common, and there is no seasonal pattern. The incubation period for HHV-6 is likely 5 to 15 days and is unknown for HHV-7.

Enteroviruses are the most common cause of exanthems in the summer and fall. They are all RNA viruses of the picornavirus group and include coxsackieviruses (groups A and B), echoviruses, and enteroviruses. Infection is spread through fecal-oral and respiratory routes as well as via fomites. There is also vertical transmission. Infection is more common in young children and people with poor hygiene. The incubation period is usually 3 to 6 days.

Kawasaki disease, an acute self-limited vasculitis, is of uncertain etiology, although an infectious cause is suspected due to epidemics occurring usually in the winter and spring. Most patients are between 6 months and 5 years of age. Males outnumber females by a ratio of 1.5:1. The incidence of the disorder among Asians is higher than in other populations, suggesting genetic factors play a role. The incubation period is unknown.

Gianotti-Crosti syndrome, also known as papular acrodermatitis of childhood, has historically been associated with hepatitis B infection. In the United States, it is believed to be a host response to multiple viral infections including, but not limited to, hepatitis B, Epstein-Barr virus (EBV), parvovirus B19, HHV-6, and the enteroviruses. It is seen most frequently in children 1 to 6 years of age.

Scarlet fever is a cutaneous reaction to several pyrogenic exotox-ins produced by group A streptococcus. It is transmitted through respiratory secretions. Scarlet fever is usually seen in young children between 1 and 10 years of age with pharyngitis. It occurs most commonly in cooler climates during the late fall, winter, and early spring. The incubation period is 2 to 5 days.

Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii, an intracellular organism. Infection is transmitted by the bite of Ixodes ticks, which are reservoirs and vectors of the organism. It can be seen throughout the United States, with most cases seen in the southern states. Children of any age are at risk, with those 5 to 9 years of age and those not recalling a tick bite, an occurrence in about one-half of pediatric cases, having the greatest mortality. The highest incidence of infection is seen between April and September. The incubation period lasts from 2 to 14 days.

Clinical Presentation

Morbilliform eruptions may involve the face, trunk, or extremities. The eruption is usually erythematous, and the lesions are flat or slightly raised. Occasionally, lesions within the mouth, referred to as enanthema, are evident. Most children are febrile (Box 139.1) and may have other symptoms.

Pathophysiology

The mechanism for development of a rash is variable. In some cases, the rash is the reaction of the body to infection or to the presence of a toxin. In general, the sequence involves exposure to an infectious agent and then acquisition of the agent, most commonly through droplet infection or fecal-oral contamination. The agent, usually a virus, then replicates, perhaps in the reticuloendothelial system. Lymph nodes enlarge, reflecting the involvement of the reticuloendothelial system. Associated viremia may be present.

In Kawasaki disease, vasculitis affects multiple organ systems. Various cytokines and autoantibodies play a role in the inflammatory response. In a toxin-mediated rash (eg, scarlet fever), previous exposure to the toxin is believed to sensitize the individual.

Diagnosis and Differential Diagnosis

While many exanthems can be easily recognized clinically, the decreased frequency of many of these usual childhood diseases means that physicians encounter these conditions less frequently than in the past. Familiarity with the appearance of these conditions is critical to diagnosis. Using a database of pictorial representations can be valuable. Such databases may also have ways to search by features such as rash morphologies, symptoms, exposures, skin color, body location, age, immune status, and many other factors. Morbilliform exanthems are associated with several infectious diseases, such as measles, rubella, erythema infectiosum, roseola, enterovirus infections, Gianotti-Crosti syndrome, Kawasaki disease, scarlet fever, and RMSF. Drugs can also cause eruptions similar to those caused by the aforementioned diseases.

The rash associated with measles is preceded by the 3 Cs of cough, coryza, and conjunctivitis in addition to fever, which last for several days before the eruption of the exanthem. Lesions on the buccal mucosa, called Koplik spots, are well-circumscribed white-gray papules (Figure 139.1) that appear during the prodrome and resolve after 3 to 4 days. This enanthema, although rare, is pathognomonic for measles. The measles rash itself usually begins on the head, particularly behind the ears and around the margin of the scalp, and then spreads cephalocaudally. After 2 to 3 days, the eruption becomes confluent and copper-colored, fades in the order it appeared, and then may des-quamate. The greatest morbidity and mortality are seen in individuals who are immunocompromised and malnourished. Complications include secondary bacterial infection, pneumonia, and encephalitis.

Rubella produces a relatively minor illness in children, although adults, particularly women, may experience painful arthritis. Up to one-half of infections are asymptomatic. There can be a prodrome of fever, headache, conjunctivitis, and upper respiratory symptoms. The eruption consists of fine erythematous macules and papules that become near confluent, starting on the face and progressing cau-dally to the trunk, resolving after 3 days. Lymphadenopathy, particularly of the postauricular or suboccipital nodes, is characteristic of the disease. Forchheimer spots are pinpoint rose-colored macules that can develop on the soft palate in patients with this infection. Congenital rubella syndrome results in multisystem anomalies that can follow maternal infection and is part of the TORCH congenital infections (toxoplasmosis, other agents [syphilis, hepatitis B, varicella-zoster virus, human immunodeficiency virus (HIV), parvovirus B19, enteroviruses, lymphocytic choriomeningitic virus], rubella, cytomegalovirus, and herpes simplex virus).

Figure 139.1. Koplik spots.

Erythema infectiosum is characterized by a distinctive eruption that may be preceded by mild prodromal symptoms, including low-grade fever, headache, myalgia, and malaise. Eruption generally occurs 7 to 10 days after the prodrome. The facial rash consists of erythematous patches on the cheeks with sparing of the nasal bridge and periorbital areas. This “slapped-cheek” appearance generally fades after several days and is considered the first stage of the illness. In the second stage, the extremities may develop a lacy reticulated rash of macules and papules 1 to 4 days later that can be pruritic. Palm and sole involvement are rare. This usually lasts about a week but may have recurrences over several weeks in the third stage, with triggers such as activity, sunlight, emotional stress, and hot baths. Most children are only mildly ill and may attend school, but children with underlying hematologic disorders may experience aplastic crises because of the affinity of parvovirus B19 for developing red blood cells. Children who are immunocompromised are also at risk for chronic anemia. Pregnant females may transmit this infection to their fetuses, which can result in fetal hydrops, growth retardation, anemia, isolated pleural and pericardial effusions, high-output congestive failure, and fetal loss. Adults with parvovirus infection frequently develop arthritis, although only 10% of children experience this symptom. Neurologic disturbances, including encephalitis and neuropathies, may follow parvovirus infection, although this is rare. Papular-purpuric gloves-and-socks syndrome is a self-limited acute eruption linked to parvovirus B19 infection. It usually occurs in the spring and summer, characterized by often-pruritic edema and erythema and progressing to purpuric macules and papules with a sharp line of demarcation at the wrists and ankles. A nonspecific enanthema of petechiae and erosions can occur. Symptoms of myalgia, lymphadenopathy, anorexia, and fatigue may follow the rash. The exanthem generally resolves after 1 to 2 weeks with no residual sequelae.

Exanthem subitum (roseola infantum) usually causes a fairly mild illness in children, although there can be associated complications. Defervescence usually accompanies the rash, which consists of fine, non-pruritic, blanchable, pink macules or papules with a surrounding halo that generally appear first on the trunk and then spread centrifugally. Some affected individuals may develop an enanthema consisting of erythematous papules on the soft palate and uvula called Nagayama spots. Periorbital edema can also be seen. On average, the rash evolves over 12 hours and usually resolves by 2 days. Infants may appear sickest during the prodromal phase, when fever is high (temperature often ≥39.5°C [≥103°F]), and infants are irritable as a result. Fever generally lasts 3 to 5 days and can be accompanied by upper respiratory symptoms and lymphadenopathy. Seizures during the febrile period can occur in up to 15% of primary infections. Workup to rule out sepsis is often warranted.

Skin eruptions associated with enterovirus infections are highly variable. They may be distinct and characteristic, such as hand-foot-and-mouth disease, most commonly associated with coxsackievirus A16 and enterovirus 71 (see Chapter 140). However, many of the enteroviral exanthems are less distinctive and have a generalized morbilliform appearance. Neurologic complications associated with enteroviral infections include aseptic meningitis and encephalitis and have been reported in infections with coxsackievirus B and enterovirus 71. Other systems affected by enteroviral infections include respiratory, GI, ophthalmic, and cardiac. In a 2011–2012 North American outbreak caused by coxsackievirus A6, affected individuals had distinctive skin findings mimicking eczema herpeticum (see Chapter 140), as well as Gianotti-Crosti syndrome-like rash and petechial or purpuric eruptions.

The rash of Kawasaki disease is also highly variable; it may be morbilliform, urticarial, or scarlatiniform or resemble erythema multiforme. During the first week of illness, there may be desquamation of the perineum. The diagnosis of Kawasaki disease requires fever (generally temperature >39.0°C [>102.2°F] lasting at least 5 days) and 4 out of the following 5 findings: bilateral non-purulent conjunctivitis; changes in the oropharyngeal mucosa including fissured lips, oral erythema, and strawberry tongue; changes in the extremities such as erythema/edema or desquamation; cervical lymphadenopathy with 1 node measuring at least 1.5 cm (0.2 in) in diameter; and the exanthem described previously. Irritability, arthralgia, abdominal pain, and diarrhea are not uncommon. Incomplete Kawasaki disease can be diagnosed when only 2 of the additional criteria are met; thus, the health professional should consider this diagnosis when persistent high fever and only 2 or 3 of these symptoms are present. The major complication of Kawasaki disease is coronary artery abnormalities, and males and those younger than 12 months are at increased risk.

The exanthem of Gianotti-Crosti syndrome consists of monomorphic, pink- to skin-colored, usually non-pruritic papules on the face, buttocks, and extremities, with sparing of the trunk. There is often a prodrome of fever and upper respiratory symptoms with associated generalized lymphadenopathy and hepatosplenomegaly. The exanthem fades after 2 to 3 weeks but can last up to several months.

Scarlet fever is primarily a disease of childhood. Onset is marked by sudden high fever, headache, vomiting, malaise, and sore throat. Within 12 to 48 hours, erythema develops on the neck, chest, and axillae. The rash quickly becomes generalized to a sandpaper-like rash of fine red papules on an erythematous background. Linear accentuation in the axillary, antecubital, and inguinal folds is known as Pastia lines. The face is flushed, except around the mouth (circumoral pallor). There is pharyngeal injection with exudate developing after a few days. The tongue is initially white with prominent red papillae (Figure 139.2), known as strawberry tongue. As the scarlet fever rash resolves, desquamation begins in 7 to 10 days, lasting up to 6 weeks.

The rash of RMSF begins as blanchable pink macules or papules that evolve into petechial or purpuric non-blanching lesions. They begin on the wrists and spread centripetally. The palms and soles are almost always involved. Exanthem is preceded by symptoms of fever, headache, and malaise. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea can be present. The rash generally develops 2 to 3 days after the prodrome.

Morbilliform rashes are the most common type of cutaneous drug eruption. The most common culprits include sulfonamides, penicillins, cephalosporins, and anticonvulsants. They generally begin as erythematous macules and papules on the trunk that spread to the extremities symmetrically. There is usually concurrent eosinophilia. Pruritus and low-grade fever can also be present, often confounding the diagnosis. Although most drug rashes begin 1 to 2 weeks after starting a drug, an eruption may develop after a drug has been discontinued. After stopping the offending medication, the rash usually resolves over 1 to 2 weeks, but some individuals show improvement even if the offending medication is continued. The underlying pathogenesis of many of these drug rashes continues to be unclear; however, recent studies found that levels of a soluble fatty acid synthetase ligand were increased in patients with drug-induced morbilliform eruptions, as well as in those with toxic epidermal necrolysis, but negative in those with viral exanthems.

Figure 139.2. Strawberry tongue.

Infection with EBV is associated with rash in young children and in adolescents on antibiotics, usually ampicillin or amoxicillin. Eruption is morbilliform, and the lesions may be erythematous or copper-colored. Fever, upper respiratory symptoms, lymphadenopathy, hepatosplenomegaly, and facial and peripheral edema, including unilateral periorbital edema, may be noted. The rash is likely due to an immunologic interaction between the infectious agent and the drug.

Evaluation

History

A thorough and detailed history should be obtained, including characteristics of the skin rash, the progression of areas involved, overall distribution, and the relationship with rash and other symptoms such as fever. This will be very helpful to make the correct diagnosis (Box 139.2).

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