Erythema infectiosum (also known as fifth disease) is usually a benign childhood condition characterized by a classic slapped-cheek appearance (see the image below) and lacy exanthem.[1] It results from infection with human parvovirus (PV) B19, an erythrovirus.[2, 3]
View Image | Classic slapped-cheek appearance of fifth disease. |
See 15 Back-to-School Illnesses You Should Know, a Critical Images slideshow, to help identify conditions that may occur in young patients after they return to the classroom.
Mild prodromal symptoms begin approximately 1 week after exposure to PV-B19 and last 2-3 days. They include the following:
These symptoms precede a symptom-free period of about 7-10 days, after which the infection progresses through the following stages:
See Clinical Presentation for more detail.
The diagnosis of erythema infectiosum usually is based on clinical presentation alone, and a workup for patients with the classic presentation is not necessary. For patients with other signs or symptoms associated with human parvovirus (PV) B19 or for exposure in a woman who is pregnant, confirmation of infection may be helpful and can be accomplished with the following specialized tests[5, 6, 7] :
See Workup for more detail.
Because erythema infectiosum most often is a benign, self-limited disease, reassuring the parents of children with the condition often is the only intervention necessary.[8] Symptomatic relief of erythema infectiosum may be provided using nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve fever, malaise, headache, and arthralgia, along with topical antipruritics and antihistamines (which also relieve pruritus). Treatment also includes plenty of fluids and rest.
See Treatment and Medication for more detail.
Erythema infectiosum (also known as fifth disease) is usually a benign childhood condition characterized by a classic slapped-cheek appearance and lacy exanthem.[1] It results from infection with human parvovirus (PV) B19, an erythrovirus. Human PV-B19 also is associated with other hematologic, rheumatologic, and neurologic conditions, including polyarthropathy, aplastic anemia, and hydrops fetalis. (See Etiology, Pathophysiology, and History and Physical Examination.)
In erythema infectiosum, a classic 3-phased cutaneous eruption follows a rarely noticed prodrome (see the image below).[9]
View Image | Classic slapped-cheek appearance of fifth disease. |
Human PV-B19, a member of the family Parvoviridae, is a heat-stable, single-stranded DNA virus[10] ; it is the only parvovirus known to cause disease in humans.
The development of erythema infectiosum in children is a normal response to infection by PV-B19. Acute infection in a host who is immunocompetent leads to a Th-1–mediated cellular immune response, with the production of specific immunoglobulin M (IgM) antibodies and subsequent formation of immune complexes. Clinical signs and symptoms of erythema infectiosum probably result from the deposition of the immune complexes in the skin and joints of individuals with this condition and not from the circulating virus.[11] The incubation period is usually 7-10 days, but it can be 4-21 days. Extremely high viral loads are noted in patients with aplastic crisis, but low-level persistent polymerase chain reaction positivity in tissues is also common among adults in a variety of tissues.[12, 13]
Arthropathy is observed most commonly in adult women and occurs in fewer than 10% of children. It is a symmetrical polyarthritis, usually involving finger joints. The onset of joint symptoms occurs 2-3 weeks after exposure.
The association of human PV-B19 with aplastic anemia is thought to be due to the affinity and cytotoxicity of the virus for erythroid progenitor cells. This complication is primarily observed in patients with underlying hemolytic anemias (eg, sickle cell disease, thalassemia) or immunodeficiency states (eg, leukemia, HIV).[14] These disease states depend on high red blood cell (RBC) production, due to shortened cell life span. The hematocrit of these patients may drop as much as 10-15% per day during acute infection. Most patients have a human PV-B19 aplastic crisis only once, and a rash following aplastic crisis is rare.
Previously healthy patients also develop transient (and usually clinically insignificant) bone marrow suppression and reticulocytopenia. In rare cases, mild lymphopenia, neutropenia, and thrombocytopenia also may occur.
Fetal transmission may result in severe anemia with resultant congestive heart failure and fetal hydrops. This occurs in fewer than 10% of primary maternal infections. Studies report a 1-9% risk of fetal death in pregnant women exposed to active human parvovirus infection, with a greater risk of fetal loss in early pregnancy.[15] Approximately one half of women of childbearing age are seropositive; therefore, they are immune and are of no risk to the fetus. No evidence suggests specific congenital malformations due to in-utero exposure to human PV-B19.[16, 17]
Associations between human PV-B19 infection and encephalitis, neuropathies, myocarditis, nephritis, systemic lupus erythematosus, Henoch-Schönlein purpura, pseudoerysipelas-like eruption, and rheumatoid arthritis have been described. Many of these associations, however, have not been validated.[18, 19]
Erythema infectiosum is caused by infection with PV-B19, a member of the Parvoviridae family that dates back 7000 years in human dental and skeletal genomic studies.[20] PV-B19, the virus with the smallest DNA known to cause illness in humans, consists of a single-stranded DNA core surrounded by an unenveloped icosahedral capsid. PV-B19 requires mitotically active cells and a globoside cellular receptor for propagation, thus making erythroid cell lines a prime target. Erythroid cell line suppression usually lasts up to 2 weeks, although in some cases it is chronic, lasting months to years.[21]
The tropism for human erythroid progenitor cells and other rare sites of the globoside receptor (eg, endothelial cells, placental cells) is responsible for the more serious complications associated with the viral infection.[22, 23]
Transmission of human PV-B19 occurs through respiratory secretions, possibly through fomites, and parenterally via vertical transmission from mother to fetus and by transfusion of blood or blood products.
In a Taiwanese study of the transmission of PV-B19 in men infected with HIV-1/AIDS, Lee et al found that HIV-1 ̶ seropositive men who were injection drug users (IDUs) were significantly more likely to be infected with PV-B19 than were seropositive men who had sex with men (MSM). Using serum samples from 553 male IDUs and 231 MSM, a portion of whom had HIV-1/AIDS, the investigators found PV-B19 infection in 35.4% of the HIV-1 ̶ positive members of the MSM group and in 78.8% of the HIV-1 ̶ positive members of the IDU group.[24]
Although sporadic cases of erythema infectiosum occur, outbreaks are more common. Up to 60% of the population is seropositive for anti ̶ human PV-B19 IgG by age 20 years. The incidence peaks in winter and early spring.[7] Human PV-B19 epidemics appear to occur in a cyclical fashion every 4-7 years and are estimated to affect 30-50% of US households. Community epidemics usually last 3-6 months. Subclinical infections are common. Adults with occupational exposures to children, such as teachers or daycare workers, have a higher risk for PV-B19 seroconversion compared with the general population.[25]
Erythema infectiosum occurs worldwide, especially in temperate climates, with various strains implicated.[26] Antiparvovirus IgG is found equally among Americans, Asians, and Europeans.[27]
Worldwide, epidemics of erythema infectiosum tend to occur in the late winter or early spring, with incidence peaking cyclically every 4-7 years. Approximately 60% of adults are seropositive for PV-B19 by age 20 years. Infection rates vary from 20-50% in schools and households during outbreaks.[28, 29, 30]
Males and females are infected equally by erythema infectiosum, although arthropathy is more common in women. In addition, women may be affected by complications from erythema infectiosum during pregnancy.[31, 32]
Approximately 70% of erythema infectiosum cases occur in children aged 5-15 years, but the disease can develop at any age.[33] PV-B19 infection can lead to the classic symptoms of erythema infectiosum in adults but more often manifests as an acute arthropathy without cutaneous eruption.
Erythema infectiosum (fifth disease) is a self-limited illness that resolves without complications or sequelae in its classic childhood form. Infection in adults, hosts who are immunocompromised, and patients who are anemic or pregnant can result in more significant morbidity.
Human PV-B19 infects erythroid cells, causing a reticulocytopenia that lasts 7-10 days. A healthy host experiences no consequences, since the normal life span of an RBC is 120 days. In patients with a background of shortened RBC survival, such as hemolytic anemia, an acute aplastic crisis ensues. At-risk patients include those with any of the following conditions:
The incidence of human PV-B19–induced aplastic crisis in patients with chronic hemolytic anemia is 2-5% per year. Patients with aplastic crisis continue to be viremic and infectious until RBC recovery occurs.
In patients who are immunocompromised and have little defense against PV-B19, a prolonged viremia may occur, affecting all cell lines of the bone marrow. Immunodeficient states that can lead to bone marrow failure include the following:
PV-B19 can cross the placenta during pregnancy and have a direct cytotoxic effect on fetal RBCs.[34] Infection may lead to the following:
The rash of erythema infectiosum usually is self-resolving but may last several weeks or months with exacerbations from heat or sunlight. The onset of erythema infectiosum rash usually indicates that reticulocytosis has returned and aplastic crisis will not occur.
This is an acute, self-limited exanthem with fine, palpable purpura usually located on the hands and feet, with sharp demarcation at the wrists and ankles. The eruption may be accompanied by fever and aphthous ulcers and occurs more commonly in adults. Rarely, in an acropetechial variant, this eruption can involve the perioral and chin area.[35, 36, 37, 38]
These occur in up to 10% of pediatric patients and up to 50% of adult patients. Arthropathy usually lasts 2-4 weeks, but on rare occasions it can last months to years.
Other illnesses that occasionally may be linked to or triggered by PV-B19 include the following:
Infected children with hemolytic disease or immunosuppression may be quite infectious. Therefore, respiratory isolation, especially from pregnant, chronically anemic, or immunosuppressed individuals, should be observed. Good handwashing and infection control techniques should be encouraged.
Emphasize in discussion with parents that otherwise healthy patients with erythema infectiosum are not infectious once the rash appears; therefore, they do not need to be isolated or restricted from school/day care.
For patient education information, see the Children's Health Center, as well as Fifth Disease and Skin Rashes in Children.
Erythema infectiosum typically has an incubation period of 4-14 days and is spread primarily via aerosolized respiratory droplets. Transmission also occurs through blood products and from mother to fetus.
Mild prodromal symptoms begin approximately 1 week after exposure and last 2-3 days. They include the following:
The symptoms above occur more frequently in adults than in children, especially joint symptoms (up to 50% of adult patients).
These symptoms precede a symptom-free period of about 7-10 days, which is followed by a typical exanthem that occurs in 3 phases (although some patients may manifest no findings).
The exanthem begins with the classic slapped-cheek appearance. The bright red, raised erythema appears abruptly over the cheeks and is marked by nasal, perioral, and periorbital sparing, as demonstrated in the image below.[4] The exanthem may appear like a sunburn, occasionally is edematous, and typically fades over 2-4 days.[1]
View Image | Classic slapped-cheek appearance of fifth disease. |
This phase occurs 1-4 days later and is characterized by an erythematous maculopapular rash on proximal extremities (usually arms and extensor surfaces) and trunk, which fades into a classic lacelike reticular pattern as confluent areas clear.[4] The palms and soles usually are spared, and pruritus is rare. (See the image below.)
View Image | Pathognomonic reticulated, lacy-appearing eruption of fifth disease. |
Frequent clearing and recurrences for weeks or occasionally months may occur due to stimuli such as exercise, irritation, stress, or overheating of the skin from sunlight or bathing in hot water
Other features of the rash are as follows:
When adults are exposed to PV-B19, an acute polyarthropathy is more likely to result than it is in classic erythema infectiosum. Polyarthropathy may start with a typical prodromal illness and some cutaneous aspect of erythema infectiosum but more often manifests simply by a new onset of symmetrical joint pain. Arthropathy is more common in women and can last for days to months.
The following, in decreasing order of frequency, are the most commonly affected sites:
Unlike rheumatoid arthritis, joint pain worsens over the day, and no joint destruction occurs. The synovial fluid is acellular and devoid of viral particles. An association with DR4 histocompatability alleles is recognized.
Rarely, patients may have some mild constitutional symptoms and/or adenopathy. Takeda et al reported renal involvement.[49]
The diagnosis of erythema infectiosum usually is based on clinical presentation alone, and a workup for patients with the classic presentation is not necessary. For patients with other signs or symptoms associated with human parvovirus (PV) B19 or for exposure in a woman who is pregnant, confirmation of infection may be helpful and can be accomplished with the following specialized tests[5, 6, 7] :
Consider determination of the complete blood count (CBC) and serologic testing in the presence of coexisting hemolytic disease, pregnancy, or arthropathy. Human PV-B19 does not grow in standard blood or tissue culture systems.
In infected pregnant patients, maternal alpha-fetoprotein levels and serial ultrasonography followed through the pregnancy may help to predict complications.
Effective noninvasive testing for PV-B19 using quantitative PCR to analyze oral fluid from swabs is currently under development.[50]
Skin biopsy does not aid in diagnosis, but it may reveal nonspecific changes, including mild basilar vacuolation, dyskeratotic cells, and a sparse perivascular infiltrate.
Antibody testing is most commonly performed with RIA and/or ELISA. IgM antibody, which always indicates acute infection, is usually detectable within 3 days of symptom onset. The level peaks at about 3 weeks. IgG antibody confirms previous infection and is observed 2-3 weeks after exposure; it persists for life.
Antibody testing usually is available only through commercial reference laboratories or state health and research laboratories. These tests are unreliable for diagnosing infection in immunosuppressed patients.
Because erythema infectiosum most often is a benign, self-limited disease, reassuring the parents of children with the condition often is the only intervention necessary.[8] For patients with arthralgias or pruritus, symptomatic relief can be obtained using oral analgesics and antihistamines or topical antipruritic lotions.
Activities may be pursued as tolerated, with sun protection or avoidance.
The following referrals are made for patients with erythema infectiosum:
Consider consultation with a hematologist and/or oncologist for patients in aplastic crisis.
Most children with aplastic crisis require hospitalization and probable transfusion and/or intravenous immunoglobulin therapy.
Hospitalized patients with erythema infectiosum need no special isolation precautions; however, patients with aplastic crisis or immunosuppression with human PV-B19 infection should be isolated.
Pregnant health-care workers should be informed of the potential risks to the fetus from PV-B19 infections. They should not be involved in treatment of immunocompromised patients with chronic parvovirus infection or patients with human PV-B19–associated aplastic crisis.
Children with erythema infectiosum are not infectious and may attend child care or school.
Pregnant women in contact with patients in the incubation period of erythema infectiosum or with aplastic crisis have a relatively low potential risk of infection. They can be referred for obstetric follow-up care for possible serologic testing and close fetal monitoring.
Routine exclusion of pregnant women from the workplace where erythema infectiosum is occurring is not recommended, due to the high prevalence of human PV-B19 infection and low incidence of fetal effects.
Because children with erythema infectiosum are contagious prior to the onset of the classic-appearing rash, preventing the spread of this common childhood exanthem is difficult. Attentive parents can only give their children the general good advice to frequently wash their hands and to avoid the sneezes, coughs, and discarded tissues of children who appear sick.
Since children with erythema infectiosum are contagious only during the asymptomatic viremic period (occurring approximately 1 wk before the rash appears), restricting them from attending school is not necessary by the time the clinical diagnosis is made.[51]
Patients with PV-B19–induced aplastic crisis or chronic anemia may be actively viremic during the illness. Patients require routine respiratory isolation, since the virus can be spread via aerosolized respiratory droplets.
Symptomatic relief of erythema infectiosum may be provided using nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve fever, malaise, headache, and arthralgia, along with topical antipruritics and antihistamines (which also relieve pruritus). Treatment also includes plenty of fluids and rest. For an acute aplastic crisis, supplemental oxygen and blood transfusions may be necessary. Intravenous immunoglobulin (IVIG) is helpful for chronic anemia in patients who are immunocompromised.
Clinical Context: This agent has analgesic, anti-inflammatory, and antipyretic properties. It inhibits inflammatory reactions and pain, possibly by decreasing prostaglandin synthesis.
Clinical Context: This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment. It is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.
Clinical Context: Piroxicam is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Clinical Context: Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Clinical Context: Flurbiprofen may inhibit cyclooxygenase, thereby inhibiting prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.
Clinical Context: Indomethacin is absorbed rapidly; it is metabolized in the liver via demethylation, deacetylation, and glucuronide conjugation. It is useful in the diagnosis of CH because it helps other headache syndromes (eg, chronic paroxysmal hemicrania).
NSAIDs provide relief for fever, malaise, headache, and arthralgia. Although the effects of NSAIDs in the treatment of pain tend to be patient specific, ibuprofen usually is the drug of choice (DOC) for initial therapy. Other options include fenoprofen, flurbiprofen, mefenamic acid, ketoprofen, indomethacin, and piroxicam.
Clinical Context: This agent has antipruritic, anxiolytic, and mild sedative effects. It antagonizes H1 receptors in the periphery and may suppress histamine activity in the subcortical region of the central nervous system (CNS).
Clinical Context: Diphenhydramine is used for the symptomatic relief of pruritus caused by the release of histamine in inflammatory reactions.
Clinical Context: Camphor/menthol lotion is a cooling, soothing, moisturizing lotion used to help alleviate pruritus.
Clinical Context: IVIG neutralizes circulating myelin antibodies via anti-idiotypic antibodies, down-regulates proinflammatory cytokines (including interferon-gamma), blocks Fc receptors on macrophages, suppresses inducer T and B cells, augments suppressor T cells, blocks complement cascade, promotes remyelination, and increases IgG in cerebrospinal fluid by 10%.
Immunoglobulin is helpful in chronic aplastic crisis or infected, immunocompromised patients. No evidence indicates that IVIG is beneficial in pregnant women with human parvovirus (PV) B19 infection.