Erythema Infectiousum (Fifth Disease, Slapped Cheek Syndrome)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Characteristic findings on physical examination

The diagnosis of erythema infectiousum (EI) is a clinical diagnosis that can be made with a careful history and physical examination. The classic course of illness involves three distinct stages:

A mild prodromal illness characterized by low-grade fever, headache, malaise, myalgia, and gastrointestinal complaints.
A bright erythematous exanthem on the face. The rash involves the malar eminences and spares the nasal bridge and perioral area, giving the characteristic “slapped-cheek” appearance.
A lacy, erythematous, maculopapular exanthem on the trunk and extremities (Figure 1).
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Characteristic lacy, erythematous maculopapular exanthem of erythema infectiosum.

The distinct stages of EI may be variable. For example, the prodromal stage (stage 1) may be very mild and may be unrecognized; the facial exanthem may be pronounced in some patients but not in others; the rash in the third stage may range from a very faint erythema to a florid confluent exanthem.

The classic facial exanthem classically occurs 3-7 days after the prodrome, while the lacy, reticular exanthem develops 1-4 days after the appearance of the facial rash. The facial eruption may become more marked with exposure to sunlight, while the lacy reticular rash on the trunk and extremities may be pruritic and often is evanescent, recurring over 1-3 weeks. Recurrences and accentuation of the exanthem may be related to environmental factors, such as exposure to sunlight, hot baths, and physical activity.

In general, patients with erythema infectiousum are well appearing, and do not appear toxic. Fever, which may be present in the prodromal stage, is low-grade and usually not present during the exanthematous stages.

Arthralgias and arthritis may accompany EI, occuring most commonly among adult women and much less commonly among children. A symmetrical polyarthropathy of the knees and fingers is common in adults, while asymmetrical involvement of the knees is most common in children.

Expected results of diagnostic studies

Diagnostic studies for EI are not needed under most circumstances because the symptoms commonly resolve in several days. Patients who have underlying disorders, such as hemoglobinopathies and immunodefiencies, or who have unusual manifestations of the illness, such as arthropathy, may require serologic testing or viral DNA detection to confirm the diagnosis.

Serum parvovirus B19-specific immunoglobulin (Ig) M antibody is the preferred diagnostic test for immunocompetent patients. The development of parvovirus B19-specific IgM antibody occurs during the first stage of EI and is detected in over 90% of patients with EI. Thus, a positive IgM test is indicative of recent infection (within the previous 2-4 months). Some caution is warranted however, as the specificity of the IgM tests vary, and false-positive tests may occur because of cross-reactions to other viruses and antigens.

Parvovirus B19-specific IgG antibody appears during stage 2 of EI and persists for life. Thus, the presence of parvovirus B19-specific IgG is not necessarily indicative of acute infection. A seroconversion from a negative test for parvovirus B19-specific IgG to a positive test, or a significant rise in IgG titer against parvovirus B19 is evidence of an acute or recent infection.

Because immunocompromised patients may not be able to mount an immune resonse to the virus, serologic tests may not be reliable. For these patients, detection of the virus from the serum with the use of polymerase chain reaction (PCR) assays or by dot blot hydridization is the optimal method. However, these assays may be too sensitive and persistence of parvovirus B19 DNA in the serum by PCR may persist for several months after viremia. Thus, similar to IgM serologic tests, false-positive test results may occur, underscoring the importance of clinical correlation.

Diagnosis confirmation

The characteristic facial eruption followed by the lace-like reticular pattern of the exanthem of EI can serve to distinguish EI from most other viral exanthems. However, when EI does not follow the classic clinical pattern, distinguishing it from other viral exanthems can be difficult. Measles, rubella, roseola, streptococcal scarlet fever, drug reactions, and vasculitis are in the differential diagnosis of EI. Reliance of epidemiologic factors and other clinical clues can be important in these cases:

Patients with measles are ill-appearing, have high grade fever throughout their exanthematous period, a marked prodrome of cough, coryza and conjunctivitis, and the presence of Koplik spots, all of which would help differentiate measles from EI.

Rubella may have a mild prodrome, a discrete exanthem on the face and trunk, and accompanying arthropathy. The nature of the facial exanthem (acneiform), presence of lymphadenopathy (especially suboccipital), and the immunization history will help differentiate rubella from EI.

Roseola (nonspecific maculopapular exanthem) follows several days of very high fever and is almost exclusively an illness of young infants (6m-2y), while EI is an illness most commonly affecting school-aged children. Streptococcal scarlet fever may mimic EI. The presence of a significant pharyngitis with tonsillar exudates or palatal petechiae, along with the characteristic rough ‘sandpapery” rash and a strawberry tongue, will help distinguish this from EI.

Drug reactions may mimic EI. A history of medications and the lack of a prodrome should help diffentiate these reactions from EI. The time course of EI (several days) would help to differentiate it from collagen vascular diseases, in which patients have prolonged illness and more chronically ill appearance.

Who is at Risk for Developing this Disease?

Most individuals acquire the infection during childhood or early adulthood. About 50% of children become infected with the virus that causes EI by the time they reach the age of 15 years. Fifty to eighty percent of adults are seropositive for antibodies to the virus. Although most individuals become infected with the virus that causes EI, most persons with infection remain asymptomatic. Thus, asymptomatic infection is the most common result of infection.

EI most commonly occurs in children between the ages of 4 and 10 years, and infection most commonly occurs in late winter and spring. Respiratory spread of the virus is the most common route of transmission. Transmission of the virus occurs readily with household exposure, as well as in school and child care centers.

What is the Cause of the Disease?

Etiology

Pathophysiology

The clinical manifestations of EI have been recognized for decades, being the “Fifth” exanthem of childhood described. However, it was not until the early 1980’s that human parvovirus B19 was found to be the definitive etiologic agent of EI.

Parvovirus B19 is a single-stranded DNA virus that has a predilection for infecting rapidly dividing cell lines, such as bone marrow erythroid pregenitor cells.

The pathogenesis of infection corresponds to the clinical stages of EI. The incubation period of the virus is 4-14 days, after which viremia occurs and causes progenitor cell depletion in the bone marrow. Constitutional symptoms (prodrome) may occur at this time. At the height of the viremia, a precipitous drop in the reticulocyte count occurs followed by anemia, which in the normal host, is clinically inapparent. This may cause severe anemia however, in persons who have chronic hemoglobinopathies, such as patients with sickle cell disease.

It is during the first stage, which corresponds to the period of viremia, that transmission of the virus can occur. Thus, persons are contagious prior to the development of the rash. The appearance of parvovirus B19-specific IgM antibodies correspond with the clearance of the viremia.

In the third week after inoculation of the virus, specific IgG antibodies develop in the serum, and this corresponds with the rash of EI and the possible appearance of arthropathy. It is important to remember the the appearance of the rash signifies the clearance of the viremia. Thus, the virus can no longer be transmitted by the time the rash appears.

Systemic Implications and Complications

Parvovirus B-19, the etiologic agent of EI, has been implicated as a cause of arthropathy, erythrocyte aplasia, chronic anemia in immunocompromised patients, and intrauterine infection.

About 60% of symptomatic parvovirus B-19 infections in adults involve arthropathy. This occurs mostly in females and is characterized by an acute onset of arthralgias or frank arthritis involving the knees, hands, wrists, and ankles. This is mostly a self-limited disorder, although 20% of women will have persistent or recurring arthropathy for months to years. Constitutional symptoms accompanying the arthropathy is rare, although a transient generalized rash and the typical facial exanthem are occasionally present.

Arthropathy associated with EI is much less common in children than adults. When present, the arthropathy in children most commonly affects the large joints such as the knees, ankles and wrists, usually in an asymmetric pattern. The illness is transient in most cases, although prolonged findings have been described.

The diagnosis of parvovirus B19 arthropathy relies on positive parvovirus B19-specific IgM antibody or a significant rise in parvorirus B19-specific IgG titers.

Because parvovirus B19 has a predilection for infecting the erythrocyte progenitor cells in the bone marrow, patients who have underlying hematologic abnormalities, such as sickle cell anemia and thallasemia, may experience a transient aplatic crisis when they are infected with this virus. Typically, these patients have a viral prodrome followed by significant anemia and reticulocytosis.

The finding of pronormoblasts on bone marrow examination of patients wtih anemia is suggestive parvovirus B19 infection. Viral DNA isolation from the blood or bone marrow by dot blot isolation or polymerase chain reaction is helpful in the diagnosis.

Chronic parvovirus B19 of infection of the bone marrow has been described in immunocompromised patients, such as patients with human immunodeficiency virus infection, hematologic transplant recipients, and solid organ transplant recipients. Infection in these hosts may result in severe, prolonged, and recurrent anemia. The diagnosis can be established by demonstrating the presence of the virus in the blood or bone marrow by DNA detection methods.

Parvovirus B19 can lead to fetal infection, possibly resulting in miscarriage or nonimmune fetal hydrops. The precise incidence of fetal infection is not known, but the likelihood of a healthy outcome is very high following parvovirus B19 infection in pregnancy. At least 50% of pregnant women are immune to the virus and thus are not susceptible to infection. Despite the occurrence of infection in susceptible women during pregnancy, fetal loss after intrauterine infection has been estimated to be very low, in the order of 1-2%.

Women of childbearing age who are concerned about parvovirus B19 infection can undergo serologic testing for IgG antibody to determine if they are susceptible to infection. Fetal ultrasonography can be used to help determine the presence of adverse effects on the fetus if there is concern about fetal parvovirus B19 infection.

Treatment Options

Management of parvovirus infection must take into account the severity of the infection and the underlying status of the host. EI in healthy hosts is self-limted and no specfic therapy is warranted.

Patients with arthropathy may be treated with nonsteroidal anti-inflammatory agents for symptomatic relief.

Patients with a transient aplastic crisis and chronic anemia may require blood tranfusions to prevent congestive heart failure from anemia.

Immunocompromised patients with parvovirus-related chronic anemia may be treated with intravenous immune globulin, which is often effective.

Intrauterine blood transfusions have been used successfully to treat cases of severe parvovirus B19-related hydrops fetalis.

Optimal Therapeutic Approach for this Disease

Management of parvovirus infection must take into account the severity of the infection and the underlying status of the host. In healthy hosts the infection is self-limited and no specfic therapy is warranted.

It is important to remember that children with EI are not contagious. The period of contagion is 1-2 weeks before the appearance of the exanthem. Thus, children wih EI may attend school or child care, because they are no longer contagious at the time that the rash appears.

Patient Management

Patients and families with EI and arthropathy should be assured that the illness is viral in nature and that the course is benign and self-limited.

Patients with hemoglobinopathies or immunodeficiency who develop aplastic anemia and chronic anemia should be counseled that anemia is a major complication and that close monitoring of serum hemoglobin levels should be undertaken. Blood transfusions should be given based on the degree of anemia, the presence of symptoms and the risk of congestive heart failure.

Unusual Clinical Scenarios to Consider in Patient Management

Women of childbearing age who are exposed to children at home or at school are at increased risk of parvovirus B19 infection. However, given the high prevalence of parvovirus infection (immunity), the low incidence of ill effect on the fetus, the fact that asymptomatic infection is common and the ubiquitous nature of the virus, exclusion of pregnant women from the workplace where EI is occurring, is not recommended. Women who are concerned can undergo serologic testing to determine if they are immune.

Patients with aplastic crisis or chronic anemia may shed the virus via the respiratory route and should be maintained in droplet isolation when admitted to the hospital.

Transmission of the virus can be decreased through the use of standard infectious control practices, such as strict handwashing, or the use of alcohol based hand sanitizers.

What is the Evidence?

Dyer, JA. “Childhood viral exanthems”. Pediatr Annals. vol. 36. 2007. pp. 21-9. (Athorough review of the classic exanthems of childhood, including the agents that most mimic erythema infectiousum.)

Young, NS, Brown, KE. “Parvovirus B19”. N Engl J Med. vol. 350. 2004. pp. 586-97. (A in-depth review of the epidemiology, clinical features,andpathophysiologic mechanisms of parvovirus infection. Includes an excellent discussion of the pathophysiologic mechanisms of infection in normal and immunocompromised hosts.)

Katta, R. “Parvovirus B19: a review”. Dermatol Clin. vol. 20. 2002. pp. 333-42. (A nice summary of the clinical features of parvovirus infections, with particular attention to the dermatologic manifestations. Includes a good discussion of at-risk populations for severe or unusual infections with this virus.)

Vafaie, J, Schwartz, RA. “Parvovirus B19 infections”. Int J Dermatol. vol. 43. 2004. pp. 747-49. (A brief review of the clinical description, diagnosis, and managment of parvovirus infections.)

Staroselsky, A, Klieger, Grossmann, Garcia, Bournissen, Koren, G. “Exposure to fifth disease in pregnancy”. Can Fam Phys. vol. 55. 2009. pp. 1195-98. (A well-done review of the risk, diagnosis, and management of the pregnant mother who is exposed to fifth disease. The abstract hghlights an actual clinical scenario in which a pregnant mother is exposed to fifth disease, and highlights the current guideline for management.)

Bonvicini, F, LaPlaca, M, Manaresi, E. “Parvovirus B19 DNA is commonly harboured in human skin”. Dermatology. vol. 220. 2010. pp. 138-42. (Well-done investigation of the presence of parvovirus B19 DNA is patients with skin lesions of patients with parvovirus B19 related diseases, parvovirus B19 unrelated diseases, and normal skin. The surprising finding that the viral DNA is found in skin tissue of patients with parvoviral-related diseases and normal skin is intruiging and suggests that the virus persists in tissue after primary infection. This report serves to remind us that caution should be exercised in attributing skin disorders to this virus.)

Kellermayer, R, Faden, H, Grossi, M. “Clinical presentation of parvovirus B19 infection in children with aplastic crisis”. Pediatr Infect Dis J. vol. 22. 2003. pp. 1100-01. (This study highlights the fact that children with hemoglobinopathies do not have the same clinical manifestations as normal children. The lack of a rash in children with hemoglobinopathis upon presentation is common.)

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