Erythema Infectiosum

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Practice Essentials

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]  Human PV-B19 also is associated with other hematologic, rheumatologic, and neurologic conditions, including polyarthropathy, aplastic anemia, and hydrops fetalis. 



View Image

Classic slapped-cheek appearance of erythema infectiosum (fifth disease).

Signs and symptoms

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 three phases:

See Clinical Presentation for more detail.

Diagnosis

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 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[4, 5, 6] :

See Workup for more detail.

Management

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. Symptomatic relief of erythema infectiosum may be provided by administering 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.

Pathophysiology

The development of erythema infectiosum in children is a normal response to infection by PV-B19. Acute infection in an immunocompetent host 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 and not from the circulating virus.

The incubation period is usually 7-10 days; however, it can be as short as 4 days or as long as 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.[7, 8]

Arthropathy

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.

Aplastic anemia

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).[9] These disease states depend on high red blood cell (RBC) production, due to a shortened cell lifespan. 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.

Bone marrow suppression

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.

Exposure in utero

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. A 1-9% risk of fetal death has been reported in pregnant women exposed to active human PV infection, with a greater risk of fetal loss in early pregnancy.[10] Approximately one half of women of childbearing age are seropositive; therefore, they are immune and are of no risk to the fetus. Specific congenital malformations due to exposure to human PV-B19 in utero have not been identified.[11, 12]

Additional morbidities

Associations between human PV-B19 infection and encephalitis,[13] neuropathies, myocarditis, nephritis, systemic lupus erythematosus (SLE), Henoch-Schönlein purpura, pseudoerysipelas-like eruption, and rheumatoid arthritis (RA) have been described. Many of these associations, however, have not been validated.[14, 15]

Etiology

Erythema infectiosum is caused by infection with PV-B19, a heat-stable virus from the Parvoviridae family that dates back 7000 years in human dental and skeletal genomic studies.[16] 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. It 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 about 2 weeks, though in some cases it is chronic, lasting months to years.[17]

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.[18, 19]

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.

PV-B19 and HIV

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).[20] 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-positive members of the MSM group and in 78.8% of the HIV-positive members of the IDU group.

Epidemiology

United States and international statistics

Although sporadic cases of erythema infectiosum have occurred in the United States, 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.[6] 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 (eg, teachers and daycare workers) have a higher risk for PV-B19 seroconversion as compared with the general population.[21]

In August 2024, the Centers for Disease Control and Prevention (CDC) issued a health advisory regarding increases in PV-B19 activity in the United States.[22]  The percentage of people with IgM antibodies to PV-B19 in all ages increased from the previous level of less than 3% in 2022-2024 to 10% in June 2024; the greatest increase was observed among children between the ages of 5 and 9 years showed the most substantial increase, from 15% in 2022-2024 to 40% in June 2024.

Erythema infectiosum occurs across the world, especially in temperate climates, with various strains implicated.[23] Antiparvovirus IgG is found equally among Americans, Asians, and Europeans.[24]  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 have ranged from 20% to 50% in schools and households during outbreaks.[25, 26, 27]

In june 2024, the European Centre for Disease Control and Prevention (ECDC) released a threat assessment brief regarding increased circulation of PV-B19 in the European Union/European Economic Area (EU/EEA).[28]  Fourteen EU/EEA countries reported unusually high numbers of PV-B19 cases in the first half of 2024.

Age- and sex-related demographics

Approximately 70% of erythema infectiosum cases occur in children aged 5-15 years, but the disease can develop at any age.[29]  PV-B19 infection can occur antenatally.[30, 31] In adults, PV-B19 infection can lead to the classic symptoms of erythema infectiosum, but it more often manifests as an acute arthropathy without cutaneous eruption.

Males and females are infected equally by erythema infectiosum, though arthropathy is more common in women. In addition, women may be affected by complications from erythema infectiosum during pregnancy.[32, 33]

Prognosis

In its classic childhood form, erythema infectiosum is a self-limited illness that resolves without complications or sequelae. However, infection in adults, hosts who are immunocompromised, and patients who are anemic or pregnant can result in more significant morbidity.

Aplastic crisis

Human PV-B19 infects erythroid cells, causing a reticulocytopenia that lasts 7-10 days. Because the normal life span of an RBC is 120 days, healthy hosts will experience no consequences. In patients with a background of shortened RBC survival (as with hemolytic anemia), however, 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.

Chronic bone marrow failure

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:

Congenital infection

PV-B19 can cross the placenta during pregnancy and exert a direct cytotoxic effect on fetal RBCs.[34] Infection may lead to the following:

Rash

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 that aplastic crisis will not occur.

Papular-purpuric gloves-and-socks syndrome

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.[36, 37]

Arthralgias/arthropathies

These occur in as many as 10% of pediatric patients and as many as 50% of adult patients. Arthropathy usually lasts 2-4 weeks, but on rare occasions it can last months to years.

Additional morbidities

Other illnesses that occasionally may be linked to or triggered by PV-B19 include the following:

Patient Education

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.

In discussions with parents, it should be emphasized 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.

History and Physical Examination

Erythema infectiosum (also known as fifth disease) 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 (as many as 50% of adult patients). In adults, parvovirus (PV)-B19 infection may sometimes be mistaken for a systemic rheumatologic disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).[31]

These symptoms precede a symptom-free period of about 7-10 days, which is followed by a typical exanthem that occurs in three phases (although some patients may manifest no findings).

Phase 1

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 (see the image below).[3] The exanthem may resemble a sunburn, occasionally is edematous, and typically fades over 2-4 days.



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Classic slapped-cheek appearance of erythema infectiosum (fifth disease).

Phase 2

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 that fades into a classic lacelike reticular pattern as confluent areas clear.[3] The palms and soles usually are spared, and pruritus is rare. (See the image below.)



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Pathognomonic reticulated, lacy-appearing eruption of erythema infectiosum (fifth disease).

Phase 3

Frequent clearing and recurrences for weeks or occasionally months may occur as a result of stimuli such as exercise, irritation, stress, or overheating of the skin from sunlight or bathing in hot water

Exanthematous characteristics

Other features of the rash are as follows:

Joints

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 is manifested simply by new-onset symmetric 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:

Erythema infectiosum differs from RA in that the 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.

Other signs and symptoms

Rarely, patients may have some mild constitutional symptoms and/or adenopathy. Renal involvement has been reported.[48]

Laboratory Studies

The diagnosis of erythema infectiosum (also known as fifth disease) usually is based on clinical presentation alone; accordingly, no workup is required for patients who have the classic presentation. For patients with other signs or symptoms associated with human parvovirus (PV)-B19 or for exposure in a woman who is pregnant, however, confirmation of infection may be helpful and can be accomplished with the following specialized tests[4, 5, 6] :

Antibody testing is most commonly performed with RIA, ELISA, or both. IgM antibody always indicates acute infection and 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.

In the presence of coexisting hemolytic disease, pregnancy, or arthropathy, serologic testing and determination of the complete blood count (CBC) should be considered. Human PV-B19 does not grow in standard blood or tissue culture systems.

In infected pregnant patients, maternal alpha-fetoprotein (AFP) levels and serial ultrasonography (US) followed through the pregnancy may help predict complications.

Effective noninvasive testing for PV-B19 using quantitative PCR to analyze oral fluid from swabs is being developed.[49]

Histologic Findings

Skin biopsy does not aid in diagnosis, but it may reveal nonspecific changes, including mild basilar vacuolation, dyskeratotic cells, and a sparse perivascular infiltrate.

Medical Care

Because erythema infectiosum (also known as fifth disease) most often is a benign, self-limited disease, it is frequently the case that reassuring the parents of children with the condition is the only intervention necessary.

Symptomatic relief of erythema infectiosum may be provided by using nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve fever, malaise, headache, and arthralgia, along with topical antipruritics and antihistamines (which also relieve pruritus). Although the effects of NSAIDs in the treatment of pain tend to be patient-specific, ibuprofen usually is the drug of choice for initial therapy; alternatives include fenoprofen, flurbiprofen, mefenamic acid, ketoprofen, indomethacin, and piroxicam.

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 in chronic aplastic crisis or infected, immunocompromised patients. IVIG has not been proved to be beneficial in pregnant women with human parvovirus (PV)-B19 infection.

Successful use of interferon alfa-2a to treat persistent PV-B19 infection was described in a case report by Mogensen et al.[50]

Activities may be pursued as tolerated, with sun protection or avoidance.

Inpatient care

Most children with aplastic crisis require hospitalization and will probably need transfusion, IVIG therapy, or both.

Most hospitalized patients with erythema infectiosum need no special isolation precautions; however, patients with human PV-B19 infection who are in aplastic crisis or are immunosuppressed should be isolated.

Pregnant healthcare 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.

Prevention

Because children with erythema infectiosum are contagious before 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 wash their hands frequently and to avoid the sneezes, coughs, and discarded tissues of children who appear sick. Given that children with erythema infectiosum are contagious only during the asymptomatic viremic period (~1 wk before the rash appears), restricting them from attending school is not necessary by the time the clinical diagnosis is made.

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.

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, given the high prevalence of human PV-B19 infection and low incidence of fetal effects.

Consultations

The following referrals are made for patients with erythema infectiosum:

For patients in aplastic crisis, consultation with a hematologist or oncologist should be considered.

Ibuprofen (Advil, Motrin, PediaCare Children's Pain Reliever/Fever Reducer IB)

Clinical Context: 

Diclofenac (Cambia, Cataflam, Dyloject)

Clinical Context: 

Piroxicam (Feldene)

Clinical Context: 

Naproxen (Aleve, Anaprox, Anaprox DS)

Clinical Context: 

Flurbiprofen (Ansaid, Flurprofen, Froben)

Clinical Context: 

Indomethacin (Indocin, Indocin SR (DSC), Tivorbex (DSC))

Clinical Context: 

Mefenamic acid

Clinical Context: 

Immune globulin IV (IGIV) (Alyglo, Asceniv, Bivigam)

Clinical Context: 

Hydroxyzine (Vistaril)

Clinical Context: 

Diphenhydramine (Alka-Seltzer Plus Allergy, Benadryl, Benadryl Allergy Dye-Free LiquiGels)

Clinical Context: 

Camphor/menthol topical (Icy Hot Arthritis Lotion, Sarna Anti-Itch Original Lotion)

Clinical Context: 

What is erythema infectiosum (fifth disease)?What are the signs and symptoms of erythema infectiosum (fifth disease)?What are stages of erythema infectiosum (fifth disease)?Which specialized tests are performed in the diagnosis of erythema infectiosum (fifth disease)?How is erythema infectiosum (fifth disease) treated?What is erythema infectiosum (fifth disease)?What is the pathophysiology of erythema infectiosum (fifth disease)?What are the indications of arthropathy in patients with erythema infectiosum (fifth disease)?What are the indications of aplastic anemia in patients with erythema infectiosum (fifth disease)?What are the indications of bone marrow suppression in patients with erythema infectiosum (fifth disease)?What are the indications of fetal transmission of erythema infectiosum (fifth disease)?What are the comorbidities of erythema infectiosum (fifth disease)?What causes erythema infectiosum (fifth disease)?What is the prevalence of erythema infectiosum (fifth disease) in the US?What is the global prevalence of erythema infectiosum (fifth disease)?What are the sexual predilections of erythema infectiosum (fifth disease)?Which age groups have the highest incidence of erythema infectiosum (fifth disease)?What is the prognosis of erythema infectiosum (fifth disease)?Which patients are at risk for aplastic crisis with erythema infectiosum (fifth disease)?Which patients are at risk for bone marrow failure with erythema infectiosum (fifth disease)?What is the mortality and morbidity associated of congenital erythema infectiosum (fifth disease)?What is the significance of rash in patients with erythema infectiosum (fifth disease)?What are the signs and symptoms of papular-purpuric gloves-and-socks syndrome in patients with erythema infectiosum?What is the prevalence of arthropathies in erythema infectiosum (fifth disease)?Which conditions may be triggered by erythema infectiosum (fifth disease)?What should be included in patient education about erythema infectiosum (fifth disease)?What is the incubation period and transmission mode of erythema infectiosum (fifth disease)?What are the prodromal symptoms of erythema infectiosum (fifth disease)?What are the phase 1 symptoms of erythema infectiosum (fifth disease)?What are the phase 2 symptoms of erythema infectiosum (fifth disease)?What are the phase 3 symptoms of erythema infectiosum (fifth disease)?How is the rash of erythema infectiosum (fifth disease) characterized?How does erythema infectiosum (fifth disease) manifest in the joints?What are constitutional signs and symptoms of erythema infectiosum (fifth disease)?Which conditions should be included in the differential diagnosis of erythema infectiosum (fifth disease)?What are the differential diagnoses for Erythema Infectiosum?What is the role of lab testing in the diagnosis of erythema infectiosum (fifth disease)?Which histologic findings are characteristic of erythema infectiosum (fifth disease)?What is the role of RIA and/or ELISA in the workup of erythema infectiosum (fifth disease)?How is erythema infectiosum (fifth disease) treated?Which specialist consultations are beneficial for patients with erythema infectiosum (fifth disease)?How is erythema infectiosum (fifth disease) prevented?What is included in inpatient care for erythema infectiosum (fifth disease)?What precautions should be taken by pregnant women to decrease the risk of contracting erythema infectiosum (fifth disease)?Which medications are used in the treatment of erythema infectiosum (fifth disease)?Which medications in the drug class Anesthetics, Topical are used in the treatment of Erythema Infectiosum?Which medications in the drug class Antihistamines, 1st Generation are used in the treatment of Erythema Infectiosum?Which medications in the drug class Immune Globulins are used in the treatment of Erythema Infectiosum?Which medications in the drug class NSAIDs are used in the treatment of Erythema Infectiosum?

Author

Glenn L Zellman, MD, Consulting Staff, Department of Internal Medicine, University Hospital, Tamarac, Florida

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Megan Boysen, MD Resident Physician, Department of Emergency Medicine, University of California Irvine Medical Center

Megan Boysen, MD, is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Kenneth T Kwon, MD Director of Pediatric Emergency Medicine, Associate Clinical Professor, Department of Emergency Medicine, University of California at Irvine Medical Center, Co-Director, Pediatric Emergency Services, Mission Regional Medical Center/Children's Hospital of Orange County at Mission

Kenneth T Kwon, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Pediatrics, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Van Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery

Disclosure: Nothing to disclose.

Debra Slapper, MD Consulting Staff, Department of Emergency Medicine, St Anthony's Hospital

Debra Slapper, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Wayne Wolfram, MD, MPH Associate Professor, Department of Emergency Medicine, Mercy St Vincent Medical Center

Wayne Wolfram, MD, MPH is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Pediatrics, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

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Classic slapped-cheek appearance of erythema infectiosum (fifth disease).

Classic slapped-cheek appearance of erythema infectiosum (fifth disease).

Pathognomonic reticulated, lacy-appearing eruption of erythema infectiosum (fifth disease).

Classic slapped-cheek appearance of erythema infectiosum (fifth disease).

Pathognomonic reticulated, lacy-appearing eruption of erythema infectiosum (fifth disease).