Parvovirus B19–Related Diseases

Parvovirus B19 causes erythema infectiosum (“fifth disease” or “slapped-cheek disease”) in children as well as the papular-purpuric “gloves-and-socks” syndrome (PPGSS). Infection may also cause polyarthritis, hydrops fetalis in pregnancy, aplastic anemia in persons with underlying hematologic disorders, and chronic anemia in immunocompromised persons.

Etiology AND PathogenesisTop

1. Etiologic agent: Human parvovirus B19 (Parvoviridae family) is a DNA virus that causes viremia and replicates exclusively in erythroid progenitor cells.

2. Reservoir and transmission: Humans are the only reservoir for parvovirus B19; the source of infection is an infected individual. Parvovirus B19 is transmitted predominantly via large infectious respiratory particles (IRPs) (historically termed droplets) but may also spread via blood products (very rarely) and transplacental infection from mother to fetus.

3. Incubation and contagious period: The disease is highly contagious, with attack rates of up to 60%. The incubation period is 4 to 14 days. In erythema infectiosum, viral loads peak within 6 to 10 days of infection, when the risk of transmission is highest, and decrease with the onset of rash. Viral shedding lasts ~1 week and patients are unlikely to be infectious after the appearance of rash. Patients may remain asymptomatic or only have nonspecific influenza-like symptoms. However, patients with PPGSS are contagious for the entire duration of rash, and patients with aplastic crisis are contagious before the onset of symptoms and for ≥1 week after symptoms have appeared.

Clinical FeaturesTop

The course of parvovirus B19 infection is frequently asymptomatic (25%) or associated with mild influenza-like symptoms (50%). Symptomatic disease most commonly manifests as erythema infectiosum.

1. Erythema infectiosum:

1) Initial prodromal symptoms are associated with viremia and include upper respiratory tract infection (rhinitis, pharyngitis, cough), fever, malaise, headache, myalgia, diarrhea, and nausea. The symptoms resolve usually within 7 days with the appearance of specific IgM antibodies.

2) Rash: Immune complex–mediated rash develops within 7 to 10 days of the onset of the disease (upon the appearance of specific IgG antibodies); this is the most characteristic sign of infection (observed in most children but in <50% of adults). Initially, a bright red, slightly elevated and well-demarcated erythema appears on the cheeks, sparing the nasal bridge and area around the mouth. Over the next 1 to 4 days, erythematous macules and papules appear on the arms, trunk, buttocks, and lower extremities, subsequently evolving into erythematous coalescent blotches with a lacy, net-like appearance, particularly distinct on the extensor surfaces and trunk. The palms and soles remain free of rash. The rash may remit and relapse over a period of 1 to 3 weeks or longer, but usually lasts ~10 days. In adults, it may be pruritic. The rash may worsen with increased physical activity or increased body temperature.

3) Arthritis: Immune complex–mediated arthritis develops predominantly in adults, more frequently in women (children are affected in ~10% of cases). Arthritis may coincide with the onset of rash or appear as the only manifestation of the disease. The clinical presentation is dominated by pain (affecting 77% of patients >20 years); swelling is less frequent (observed in 57% of patients >20 years) and usually affects the small joints of the hand, wrist, knee, and ankle. The disease is self-limiting (usually resolves within 3 weeks, but may persist for several months) and does not cause joint damage.

2. PPGSS:

1) A mild prodromal phase: Fever, loss of appetite, arthralgia.

2) The onset of rash during the prodromal phase with viremia; painful edema and erythema involve both hands and feet and are associated with petechial and purpuric eruptions. The lesions may also involve the dorsal surfaces of hands and feet, with sharp demarcation at the wrists and ankles, and are frequently accompanied by a burning sensation and pruritus. The rash usually disappears within 1 to 3 weeks.

3) Development of oral mucosal lesions: Erosions, vesicles, lip edema, petechiae on the hard palate and the pharyngeal and lingual mucosa. The lesions of the oral mucosa may appear concomitantly with skin lesions and resolve spontaneously after 7 to 14 days.

3. Chronic anemia results from an inadequate or absent antibody response that allows the virus to persist, leading to red cell aplasia. Chronic anemia occurs in immunocompromised patients (those with primary immunodeficiency syndromes, malignancy, HIV infection, transplant recipients, and those with other causes of immunosuppression) as a consequence of a chronic parvovirus B19 infection of erythroid progenitor cells. The clinical picture may be that of pure red cell aplasia (PRCA), but also that of pancytopenia.

4. Transient aplastic crisis: This may occur in patients with hemolysis or decreased red blood cell production (sickle cell disease, thalassemia, hereditary spherocytosis), in whom viral replication results in a further decrease of red blood cell production and rapid hemolysis with an abrupt fall in hemoglobin concentrations. Usually there is no rash and no reticulocytes are seen. Transient aplastic crisis is associated with the clinical features of severe anemia.

5. Hydrops fetalis: Parvovirus infection in pregnant women may result in fetal anemia and hydrops fetalis, or may lead to miscarriage, particularly when infection occurs before 20 weeks’ gestation.

6. Rarely, parvovirus manifests as hepatitis, myocarditis, vasculitis, leukocytopenia, hemophagocytic lymphohistiocytosis, or encephalitis. Hepatitis affects ~4% of patients with parvovirus B19 infection and resolves spontaneously.

DiagnosisTop

Diagnosis is based on the clinical features. Diagnostic tests are usually not needed. When necessary, the diagnosis is confirmed by the following:

1) In immunocompetent patients: A positive serology result; detection of parvovirus B19 IgM antibodies in serum indicates an infection within the previous 7 to 120 days; detection of a 4-fold increase of IgG also indicates acute infection. Specific IgG antibody appears within 2 weeks of infection and persists for many years (indicating a past infection). The presence of low-avidity antibodies suggests a recent infection. False-positive IgM antibodies may occur in the presence of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti–Epstein-Barr virus (EBV) IgM (cross-reactivity).

2) In immunocompromised patients, patients with transient aplastic crisis, or pregnant patients: Detection of parvovirus B19 DNA in blood or amniotic fluid by molecular testing (polymerase chain reaction [PCR]). Serologic tests may be negative. PCR may remain positive for 9 months after infection, and therefore is unhelpful in diagnosing acute infection.

Bone marrow examination reveals features of hypoplasia and the presence of characteristic giant pronormoblasts.

Differential Diagnosis

1. Erythema infectiosum: Rash of other viral (echovirus 12, rubella, measles, enterovirus, or adenovirus infections) or bacterial (scarlet fever) etiology, erythema multiforme, arthritis and vasculitis in connective tissue diseases, and drug-induced reactions (including serum sickness).

2. PPGSS: Thrombocytopenia; IgA-associated vasculitis (Henoch-Schönlein purpura); hand-foot-and-mouth disease (HFMD) (coxsackievirus or enterovirus infection); infectious mononucleosis; cytomegalovirus infection; human herpesvirus 6 (HHV-6) infection; hepatitis B.

3. Chronic anemia and aplastic crisis (see Aplastic Anemia).

TreatmentTop

Antiviral Treatment

No antiviral treatment is available. In immunocompromised patients with chronic infection, intravenous immunoglobulin (IVIG) is suggested.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the only observational nature of the existing data. Crabol Y, Terrier B, Rozenberg F, et al; Groupe d’experts de l’Assistance Publique-Hôpitaux de Paris. Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a retrospective study of 10 patients and review of the literature. Clin Infect Dis. 2013 Apr;56(7):968-77. doi: 10.1093/cid/cis1046. Epub 2012 Dec 12. Review. PMID: 23243178. No standard dosage has been established; the recommended doses are 1 to 1.5 g/kg for 3 days or 400 mg/kg for 5 to 10 days. The use of IVIG in immunocompetent individuals with arthritis is controversial. In patients receiving immunosuppressive therapy, consider reducing immunosuppression. IVIG dosed 400 mg/kg daily for 5 to 10 days is used to treat parvovirus B19–associated transient aplastic crisis.

Symptomatic Treatment

When needed, use antipyretics (acetaminophen [INN paracetamol], ibuprofen) or other nonsteroidal anti-inflammatory drugs (to reduce arthralgia). It is recommended that antiretroviral therapy and IVIG be administered to patients with HIV infection, and that patients with aplastic crisis and chronic anemia be administered packed red blood cells and IVIG.

Follow-UpTop

Follow-up visits are recommended in immunocompromised patients and patients with chronic hemolysis to monitor for severe anemia.

It is recommended that pregnant women exposed to parvovirus B19 should be tested for specific serum IgG. If parvovirus IgG is present and IgM is negative, the woman is immune. While a negative IgG indicates susceptibility to infection, the absolute risk of fetal infection is low. A diagnosis of an acute parvovirus B19 infection during pregnancy (positive IgM or positive viral DNA) would be an indication for ultrasonography repeated every 1 or 2 weeks for 10 to 12 weeks to detect the development of fetal anemia and hydrops.

ComplicationsTop

Complications of parvovirus B19 infection include transient anemia and reticulocytopenia (rare in otherwise healthy individuals, usually asymptomatic); erythema multiforme; severe anemia with hydrops fetalis (the most frequent cause for nonimmune generalized fetal edema), miscarriage, or fetal death. The rate of transplacental transmission of parvovirus B19 is ~30%; the risk of pregnancy loss due to infection is 8% to 10%, highest before 20 weeks’ gestation. The overall incidence of hydrops fetalis following maternal infection is 2.9%, but it is higher if infection occurs earlier in pregnancy. Rare complications include myocarditis, vasculitis, glomerulonephritis, and encephalitis.

PrognosisTop

In low-risk patients the course of infection is mild and infection resolves spontaneously without sequelae. Rash may continue to recur over several months; arthritis can persist for several months, occasionally even years. Immunocompetent individuals acquire long-term immunity upon recovery. Immunocompromised patients are at risk of chronic infection.

PreventionTop

In health care settings, IRP (droplet) precautions are recommended for symptomatic individuals, in particular patients with aplastic crisis or immunocompromised persons who remain contagious for a longer time. Pregnant women should avoid contact with patients with prolonged viral replication. Vaccine is not available.