Parvovirus infection

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Parvovirus infection

Andrea L. Zaenglein and Heather L. Salvaggio

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Infection with human parvovirus B19 (HPB19) causes a variety of well-described exanthems and can result in a spectrum of systemic illness. Erythema infectiosum, also known as ‘Fifth’ disease according to the original classification of childhood exanthems, is the classic and most common eruption associated with HPB19 infection. Outbreaks occur in the winter and spring, and affect school-aged children between 5 and 15 years of age. The infection is transmitted via respiratory droplets. Following a short variable prodrome of fever, malaise, diarrhea, and pharyngitis, the classic features of the exanthem appear. Bright pink macular erythema of the cheeks (‘slapped cheek sign’) together with nasal bridge and circumoral pallor precedes an evanescent macular, reticulated or ‘lace-like’ rash over the trunk and proximal limbs. The rash may last for up to 4 weeks and subsequently may recur following exposure to sun, warm temperature, and intense physical activity (see Figure). Purpuric eruptions, most commonly the papular purpuric gloves and socks syndrome, are also reported in association with HBP19. Arthropathy is another common finding particularly in older patients affected with HPB19. Other systemic manifestations of HBP19 infection include idiopathic thrombocytopenic purpura, hemophagocytic syndrome, lymphadenitis, meningitis and encephalitis, hepatitis, myocarditis, nephritis, and vasculitis. In patients with a predisposing hematological condition, infection with HPB19 may cause a transient aplastic crisis. Chronic and secondary infections have been encountered in immunosuppressed patients and rarely in immunocompetent patients. Primary infection during pregnancy may place the fetus at risk for severe anemia, thrombocytopenia, hydops fetalis, neurologic sequelae, and intrauterine fetal demise.

Management strategy

Erythema infectiosum is typically a self-resolving exanthem. In the majority of cases, supportive care and reassurance is all that is required. The rash of erythema infectiosum is immune complex mediated so patients are assumed to be no longer infectious by the time that it appears. HPB19 IgG is detectable in the blood once the eruption occurs. Once a clinical diagnosis has been made, parents can be reassured and advised on simple supportive measures such as antipyretics, fluids, and simple emollients for the rash. The condition is self-resolving in the majority of immunocompetent patients.

The clinician should be aware of a variety of other less common cutaneous presentations of HPB19 infection, including both petechial and non-petechial eruptions. The most common is the papular-purpuric ‘gloves and socks’ syndrome (PPGSS). This consists of pruritic to painful edema, erythema, and petechiae of the hands and feet with a classic sharp demarcation at the wrist and ankles. This eruption may be seen together with the ‘slapped cheek’ sign. An enanthem may occur with palatal, pharyngeal, labial and lingual erythema, petechiae, and ulcerations. A diffuse papular exanthem, fever, and other non-specific viral symptoms may accompany the eruption. PPGSS is seen more often in the spring and summer and typically occurs in adolescents and young adults. Unlike in erythema infectiosum, patients with PPGSS have been reported to be viremic while the rash is present and are thus contagious. The eruption typically resolves within 1 to 2 weeks with simple supportive measures. More generalized petechial eruptions have been reported either primarily or following classic erythema infectiosum. The acropetechial syndrome involves the perioral skin in addition to the hand and foot involvement classically seen in PPGSS. A petechial eruption in a bathing trunk distribution has also been described. Parvovirus should be suspect with all petechial rashes whose origin is undetermined. Asymmetric periflexural exanthema (unilateral lateral thoracic syndrome) and papular acrodermatitis of childhood (Gianotti–Crosti syndrome) have been described following HPB19 infection. HPB19 is also in the differential diagnosis of the ‘blueberry muffin’ baby. Other possible associations with cutaneous manifestations include erythema nodosum, erythema multiforme, livedo reticularis, vasculitis, Sweet’s syndrome, and Behçets disease.

HPVB19 infection may cause a symmetric arthropathy in many adults, most commonly women, and up to 10% of children. It is similar to rheumatoid arthritis involving the wrists, ankles, knees, metacarpophalangeal and proximal interphalangeal joints. Arthropathy may accompany the cutaneous eruption, but frequently follows it. The arthritis is usually self-limited in both adults and children, requiring only non-steroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief. Occasionally the arthritis may lead a more chronic course and it has been suggested that infection with HPB19 may be a trigger for autoimmune arthritis and connective tissue disease.

HPB19 is extremely tropic for proerythroblasts, granulocytes, and platelets. It binds to globoside on the erythrocyte precursor cell membrane, where it is endocytosed, replicates, and causes cellular apoptosis. In predisposed individuals with either an underlying disorder of hemolysis, decreased erythrocyte production, or active bleeding, HPB19 infection can cause a transient aplastic crisis. This acute anemia may be self-limited and asymptomatic but transfusion may be indicated if severe. In addition to anemia, there may be moderate neutropenia and thrombocytopenia. Potentially fatal marrow necrosis rarely occurs in very young children. Severe cases of transient aplastic crisis not responding to transfusion may require intravenous immune globulin (IVIG) and even bone marrow transplantaion. Chronic HPB19 infection in immunosuppressed patients can result in pure red blood cell aplasia, a form of chronic anemia which results from the inability to create neutralizing antibodies to the virus. This is treated with IVIG, which is often curative. Of interest, parvovirus B19 can contaminate blood products, including bone marrow, and may have the ability to transmit infection through this means. Children who are already anemic due to other causes, such as malaria, malnutrition or parasites, can become profoundly anemic with HPB19 infection.

Patients with AIDS and chronic anemia secondary to HPB19 infection, who are treated with highly active antiretroviral therapy (HAART), with recovery of CD4 counts, have had resolution of their anemia with documented seroconversion from IgM to IgG antiparvovirus antibodies. Other AIDS patients started on HAART experienced an immune reconstitution syndrome. With the development of renewed immunity, AIDS patients can experience overwhelming systemic involvement of parvovirus, resulting in encephalitis, severe anemia or other severe sequelae.

Fetal infection with parvovirus B19 may result in mild to severe anemia, thrombocytopenia, high output congestive heart failure, non-immune hydrops fetalis, and fetal death. Fetal stroke and other neurologic sequelae have been reported. Fetal infection occurs usually during the first 20 weeks of pregnancy, though third trimester hydrops related and spontaneous non-hydrops related fetal demise have been reported. One-third or more women of childbearing age do not have IgG antibodies to HPB19 and are susceptible to primary infection. Vertical transmission occurs in 33% of women and fetal complications occur in 3% of infected women. Vertical transmission is higher during epidemics. Testing maternal serum for IgM and IgG titers and/or HPB19 DNA with PCR analysis should be performed in pregnant women who develop symptoms of HBP19 infection or are in contact with children with a known parvovirus infection. If they have serologic evidence of primary infection, serial fetal ultrasonography should be performed to evaluate for signs of fetal anemia and hydrops fetalis. If hydrops fetalis is present, cordocentesis to confirm the presence of anemia and intrauterine transfusion should be strongly considered. Treatment with transfusion is life-saving in appropriately selected patients, and results in favorable long-term neurodevelopmental outcomes. If the pregnancy is near or at term, delivery should be considered. Pregnant women with normal immunity and IgG antibodies to HPB19, or those with a remote history of infection, can be reassured that exposure to HPB19 during pregnancy will not have adverse outcomes on their pregnancy.

Rarely additional systemic involvement including renal, neurologic, hepatic, respiratory, ocular, and endocrine has been reported during acute infection with HPB19. Viral myocarditis can also occur, resulting in significant morbidity and mortality, including ventricular dysfunction and heart failure. HPB19 infection can mimic various connective tissue disorders, in particular systemic lupus erythematosus, dermatomyositis, and vasculitis. Infection with HPB19 has also been implicated to a play a role in the development of a multitude of chronic conditions including, but not limited to, other connective tissue disease, hepatitis, nephritis, neurologic disease, and malignancy. However, a causal relationship has not been established.

Specific investigations

IgM antibodies to HPB19 indicate recent infection. HPB19 specfic IgG antibodies indicate past exposure and may be positive in over half the adult population.

A typical clinical appearance together with supportive serology is sufficient to establish the diagnosis in the majority of cases. In at-risk patients, or those who have symptoms of anemia, a complete blood count will establish whether there is any significant level of anemia requiring transfusion.

It is possible to detect parvovirus DNA, in both the blood and lesional skin. PCR techniques are considered extremely sensitive and may be useful in the following clinical scenarios: patients with an atypical presentation of HPB19 infection, where the clinical suspicion of infection is high and antibody studies are negative, and in immunocompromised patients who cannot mount an appropriate immunoglobulin response. In addition, a window period exists during the first 7 days after exposure when IgG and IgM are negative and a second period exists where IgM has become undetectable. PCR may also be helpful during these periods.

Second-line therapies

imageNSAIDs E
imageSystemic corticosteroids E
imageBlood transfusion C

Third-line therapies

imageImmunoglobulin infusion C
imageBone marrow/stem cell transplantation D
imageIntrauterine transfusion C
imageHAART E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Parvovirus infection

Andrea L. Zaenglein and Heather L. Salvaggio

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Infection with human parvovirus B19 (HPB19) causes a variety of well-described exanthems and can result in a spectrum of systemic illness. Erythema infectiosum, also known as ‘Fifth’ disease according to the original classification of childhood exanthems, is the classic and most common eruption associated with HPB19 infection. Outbreaks occur in the winter and spring, and affect school-aged children between 5 and 15 years of age. The infection is transmitted via respiratory droplets. Following a short variable prodrome of fever, malaise, diarrhea, and pharyngitis, the classic features of the exanthem appear. Bright pink macular erythema of the cheeks (‘slapped cheek sign’) together with nasal bridge and circumoral pallor precedes an evanescent macular, reticulated or ‘lace-like’ rash over the trunk and proximal limbs. The rash may last for up to 4 weeks and subsequently may recur following exposure to sun, warm temperature, and intense physical activity (see Figure). Purpuric eruptions, most commonly the papular purpuric gloves and socks syndrome, are also reported in association with HBP19. Arthropathy is another common finding particularly in older patients affected with HPB19. Other systemic manifestations of HBP19 infection include idiopathic thrombocytopenic purpura, hemophagocytic syndrome, lymphadenitis, meningitis and encephalitis, hepatitis, myocarditis, nephritis, and vasculitis. In patients with a predisposing hematological condition, infection with HPB19 may cause a transient aplastic crisis. Chronic and secondary infections have been encountered in immunosuppressed patients and rarely in immunocompetent patients. Primary infection during pregnancy may place the fetus at risk for severe anemia, thrombocytopenia, hydops fetalis, neurologic sequelae, and intrauterine fetal demise.

Management strategy

Erythema infectiosum is typically a self-resolving exanthem. In the majority of cases, supportive care and reassurance is all that is required. The rash of erythema infectiosum is immune complex mediated so patients are assumed to be no longer infectious by the time that it appears. HPB19 IgG is detectable in the blood once the eruption occurs. Once a clinical diagnosis has been made, parents can be reassured and advised on simple supportive measures such as antipyretics, fluids, and simple emollients for the rash. The condition is self-resolving in the majority of immunocompetent patients.

The clinician should be aware of a variety of other less common cutaneous presentations of HPB19 infection, including both petechial and non-petechial eruptions. The most common is the papular-purpuric ‘gloves and socks’ syndrome (PPGSS). This consists of pruritic to painful edema, erythema, and petechiae of the hands and feet with a classic sharp demarcation at the wrist and ankles. This eruption may be seen together with the ‘slapped cheek’ sign. An enanthem may occur with palatal, pharyngeal, labial and lingual erythema, petechiae, and ulcerations. A diffuse papular exanthem, fever, and other non-specific viral symptoms may accompany the eruption. PPGSS is seen more often in the spring and summer and typically occurs in adolescents and young adults. Unlike in erythema infectiosum, patients with PPGSS have been reported to be viremic while the rash is present and are thus contagious. The eruption typically resolves within 1 to 2 weeks with simple supportive measures. More generalized petechial eruptions have been reported either primarily or following classic erythema infectiosum. The acropetechial syndrome involves the perioral skin in addition to the hand and foot involvement classically seen in PPGSS. A petechial eruption in a bathing trunk distribution has also been described. Parvovirus should be suspect with all petechial rashes whose origin is undetermined. Asymmetric periflexural exanthema (unilateral lateral thoracic syndrome) and papular acrodermatitis of childhood (Gianotti–Crosti syndrome) have been described following HPB19 infection. HPB19 is also in the differential diagnosis of the ‘blueberry muffin’ baby. Other possible associations with cutaneous manifestations include erythema nodosum, erythema multiforme, livedo reticularis, vasculitis, Sweet’s syndrome, and Behçets disease.

HPVB19 infection may cause a symmetric arthropathy in many adults, most commonly women, and up to 10% of children. It is similar to rheumatoid arthritis involving the wrists, ankles, knees, metacarpophalangeal and proximal interphalangeal joints. Arthropathy may accompany the cutaneous eruption, but frequently follows it. The arthritis is usually self-limited in both adults and children, requiring only non-steroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief. Occasionally the arthritis may lead a more chronic course and it has been suggested that infection with HPB19 may be a trigger for autoimmune arthritis and connective tissue disease.

HPB19 is extremely tropic for proerythroblasts, granulocytes, and platelets. It binds to globoside on the erythrocyte precursor cell membrane, where it is endocytosed, replicates, and causes cellular apoptosis. In predisposed individuals with either an underlying disorder of hemolysis, decreased erythrocyte production, or active bleeding, HPB19 infection can cause a transient aplastic crisis. This acute anemia may be self-limited and asymptomatic but transfusion may be indicated if severe. In addition to anemia, there may be moderate neutropenia and thrombocytopenia. Potentially fatal marrow necrosis rarely occurs in very young children. Severe cases of transient aplastic crisis not responding to transfusion may require intravenous immune globulin (IVIG) and even bone marrow transplantaion. Chronic HPB19 infection in immunosuppressed patients can result in pure red blood cell aplasia, a form of chronic anemia which results from the inability to create neutralizing antibodies to the virus. This is treated with IVIG, which is often curative. Of interest, parvovirus B19 can contaminate blood products, including bone marrow, and may have the ability to transmit infection through this means. Children who are already anemic due to other causes, such as malaria, malnutrition or parasites, can become profoundly anemic with HPB19 infection.

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