FINAL DIAGNOSIS: ACUTE PARVOVIRUS INFECTION.
Parvovirus (Parvoviridae) are small (18-26 nm) non-encapsulated icosahedral viruses found all over the world. They are separate from many of the other human pathologic viruses in that they contain single-stranded DNA as their nucleic acid. Transmission is typically person to person, although the exact mechanism for this dissemination is unknown. Transfusion associated infection has been documented, but parvovirus is not routinely screened in the blood donor population short of exclusion of donors with a viral exanthem at time of collection. Development of anti-parvovirus IgG following acute exposure is protective through life, although reactivation of persistent infection can occur.
The most notorious member of family Parvoviridae is parvovirus B19, which has been associated with erythema infectiosum (aka Fifth's disease) and aplastic crisis in up to 67% of patients with sickle cell disease (1,2). Erythema infectiosum is a common illness in pediatric populations, and is characterized by a low-grade fever accompanying a classic "slapped cheek" maculopapular to vesiculopustular rash. B19 is tropic for the high-incidence P antigen, particularly targeting red cell precursors. Because of this tropism, normal individuals may experience a transient mild anemia while those with underlying anemias (i.e. reduced peripheral survival in sickle cell disease, or reduced production due to marrow involvement with malignancy) may experience a severe anemia or aplastic crisis as replicating parvovirus B19 in acute infection eliminates immature red cells.
Parvovirus infection is ordinarily transient with no serious sequlae, although additional support may be required in patients who develop severe anemia or aplastic crises. As such, the disease is often diagnosed clinically with no serologic or molecular confirmation needed. Certain populations at risk (i.e. young children with sickle cell anemia) for more severe acute parvovirus infection may require confirmation of acute infection or previous exposure status. In addition, association of hemolytic disease of the newborn with acute parvovirus B19 in a previously unexposed mother may prompt prenatal testing for parvovirus immune status in a pregnant woman presenting with a rash. A survey of the Society of Perinatal Obstetricians in 1997 showed that most members used Doppler ultrasonography to assess the risk of fetal anemia during pregnancies complicated by parvovirus B19, as previous studies had shown a fetal loss rate of 9% (3,4). Serologic diagnosis is available by ELISA and/or immunoblot assay. Parvovirus-specific IgM appears 3-10 days after clinical illness and may remain slightly elevated for several months after resolution of disease. IgG follows, typically at 7-14 days after clinical illness and in immunocompetent patients remains detectable for life.
PCR assays for the diagnosis of parvovirus B19 are available at reference laboratories, but have not yet been FDA approved. They are, however, the test of choice for immunocompromised patients who may not be able to mount a sufficiently robust antibody response for serologic diagnosis. In addition, quantitative real-time PCR for parvovirus viral-load is under investigation for blood product manufacturing applications, wherein a "CMV-like" model of screening blood products for parvovirus prior to transfusion of risk populations (i.e. pregnant, hematologically abnormal, and immunocompromised) (5). Parvovirus PCR can be positive prior to the development of the antibody response, but much will depend on the initial exposure viral load, success of invasion and replication, and speed of the serologic response making the exact number of days that PCR will detect parvovirus post-exposure prior to serologic diagnosis unclear.
This patient also had high-titer ANA, prompting the initial referral to rheumatology, where the ANA remained positive, but falling in titer. While this may be a true decline in titer, it might also represent inter-laboratory variation. Unfortunately, repeat ANA levels had not been drawn by the publication of this report to be certain. However, a review of 7 children aged 6-15 by Moore et al. (6) with serology proven acute parvovirus infection accompanied by arthralgias and fatigue (six had a malar rash) identified simultaneous elevations of ANA to titers greater than 1:640. The authors did not comment on family history of connective tissue disease or autoimmune disease in these patients. In addition to positive ANA, two patients had antibodies to Scl-70, two had elevated rheumatoid factor, and others had antibodies to Sm, RNP, SS-A (Ro) or SS-B (La). Treated symptomatically for a systemic lupus erythematosus-like syndrome, all patients recovered completely, with resolution of the arthralgias, fatigue and rash. Complete resolution of positive ANA was observed in 3 of the 7, with low level persistence in the other 4. Of the other autoantibodies, low-level SS-A and SS-B persisted in one patient, and elevated rheumatoid factor persisted in another. None progressed to classic SLE or other rheumatologic disorder, and the authors proposed that parvovirus infection in children may be accompanied by a self-limited SLE-like syndrome including high-titers of positive auto-antibodies without known progression to autoimmune disease.
The low complement protein C4 level in this patient may be due to immune complex formation by anti-parvovirus IgM and the virus with some complement activation, but low C3 levels would also be expected. However, C3 levels may be artificially "normal" due to an acute phase increase in C3 followed by consumption in immune complexes back to a normal level. Again, however, C4 levels would also have been expected to increase as part of an acute phase reaction. Thus, testing error or congenital deficiency of C4 must also be considered in this patient. Null mutations of C4 genes are present in up to 16% of normal persons, and analysis of 35 studies over the past 50 years has revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from virtually every corner of the globe (7). If the patient is congenitally deficient in C4, her positive ANA may not be entirely the result of parvovirus infection. Retesting complement C4 level when the patient is past her infection and in a more "steady state" to screen for genetic deficiency would be recommended in this case.
C-reactive protein is an extremely sensitive acute phase reactant, and generally more useful than erythrocyte sedimentation rate for most rheumatologic purposes. However, CRP is notoriously insensitive for viral infection and SLE (8,9), and a normal value in this patient is unsurprising given her differential diagnosis.
Contributed by Gerard Joey Oakley, MD