Human parvovirus B19 infection

Human Parvovirus Infection Fifth disease (erythema infectiosum) has recently been linked to human parvovirus (HPV) infection. HPV is also capable of causing aplastic anemia, arthritis and perinatal complications, including hydrops fetalis and spontaneous abortion. Clinically suspected cases of HPV infection can now be confirmed serologically. IgM antibodies peak early in the course of infection and are usually undetectable by two months. New procedures, including HPV-specific DNA probes, are being used to confirm in utero infections. In 1889, Tschamer described "ortliche Rotheln," a curious childhood exanthem characterized by a "slapped cheek" appearance and a lacy reticular rash of the extremities. Ten years later, Sticker named the illness erythema infectiosum. In 1905, Cheinisse designated the condition as the "fifth rash disease." This term referred to a numbering system in which rubeola, scarlet fever, rubella and "Dukes' disease" were ranked first, second, third and fourth in a list of exanthematous disorders. Thus, erythema infectiosum has commonly been called "fifth disease."

As recently as 1982, little more was known about the etiology of fifth disease than was known at the turn of the century.(1) In 1983, however, IgM antibodies to human parvovirus (HPV), now designated B19, were measured during an outbreak of erythema infectiosum in London.(2) Subsequently, HPV infection was found to be associated with stillbirths(3) and with acute arthritis.(4) During the past six years, numerous articles about HPV infection have appeared in the literature.

Clinical Manifestations

ERYTHEMA INFECTIOSUM

Anderson and co-workers(5) have confirmed the accuracy of the classic description of HPV-induced erythema infectiosum. Of 162 children studied during the 1983 outbreak in London, 85 percent had red cheeks; the rash, although frequently involving the arms, legs, chest and abdomen, was present on the cheeks 87 percent of the time. Research with experimentally induced HPV infection suggests that the rash may be less likely to involve the cheeks in adults.(6) In addition, the symptoms of chills, fever, headache, myalgia and pruritus are more common in adults and coincide with an intense viremia that occurs one week after exposure.

The rash and arthralgia usually do not begin until the 17th or 18th day, when both viremia and virus excretion have ceased. Arthralgia or arthritis may develop shortly after the onset of the rash. Interestingly, a vesiculopustular skin eruption has been noted in one serologically documented case of acute HPV infection.(7)

APLASTIC ANEMIA

In 1985, HPV was implicated as the cause of systemic infection in patients who either were asymptomatic or had mild, nonspecific symptoms such as headache, pyrexia, malaise, fatigue and myalgia.(6) Further studies have shown that HPV infection is common in childhood and that antibody to HPV is generally acquired between five and ten years of age.

Later, it became apparent that when HPV infection occurs in either a child or an adult with chronic hemolytic anemia, an aplastic crisis may result from the temporary arrest of erythropoiesis. Experimentally induced HPV infection was found to produce a decrease in cell counts in all three cell lines.(6) The reticulocyte count fell to zero on the 10th to 14th days.

ARTHRALGIA AND ARTHRITIS

Arthralgia (and/or arthritis) appears to be more common in adults than in children with HPV infection. In one outbreak,(5) arthralgia occurred in only 12 of 162 children (7 percent), whereas 13 of 16 adult patients (81 percent) reported arthralgia. Although an early report(8) suggested that large joints are typically involved, recent studies(4,9) have found more frequent involvement of the small joints of the hand, especially the metacarpophalangeal and proximal interphalangeal joints. Infected patients may have symmetric polyarthritis of sudden onset and moderate severity; some patients are unable to get out of bed. Women are more likely to be affected than men.

Cases of HPV-associated arthritis may meet the American Rheumatism Association's diagnostic criteria for rheumatoid arthritis.(9) The clinical presentation resembles seronegative rheumatoid arthritis, and symptoms may persist for weeks or even months. A few patients may have a positive latex test for rheumatoid factor.(10,11)

PERINATAL INFECTIONS

HPV infection and rubella are similar in that both include a rash, arthralgia or arthritis, and possible adverse effects on the fetus. In a series of six pregnant women with serologic evidence of recent HPV infection,(12) two had midtrimester abortions; the other four were delivered of apparently healthy infants. The aborted fetuses were grossly hydropic, and B19-specific DNA probes were positive for HPV infection. Woernle and colleagues(13) reported the perinatal outcome in four pregnant women with serologic evidence of HPV infection. One woman gave birth to a stillborn hydropic fetus. The other three IgM-positive women gave birth to normal offspring: one infant had IgM-positive cord serum, and another had IgG seropositivity that persisted for at least nine months.

The number of pregnancy-associated HPV infections is small, and the magnitude of the risk has not been precisely defined. Preliminary studies suggest that transplacental transmission probably occurs in 10 to 25 percent of maternal infections.(14) Fetal survival after a severe in utero infection that was later associated with developmental anomalies has been observed by one of the authors (S.N.).

Diagnosis

Knowledge of a local outbreak of HPV infection, especially if it is serologically confirmed, aids in the diagnosis of cases with characteristic signs and symptoms.

In the past, the diagnosis of erythema infectiosum was based solely on the clinical impression. Although no studies have investigated the accuracy of this method, many cases of HPV infection may be misdiagnosed.(15) A recent development is the ability to confirm HPV infection serologically.

In nearly all cases, the IgM titer is positive when either rash or arthritis develops.(5,9) This circumstance obviates the need for a convalescent serum determination. The IgM titer peaks in the first few days after the onset of rash or arthritis and, in many cases, is essentially undetectable by two months. Thus, the physician has a relatively brief "window of opportunity" for confirming the diagnosis serologically. In the United States, the HPV-specific IgM and IgG tests(16) are available to clinicians only through the Centers for Disease Control and the University of Iowa. These tests, unlike the British tests, are qualitative and are reported as either positive or negative at an arbitrary serum dilution of 1:100. A positive HPV-specific IgG test indicates prior infection.

In Great Britain and elsewhere, the serologic tests are reported in quantitative terms (i.e., RIA antibody units). A Japanese study(17) found the prevalence of IgG antibodies to be near zero at birth but greater than 50 percent in subjects 60 years of age or older. In a German study of adolescents and adults, however, 35 to 40 percent of the subjects showed IgG antibodies.(15) Anti-B19 IgG antibodies are thought to be protective but may not be in every case.(6)

State-of-the-art procedures, including nucleic acid hybridization with radiolabeled human parvovirus DNA probes and transmission electron microscopic (TEM) examination of serum, have also been used to confirm cases of HPV infection.(12) Ultrasonography may aid in the diagnosis of a hydropic fetus. The combination of in utero fetal blood or ascites sampling with TEM examination of serum may permit the presumptive diagnosis of in utero HPV infection. The diagnosis may be confirmed by demonstration of the following: anti-HPV IgM in fetal blood; persistence of an elevated serum IgG titer in the newborn beyond six months of age, or identification of the virus by immune electron microscopy, enzyme-linked immunosorbent assay or nucleic acid hybridization with an HPV-specific probe.(16,18)

Treatment

In children, symptoms of arthralgia or arthritis are generally minimal or nonexistent. If pruritus is present, an antihistamine may be prescribed. HPV arthritis in adults may be treated with aspirin or a nonsteroidal anti-inflammatory drug. In HPV-infected patients with hemolytic disease, the aplastic crisis, although self-limited, may necessitate transfusions.

Prevention

Although there have been no national recommendations for the prevention of fifth disease in the community, the American Academy of Pediatrics Committee on Infectious Diseases(19) has recommended respiratory isolation for seven days after the onset of illness in hospitalized patients. This recommendation has limited application and does not address the management of high-risk groups, including pregnant health care workers and teachers, or of persons with chronic hemolytic anemia.

Numerous attempts to isolate the virus during the rash have been unsuccessful,(20) but these attempts have not allowed for the unique growth requirements of HPV.(18) The child with the rash of fifth disease appears to represent minimal infectious risk to other classmates or to a pregnant teacher; that is, exposure probably poses little risk once the infection is clinically apparent. Research is under way to assess the fetal risk that a pregnant teacher faces. REFERENCES (1)Morens DM. Fifth disease: still hazy after all these years [Editorial]. JAMA 1982;248:553-4. (2)Anderson MJ, Jones SE, Fisher-Hoch SP, et al. Human parvovirus, the cause of erythema infectiosum (fifth disease)? [Letter] Lancet 1983;1(8338):1378. (3)Brown T, Anand A, Ritchie LD, Clewley JP, Reid TM. Intrauterine parvovirus infection associated with hydrops fetalis [Letter]. Lancet 1984;2(8410):1033-4. (4)Reid DM, Reid TM, Brown T, Rennie JA, Eastmond CJ. Human parvovirus-associated arthritis: a clinical and laboratory description. Lancet 1985;1(8426):422-5. (5)Anderson MJ, Lewis E, Kidd IM, Hall SM, Cohen BJ. An outbreak of erythema infectiosum associated with human parvovirus infection. J Hyg [Lond] 1984;93:85-93. (6)Anderson MJ, Higgins PG, Davis LR, et al Experimental parvoviral infection in humans. J Infect Dis 1985;152:257-65. (7)Naides SJ, Piette W, Veach LA, Argenyi Z. Human parvovirus B19-induced vesiculopapular skin eruption. Am J Med 1988;84:968-72. (8)Ager EA, Chin TD, Poland JD. Epidemic erythema infectiosum. N Engl J Med 1966;275:1326-31. (9)White DG, Woolf AD, Mortimer PP, Cohen BJ, Blake DR, Bacon PA. Human parvovirus arthropathy. Lancet 1985;1(8426):419-21. (10)Luzzi GA, Kurtz JB, Chapel H. Human parvovirus arthropathy and rheumatoid factor [Letter]. Lancet 1985;1(8439):1218. (11)Cohen BJ, Buckley MM, Clewley JP, Jones VE, Puttick AH, Jacoby RK. Human parvovirus infection in early rheumatoid and inflammatory arthritis. Ann Rheum Dis 1986;45:832-8. (12)Anand A, Gray ES, Brown T, Clewley JP, Cohen BJ. Human parvovirus infection in pregnancy and hydrops fetalis. N Engl J Med 1987;316:183-6. (13)Woernle CH, Anderson LJ, Tattersall P, Davison JM. Human parvovirus B19 infection during pregnancy. J Infect Dis 1987;156:17-20. (14)The Working Party. PHLS Working Party on fifth disease: study of human parvovirus (B19) infection in pregnancy. Communicable Disease Report 1987;22(May):20. (15)Schwarz TF, Roggendorf M, Deinhardt F. Human parvovirus B19 infection in United Kingdom 1984-86 [Letter]. Lancet 1987;1(8535):738-9. (16)Anderson LJ, Tsou C, Parker RA, et al. Detection of antibodies and antigens of human parvovirus B19 by enzyme-linked immunosorbent assay. J Clin Microbiol 1986;24:522-6. (17)Nunoue T, Okochi K, Mortimer PP, Cohen BJ. Human parvovirus (B19) and erythema infectiosum. J Pediatr 1985;107:38-40. (18)Ozawa K, Kurtzman G, Young N. Replication of the B19 parvovirus in human bone marrow cell cultures. Science 1986;233(4766):883-6. (19)Peter G, Giebink GS, Hall CB, Plotkin SA, eds. Report of the Committee on Infectious Diseases. 20th ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 1986:150-1. (20)Brass C, Elliott LM, Stevens DA. Academy rash. A probable epidemic of erythema infectiosum (`fifth disease'). JAMA 1982;248:568-72.

PHOTO : "Slapped cheek" rash in young girl with clinically diagnosed erythema infectiosum.

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