Dermatologic Effects of Parvovirus B19 Infection
P arvovirus B19 is a non-enveloped single-stranded DNA virus, the only virus in the parvoviridae family known to cause human disease. It was first identified by Cossart et al in 1975.1 In 1983, Anderson et al demonstrated Parvovirus B19 as the etiological agent in erythema infectiosum (EI).2 Infection with parvovirus B19 occurs worldwide; however, it seems to be more common in temperate rather than tropical climates.1 It spreads through the respiratory route and is more prevalent in school children in the late winter and early spring months.1 The chances of exposure to the virus increases with age, as reflected by the serologic data. Parvovirus B19 antibodies are found in 2% to 15% of children aged 1 to 5 years, 15% to 60% of children 6 to 15 years of age, 30% to 60% of adults and in more than 85% of the geriatric population.1,3 The incubation phase of parvovirus B19 is between 13 and 17 days. Patients are normally asymptomatic4 or experience a non-specific prodrome (including fever, sore throat, myalgias and/or arthralgias) as a result of the viremia.1 Anemia, caused by the parvovirus tropism for the erythroid precursors, may also be encountered during viremia.5 Patients who depend on a rapid bone marrow turnover to maintain a normal hemoglobin (hemoglobinopathies, red blood cell membrane or enzymatic defects) may develop a transient aplastic crisis manifested by a rapid drop in the red cell or all cell lines before any other signs of infection are obvious.6 The prodromal phase is typically followed by the distinctive skin findings of EI3. Erythema Infectiosum Erythema infectiosum coincides with the presence of the IgM antibodies; therefore, a patient is no longer considered infectious during this stage.2 Clinical findings of EI are more classic in children, whereas in adults they can be subtle and may be associated with more severe constitutional symptoms and arthritis or arthralgias.1 Typically, the slapped cheek appearance with perioral sparing is the first stage of the exanthem. In the next 1 to 4 days, an erythematous maculopapular rash develops on the trunk and extremities. Lastly, once central clearing of the maculopapular rash occurs, a reticular or ‘lacy’ appearance results. This last stage of the rash can persist for 1 to 3 weeks from its onset. Although typical EI presentation is the most common manifestation of parvovirus B19 infection, over the last two decades there has been an increasing number of reports of other unusual dermatological manifestations linked to parvovirus B19 infection. (See Table 1.) Petechial Eruptions Papular-purpuric gloves and socks syndrome (PPGSS) was first described in 1990 by Harms et al.7 Its etiologic association with parvovirus B19 was postulated in 1991 by Bagot and Revuz when they discovered that anti-parvovirus B19 IgM antibodies were present in the serum of a patient with PPGSS.8 More than 50 cases have been documented worldwide, most of which were Caucasian young adults, with equal distribution among males and females. Cases of PPGSS tend to occur mostly in the late spring and summer months, which differs from the common parvovirus B19 season.2,9 Roughly two-thirds of the PPGSS reported cases have been associated with acute parvovirus B19 infection.10 Other viruses implicated in the PPGSS presentation include cytomegalic virus, coxsackie virus, measles virus and human herpes viruses (HHV) 6 and 7.1,11 In contrast to EI, patients with PPGSS are considered infectious when presenting with the rash. This is based on reports where viral DNA, suggestive of viremia, has been found in the absence of the IgM antibodies.12 (See Figure 1.) Patients with PPGSS present with symmetric pruritic erythema and edema in an acral distribution. This stage is quickly replaced by palpable purpuric lesions over the hands and feet with a sharp demarcation at the wrists and ankles. The rash can be painful and/or pruritic. There are often associated mucosal changes including oral petechiae, pharyngeal erythema, swollen lips and painful oral erosions.9 Patients may experience systemic symptoms, such as low-grade fever (52%), fatigue (20%), myalgias (16%), anorexia (16%) and arthralgias (12%).13 Usually, the illness resolves spontaneously without sequelae in 7 to 14 days.14 Often toward the end of the illness, slight desquamation of the hands and feet can occur.15 Mild leukopenia, transient thrombocytopenia, increased liver enzymes, and increased inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) may be encountered during the symptomatic phase.16 The presence of mild hematologic abnormalities in the context of purpura should alert the physician to the possibility of parvovirus etiology. Acropetechial syndrome is a new clinical entity linked to the Parvovirus infection. It consists of petechiae on the extremities, as well as the perioral and chin areas. The term was coined by Harel et al. after observation of three children who had involvement of the perioral region and the chin in addition to PPGSS-like presentation.10 The reported cases were a 12-year-old female and two males, aged 17 and 18 years. All findings resolved spontaneously over a 2-week period. The three patients were IgM positive for parvovirus B19, two were negative for IgG and the last was weakly positive for parvovirus B19 IgG, suggesting acute parvovirus B19 infection in all three patients. Recently, a generalized petechial eruption in addition to prominent acropetechial involvement was documented in a 7-year-old boy with evidence of parvovirus DNA (personal communication, in press, Journal of the American Academy of Dermatology 2005). Mucosal Membranes Manifestations Various mucosal findings have been documented, particularly in the context of PPGSS, with more than 50% of reported cases presenting with an exanthem.13 The most common manifestations are multiple petechiae on both the hard and soft palate, erythema, small erosions and even ulcerations.7,8,9,17 In addition, one case of Koplik spots has been reported.18 All documented mucosal involvement cases had findings simultaneous with the petechial eruption, suggesting a similar mechanism. Mucosal lesions can be painful or itchy. No pathognomonic location pattern has been noted with respect to the mouth lesions. Genital mucosa involvement has also been reported,7,19 consisting of painful erythema, edema and small ulcerations of the vagina and the glans penis. Parvovirus Infection and Systemic Disease Association The list of systemic diseases that has been linked to parvovirus infection is long and growing steadily. (See Table 1.) Current data is not helpful in delineating the role of parvovirus as a causative agent, a contributing agent or an ‘innocent bystander.’ There are very few cases where biopsy specimens revealed the presence of the parvovirus DNA in the specimens. However, even in these cases parvovirus may act only as an inciting agent. The association between Henoch-Schonlein purpura (HSP) and acute parvovirus infection is more consistently reported in isolated cases.20 However, in a retrospective review of 29 pediatric HSP cases compared with 36 healthy volunteers, only one patient had evidence of viral DNA at the time of the HSP diagnosis, while 28% of the patients and 42% of the volunteers had evidence of parvovirus IgG antibodies.15 Pathogenesis The pathogenesis of the cutaneous and extracutaneous manifestations is still unclear. Parvovirus DNA has been found in the epidermis and the epithelial cells of sweat glands or ducts.12,21 This correlates with pathologic findings of a lymphocytic, perivascular infiltrate with evidence of red cell extravasation. In other cases, direct immunofluorescence revealed granular deposits of IgM antibodies and C3 in the walls of the dermal vessels, suggesting a vascular reaction to an antigenic stimulus.12 Two weeks from the inoculation, IgM antibodies are detected, which correlates with the appearance of EI. The pathogenetic pattern and subsequent clinical presentation may be the result of a complex interplay of the host’s humoral and/or cellular response, viral load and even coinfection with another virus, such as HHV 6.22 Considering Parvovirus in a Work-Up This review highlights the protean manifestations of parvovirus infection. Unusual presentations, such as petechial eruptions, should be added to the more classical EI type of picture. Testing for parvovirus infection should be considered in the initial work-up of any patient presenting with a petechial/purpuric eruption of unclear etiology. In addition, a patient with a purpuric eruption due to parvovirus infection may still be infectious at the time of diagnosis, with significant implications for susceptible contacts.