Parvovirus B19 Infection in Transplant Recipients

Authors: Albert Eid, M.D.

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Virology

Parvovirus B19 is a small non-enveloped ubiquitous virus measuring 22 to 24 nm in diameter. It is a member of the family Parvoviridae, subfamily parvivirinae, genus Erythrovirus. The genome consists of single-stranded linear DNA encoding two structural proteins, VP1 and VP2, and a major non-structural protein, NS1. The virus is classified into three different genotypes: genotype 1, Au and Wi strains; genotype 2, LaLi and A6 strains; and genotype 3, V9 strains. Parvovirus B19 uses the P-antigen, a globoside member of the P blood group system, in addition to other coreceptors to enter the cell. Hence, its predilection for erythroid progenitor cells.

Epidemiology

Parvovirus B19 is easily transmitted among children and susceptible adults caring for them (i.e. day-care workers, teachers, and mothers) through the respiratory route. The secondary attack rate for exposed household members is around 50%. Therefore, most people get infected during childhood and the rate of seropositivity among adults is as high as 87% (1). Even though less common, vertical transmission and transmission via blood products and transplanted organs have also been reported. Once infected with Parvovirus B19, immunocompetent individuals are considered immune. However, reinfection was suspected in some cases (1). Furthermore, the detection of Parvovirus B19 DNA in the bone marrow and various tissue specimens (2, 3) long after the initial infection of some patients raised the question of viral reactivation, especially in the context of immunosuppression. Clinical data supporting this hypothesis are lacking, however. Transplant recipients can get infected via droplet inhalation, blood-products transfusion (4) and allograft tissue (5, 6). Nosocomial outbreaks in transplant units have been reported (7). The incubation period of Parvovirus B19 in immunocompetent individuals ranges from 4 to 21 days. Typically, patients are contagious during the week preceding the development of symptoms. Once symptomatic, the risk of transmission decreases significantly, which limits the effectiveness of infection control measures aimed at reducing the risk of transmission to immunosuppressed patients. On the other hand, due to immunosuppression, transplant recipients may shed the virus in respiratory secretions for prolonged period of time. Therefore, those patients should be placed on standard and droplet isolation for the entire duration of hospitalization.

Clinical Manifestations Pertinent to Transplant Recipients

Among solid organ transplant and hematopoietic stem cell transplant recipients, Parvovirus B19 infection occurs on average 7 weeks (range, 1 week - 8 years) after transplantation. Up to 65% of transplant recipients with Parvovirus B19 infection present within the first 3 months following transplantation. Anemia is a constant finding in both solid organ transplant and hematopoietic stem cell transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18% of solid organ transplant recipients and 62% and 38% of hematopoietic stem cell transplant recipients, respectively. Fever is present in only one out of four patients. Arthralgia occurs in 6% of transplant recipients while rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) (8). Tissue-invasive disease was reported in 11% of transplant recipients and consisted of hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis (9, 10, 11, 12, 13, 14, 15). Allograft rejection, dysfunction, or loss in solid organ transplant recipients and failure of stem cell engraftment in relation to Parvovirus B19 infection was seen in 10% of patients (6, 16). The manifestations of Parvovirus B19 infection in both solid organ transplant and hematopoietic stem cell transplant recipients are summarized in Table 1. In transplant recipients, ineffective humoral or cellular immunity allow sustained or recurrent viremia (17). Therefore, relapse of symptomatic infection is not uncommon.

Laboratory Diagnosis

Parvovirus B19 can be detected directly via molecular techniques or indirectly through measurement of viral antibodies. In transplant recipients, Parvovirus B19 serology is not reliable due to inadequate or delayed humoral response to infection (18, 19). Parvovirus B19 IgM antibody was present in only 71% of solid organ transplant and hematopoietic stem cell transplant recipients at the time of diagnosis. In addition, the presence of Parvovirus B19 IgG antibody alone is uncommonly seen among transplant recipients with active Parvovirus B19 infection (7% of patients) and is rather consistent with remote infection (8). The limitations of serological testing in the transplant population mandate the use of molecular techniques in order to improve sensitivity. Parvovirus B19 DNA can be detected in specimens such as blood, bone marrow and tissue from infected organs (i.e. liver, lung, and kidney). Assays using polymerase chain reaction (PCR) have high sensitivity and specificity (20); however, some of them do not detect or poorly detect non-B19 strains (genotypes 2 and 3) (21, 22, 23, 24). The detection of Parvovirus B19 DNA in transplant recipients should be interpreted with caution because it was reportedly detected in the serum and tissue samples (3, 11, 25) from asymptomatic individuals long after the initial infection. However, the detection of viral DNA in transplant recipients in presence of clinical findings suggestive of active infection (i.e. anemia, pancytopenia, fever, and rash) is likely to represent active infection. When the diagnosis is in doubt or when Parvovirus B19 serology and PCR are negative but the clinical suspicion is high, the examination of bone marrow specimen and the use of immunohistochemical staining or in situ hybridization could be very helpful in establishing the diagnosis (8). Typical bone marrow findings include overall hypercellularity, presence of giant pronormoblasts, and absence of late normoblasts.

ANTIVIRAL THERAPY

Specific antiviral agents to treat Parvovirus B19 infection are not available.

ADJUNCTIVE THERAPY

Reduction of immunosuppression The dose of immunosuppressive drugs should be reduced if at all possible when symptomatic Parvovirus B19 infection is diagnosed in transplant recipients.

Intravenous immunoglobulin (IVIG) Resolution of Parvoviremia is typically seen when patients develop specific viral antibodies. This observation led to the common practice of using IVIG in patients with symptomatic parvovirus B19 infection. Many transplant recipients were clinically improved after receiving IVIG (8, 26, 27, 28). However, some others experienced long-lasting resolution of the infection without receiving IVIG (8). The optimal dose of IVIG and the schedule of administration are not known. Most physicians recommend 400 mg/kg/day for 5 days. This is supported by the fact that transplant recipients who received a total dose of ≤ 2 gm/kg did not experience more relapse compared to those who received > 2 gm/kg. Despite therapy, up to 28% of SOT recipients and 9.5% of hematopoietic stem cell transplant recipients experienced relapse after receiving IVIG (8). In case of Parvovirus B19 infection relapse, patients can be successfully treated with additional courses of IVIG (29, 30, 31).

ENDPOINTS FOR MONITORING THERAPY

The use of PCR to monitor the response to therapy is not recommended since Parvoviremia may persist for months in asymptomatic patients following primary infection (29, 30). It is recommended, however, to follow the hemoglobin concentration and consider obtaining Parvovirus B19 PCR in case of recurrence of anemia.

VACCINES

No Parvovirus B19 vaccine is currently approved or commercially available for clinical use. However, the development of two recombinant human Parvovirus B19 vaccines (MEDI-491 and VAI-VP705) is underway. Both vaccines are composed of viral capsid proteins VP1 and VP2. The results of a study using MEDI-491 were promising 32 while another phase I/II randomized, controlled, double-blind clinical trial using VAI-VP705 is still in progress.

ANTIVIRAL PROPHYLAXIS

Primary antiviral prophylaxis is not recommended for solid organ transplant and hematopoietic stem cell transplant recipients to prevent Parvovirus B19 infection.

INFECTION CONTROL MEASURES

Since patients with Parvovirus B19 are contagious prior to becoming symptomatic, efforts aimed at containing the virus are unlikely to be effective. Therefore, transplant recipients should not be asked to avoid exposure to children and adults susceptible to or already symptomatic with Parvovirus B19 infection. The low incidence of this infection among transplant recipients, especially pediatric transplant recipients, does not support such recommendation. Furthermore, Parvovirus B19 serostatus of donors and recipients is not routinely determined. When Parvovirus B19 infection is suspected or confirmed in hospitalized transplant recipients, standard and droplet precautions should be implemented to avoid nosocomial transmission. Specifically, pregnant health-care workers should avoid contact with those patients if they have not been previously infected. Since immunosuppressed patients shed the virus for a prolonged period of time, precautions should be implemented for the entire duration of their hospital stay.

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