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Wednesday, November 16, 2011

PB19 infection in transplantation

The first report of PVB19 infection after transplantation was published in 1986 [7]. Since then, numerous cases of PVB19 infections after solid-organ transplan-tation (SOT) and hematopoietic stem cell transplantation (HSCT) have been reported. Anemia is the predominant clinical manifestation. However, PVB19 has also been associated with hepatitis, pneumonitis, myocarditis, and allograft dysfunction. Nonetheless, the full spectrum of clinical manifestations of PVB19 infection among transplantat recipients is not well characterized.

The suppression of the RBC population that clinically results in anemia as the hallmark of PVB19 infection is consistent with the cellular tropism of this virus [71]. PVB19 infects erythroid progenitor cells by binding to the receptor known as the P antigen [71]. Subsequent PVB19 replication in erythroid progenitor cells leads to cellular lysis [72], which is characteristically manifested as pure red cell aplasia on bone marrow examination.
Immunocompetent individuals respond to PVB19 infection by producing virus-specific Ig [73–75]. Experimental studies have demonstrated that the generation of PVB19- specific Ig is temporally accompanied by reduction in the degree of parvoviremia [75]. The impairment in immunity that results
from pharmacologic immunosuppression limits the ability of transplant patients to produce neutralizing antibody, which leads to persistent PVB19 infection that manifests as chronicanemia. Not surprisingly, almost all patients in transplants patients series had chronic anemia, many patients did not possess PVB19-specific Ig at the onset of clinical disease, and almost all transplant patients without PVB19 IgM had parvoviremia. Demonstrates that the spectrum of clinical illness related to PVB19 is broad. This reflects the ability of PVB19 to infect other cells [76]. The cardiotropism of PVB19 is suggested by its association with myocarditis [77–79] and left ventricular
dysfunction [80] and by the demonstration of PVB19 DNA in fetal myocardial cells [81]. These data support the suggestion that myocarditis may occur in transplant patients with PVB19 disease, and this may be misdiagnosed as acute rejection and could result in death from cardiogenic shock [17, 28, 43]. The most likely cardiac target of PVB19 is the endothelium [81–83], because endothelial cells in small cardiac vessels also carry P antigen [54]. Likewise, endothelial infection could serve as the mechanism for PVB19-associated thrombotic microangiopathy [54].
Studies of parvoviruses that infect animals demonstrate the virions in various organs [84]. Parvovirus related to Aleutian mink disease was detected in alveolar cells in mink with acute interstitial pneumonitis [85]. Intact Aleutian mink disease parvoviral DNA has also been detected in glomeruli [85]. These animal data support the suggestion that PVB19 is a potential cause of pneumonitis [22, 31, 68], hepatitis [28, 58, 63, 66, 86], and collapsing glomerulopathy [26] in humans. Indeed, PVB19 has been demonstrated in the renal tissue and blood of patients with collapsing glomerulopathy and in hepatocytes of a patient with fibrosing cholestatic hepatitis [58]. Nevertheless, the reported associations between PVB19 and organ-specific syndromes do not definitely indicate causality.
The inability of transplant patients to mount sufficient anti-PVB19 Ig could present a diagnostic dilemma and delay treatment in patients seen at centers who rely on serological examination for the diagnosis PVB19. All except 1 of the patients who did not have PVB19 IgM detected had positive PCR assay results, suggesting the clinical utility of this molecular assay. Our
observation suggests that a negative PVB19 IgM serological test result does not rule out the diagnosis of PVB19 infection, and PCR should be used whenever a diagnosis of acute PVB19 infection is suspected in immunocompromised patients. Among patients who are highly suspected to have PVB19 disease but whose peripheral blood PCR assay result is negative, the diagnosis may be confirmed by bone marrow examination.
If feasible, reduction in immunosuppression should be a part of the treatment of PVB19 disease. Theoretically, this would allow the immune system to mount specific immunity against PBV19. The observation that parvoviremia ceases with generation of Ig [75] led to the current practice of intravenous Ig
treatment of PVB19. Intravenous Ig contains PVB19-specific antibodies. However, the dose and duration of treatment are not standardized. Clinical relapses are commonly observed (i.e. 1 relapse occurs for every 4–5 patients treated), which suggests that the patient experiences a continued state of severe immunosuppression and that there is a need to further reduceimmunosuppression or administer intravenous Ig for a longer period to neutralize parvoviremia. The rarity of this infection limits the conduct of a prospective trial to assess the optimal dose and duration of treatment.
In conclusion, PVB19 can cause rare but significant infectious complication after transplantation. The predominant clinical manifestation of PVB19 disease is anemia, although organ invasive manifestations, such as hepatitis, myocarditis, and pneumonitis, can be observed. However, whether these organ specific syndromes are causally linked to PVB19 infection remains to be proven. A high index of suspicion is advised when patients present with refractory and severe anemia after transplantation. In this clinical setting, PVB19 infection should be considered in the differential diagnosis, together with the other, more likely causes, such as an adverse reaction to treatment,blood loss, and anti-erythropoietin antibody, among others. In this regard, PCR may be a more useful noninvasive test for the confirmation of the diagnosis, because the PVB19 serological test results of many transplant patients are negative at the onset of clinical disease.
A retrospective study of parvovirus B19 antibody titres 2 to 3 years after bone marrow transplantation showed persisting IgG, suggesting that persistence of B19 antibody depends on prior recipient, but not donor, immunity.1
allogeneic peripheral blood stem cell transplantation (PBSCT(consistently results in severe immunodeficiency. It is known that human parvovirus B19 can persist in red blood cell precursors in the bone marrow of immunocompromised patients. An infection can cause severe complications including chronic bone marrow failure or pure red cell aplasia because of the inability of patients to produce neutralizing antibodies against the virus.3 The major route of transmission of parvovirus B19 is inhalation of respiratory droplets from infected people. Both of these patients were treated in special air-filter rooms designed to create a pathogen-reduced environment and no clinical infections were in family members or hospital staff. There is evidence for parvovirus B19 transmission via blood products, PBSC or bone marrow.4, 5 Patients required erythrocyte infusions during conditioning before transplantation. Parvovirus B19 is known to be a frequent contaminant of blood products,6 but as parvovirus B19 screening is not part of the routine control of blood products is not routinely followed in many countriesand so infection via this route cannot be excluded. Another route of infections in those patients is reactivation of old infection. with parvovirus B19 during immunosuppressive conditioning and further immunosuppression. This concept is supported by several reports both in PBSCT and in solid organ transplantation.7
parvovirus B19-induces erythematous infection in immuncompromised patients early after PBSC transplantation and should be considered in the differential diagnosis of acute GvHD of the skin. It highlights the importance of excluding the possibility of a viral infection before initiating treatment for acute GvHD. Furthermore, parvovirus B19 infection should be considered in cases of late anaemia after PBSC or bone marrow transplantation, occurring in patients known to be seropositive for parvovirus B19 IgG.
Lectures on applied clinical microbiology
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