Parvovirus B19 and the Kidney

Meryl Waldman and Jeffrey B. Kopp

Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Department of Health and Human Services, Bethesda, Maryland

Infection with parvovirus B19 causes several clinical syndromes (fifth disease, transient aplastic crisis, pure red cell aplasia,
and hydrops fetalis) and may contribute to other illnesses. B19 has been linked to renal disease in three settings: As a cause
of acute glomerulopathy and as a cause of anemia in ESRD and kidney transplantation. Case reports implicate parvovirus in
the pathogenesis of proliferative glomerulonephritis and collapsing glomerulopathy, but a causal relationship has not been
established. A proposed role for B19 infection is based on the temporal association of renal findings with viral infection,
positive serology, and identification of the viral genome in the glomerulus. Mechanisms may include cytopathic effects on
glomerular epithelial cells and/or endothelial cells and glomerular deposition of immune complexes. Patients who require
dialysis may have increased susceptibility to acute and chronic anemia after parvoviral infection. Factors that predispose this
population to complications of B19 infection include impaired immune response, deficient erythropoietin production, and
possibly decreased erythrocyte survival. The clinical burden of parvovirus B19 infection in renal transplant recipients may be
underestimated; these individuals may develop persistent viremia as a result of a dysfunctional immune response. Chronic
anemia and pure red blood cell aplasia are the most common complications of parvovirus infection in this population; the
diagnosis should be considered in transplant recipients with unexplained anemia or pancytopenia. Allograft rejection and
dysfunction have been reported in association with infection, but a cause– effect relationship has not been proved. Further
investigation of the relationship between B19 and kidney disease is warranted.
Clin J Am Soc Nephrol 2: S47–S56, 2007. doi: 10.2215/CJN.01060307

P
arvovirus B19 is a small, nonenveloped, single-
stranded DNA virus that was discovered in 1975 (1)
and first linked with human disease in 1981 (2). It is a
member of the Parvoviridae family and belongs to the Erythro-
virus genus, the name of which describes the virus’s pro-
nounced tropism for erythroid precursor cells (3,4). The human
parvovirus B19 is divided into three genotypes (B19, LaLi-like,
and V9-like) which have 10% nucleotide divergence (5–7).
Whereas these genotypes generally cross-react serologically,
PCR amplification may require specific primers. Humans are
the only known host for B19, and it is an autonomous virus that
does not require the presence of a helper virus.
The B19 genome encodes two structural capsid proteins, viral
protein 1 (VP1) and viral protein 2 (VP2), and a nonstructural
protein (NS1) (8). B19 viral particles possess icosahedral sym-
metry (20 sided), consisting of 60 capsomers that are composed
predominantly of VP2 (9). VP2 appears to facilitate viral attach-
ment onto cells via its amino terminal end, which protrudes
from the external virion surface (10). NS1 is a multifunctional
protein; it has regulatory functions in the viral life cycle, allow-
ing for replication of viral DNA and viral packaging; and it
interferes with cellular signaling pathways, leading to apopto-
sis of host cells (11) and target cell cytotoxicity (12). NS1 trans-
activation of proinflammatory cytokine promoters such as IL-6
may trigger inflammation that is associated with infection (13).
Address correspondence to: Dr. Meryl Waldman, National Institute of Health, 10
Center Drive, Clinical Research Building 10, Bethesda, MD 20892-1268. Phone:
301-451-6990; Fax: 301-480-1640; E-mail: merylw@.niddk.nih.gov
These data suggest that NS1 plays a critical role in B19-induced
disease.
Epidemiology
Infection with parvovirus is very common and occurs world-
wide. Acquisition is often during childhood and continues at
lower rates throughout adulthood such that between 70 and
85% of adults show serologic evidence of past infection (14,15).
Infectivity shows seasonal variation in temperate climates, be-
ing more common in winter and spring. Transmission of infec-
tion usually occurs by inhalation of virus in aerosol droplets
(16). Infection also can be transmitted vertically from mother to
fetus (17) and less commonly through transfusion of blood
products (18), bone marrow transplants (19), and solid-organ
transplants (20,21).
Pathogenesis and Immune Response
After gaining access to the human host, B19 targets the
erythroid progenitors in the bone marrow by binding to the
glycosphingolipid globoside (Gb4), also known as blood group
P antigen (12). P antigen is expressed abundantly on erythro-
blasts and at lower levels in a limited number of other noner-
ythroid cell types (22). Although the P antigen is necessary for
binding of the virus to the cell surface, it is not sufficient for
entry and replicative infection in human cells (22,23). Recent
studies support the existence of a cellular co-receptor, ␣5␤1
integrin, for successful infection (24), although this remains
controversial. This integrin is expressed at high levels on ery-
throid progenitors, whereas P antigen–positive nonerythroid
cells that do not express this co-receptor are considered non-

Copyright © 2007 by the American Society of Nephrology ISSN: 1555-9041/204 –S0047

S48 Clinical Journal of the American Society of Nephrology
permissive for efficient infection. A third molecule, Ku80, has
also been suggested as a possible co-receptor for B19 infection
(25).
After B19 infection of erythroid progenitors, cell death ensues
either by lysis (3) or by apoptosis (26) mediated by the NS1
protein. In normal infection, intense viremia lasts several days,
during which time the reticulocyte count can drop to zero.
Recovery is associated with production of virus-specific IgM
antibodies 10 to 12 d after infection (27). This is followed by the
production of IgG antibodies that are directed against both
viral capsid proteins, although antibodies to the unique amino
terminal region of VP1 seem most important (28). It has been a
long-held belief that the development of antibodies results in
rapid and complete clearance of viremia. However, emerging
evidence challenges this notion. With the use of sensitive quan-
titative techniques such as dot blot and nested PCR assays, B19
DNA has been detected in bone marrow and in peripheral
blood for months and even years in seemingly immunocompe-
tent individuals, despite the presence of neutralizing antibody
(29,30). The clinical significance of this delayed clearance and
low-level viremia is unknown.
Traditionally, the humoral immune response has been con-
sidered most important for clearance of parvoviral infection
and for long-term protection from re-infection. However, accu-
mulating data suggest that humoral immunity alone may be
insufficient for virus eradication. The cellular immune response
is now attracting more attention, and its contribution to control
of infection is gaining appreciation. Although limited data are
available, studies have shown a striking CD8⫹ T cell response
mounted predominantly against B19 NS1 (31). Moreover, acti-
vated CD8⫹ T cells against B19 epitopes have been detected for
up to 2 yr after infection, which may suggest that T cells
contribute to long-term pathogen control (32). It is interesting
that Isa et al. (33) showed a discordance between the distribu-
tion of the cellular immune response in healthy seropositive
individuals compared with those with B19 persistence with
skewing of the CD8⫹ T cell response toward structural VP
proteins in the latter. Thus, lack of B19 clearance could poten-
tially be related to failure or perhaps “exhaustion” of the NS1
response (34). However, this remains to be proved. Less is
understood about the role of B19-specific CD4⫹ T cells in acute
infection, but it does seem that CD4⫹ T cell proliferative re-
sponses are directed against VP1 and VP2 (35,36). Further
studies are required to clarify the role of the cellular immune
response in viral clearance, in establishment of persistent infec-
tion, and in relation to clinical manifestations.
Clinical Manifestations and Complications
The clinical spectrum of disorders that are associated with
B19 infection ranges from benign to life threatening depending
on the age, hematologic status, and immunologic status of the
host. Many immunocompetent individuals with detectable B19-
specific IgG have no recollection of specific symptoms or recall
only nonspecific symptoms of an upper respiratory tract illness.
There are several common and well-established outcomes of
B19 infection. Erythema infectiosum, also referred to as fifth
Clin J Am Soc Nephrol 2: S47–S56, 2007
disease, is the most common manifestation of infection in chil-
dren (37). It is characterized by low-grade fever, malaise, a
“slapped cheek” facial rash, and later by the spread of a lacy
maculopapular rash involving the trunk and limbs. The rash
normally disappears within 1 wk, although recrudescences can
occur for several months after emotional or physical stress or
exposure to sunlight or heat (38). Arthralgias and arthritis can
occur in the setting of erythema infectiosum, but arthropathy is
a more common manifestation of infection in adults, particu-
larly in women (39). It typically manifests as sudden onset of
symmetric polyarthralgia or polyarthritis with a rheumatoid-
like distribution involving knees, wrists, ankles, and metacar-
pophalangeal joints. Although the joint symptoms are usually
of brief duration, some do have prolonged symptoms that last
weeks to years. The pathogenesis of the cutaneous eruptions
and joint symptoms are presumed to be, at least in part, due to
deposition of immune complexes in skin and synovial tissue
because onset of manifestations coincides with appearance of
B19-specific antibodies in the serum. Immunocompromised pa-
tients who cannot mount an antibody response to B19 typically
do not develop these symptoms, whereas treatment of these
patients with intravenous Ig (IVIG) may produce rash and/or
joint pains. Nevertheless, other mechanisms besides immune
complex deposition may be involved in the inflammatory re-
sponse; skin biopsies from infected patients suggest that direct
infection of dermal vessels and cellular infiltration may con-
tribute to tissue injury (40,41). Moreover, because all immuno-
competent individuals mount an antibody response but only
some patients develop manifestations, other factors that are
unique to the host likely play a role, such as elaboration of
particular cytokine profiles (42,43).
Transient aplastic crisis as a result of B19 infection is of
particular concern in patients with either decreased red blood
cell production or increased turnover (e.g., hereditary sphero-
cytosis, sickle cell disease) (44). In healthy individuals, tempo-
rary suppression of erythropoiesis during the viremic phase is
usually well tolerated owing to the long life span of erythro-
cytes (120 d), and hemoglobin levels remain fairly stable. In
contrast, a severe and sometimes life-threatening drop in he-
moglobin can occur in those with shortened red cell lifespan (5
to 15 d), as is the case with chronic hemolytic disorders. Al-
though supportive care with transfusion is often required, the
aplastic crisis is usually self-limiting, rarely lasting for ⬎2 wk,
as a result of the production of neutralizing antivirus antibod-
ies. Finally, B19 infection during pregnancy may lead to hy-
drops fetalis and intrauterine fetal death (45).
Although these are the best described clinical illnesses that
are caused by B19 infection in the immunocompetent host, the
virus has been implicated in an expanding spectrum of other
clinical disorders (Table 1). These associations have been pro-
posed on the basis of the temporal association of symptoms in
the context of serologic documentation of recent infection or
detection of B19 in peripheral blood or affected tissue. How-
ever, clear causality has been difficult to prove in many cases,
and many of these associations remain controversial.
Clin J Am Soc Nephrol 2: S47–S56, 2007 Parvovirus B19 and the Kidney S49

Table 1. Complications after B19 infectiona

Well-Established Syndromes Other Associations Based on Organ System

Fifth disease Renal: Proliferative glomerulonephritis (46–49,51,52,58–60),

Arthropathy collapsing glomerulopathy (50,53,88), FSGS (55,61),
Hydrops fetalis, intrauterine fetal death, thrombotic microangiopathy (56), renal transplant dysfunction
miscarriage (after maternal infection (82,83), acute allograft rejection (81)
during pregnancy) Rheumatic: Rheumatoid arthritis, systemic lupus erythematosus,
Transient aplastic crisis (in patients with chronic fatigue syndrome, dermatomyositis, uveitis, systemic
chronic hemolytic disorders) sclerosis (reviewed in reference 关98兴)
Chronic pure red blood cell aplasia (in Cardiac: Myocarditis (99), cardiomyopathy (99), diastolic
immunocompromised patients) dysfunction (100)
Hepatobiliary: Hepatitis (101), fulminant liver failure (102)
Hematologic: Hemophagocytic syndrome (103), idiopathic
thrombocytopenic purpura (104), hemolytic uremic syndrome
(62)
Dermatologic: ⬙Gloves and socks⬙ syndrome (41), Gianotti-Crosti
syndrome (98), erythema nodosum (41)
Vasculitis: Kawasaki disease (105), Henoch-Schönlein purpura
(54,63), microscopic polyarteritis nodosa (62), Wegener’s
granulomatosis (64)
Neurologic: Encephalopathy, meningitis, seizures, transverse
myelitis, Guillain-Barré syndrome, acute cerebellar ataxia,
neuropathy (reviewed by Barah et al. 关106兴)
Pulmonary: Idiopathic pulmonary fibrosis, scleroderma-
associated pulmonary fibrosis, lymphocytic interstitial
pneumonitis, septal capillaritis (107)
a
Five well-established syndromes that are associated with B19 infection are shown. In addition, a wide range of
manifestations have been reported in association with infection, but a causal role for B19 in many of these has not been
conclusively established.

Glomerular Diseases Associated with Parvovirus
The possibility of a link between B19 infection and glomer-
ular disease has been suggested from numerous case reports
that describe onset of nephritis or nephrotic syndrome after
onset of parvovirus infection. Several clinical presentations and
histologic patterns have been described (46 –56). Acute ne-
phritic syndrome with hypocomplementemia often following a
prodrome of fever, rash, and arthritis is most common, but
nephrotic-range proteinuria is seen as well (46 – 49,51,52,57– 60).
Reported histologic features include endocapillary and/or mes-
angial proliferation often with subendothelial deposits together
with granular deposition of C3 and IgG along capillary walls
and mesangium, a pattern that is consistent with acute postin-
fectious glomerulonephritis. Viral genome has been detected in
renal biopsies by PCR, and immunohistochemical analysis has
demonstrated B19 antigen within glomeruli in some cases
(48,51,52). Spontaneous recovery is common, but some have
persistent renal dysfunction and/or proteinuria.
Several case reports have linked acute B19 infection to ne-
phrotic syndrome in patients with sickle cell disease. Wirenga
et al. (61) reported on seven patients who had homozygous
sickle cell disease and developed glomerulonephritis and pro-
teinuria 1 to 7 wk after aplastic crisis as a result of B19 infection.
Renal biopsies showed segmental proliferative glomerulone-
phritis in four patients and FSGS in one patient who underwent
biopsy 4 mo after onset of symptoms. Spontaneous recovery
occurred in one patient, one died with chronic renal failure, and
the others had impaired creatinine clearance, four with persis-
tent proteinuria. Tolaymat et al. (55) similarly reported onset of
hematuria and proteinuria 10 d after B19-associated aplastic
crisis in a patient with sickle cell disease. Renal biopsy at 3 mo
showed focal mesangial proliferative glomerulonephritis with
mesangial deposits, extensive foot process effacement, and tu-
buloreticular structures, but no viral particles were observed.
Viral genome was detected in renal tissue by PCR. Follow-up
biopsy done 1 yr later because of persistence of the nephrotic
syndrome showed FSGS, and B19 DNA remained detectable by
PCR. Thrombotic microangiopathy (49,56), hemolytic uremic
syndrome (62), and renal involvement in association with sys-
temic vasculitides such as Henoch Schönlein purpura (54,63),
polyarteritis nodosa (64) and Wegener’s granulomatosis (64)
have also been associated with B19 infection.
Several investigators have attempted to characterize the po-
tential association between B19 infection and glomerular dis-
ease. Tanawattanacharoen et al. (53) tested for B19 genome by
PCR in native renal biopsies that were derived from 44 patients
with various glomerular diseases (collapsing glomerulopathy
and idiopathic FSGS, membranous nephropathy, minimal-
change nephropathy, and controls) and found that the preva-
S50 Clinical Journal of the American Society of Nephrology
lence of parvovirus B19 was greatest among patients with
collapsing glomerulopathy and FSGS compared with other re-
nal diseases, although the difference was marginally signifi-
cant. However, in situ hybridization failed to detect parvovirus
B19 nucleic acid in any samples. In a similar study, Moudgil et
al. (50) found a significantly higher prevalence of B19 DNA in
renal biopsies from patients with collapsing glomerulopathy
(78%), compared with other nephropathies (idiopathic FSGS
22%; HIV-associated collapsing glomerulopathy 16%; controls
26%). In situ hybridization detected B19 in the majority of
biopsies that tested positive for virus by PCR (100% collapsing
glomerulopathy; 75% idiopathic FSGS; 67% HIV-associated col-
lapsing glomerulopathy; 0% controls). It is interesting that B19
DNA was localized to glomerular podocytes and parietal epi-
thelial cells, both of which have been implicated in the patho-
genesis of collapsing glomerulopathy. In contrast to these find-
ings, Swaminathan et al. (65) were unable to detect parvovirus
DNA sequences (by in situ hybridization) in 29 cases of FSGS
and collapsing glomerulopathy that occurred after renal trans-
plantation.
These conflicting results make it difficult to draw definitive
conclusions regarding the role of parvovirus in the pathogen-
esis of certain glomerular disease. Nevertheless, the data are
certainly provocative and are fairly convincing in the cases of
proliferative glomerulonephritis that are temporally associated
with primary B19 infection. Large-scale studies are warranted
to help further define the potential relationship between infec-
tion and disease manifestations and to provide answers to
important questions regarding the interaction of this virus with
humans. For example, what is the clinical significance of the
detection of viral DNA in nonerythroid cells such as in the
kidney? It has been shown that B19 DNA can remain detectable
by nucleic acid amplification testing in a variety of tissues (30),
including bone marrow (66), synovial tissue (67), and skin (6),
for extended periods without evidence of disease in some (30).
As discussed, viral DNA has been detected in seemingly “nor-
mal, control” kidneys (50). The mechanisms that facilitate this
persistence in human tissues are unclear. It is also not known
whether this represents intact infectious virions or residual
DNA from remote infection and to what extent, if any, it can be
reactivated. Therefore, detection of viral DNA in tissues does
not necessarily indicate active viral infection and must be in-
terpreted with caution because the virus may be an “innocent
bystander.” It is noteworthy that, to date, intact virions have
not been visualized within the kidney despite that viral DNA is
detected; however, this is also true for other viral nephropa-
thies, such as HIV-associated collapsing glomerulopathy.
Whether this is related to a low viral load, small size of the B19
virus (22 to 24 nm), or false-positive results is not known.
Alternatively, restricted production of viral proteins may occur;
indeed, isolated expression of the B19 nonstructural protein,
NS1, has been demonstrated in some nonpermissive, noneryth-
roid cells even in the absence of complete viral propagation and
has been shown to be cytotoxic (68). It is not known whether
this process occurs in kidney cells, but it cannot be excluded as
a possible mechanism of glomerular cell injury and deserves
further study.
Clin J Am Soc Nephrol 2: S47–S56, 2007
Even if one assumes that the virus can enter glomerular cells,
the mechanism of cell entry is incompletely understood. The P
antigen receptor has been found in kidney tissue (22), but its
cellular localization is unknown. In addition, whether the level
of expression, distribution, or accessibility of this and other
co-receptors influences disease susceptibility has not been stud-
ied. Nevertheless, it is unlikely that a direct cytopathic effect on
glomerular epithelial cells is the sole mechanism of viral injury.
Several histologic patterns have been reported in association
with infection, and this suggests that other mechanisms may
play a role. Deposition of circulating immune complexes that
involve viral antigens and host antiviral antibodies could lead
to a pattern of injury that is consistent with postinfectious
glomerulonephritis. Development of autoantibodies to cardio-
lipin, phospholipids, and double-stranded DNA have been re-
ported during parvovirus infection (69), and these could also
potentially contribute to preformed circulating immune com-
plexes or in situ deposition. Direct infection of glomerular en-
dothelial cells has been proposed as the mechanism of renal
injury in cases of thrombotic microangiopathy and vasculitis.
The P antigen has been demonstrated on endothelial cells (22),
and B19 DNA has been localized to these cells in cases of
B19-associated vasculitis (70). Thus, infection could result in
endothelial cell dysfunction or cell death, leading to capillary
thrombosis and glomerular ischemia. The cellular immune re-
sponse to infection is not well characterized, but perhaps as we
gain more insight into this area, we may find that an aberrant
T cell response after infection also contributes to glomerular
disease.
Given the ubiquitous nature of B19 infection, factors that are
unique to the host likely increase susceptibility to glomerular
disease after infection. This has not been studied specifically as
it relates to glomerular diseases, but investigation of other
infection-associated manifestations have revealed interesting
findings that may have relevance (71). Inherent variability in
cytokine expression and cytokine genetic polymorphisms may
affect symptoms and outcome of infection; for example, in-
creased levels of TNF-␣ and IFN-␥ during acute and convales-
cent infection are associated with chronic fatigue, whereas
lower levels of TNF and IL-6 have been detected in patients
with postinfectious arthritis. A particular allele of TGF-␤ has
been associated with development of skin rash during acute
infection (42). Certain human leukocyte antigen alleles (HLA-
DRB1*01, *04, *07, and B49) have been associated with symp-
tomatic parvovirus infection (71). Single-nucleotide polymor-
phisms in genes that are linked to apoptosis, cell cycle and
growth, and cytoskeleton were also found to associate with
symptomatic B19 infection (71).
Further work is needed to better define the role of B19 in
kidney disease. We need more detailed case reports that in-
clude careful longitudinal virologic analysis of serum and renal
tissue. We also need well-designed epidemiologic studies with
appropriate controls. If further evidence of a link can be estab-
lished, then there will be a need to characterize the immune
response to B19 infection in such patients and to identify ge-
netic and other factors that increase susceptibility for renal
complications.
Clin J Am Soc Nephrol 2: S47–S56, 2007
Parvovirus Infection in Dialysis Populations
The impact and role of parvovirus B19 infection in patients
with chronic kidney disease or ESRD is not known. Neverthe-
less, there are several reasons to think that parvovirus may be
an important pathogen in these populations. For most patients,
erythropoiesis is maintained by erythropoiesis-stimulating
agents, and red blood cells may have a shortened life span in
the setting of uremia. This combination of factors may predis-
pose these patients to potentially life-threatening transient
aplastic crisis associated with parvovirus infection (72). Fur-
thermore, some believe that administration of erythropoietin
during B19 infection can facilitate viral replication by providing
new target cells (73), thereby prolonging viremia and its asso-
ciated complications. However, this remains controversial.
Nosocomial spread of infection in an enclosed dialysis unit is
also a potential threat, but this is not well described in the
literature (74).
In addition to the acute complications, the immunocompro-
mised state in some dialysis patients (related to underlying
diseases or medications) may prevent an effective antiviral
immune response that can potentially lead to persistent viremia
and chronic anemia that is resistant to erythropoietin. The
frequency of this complication in chronic dialysis patients is not
clear because this has not been systematically evaluated in a
large cohort of anemic dialysis patients. Finally, it is possible
that persistent B19 infection in these chronic dialysis patients
can become clinically relevant after renal transplantation and
introduction of immunosuppressants, as discussed in the next
section.
Parvovirus in Kidney Transplant Recipients
Transplant recipients are susceptible to many primary viral
infections and to reactivation of persistent viruses. Most clini-
cally relevant infections in the posttransplantation period are
caused by the Herpesviridae group, respiratory viruses, and
hepatitis viruses B and C. The first report of parvovirus B19
infection in a kidney transplant recipient was published in 1986
(75). Since then, numerous cases of B19 infection after solid-
organ transplantations have been reported (20,76 –79). How-
ever, the clinical burden and true overall impact of B19 infec-
tion in the renal transplant population is not well characterized.
The prevalence of B19 infection in organ transplant recipients
is difficult to estimate because much of the literature consists of
case reports rather than carefully monitored cohorts. Further-
more, interpretation is difficult given different selection criteria,
diagnostic methods with different detection sensitivities, differ-
ent definitions of infection, and various (but limited) lengths of
follow-up, together with confounding by concurrent viral epi-
demics (80). Nevertheless, on the basis of several longitudinal
studies, between 1 and 12% of unselected, mainly adult, renal
transplant recipients have symptomatic B19 infection during
the first year after transplantation (79 – 81). Given the preva-
lence of parvovirus in the general population, the increased
susceptibility to viral infections after transplantation, and the
increasing number of patients who have additional immuno-
compromised states (e.g., HIV infection, advanced age, diabe-
Parvovirus B19 and the Kidney S51
tes) and undergo transplantation, it is possible that this is an
underestimation.
Although the mode of transmission of B19 infection in the
normal host is mostly via the respiratory tract, it is less well
defined in the transplant setting. Onset of symptoms has been
reported to occur from a few days to ⬎1 yr after transplanta-
tion, suggesting different paths of transmission (20,76,78,79).
Certainly, the short time lapse between transplantation and
onset of illness that has been reported in some has the charac-
teristic of donor-transmitted disease, but this is often difficult to
prove (56,81,82). Other possible routes of B19 infection besides
airway transmission include transfusion of blood products and
viral reactivation in the setting of intense immunosuppression.
The clinical picture of B19 infection in the immunocompro-
mised host differs significantly from that of immunocompetent
individuals. Because of the inability to mount an efficient hu-
moral and/or cellular immune response, viral clearance is sig-
nificantly delayed, or, in some cases, infection remains persis-
tent, resulting in prolonged suppression of erythropoiesis.
Therefore, it is not surprising that both acute anemia and
chronic pure red blood cell aplasia are the most frequently
reported consequences of B19 infection in organ transplant
recipients (21,77,78,81,83). Several case series have evaluated
the incidence of active B19 infection in renal transplant patients
who present with anemia. Egbuna et al. (21) screened for ane-
mia in 212 patients who were seen at a transplant clinic during
a 3-mo period in late winter to early spring. Of eight patients
selected with severe unexplained anemia (defined as hemato-
crit ⬍30%) and erythropoietin resistance, three (38%) were
found to be positive for B19 by PCR. Cavallo et al. (83) reported
that 11 (23%) of 48 transplant recipients with anemia had B19
detected in serum by nested PCR compared with one (5%) of 21
without anemia. Similarly, Bertoni et al. (76) reported that four
(44%) of nine transplant recipients with severe hypoprolifera-
tive anemia (hemoglobin ⬍7 g/dl) were found to have parvo-
virus DNA in serum.
Hematologic findings consist of normochromic normocytic
anemia, usually lacking reticulocytes, and the anemia is typi-
cally resistant to erythropoietin therapy (21,83). Onset of B19-
associated anemia has been reported from 2 wk to 63 mo after
transplantation (76 –79). The diagnosis of B19-associated ane-
mia in this population can be challenging for many reasons.
There is often a lack of classical B19-associated symptoms, such
as rash and arthritis, that could provide clues to the diagnosis.
Anemia is relatively common after transplantation, particularly
in the early posttransplantation period, and can be multifacto-
rial. Therefore, B19 is often not considered in the very long list
of causes of anemia, which include acute and chronic blood
loss, generalized bone marrow suppression from immunosup-
pressants and antiviral medications, allograft dysfunction, iron
deficiency, hyperparathyroidism, use of angiotensin-convert-
ing enzyme inhibitors and angiotensin receptor blockers, and
other, more common viral infections, such as cytomegalovirus.
Furthermore, neutropenia, thrombocytopenia, or pancytopenia
may occasionally accompany the anemia, further broadening
the differential diagnosis (77). Other clinical complications that
have been linked with B19 infection in renal transplant recipi-
S52 Clinical Journal of the American Society of Nephrology
ents include liver dysfunction (84), fibrosing cholestatic hepa-
titis (85), encephalitis (86), and cerebral vasculitis (87). How-
ever, causality has been difficult to infer in many cases.
Allograft Dysfunction and Acute Rejection
There are many data to support that certain viral infections
such as cytomegalovirus and polyomavirus (BK) are associated
with allograft rejection or dysfunction in renal transplant recip-
ients. The evidence for a role of parvovirus in such processes is
not as compelling. Isolated case reports describe elevated
plasma creatinine and proteinuria at the time of acute B19
infection, but most reports lack renal biopsies and follow-up.
Yango et al. (82) described a patient who presented 8 d after
transplantation with fever, myalgia, polyarthralgia, and pancy-
topenia and 2 wk later developed graft dysfunction associated
with elevated IgM and IgG titers against B19. Kidney biopsy
revealed tubular cell damage, and parvovirus DNA was de-
tected by PCR in biopsy. Zolnourian et al. (81) implicated acute
parvovirus infection as a cause of acute rejection and graft loss
in one pediatric patient. Several series have reported different
rates of allograft dysfunction associated with infection. Ki et al.
(80) found no association between allograft dysfunction and
B19 infection. In contrast, Cavallo et al. (83) reported that 36% of
patients with active infection had elevated serum creatinine,
levels but none developed rejection or glomerulopathy.
Murer et al. (56) implicated B19 infection in four cases of renal
allograft dysfunction, all of which had histologic findings of
thrombotic microangiopathy. Renal dysfunction was simulta-
neous or within days of an aplastic crisis that occurred 6 to 45 d
after transplantation. Viral genome was isolated by PCR in all
renal biopsies and in the peripheral blood of those tested. All
patients subsequently became serologically positive for anti-
B19 IgM. One patient was treated with IVIG, but the others
improved spontaneously with gradual resolution of anemia
(after 22 d to 12 mo) and recovery of graft function 22 to 110 d
after onset. Direct viral infection of endothelial cells has been
proposed as the mechanism of injury. Sensitization of glomer-
ular endothelium as a result of other forms of injury such as
acute rejection may have increased susceptibility to B19-in-
duced damage. Collapsing glomerulopathy and subsequent
graft failure (69,88) associated with parvovirus infection have
been reported in renal transplant patients, but, as previously
discussed, a larger series was unable to find a relationship
between B19 infection and collapsing glomerulopathy in kid-
ney transplants (65).
Given the paucity of available data, it is difficult to defini-
tively establish a causal relationship between B19 and allograft
rejection or dysfunction. Nevertheless, this does not exclude a
role for this virus in such processes. It is possible that we have
failed to recognize a pattern of renal injury associated with
infection as a result of a lack of suspicion and inadequate
testing. Large-scale studies that systematically test for parvovi-
rus in allograft specimens would be beneficial but may not be
practical.
Clin J Am Soc Nephrol 2: S47–S56, 2007
Screening
There are no established guidelines for screening for B19
infection in organ transplant recipients. Although there is in-
sufficient evidence for universal screening of all donors and
recipients, there is evidence to support screening in patients
who have moderate to severe anemia and for whom other
causes of anemia have been excluded. In addition, the index of
suspicion for this infection should be even greater during high-
risk periods such as early after transplantation during the
highest level of immunosuppression and after treatment for
rejection. Increased vigilance is also required for pregnant
transplant recipients (because of the risk of fetal complications
associated with infection) and in patients with possible in-
creased exposure related to occupation, including nurses,
teachers, and child care providers.
Diagnosis of B19 Infection
The choice of diagnostic tests for detection of parvovirus
must take into account the immunologic status of the patient
(89). For most immunocompetent individuals, serologic testing
for B19 virus–specific antibodies is most practical and is mea-
sured using enzyme immunoassays, which usually use recom-
binant capsid proteins (90). IgM antibodies directed to viral
capsid antigens indicate acute infection, although, in some
cases, these antibodies persist and can be detected for months.
Previous infection is usually confirmed by detecting IgG anti-
bodies toward viral capsid proteins in the absence of IgM
antibody (27).
If only viral serologies are obtained, then the diagnosis of B19
infection can be missed in immunosuppressed patients who
may not mount an antibody response. Furthermore, in organ
transplant recipients, diagnosis by serology can be confounded
by administration of blood products or Ig after transplantation,
because these therapies may produce false-positive IgG anti-
body tests. Thus, identification of the viral DNA by PCR is
preferred for diagnosis in these patients (91).
Treatment
Specific antiviral therapy is not available to treat B19 infec-
tion. The approach to therapy of infection depends on host
factors such as immune status, underlying conditions, and
manifestations of infection. Most cases of infection in immuno-
competent hosts do not need treatment because the symptoms
are transient, although nonsteroidal anti-inflammatory agents
may be helpful in cases of arthropathy. Patients with transient
aplastic crisis may need supportive therapy with blood trans-
fusions until neutralizing antibody response can clear the virus
and hematopoiesis is restored.
There are several options for the treatment of pure red cell
aplasia and persistent infection in immunocompromised pa-
tients in whom B19-specific antibody response is absent or
minimal. Commercial Ig (IVIG), a significant source of anti-B19
antibodies, has proved to be efficacious, although no controlled
studies have been carried out (21,69,76,78 – 81,92,93). Various
regimens have been reported with favorable outcomes, but on
the basis of the pooled data, 400 mg/kg per d for 5 to 10
consecutive days seems to be clinically useful in most cases.
Clin J Am Soc Nephrol 2: S47–S56, 2007
Although clinical response is common as evidenced by reticu-
locytosis, increased hemoglobin levels, and decline in serum
viral DNA, complete eradication of viremia may not occur in
some patients, particularly in transplant patients, who are
highly immunosuppressed. Thus, relapses of anemia can occur
up to several months after completion of treatment. Repeated
administration of IVIG may be helpful, but some patients ex-
perience multiple relapses (79). Reduction of immunosuppres-
sive medication is often recommended in addition to IVIG (or
without IVIG in less severe cases) to allow the patient’s own
immune response to mature and neutralize the virus (78,93–95).
Several reports have concluded that symptomatic B19 infection
is linked specifically to the use of tacrolimus rather than the
overall state of immunosuppression. This is based on observa-
tions that a switch from tacrolimus to cyclosporine was fol-
lowed by viral clearance and complete resolution of anemia in
some patients (78,96,97). Accordingly, some have suggested
this change in drug regimen for infected recipients who fail to
respond to IVIG. The mechanism for this difference, if it is real,
remains unknown. Spontaneous recovery has also been re-
ported in some patients without therapy (77,83).
Conclusions
Parvovirus B19 infection is associated with a wide spectrum
of clinical manifestations, some of which are well established
and some of which are controversial. The role of parvovirus
infection as a trigger of glomerular disease has yet to be firmly
established but deserves further attention because it may have
implications in prevention strategies and treatment. The clinical
significance of B19 infection in patients who have ESRD and are
on hemodialysis is not clear, but this population may be vul-
nerable to transient aplastic crisis or chronic anemia as a result
of viral infection. Although B19 infection is relatively uncom-
mon in the renal transplant population, parvovirus B19 infec-
tion should be included in the differential diagnosis of moder-
ate to severe unexplained anemia or pancytopenia in this
population. B19 serology is of limited value for diagnosis, and
PCR is better for confirmation of infection in immunocompro-
mised patients. IVIG has been shown to be beneficial in trans-
plant recipients with anemia associated with parvovirus infec-
tion, but relapses can occur. The combination of decreased
immunosuppression and IVIG may promote viral clearance.
The association of parvoviral infection with allograft rejection
or dysfunction is not clearly established. Further studies are
warranted to understand better the relationship between B19
infection and glomerular diseases and the impact of the disease
in the ESRD and transplant populations.
Acknowledgments
This research was supported by the National Institute of Diabetes
and Digestive and Kidney Diseases intramural research program.
We thank Dr. Monique Cho for critical review of the manuscript.
Disclosures
None.
Parvovirus B19 and the Kidney S53
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