Anadayr Leite

Anna Ricordi Bazin

Jussara Pereira Do Nascimento

Maria Cristina Jorge-Pereira

Martins De Sant&apos

Solange Artimos De Oliveira

Sérgio Setúbal

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299
Revista da Sociedade Brasileira de Medicina Tropical
36(2):299-302, mar-abr, 2003.
RELATO DE CASO
Clinical presentation of  parvovirus B19 infection in
HIV-infected patients with and without AIDS
Manifestações clínicas da infecção por parvovírus B19 em
pacientes HIV-positivos com e sem AIDS
Sérgio Setúbal1, Maria Cristina Jorge-Pereira2, Anadayr Leite Martins de Sant’Anna2,
Solange Artimos de Oliveira1, Anna Ricordi Bazin 
and Jussara Pereira do Nascimento3, 4
Abstract Human parvovirus B19 replicates in erythrocyte precursors. Usually, there are no apparent
hematological manifestations. However, in individuals with high erythrocyte turnover, as in patients with sickle-
cell disease and in the fetus, the infection may lead to severe transient aplasia and hydrops fetalis, respectively.
In AIDS patients, persistent infection may result in chronic anemia. By contrast, in HIV-positive patients without
AIDS the infection evolves as a mild exanthematous disease. Two clinical descriptions exemplify these forms of
presentation. In the first, an AIDS patient presented with bone marrow failure that responded to immunoglobulin.
In the second, an HIV-positive patient without AIDS had a morbilliform rash, and needed no treatment. Knowing
that an AIDS patient has chronic B19 anemia lessens concern about drug anemia; protects the patient from
invasive diagnostic maneuvers; and prevents the patient from disseminating the infection. In AIDS patients with
pure red cell aplasia, a search for parvovirus B19 DNA in the serum or in the bone marrow is warranted.
Key-words: Erythema infectiosum. Sickle cell anemia. Parvovirus. Pure red cell aplasia. AIDS.
Resumo O parvovírus B19 replica-se em precursores eritróides. Não há geralmente manifestações
hematológicas aparentes. Entretanto, nas altas taxas de reposição de eritrócitos, como as que ocorrem na
anemia falciforme ou no feto, a infecção pode resultar, respectivamente, em aplasia transitória e hidropisia
fetal. Em pacientes com AIDS, a infecção persistente pode resultar em anemia crônica. Já num paciente HIV-
positivo sem AIDS, a infecção evolui como uma doença exantemática leve. Duas descrições exemplificam
estas diferentes modalidades de apresentação clínica. Na primeira, um paciente com AIDS apresentou aplasia
medular que respondeu a imunoglobulina. Na segunda, um paciente HIV-positivo sem AIDS apresentou um
exantema morbiliforme, que cedeu sem tratamento. Diagnosticar a anemia crônica por B19 diminui as
preocupações infundadas sobre anemia por drogas, evita que o paciente seja submetido a manobras
diagnósticas invasivas, e impede que o paciente dissemine a infecção. Em pacientes com AIDS acometidos de
aplasia eritrocítica pura, está indicada a pesquisa de DNA do parvovírus B19 no soro ou na medula óssea.
Palavras-chaves: Eritema infeccioso. Anemia falciforme. Parvovírus. Aplasia eritrocítica pura. AIDS.
1. Departamento de Medicina Clínica da Universidade Federal Fluminense, Niterói, RJ, 2. Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti,
Rio de Janeiro, RJ. 3. Departamento de Desenvolvimento Tecnológico, BioManguinhos da Fundação Oswaldo Cruz. 4. Departamento de Microbiologia e
Parasitologia da Universidade Federal Fluminense, Rio de Janeiro, RJ.
This work was supported by grants from FAPERJ, CNPq and the British Council.
Address to. Dr. Sérgio Setúbal. R. Gavião Peixoto 112/1002, Icaraí, 24230-101 Niterói, RJ, Brazil.
e-mail: labutes@attglobal.net
Recebido para publicação em 17/6/2002.
Parvovirus B19 replicates in erythrocyte precursors.
Because of the rapid development of an immune
response, parvovirus B19 infection is self-limited in most
individuals, resolving with rash, arthropathy or no
symptoms at all. In most cases there are no clinically
expressed hematological manifestations. In individuals
with high erythrocyte turnover, however, parvovirus B19
infection may be critical, as may occur in patients with
sickle-cell disease (transient aplasia) and in the fetus
(hydrops fetalis)3. In AIDS patients persisting B19
infection due to impaired immunity may, as it approaches
or exceeds the normal red cell life span, result in anemia.
This anemia is not as severe as that resulting from
transient aplastic crisis in sickle-cell disease but may
last months or even years, and be confused with other
anemias that may complicate the course of AIDS. The
clinical picture is one of bone marrow failure or
hypoplasia and is usually restricted to the erythrocytic
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Setúbal S et al
lineage (acquired pure red cell aplasia). In HIV-positive
patients without AIDS, by contrast, B19 infection evolves
as an exanthematous disease, or may be entirely
asymptomatic. Descriptions of persistent anemia due
to B19 infection in AIDS patients are plentiful3 4 but there
are fewer accounts9 of exanthematous disease or
asymptomatic infection in HIV positive patients without
AIDS. The dual presentations of B19 infection in HIV
carriers are exemplified in the two clinical descriptions
that follow.
CASE REPORTS
Case 1. AIDS patient. This patient, a 32-year-old
white HIV-positive male, presented in November 1994
with tiredness for five months, attributed to chronic
exposure to insecticides. He had been working for seven
years as a sanitary agent. He was a heavy drinker and
smoker, and reported intravenous drug use. He denied
homosexual relations, but reported unprotected sex with
many partners. He had a hematocrit of 23% and a
hemoglobin concentration of 7.5g/dl. A bone marrow
aspirate showed overall hypocellularity, with a myeloid/
erythroid ratio of 9:1. The diagnosis was bone marrow
failure due to chemical hazard and the patient, after
being transfused five times with no improvement, was
referred from his hometown to the Instituto de
Hematologia Arthur de Siqueira Cavalcanti, in Rio de
Janeiro.
He was admitted there on January 1st, 1995, with a
temperature of 39oC and a parotid abscess. He was
anemic and toxemic, but showed no signs of body
wasting. He soon became well on oxacillin treatment,
but continued to need transfusions. He was anti-HCV
positive and had a CD4 count of 32/mm3. The viral load
was not measured. The diagnosis was auto-immune
hemolytic anemia due to HIV virus, and he was started
on prednisone, 40mg PO qd. On January 19th a
peripheral blood dot blot8 and IgG antibody test12 were
both positive for parvovirus B19. A new bone marrow
biopsy confirmed previous findings. He was discharged
for follow-up, with complete regression of his parotid
swelling, but still anemic and tired. Despite his anemia,
he started zidovudine and sulfamethoxazole-
trimethoprim in February 1995. The peripheral blood
parvovirus dot blot and IgG test were repeated in April
1995 and were again found positive. He was readmitted
in May 1995 for specific treatment with intravenous
human immunoglobulin, 400mg/kg/day for seven days.
A third bone marrow biopsy revealed erythroid and
myeloid hypoplasia, as well as reticulinic fibrosis. The
patient showed improvement after immunoglobulin
treatment (Figure 1). Didanosine was added to
the  zidovudine treatment. Another course of
immunoglobulin was planned, but it could not be
obtained and given until June 1996. At that time he
greatly improved and was discharged to be followed
as an outpatient. In August 1996 new B19 peripheral
blood dot blot and anti-B19 IgG tests were again
positive, but not so strongly as before. He remained
well until June 1997, when lost to follow-up.
Short arrows. Immunoglobulin infusions. Long arrows. Packed red cells transfusions.
Figure 1 - Evolution of patient 1.
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Revista da Sociedade Brasileira de Medicina Tropical 36:299-302, mar-abr, 2003
Case 2. HIV patient without AIDS defining conditions.
This patient, a 36-year-old white male homosexual,
presented on August 6, 1999, with a morbilliform rash
and mild pruritus. The rash began six days before
presentation, having started on the trunk and spreading
afterwards over the trunk and limbs, involving the palms,
soles and, less intensely, the face. There was also a
temperature exceeding 38.5oC and arthritis. There was
no cough or nasal discharge, but the patient reported
pharyngitis and conjunctivitis. These had already
subsided on presentation and there were neither
myalgias nor lymphadenitis. The rash did not
desquamate and was not hemorrhagic. The patient was
given symptomatic therapy and returned to work in less
than a week, with a fading rash and a provisional
diagnosis of non-specified exanthema. A serum sample
obtained on presentation was reactive for IgM and IgG
antibodies12 to parvovirus B19. This sample was not
reactive for acute rubella, dengue or measles. Viremia
(B19 DNA dot blot) could not be demonstrated. No blood
count was obtained on presentation. A VDRL test was
done subsequently and was negative. The patient was
taking zidovudine (600mg bid) and zalcitabine (0.75mg
tid) for established HIV infection. His last CD4 count was
468/mm3, with a viral load of 14.000/ml3, on November
1998. He had never had an AIDS defining disease. His
blood counts were unexceptional, except for a relatively
low hematocrit in January 1999 and the increased
medium corpuscular volume commonly observed in
patients taking zidovudine. This patient was among an
HIV-positive cohort followed by us in a previous study1,
in which he had been repeatedly found reactive for serum
IgG against parvovirus B19. On that occasion (November
1997) his serum dot blot and IgM against parvovirus B19
were both negative. His lowest CD4 count was 374/mm3
on May 1995 (viral load not available at this time).
DISCUSSION
The diagnosis of parvovirus B19 infection may be difficult
in immunodeficient patients. Although IgG and IgM anti-
parvovirus B19 antibodies may be more prevalent in AIDS
patients than in the general population1 11, in AIDS patients
with pure red cell aplasia anti-B19 antibodies may be
undetectable or show only weak IgM titers. The inconstant
humoral response may preclude the serologic diagnosis in
this setting, compelling to the use of more sophisticated
diagnostic methods, such as PCR, in situ hybridization, dot-
blot, and, notwithstanding its lower sensitivity,
immunohistochemistry with monoclonal antibodies4.
The above does not necessarily apply to HIV-positive
patients with normal or near normal immune responses,
in whom a serologic diagnosis is frequently possible.
Erythema infectiosum and/or the articular syndrome
normally accompanying parvovirus B19 infection are
thought to be due to immune complex depositions in
vessels and synovia4 and once the patient has produced
antibodies, these symptoms ensue. The appearance of
the same symptoms after human immunoglobulin
administration to immunodeficient patients with hitherto
asymptomatic B19 infection is consistent with this4. The
diagnosis in our second patient was a serologic one.
We could not find an explanation for the previous
presence of IgG against B19 almost two years earlier.
Perhaps, despite his good CD4 counts, the patient
already had some kind of immunologic impairment and
it is possible to have a persistent B19 infection with
delayed clinical manifestations. Musiani and colleagues9
described two HIV-positive patients with persistently
positive PCR (ascribed to low level viremia) and one of
them was PCR positive two years before the onset of
an aplastic crisis and the other seven months before
the onset of an illness similar to fifth disease. Antibody
assays for B19 were not done, however. The HIV
infections in these patients were described as
grade II (asymptomatic), according to the CDC 1987
classification system, but they both progressed to grade
IV during the observation period. It is not clear at what
stage in this progression have they developed B19-
related clinical manifestations. It is also possible to have
B19 IgG antibodies prior the detection of B19 viremia,
as was the case in one HIV positive patient prospectively
followed by Goedert and colleagues5. He had IgG B19
antibodies some three years before developing a positive
nested PCR for B19 DNA in the serum. It is impossible
to exclude the passive acquisition of antibodies by blood
transfusion. The PCR reaction turned to negative, but
the patient remained IgG positive.
The diagnosis of B19 infection may also be hinted
at by the histopathological aspect of bone marrow:
overall hypocellularity, and the presence of giant
pronormoblasts with finely granulated cytoplasm and
glassy, variably eosinophilic, intranuclear inclusions with
a clear central halo (lantern cells) are thought to be
indicative of parvovirus B19 infection6. These giant
pronormoblasts were not described in our first patient,
whose diagnosis resulted from the systematic dot-blot
testing of persistently anemic AIDS patients.
Despite the difficulties, the diagnosis of chronic B19
anemia in AIDS patients is important for several reasons:
1) it lessens concerns about zidovudine associated
anemia; 2) it prevents the patient being submitted to
invasive maneuvers aimed to clarify the causes of the
anemia; and 3) it prevents the patient from disseminating
the infection to other immunodeficient patients (with
whom he or she may associate in wards and outpatient
sectors) or to pregnant women at home4. The presence
of pure red cell aplasia in an AIDS patient, (specially
when accompanied with compatible bone marrow
pathological findings) warrants a laboratory search for
B19 infection, for intravenous immunoglobulin therapy
is expensive and should not be used simply on an
empirical basis or as a therapeutic test. Also, the effect
302
of some therapies used to treat anemia in AIDS patients,
e.g., erythropoietin2, can be harmful in B19-infected
patients, as they may increase the substrate for viral
replication. Other drugs, such as the corticosteroids
given to our first patient, can also be dangerous in the
long run, as they may enhance immunodeficiency. In
AIDS patients with pure red cell aplasia not otherwise
explained, a search for parvovirus B19 DNA in the serum
must be done through dot-blot and PCR, or in the bone
marrow through immunohistochemistry or in situ
hybridization7.
Treatment can be with intravenous standard human
immunoglobulin, which generally has sufficient
antibodies to clear viremia4. It is used in doses of
400mg/kg qd over 1 to 5 days. This can be repeated in
case of relapse. Patients with CD4 counts over 300/mm3
tend to have sound responses, without relapses. More
immunodeficient patients usually relapse, and need
repeated therapy, or suppressive prophylaxis3 4 6. It
seems to have been the case with our first patient, who
only had a partial response after the first course of
treatment, and needed another one. Reconstitution of
immunity by HAART can also lead to resolution of
anemia10.
In short, HIV patients with unimpaired immunity are
likely to manifest their parvovirus B19 infection as an
exanthematic or joint disease, without hematologic
involvement. In HIV patients with more advanced
immunodeficiency, there may be persistent anemia and
no rash.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Philip Mortimer for reviewing the text.
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Setúbal S et al


Clinical presentation of parvovirus B19 infection in HIV-infected patients with and without AIDS Manifestações clínicas da infecção por parvovírus B19 em pacientes HIV-positivos com e sem AIDS

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Clinical presentation of parvovirus B19 infection in HIV-infected patients with and without AIDS Manifestações clínicas da infecção por parvovírus B19 em pacientes HIV-positivos com e sem AIDS

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