Spontaneous Resolution of Hemophagocytic Syndrome and
Parvovirus B19 Infection in a Previously Healthy Child
Zühre Kaya*, Gülyüz Oztürk, Türkiz Gürsel and Gülendam Bozdayı1
Department of Pediatric Hematology and 1Department of Microbiology,
(Received August 30, 2004. Accepted January 28, 2005)
SUMMARY: A 10-year-old male with a brain abscess developed pancytopenia, liver dysfunction, disseminated
and anticonvulsant therapy. A bone marrow examination revealed hemophagocytosis. Real-time PCR revealed
this is the first report of a spontaneous resolution of parvovirus B19-associated hemophagocytic syndrome and
Disseminated Intravascular Coagulation Associated with
Gazi University Medical School, Ankara, Turkey
intravascular coagulation (DIC) and decrease of immunoglobulin A (IgA) level during postoperative antibiotic
parvovirus B19 infection. The hemophagocytic syndrome resolved without specific treatment. To our knowledge,
Virus-associated hemophagocytic syndrome (VAHS) is a
proliferation. Activated macrophages in bone marrow engulf
cytopenia. The diagnostic criteria of VAHS include clinical
and rash, and laboratory findings such as pancytopenia,
(DIC), hypertriglyceridemia, and bone marrow changes. VAHS
tions, particularly with Epstein-Barr virus (EBV) (1-3), and
patients usually recover in weeks with antimicrobial therapy,
knowledge, this is the first report of a spontaneous recovery
Jpn. J. Infect. Dis., 58, 149-151, 2005
*Corresponding author: Mailing address: Birlik mahallesi 68.
495-4272, E-mail: firstname.lastname@example.org
sokak No:16/4, Çankaya, Ankara 06610, Turkey. Tel: +90-312-
rare disorder characterized by macrophage activation and
erythrocytes, leukocytes, platelets and their precursors, causing
signs such as fever, hepatosplenomegaly, lymphadenopathy,
liver dysfunction, disseminated intravascular coagulation
is usually associated with a number of systemic viral infec-
occasionally occurs in association with parvovirus B19. The
or in some cases the syndrome resolves naturally. To our
of parvovirus B19-associated VAHS in the presence of DIC
PATIENT AND LABORATORY INFORMATION
A 10-year-old boy was admitted to our hospital with a com-
over the previous 3 days. On examination he was found to have
a mass of 4 cm diameter appearing as a ring-enhancing
lobe. The abscess was drained by open surgery, and a combi-
meropenem, and phenytoin as an anticonvulsant was started.
3 weeks after surgery. Preoperative laboratory findings,
coagulation parameters and serum immunoglobulin levels,
the brain specimen strongly suggested an abscess with infil-
seen. A culture of the abscess material did not show bacterial
plaint of numbness and weakness on the left side of his body
left hemiplegia and facial palsy. Cranial tomography showed
lesion and indicating an abscess cavity on the right parietal
nation antimicrobial treatment with ornidazole, vancomycin,
Phenytoin was given at 5 mg/kg/day in two divided doses for
including complete blood count, liver and renal function tests,
were within the normal range. Histopathological analysis of
tration of predominantly neutrophils. No atypical cells were
growth. One week later, the child’s condition suddenly wors-
Table 1. Patient’s clinical course including coagulation and fibrinolysis
Ab, antimicrobial therapy; Phen, phenytoin; FFP, fresh frozen plazma; Plt conc, platelet concentrate; Hb, hemoglobulin; WBC, white blood cell; ANS,
Postopt 7 days
Postopt 11 days
Postopt 5 days
Postopt 10 days
Postopt 12 days
Postopt 13 days
Postopt 15 days
Ab, Phen FFP,
absolü neutrophil count; PT, prothrombin time; PTT, partial thromboplastin time; Fib, fibrinogen; FDP, fibrin degradation product; IgA, immunoglobulin A.
Postopt 14 days
Postopt 17 days
ened. He developed high fever that rose as high as 40.5°C,
bilateral facial rash and generalized maculopapular eruption
liver enzymes, pancytopenia and coagulopathy (Table 1). The
were 283 mg/dl, 832 U/l and 526 mg/dl, respectively. The
while the IgG and IgM levels were within the normal limits.
was weakly positive for anti-parvovirus B19 IgM and nega-
for anti-parvovirus B19 IgG was apparent. A very low
1.31×102 copy/reaction (2,600 copy/ml) by a very sensitive,
detection limit of 10 copies per reaction (Light Cycler,
(Fig. 1). None of the other viral (EBV, cytomegalovirus, hepa-
were positive. Bone marrow aspiration showed numerous
their precursors and giant normoblasts. Platelet and fresh
ing. Antimicrobial and phenytoin therapy were continued for
abnormalities recovered gradually.
Parvovirus B19 infection occurs in 50% of children under
infectiosum. However, a wide variety of hematological mani-
B19 infection, including transient aplastic crisis in patients
diseases and, rarely, hemophagocytic syndrome (4,5). The
morphology in the presence of typical clinical and laboratory
syndrome was diagnosed based on the presence of high
generalized lymphadenopathy, hepatomegaly, splenomegaly,
all over the body. Laboratory investigations revealed elevated
serum levels of triglyceride, lactic dehidrogenase and ferritin
serum IgA level declined to 13 mg/dl (normal range: 60-294),
Blood, throat, and urine cultures were negative. The serum
tive for anti-parvovirus B19 IgG, but 5 days later, positivity
level of parvovirus B19 positivity was detected in the serum,
commercially available real-time PCR assay with a lower
Parvovirus B19 Quantification Kit, Mannheim, Germany)
titis A virus, hepatitis C virus, rubella) serological markers
macrophages engulfing erythrocytes, leukocytes, platelets and
frozen plasma were given only once to stop gingival bleed-
a total of 3 weeks, during which the clinical and laboratory
the age of 15 worldwide and is known as the cause of erythema
festations can be observed during the course of parvovirus
with chronic hemolytic anemia and immunodeficiency
diagnosis of VAHS is made by characteristic bone marrow
abnormalities. Thus, in the present case, hemophagocytic
fever, generalized lymphadenopathy, hepatosplenomegaly,
and maculopapular eruption in association with pancytopenia,
extensive hemophagocytosis, and proliferation of histiocytes
PCR analysis suggested that hemophagocytic syndrome may
Hemophagocytic syndrome has been reported in a 9-year-
parvovirus B19 despite the fact that fever, erythematous rash
role of phenytoin in the pathogenesis of hemophagocyctic
There have been a total 22 cases of parvovirus B19-
(7,8). Nine of these were children, and 3 of the 9 recovered
ered children had DIC, which is a severe complication of
(9). Elevated levels of cytokines such as tumor necrosis
with the severity of manifestations in VAHS (10). Unlike these
without specific treatment for parvovirus B19, such as intra-
to surgical drainage of the abscess may also have contributed
improvement of our patient was neither due to occurrence of
unit of fresh frozen plasma and platelet concentrate for
Although hemophagocytic syndrome can occur in the
patient had no clinical or laboratory evidence of underlying
observed during the hemophagocytic syndrome may have
itself, since the level returned to normal 2 months later (12,13).
course of the disease by enhancing the susceptibility to
To our knowledge, this is the first report of spontaneous
liver dysfunction, DIC, hyperferritinemia, hypertriglyceridemia,
in bone marrow. Positive anti-parvovirus B19 serology and
be caused by this virus. The child was also taking phenytoin.
old boy receiving phenytoin, but he was not tested for
and lymphadenopathy indicated this infection. Therefore, the
syndrome is not yet clear (6).
associated hemophagocytic syndrome reported so far
spontaneously. However, none of these spontaneously recov-
VAHS resulting from cytokine-induced tissue factor release
factor-alpha (TNF-α) and interleukin-1 (IL-1) are associated
cases, our patient had DIC but showed spontaneous recovery
venous immunoglobulin. In our case, brain tissue injury due
to the development of DIC (11). We think that the clinical
anti-parvovirus B19 antibody nor due to transfusion of a single
setting of congenital or acquired immunodeficiency, our
immunodeficieny. The marked decrease in serum IgA level
been due to the phenytoin use or to the hemophagocytosis
A decrease of serum immunoglobulins may complicate the
infection and therefore should be closely followed up.
resolution of parvovirus B19-induced hemophagocytic
Fig. 1. Real-time PCR result for parvovirus B19 in patient serum sample.
2530 35 40 45
Standard 1 6.77×104
Standard 2 6.4×102
Standard 3 6.89×101
syndrome associated with DIC in a previously healthy child.
ciated with a milder inflammatory response than EBV or other
cytokines and acute-phase reactants, leading to severe
or antiviral therapy.
1. Soult Rubio, J. A., Garcia Bernabeu, V., Sanchez Alvarez,
Tovaruela Santos, A. (2002): Macrophage activation
failure syndromes. p. 222-224. In D. G. Nathan and F.
4th ed. Section 7. Pennsylvania.
Vavrinec, J., Komrska, V., Roubalova, K., Vandasova,
Infection-associated hemophagocytic syndrome compli-
Pediatr. Hematol. Oncol., 13, 143-150.
R. and Barak, Y. (2002): Human parvovirus B19 infec-
Med. Assoc. J., 4, 763-765.
hematologic effects of parvovirus B19 infection. Pediatr.
Parvovirus B19 mainly infects normoblasts, is usually asso-
viruses, and can cause markedly elevated inflammatory
hemophagocytic histiocytosis requiring immunosuppressive
M. J., Munoz Saez, M., Lopez Castilla, J. D. and
syndrome: a diagnostic challenge. An. Esp. Pediatr., 56,
2. Blanche, P. A. and Neal, S. Y. (1993): The bone marrow
A. Oski (ed.), Hematology of Infancy and Childhood.
3. Syruckova, Z., Stary, J., Sedlacek, P., Smisek, P.,
J., Sintakova, B., Houskova, B. and Hassan, M. (1996):
cated by infectious lymphoproliferation: a case report.
4. Barash, J., Dushnitzky, D., Sthoeger, D., Bardnestein,
tion in children: uncommon clinical presentations. Isr.
5. Mustafa, M. M. and Mcclain, K. L. (1996): Diverse
Clin. North Am., 43, 809-821.
6. Pecero, V. M. G. R., Marquez, R. L., Lerchundi, M.
hemocytophagic histiocytosis indistinguishable from
7. Larroche, C., Scieux, C., Honderlick, P., Piette, A. M.,
tion of hemophagocytic syndrome associated with acute
virus reactivation in an otherwise healthy adult. Eur. J.
8. Shirono, K. and Tsuda, H. (1995): Parvovirus B19-
Br. J. Haemotol., 89, 923-926.
Imashuku, S. (1988): High serum ferritin level as a
hemophagocytic syndrome. Cancer, 61, 2071-2076.
Hypercytokinemia in hemophagocytic syndrome. Am.
11. Huang, P. S. and Koo, K. E. (1990): Diffuse intravascular
dren. Pediatr. Neurosurg., 16, 43-47.
Thomas, K., Singh, S., Sarpel, S. and Jovanovic, L.
syndrome associated with lymphoproliferative disorders.
13. Woo, P., Pereira, R. S. and Lever, A. M. (1984): Persis-
antiepileptic therapy in a C2 deficient patient with
A. A. and Jurado, A. F. (1991): Phenytoin-induced
malignant histiocytosis. South Med. J., 84, 649-650.
Morinet, F. and Bletry, O. (2002): Spontaneous resolu-
parvovirus B19 infection and concomitant Ebstein-Barr
Clin. Microbiol. Infect. Dis., 21, 739-742.
associated hemophagocytic syndrome in healthy adults.
9. Esumi, N., Ikushima, S., Shigeyoshi, H. B., Todo, S. and
marker of malignant histiocytosis and virus-associated
10. Fujimara, F., Hibi, S. and Imashuku, S. (1993):
J. Pediatr. Hematol. Oncol., 15, 92-93.
coagulation associated with brain tumor surgery in chil-
12. Ezdinli, E. Z., Kucuk, O., Chedid, A., Sinclair, T. F.,
(1986): Hypogammaglobulinemia and hemophagocytic
Cancer, 57, 1024-1037.
tent immunoglobulin deficiency after prednisolone and
lupus-like syndrome. J. Rheumatol., 11, 828-831.