Blood, 15 November 2001, Vol. 98, No. 10, pp. 3173-3174
CORRESPONDENCE
To the editor:
Mosquito allergy and Epstein-Barr virus-associated T/natural
killer-cell lymphoproliferative disease
Mosquito allergy is characterized by intense local skin symptoms
that consist of not only erythema or bulla but also ulcer or scar and
general symptoms such as high fever following mosquito bites. Most of
the reported cases were from East Asia, and the majority of patients
tended to die of hemophagocytic syndrome.1 On the other
hand, nearly one third of patients with chronic active Epstein-Barr
virus (EBV) infection may also have mosquito allergy and
natural killer (NK)-cell proliferation.2-5 However, until recently the relationship between EBV infection and mosquito allergy remained unclear. More recently, we showed a close relationship between
mosquito allergy and EBV-infected NK-cell
lymphoproliferation.1 One of the unanswered questions is
whether EBV-infected NK cell lymphoproliferative disease (LPD) precedes
the onset of mosquito allergy among these patients.
We report here a case in which the time of primary EBV infection,
serial analyses of lymphocytes subsets, EBV-infected cells, and skin
lesions of mosquito allergy were analyzed to clarify this issue. A
6-year-old female was admitted to our hospital for diagnosis and
treatment of mosquito allergy that had started 6 months previously. Her
clinical history was as follows. At 6 months old, she developed
pancytopenia resulting in B-precursor acute lymphoblastic leukemia
(ALL) without typical chromosomal abnormalities. Although she
entered complete remission following our ALL protocol, continuous
chemotherapy became difficult because of severe myelosuppression and
repeated infections. Because she had no HLA-matched related or
unrelated donors, we decided to perform CD34-positive cell transplantation from her HLA-haploidentical father when she was aged 1 year and 11 months.6 At the time of transplantation she
was negative for EBV serology and her father was positive. Preconditioning regimen consisted of total body irradiation (TBI) (12 Gy) and melphalan (140/m2), and
4.54 × 106/kg of CD34-positive cells were infused on
February 6, 1996. Tacrolimus was used for graft-versus-host disease
(GVHD) prophylaxis. Since her posttransplantation clinical course was
uneventful except for delayed platelet recovery, tacrolimus was stopped
on day 64. Two months later, due to development of chronic GVHD of the
skin, cyclosporine was started. Although tests for sex chromatin by fluorescence in situ hybridization (FISH) showed complete donor engraftment, poor recovery of platelet count still continued. Therefore
additional 9.64 × 106/kg of CD34-positive cells from her
father were reinfused on day 148, resulting in complete
recovery of platelets.
Because EBV serology was still negative after complete engraftment, we
considered that there was no contamination of transmissible EBV-infected B cells in the purified CD34-positive cells obtained from
her father.
Seven months after transplantation, the patient, aged 2 years
and 6 months, developed primary EBV infection with atypical manifestations such as fever, eruptions, hypergammaglobulinemia (IgG,
3030 mg/dL; IgM, 300 mg/dL), liver dysfunction, abdominal lymph nodes
swelling, and pancytopenia. Seroconversion against EBV (VCA
IgG; 320 × , EA IgG; 10 × , EBNA; < 10 × ) was
confirmed, and clinical symptoms as well as laboratory findings were
resolved by stopping cyclosporin. Two months later she developed fever and otitis media. Laboratory findings on this occasion revealed that
T cells were 16% in the peripheral blood mononuclear
cells (healthy control < 5%).
She had been healthy until she developed mosquito allergy at
age 5 years and 5 months. Upon admission at this time she had multiple
skin lesions especially on the extremities and laboratory findings
revealed liver dysfunction and a reactivation pattern of antibodies
against EBV.
As shown in Figure 1, T cells
gradually increased with time. T-cell receptor gene rearrangements
were observed and EBV DNA was detected in the sorted T cells. A
skin biopsy specimen revealed infiltrating lymphocytes,
EBER+ (EBV-encoded RNA), CD3+,
CD4
, CD8, and CD56, in the
skin lesion. This phenotype indirectly suggested T-cell type
(data not shown).
View larger version (12K):
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| Figure 1.
Clinical course and changes of T cells in
peripheral blood mononuclear cells after CD34-positive cell
transplantation.
PBSCT indicates peripheral blood stem cell transplantation; LPD,
lymphoproliferative disease; Pred, prednisolone; CyA, cyclosporine
A.
|
|
Based on these findings, we considered that the patient had
developed EBV-infected T-cell proliferation after primary EBV infection. We speculated that the infiltrating cells in the skin may
play an important role in the development of mosquito allergy. The
patient is currently undergoing chemotherapy and the skin lesions have
improved and the number of T cells has been reduced (Figure 1).
Similar to the recent report we are also treating a patient with hydroa
vacciniforme accompanying with EBV-infected NK-cell proliferation,7 and considering this patient and the
patient in this case report, we speculate that there is a common
pathogenesis for chronic active EBV infection, mosquito allergy, and
hydroa vacciniforme that may be EBV-associated T/NK-cell LPD.
Parallel with human T-cell leukemia virus type
1(HTLV-1)-associated T cell leukemia/lymphoma (ATL), which is
a distinct disease entity, we would like to propose EBV-associated
T/NK-cell LPD as a disease entity. 8
EBV-associated T/NK-cell LPD includes mosquito allergy as well as a variety of other diseases such as chronic active EBV infection (CAEBV), EBV-associated hemophagocytic syndrome (EBV-AHS),
peripheral T-cell lymphoma, chronic granular LPD, aggressive NK-cell
leukemia, nasal/nasal type lymphoma, and hydroa vacciniforme.
Reduction and elimination of EBV-infected T/NK cells seems to be
essential for the treatment of EBV-associated T/NK-cell LPD and it is
important to distinguish it from ordinary EBV-associated B-cell
LPD.8,9
Keisei Kawa, Takayuki Okamura, Keiko Yagi, Makoto Takeuchi, Masahiro Nakayama, and Masami Inoue
Correspondence: Keisei Kawa, Director, Department of Pediatrics,
Osaka Medical Center and Research Institute for Maternal and Child
Health, 840 Murodo, Izumi City, Osaka 594-1101, Japan; e-mail:
kawakei{at}mch.pref.osaka.jp
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