Mdr1 gene c3435t polymorphism and the risk of acquired aplastic anaemia

British Journal of Haematology, 2002, 117, 768-774 PROLONGED COMPLETE REMISSION IN TWO CASES OF ACUTE PROMYELOCYTIC LEUKAEMIATREATED WITH ATRA ALONE The use of all-trans retinoic acid (ATRA) therapy for platelet count was normal. On day 58, bone marrow induction for acute promyelocytic leukaemia (APL) is well showed morphological remission, with normal cytogenetics established and leads to a complete remission rate of > 70%.
and negative RT-PCR. Further RT-PCR analyses on periph- However, remissions are short and consolidation with eral blood have remained negative, most recently performed chemotherapy is required. Continuous treatment with in July 2001. The patient remains alive and well with ATRA has been associated with a decrease in plasma normal blood counts as of September 2001, 4 years after concentrations of the drug, which may lead to resistance.
Recently, a case has been reported successfully treated with The mechanism by which our patients achieved pro- ATRA alone, followed by maintenance with intermittent longed complete remissions is unclear. It is unlikely that we ATRA and continuous low-dose methotrexate and 6-mer- observed spontaneous remissions as they are rare and of captopurine (Sanz et al, 2000). Here, we report two cases of short duration (Enck, 1985). It is likely that ATRA was APL with prolonged remissions after treatment with ATRA important in inducing the remissions.
ATRA in supraphysiological doses causes differentiation An 81-year-old woman presented with pancytopenia due of the promyelocyte by dissociation of a transcriptional to APL in October, 1992. Cytogenetic analysis revealed corepressor complex, that exerts a dominant-negative effect t(15;17) as the sole abnormality, and the rearrangement on normal RAR-a-regulated gene transcription (Melnick & was confirmed by Southern blot analysis. She was started Licht, 1999). Continuous treatment leads to decreased on ATRA at 45 mg ⁄ m2. Chemotherapy was not given plasma concentration and clinical resistance. However, because of her age and history of cardiovascular disease.
leukaemic cells from relapses can continue to differentiate Her leucocyte count increased to 25. 109 ⁄ l on day 1. On in vitro, though not in vivo. Moreover, the efficacy of day 10, bilateral pleural effusions and culture negative liposomal ATRA suggests that the intracellular concentra- fever developed, which was treated successfully with tion of ATRA is critical, as use of this formulation dexamethasone. The dose of ATRA was decreased to maintains plasma concentrations of tretinoin and response 25 mg ⁄ m2 on day 30 because of abnormal liver function in relapsed patients, but the response does not correlate tests, and she remained on this dose for another 95 d. Bone with plasma concentration (Estey et al, 1996). Further- marrow on day 73 showed morphological remission with more, the use of liposomal ATRA alone can induce persistence of t(15:17). No further bone marrow examina- prolonged molecular remissions (Estey et al, 1999). Thus, tions were performed, but her blood counts remained maintaining adequate intracellular concentrations of reti- normal, and reverse transcription-polymerase chain reac- noids in the relevant target cell may permit ongoing tion (RT-PCR) for the PML ⁄ RAR transcript on peripheral blood was negative, with normal blood counts assessed 4 The prolonged complete responses in our patients indi- and 6 years after diagnosis. She died of unrelated cardio- cate that the metabolism of ATRA in some patients may be vascular complications in November 1999, 7 years after endogenously altered to permit persistent and clinically effective intracellular concentrations of the ligand. Alter- The second case involved a 76-year-old woman who natively, the unusual response to ATRA may indicate that presented in September 1997 with extensive mucosal the disease pathogenesis in our patients may have differed bleeding. Laboratory investigations showed pancytopenia from the norm, as it is clear from animal models that the and disseminated intravascular coagulation due to APL, translocation is necessary but not sufficient to produce and RT-PCR confirmed the presence of the short isoform of leukaemia, and that other cytogenetically silent lesions the hybrid transcript generated by t(15;17). She was must contribute (Zimonjic et al, 2000). The mechanisms treated with ATRA at 45 mg ⁄ m2 for 149 d. She declined mediating induced differentiation by ATRA have been treatment with chemotherapy. Her coagulation parameters intensively investigated (Melnick & Licht, 1999), but only normalized by day 2, and the leucocyte count reached a recently has the means of cell death been elucidated (Altucci peak of 40. 109 ⁄ l on day 12. She developed a cough and et al, 2001). It is conceivable that differing clinical outcomes dyspnoea, which responded to dexamethasone. By dis- to ATRA treatment may be due to intrinsic variations in charge on day 18, she was feeling well with normal blood leukaemic stem cells in their susceptibility to retinoid- counts except for platelets at 60. 109 ⁄ l; by day 35, the induced, TRAIL ⁄ DR5-mediated paracrine apoptosis.
Estey, E.H., Giles, F.J., Kantarjian, H., O'Brien, S., Cortes, J., Freireich, E.J., Lopez-Berestein, G. & Keating, M. (1999) Mole- cular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia.
Melnick, A. & Licht, J.K. (1999) Deconstructing a disease: RARa, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood, 93, 3167-3215.
Sanz, M.A., Martinez, J.A., Barragan, E., Martin, G. & Lo Coco, F.
Altucci, L., Rossin, A., Raffelsberger, W., Reitmair, A., Chomienne, (2000) All-trans retinoic acid and low-dose chemotherapy for C. & Gronemeyer, H. (2001) Retinoic acid-induced apoptosis acute promyelocytic leukemia. British Journal of Haematology, in leukemia cells is mediated by paracrine induction of tumor-selective death ligand TRAIL. Nature Medicine, 7, 680- Zimonjic, D.B., Pollock, J.L., Westervelt, P., Popescu, N.C. & Ley, T.J.
Enck, R. (1985) Spontaneous complete remission in acute prom- associated with the development of acute promyelocytic leuke- yelocytic leukemia. New York State Medicine Journal, 11, 662.
mia in transgenic mice. Proceedings of the National Academy of Estey, E., Thall, P.F., Mehta, K., Rosenblum, M., Brewer, T., Jr, Science of the United States of America, 97, 13306-13311.
Simmons, V., Cabanillas, F., Kurzrock, R. & Lopez-Berestein, G.
(1996) Alterations in tretinoin pharmacokinetics following Keywords: leukaemia, promyelocytic, retinoic acid, remis- administration of liposomal all-trans retinoic acid. Blood, 87, MDR1 GENE C3435T POLYMORPHISM AND THE RISK OF ACQUIRED APLASTIC ANAEMIA Although aplastic anaemia (AA) is thought to be mediated donors) from the same geographical area were studied as by an autoimmune destruction of haematopoiesis (Young, controls. Blood and bone marrow samples were collected 2000), the aetiology of autoimmunity in AA is not fully after informed consent. DNA was extracted from peripheral understood. Some cases of acquired AA are an idiosyncratic leucocytes to genotype patients and controls for the MDR1 consequence of exposure to certain drugs and chemicals C3435T polymorphism using polymerase chain reaction but, even in this context, the mechanisms by which (PCR) followed by DpnII enzyme digestion (Hoffmeyer et al, xenobiotics trigger the immune system have yet to be 2000). A technician, who was unaware of the sample determined. Altered drug disposition and metabolism may status, performed the genotyping. Odds ratios (OR) as a be responsible for increased susceptibility, and pharmaco- measure of relative risks and 95% confidence intervals (CI genetic variations are possible risk factors for idiosyncratic 95) were calculated by standard methods.
drug-induced AA (Marsh et al, 1999). The MDR1 gene Carrier frequency of 3435t was 62Æ8% amongst patients encoded P-glycoprotein (P-gp), linked to multidrug resist- and 61% amongst controls, yielding an OR of 1Æ1 (CI 95, ance in leukaemia and expressed by normal haematopoietic 0Æ5-2Æ4). or for heterozygosity was 1Æ3 (CI 95, 0Æ6-2Æ9); it cells, protects stem cells from toxins by actively extruding a was 0Æ6 (CI 95, 0Æ1-2Æ2) for mutant homozygosity (Table I).
variety of drugs (Chaudhary & Roninson, 1991). We When patients with drug-induced AA were analysed observed previously that P-gp function was significantly separately (n ¼ 13), the overall OR linked to the mutant reduced in T-cells (Calado et al, 1998) and bone marrow genotype was 0Æ7 (CI 95, 0Æ2-2Æ3). Heterozygous and CD34+ cells of patients with AA, most significantly in mutant homozygous states yielded or of 0Æ5 (CI 95, 0Æ1-2Æ1) patients with drug-induced AA (Calado et al, 2001). These and 1Æ2 (CI 95, 0Æ2-6Æ3) respectively.
findings point to a role of impaired P-gp function in The MDR1 gene C3435T polymorphism is linked to determining predisposition to AA. However, the reason for reduced P-gp expression and function, and bone marrow reduced P-gp activity in this setting is elusive.
CD34+ cells from 26 out of the 35 AA patients studied Strong evidence has emerged recently to demonstrate presented P-gp function (measured by the rhodamine 123 that P-gp expression is genetically determined. The C3435T efflux assay) below the 25% percentile of previously studied transition of the MDR1 gene correlates with reduced P-gp normal controls (Calado et al, 2001). However, we failed to expression and function in the duodenum and CD56+ demonstrate a relationship between AA and C3435T. This natural killer (NK) cells (Hoffmeyer et al, 2000; Hitzl et al, lack of association may be explained by different reasons.
2001). To evaluate whether the MDR1 gene C3435T First, the proportion of individuals developing AA after drug polymorphism is associated with the occurrence of AA, we or chemical exposure is minimal compared with the studied 35 patients with acquired AA (median, 26 years; prevalence of the C3435T polymorphism. It is possible that range, 2-67 years). Classification was very severe in five, the decreased P-gp function observed in AA might be severe in 20 and moderate in 10 patients; 20 AA cases were associated with other rare unknown MDR1 gene muta- idiopathic, 13 were related to drugs or chemicals (anti- tion(s) which might determine P-gp function in haemato- inflammatory drugs in two, pesticides in nine and solvents poietic cells. Second, impaired P-gp function in AA might be in two) and two were hepatitis-associated AA cases; 105 the result of acquired rather than genetic factors. Testing age-, sex- and ethnicity-matched healthy subjects (blood whether defective P-gp expression is restricted to the Ó 2002 Blackwell Science Ltd, British Journal of Haematology 117: 768-774 Table I. C3435T MDR1 gene polymorphism distribution in aplastic anaemia (AA) patients and controls.
*OR ¼ 1Æ0 (reference category).
AA, aplastic anaemia; CC, wild-type genotype; CT, heterozygous state; TT, mutant homozygous state; OR, odds ratio; CI 95, haematopoietic tissue may serve to address this question.
anaemia: possible pathophysiologic implications. British Journal Finally, the number of patients analysed here was relatively small making it difficult to definitively rule out an associ- Calado, R.T., Garcia, A.B., Gallo, D.A.P. & Falca˜o, R.P. (2001) ation between MDR1 C3435T polymorphism and AA.
P-glycoprotein function is impaired in CD34+ cells from patientswith aplastic anemia. Blood, 98, Abstract 933.
In conclusion, although P-gp activity is decreased in AA Chaudhary, P.M. & Roninson, I.B. (1991) Expression and activity of patients, the MDR1 gene C3435T polymorphism does not P-glycoprotein, a multidrug efflux pump, in human hemato- seem to be a genetic risk factor for acquired drug-induced poietic stem cells. Cell, 66, 85-94.
Hitzl, M., Drescher, S., van der Kuip, H., Scha¨ffeler, E., Fischer, J., Schwab, M., Eichelbaum, M. & Fromm, M.F. (2001) The C3435Tmutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from The authors thank Se'rgio M. Gabellini for technical assist- CD56+ natural killer cells. Pharmacogenetics, 11, 293-298.
ance. This work was supported by Fundac¸a˜o de Amparo a` Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H.P., Brockmo¨ller, Pesquisa do Estado de Sa˜o Paulo (FAPESP) grant 98 ⁄ 14247-6.
J., Johne, A., Cascorbi, I., Gerloff, T., Roots, I., Eichelbaum, M. &Brinkmann, U. (2000) Functional polymorphisms of the human R.T.C. was a recipient of FAPESP grant 00 ⁄ 13885-0.
multidrug-resistance gene: multiple sequence variations andcorrelation of one allele with P-glycoprotein expression and activity in vivo. Proceedings of the National Academy of Sciences of the United States of America, 97, 3473-3478.
Marsh, J.C.W., Chowdry, J., Parry-Jones, N., Ellis, S.W., Muir, K.R., Gordon-Smith, E.C. & Tucker, G.T. (1999) Study of the associa- tion between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug and chemical induced idiosyncratic aplastic anaemia.
British Journal of Haematology, 104, 166-270.
Young, N.S. (2000) Acquired aplastic anemia. In: Bone Marrow Failure Syndromes (ed. by N.S. Young), pp. 1-46. Saunders,Philadelphia.
Keywords: aplastic anaemia, MDR1, P-glycoprotein, poly- Calado, R.T., Garcia, A.B. & Falca˜o, R.P. (1998) Decreased activity of the multidrug resistance P-glycoprotein in acquired aplastic INTERLEUKIN 8 IS NOT INVOLVED IN G-CSF-INDUCED PERIPHERAL BLOOD STEM CELLTRANSPLANTATION Granulocyte colony-stimulating factor (G-CSF) is widely and allogeneic stem cell transplantation. However, the used to mobilize haematopoietic progenitor cells (HPCs) into mechanisms of G-CSF-induced peripheral blood stem cell the peripheral blood as a source of stem cells in autologous (PBSC) mobilization remains unclear. Interleukin 8 (IL-8) is Ó 2002 Blackwell Science Ltd, British Journal of Haematology 117: 768-774 another cytokine that mobilizes HPCs into blood. Recently, together with ours, suggested that IL-8 was not involved the mechanism of IL-8-induced PBSC mobilization has been in the G-CSF-induced PBSC mobilization in normal donors.
extensively studied. The release of matrix metalloproteinase- Other mechanisms of PBSC mobilization by G-CSF inter- 9 (MMP-9) from neutrophils by IL-8 induces HPCs mobil- vened by other cytokines, including IL-6 or metallopro- ization by cleaving matrix molecules to which HPCs attach teinases, are now under investigation (Carstanjen et al, (Laterveer et al, 1995; Pruijt et al, 1999). In addition, Watanabe and colleagues (Watanabe et al, 1999) demon-strated a surge of endogenous IL-8 after G-CSF administra- tion in normal donors, suggesting the critical role of IL-8 in G-CSF-induced PBSC mobilization. We therefore examined the kinetics of serum and plasma levels of IL-8 after G-CSF administration in 10 normal donors for allogeneic PBSC transplantation. After informed consent had been obtained, blood samples were collected by venepuncture before and during G-CSF administration at a dose of 10 lg ⁄ kg s.c. for 5 d. Plasma and serum IL-8 levels were measured using two specific enzyme-linked immunosorbent assay (ELISA) kits(TFB, Tokyo, Japan; R&D Systems, Minneapolis, MN) according to the manufacturers' instructions. Each samplewas analysed in duplicate, and the average value was used Carstanjen, N., Ulbrecht, A., Iacone, A., Regenfus, M. & Salama, A.
for calculation. The minimal detectable concentration was (2001a) MMP-9 (Gelatinase B) is elevated during mobilization of estimated as 10 pg ⁄ ml. In all donors except one, who peripheral blood stem cells by G-CSF. Experimental Hematology, obtained a total of 1Æ04. 106 ⁄ kg CD34+ cells by three aphereses, more than 3. 106 ⁄ kg CD34+ cells could be Carstanjen, D., Regenfus, M., Muller, C. & Salama, A. (2001b) Interleukin 6 is a major effector molecule of short-term G-CSF harvested by one to three aphereses. The serum and plasma treatment inducing bone metabolism and an acute-phase levels of IL-8 before G-CSF administration in all samples response. Experimental Hematology, 29, 812-821.
were < 10 pg ⁄ ml, and were below the level of detection Laterveer, L., Lindley, I.J.D., Hamilton, M.S., Willemze, R. & during G-CSF administration. These observations were in Fibbe, W.E. (1995) Interleukin 8 induces rapid mobilization of contrast to the report by Watanabe and colleagues hematopoietic stem cells with radioprotective capacity and (Watanabe et al, 1999), who demonstrated a surge of endogenous IL-8 (mean: 200 pg ⁄ ml) on days 5 and 6 of G-CSF administration. They used serum samples and Michon, J.M, Gey, A., Moutel, S., Tartour, E., Meresse, V., Fridman, measured the level of IL-8 using the same ELISA kit (TFB) W., Teillaud, J.L. (1998) In vivo induction of functional FccRI as we used. We therefore measured serum as well as plasma (CD64) on neutrophils and modulation of blood cytokine mRNAlevels in cancer patients treated with G-CSF (rMetHuG-CSF).
samples, although the manufacturer's instructions recom- British Journal of Haematology, 100, 550-556.
mended using plasma samples. In addition, we confirmed Pruijt, J.F., Fibbe, W.E., Laterveer, L., Pieters, R.A., Lindley, I.J.D., our data using another ELISA kit (R&D Systems). The Paemen, L., Masure, S., Willemze, R. & Opdenakker, G. (1999) reason for the differences in serum IL-8 levels between the Prevention of interleukin 8-induced mobilization of hemato- poietic progenitor cells in rhesus monkeys by inhibitory Michon and colleagues (Michon et al, 1998) demonstra- antibodies against the metalloproteinase gelatinase B (MMP-9).
ted the increased IL-8 mRNA levels in peripheral blood Proceedings of the National Academy of Sciences of the USA, 96, cells after 24 h of G-CSF administration at a dose of 10 lg ⁄ kg s.c. after recovery of the previous chemotherapy Watanabe, T., Kawano, Y., Kanamaru, S., Ohnishi, T., Kaneko, S., cycle cytopenia in cancer patients. However, they could Wakata, Y., Nakagawa, R., Makimoto, A., Kuroda, Y., Takaue,Y. & Talmadge, J.E. (1999) Endogenous interleukin 8 (IL-8) not detect circulating IL-8 in the serum samples, and surge in granulocyte colony-stimulating factor-induced periph- speculated that IL-8 is either not synthesized ⁄ secreted or is eral blood stem cell mobilization. Blood, 93, 1157-1163.
rapidly trapped by IL-8 receptor on neutrophils. Recently,Carstanjen and colleagues (Carstanjen et al, 2001a) also Keywords: granulocyte colony-stimulating factor, peri- demonstrated no increased plasma level of IL-8 after G-CSF pheral blood stem cell, mobilization, interleukin 8.
administration in normal donors. These observations, EFFECTIVENESS OF RITUXIMAB FOR CHEMOTHERAPY-RESISTANT MULTIPLE TUMORAL B-LPDIN A HAEMOPOIETIC STEM CELL RECIPIENT We read with great interest the recent article by Faye et al transplant B-lymphoproliferative disorder (B-LPD) following (2001). They described eight responders and four non- haemopoietic stem cell transplantation in 12 paediatric responders in a therapeutic trial of rituximab for post- Ó 2002 Blackwell Science Ltd, British Journal of Haematology 117: 768-774 non-responders died, and non-responsiveness was associ- copies ⁄ ml. A needle biopsy of the liver mass revealed an ated with a high number of tumour sites involved (median EBER (EBV-encoded RNA)-positive B-LPD, which showed 3Æ5), a mediastinal localization, and a significantly low CD4 clonal rearrangement of immunoglobulin heavy chain gene.
The tumours did not resolve by withdrawal of immunosup- The patient we report here was a 20-year-old man, who pressants; in addition, donor lymphocytes were unavailable had been treated for aplastic anaemia for 4 years with from bank donations, so chemotherapy (one course of methylprednisolone (mPSL) ⁄ cyclosporine A (CSA) ⁄ granulo- vincristine ⁄ cyclophosphamide ⁄ prednisolone, and another cyte colony-stimulating factor, and received an allogeneic course of adriamycin ⁄ vincristine ⁄ cyclophosphamide ⁄ pred- bone marrow transplantation (BMT) from a human leuco- nisolone) was administered. The tumours responded only cyte antigen (HLA)-matched unrelated donor in November temporarily, then exacerbated in November 1999 as multi- 1998. Epstein-Barr virus (EBV) status (donor ⁄ recipient) at ple liver tumours (Fig 1B), with an sharp increase of serum the transplant was - ⁄ +. The conditioning regimen was total EBV load up to 15. 105 copies ⁄ ml. The second liver biopsy irradiation ⁄ cyclophosphamide ⁄ antithymocyte at day 360 also showed an EBER-positive B-LPD. Four more globulin with graft versus host disease (GVHD) prophylaxis courses of chemotherapy including MTX and cytosine of CSA ⁄ short-term methotrexate (MTX) ⁄ mPSL. The imme- arabinoside were not effective. Therefore, in April and May diate post-transplant course was uneventful except for Grade 2000, rituximab (375 mg ⁄ m2 ⁄ weekly.8 doses) was given.
I acute GVHD. At 2 months post transplant, the patient There was no prompt response, and para-aortic lymph nodes' developed cytomegalovirus (CMV) retinitis, which was trea- swelling indicated a new LPD 2 months later, associated ted with gancyclovir and foscarnet. At day 150, he started with abdominal pain. Accordingly, a second course of complaining of abdominal discomfort in the right upper rituximab (375 mg ⁄ m2 ⁄ weekly.8 doses) was administered quadrant. At day 210 (June 1999), ultrasound and a in October-November 2000. Since then, the adrenal, hepatic computed tomography (CT) scan revealed bilateral adrenal and para-aortic masses gradually resolved over the following tumours associated with a mass in the liver (Fig 1A) and year, leaving only one regressing liver tumour, with unde- another mass in the right kidney. A CT scan of the chest also tectable EBV load in serum. During the period, no treatment disclosed multiple infiltrating shadows. At the time the was given except for high-titre anti-CMV-gamma-globulin patient was afebrile and had no gammanopathy. His CD4 replacement therapy. The patient has been doing well, with a count was 14-36 ⁄ ll and CD20 count, 4-26 ⁄ ll. Serum EBV 100% Karnofsky score as of November 2001 (36 months load, determined by real-time polymerase chain reaction from the BMT and 28 months from the development of LPD).
In this case, the rituximab therapy, which began at10 months from the development of B-LPD, was veryeffective, although the patient had chemotherapy-resistantmultiple tumoral B-LPD. To achieve better control, a total oftwo courses was needed within a 4-month interval. A goodresponse was reflected by monitoring the serum viral load, asreported by van Esser et al (2001). A gradual, but steady,regressive effect on the tumours over a period of 1 year mighthave been due to a synergistic activity with the chemother-apy administered before the rituximab, as described inlymphoma therapy (Vose et al, 2001). Further evaluationof rituximab is necessary for multiple tumoral B-LPD inhaemopoietic stem cell transplant recipients.
van Esser, J.W., Niesters, H.G., Thijsen, S.F., Meijer, E., Osterhaus, A.D., Wolthers, K.C., Boucher, C.A., Gratama, J.W., Budel, L.M.,van der Holt, B., van Loon, A.M., Lowenberg, B., Verdonck, L.F.
Fig 1. (A) The right adrenal tumour (arrowhead) and an intrahe- & Cornelissen, J.J. (2001) Molecular quantification of viral load patic mass at onset of LPD. (B) Large masses in the liver with right in plasma allows for fast and accurate prediction of response to adrenal tumour (arrowhead) at exacerbation.
Ó 2002 Blackwell Science Ltd, British Journal of Haematology 117: 768-774 therapy of Epstein-Barr virus-associated lymphoproliferative genome copy numbers in patients with EBV-associated hemop- disease after allogeneic stem cell transplantation. British Journal hagocytic lymphohistiocytosis. Leukemia and Lymphoma, in press.
Vose, J., Link, B., Grossbard, M.L., Czuczman, M., Grillo-Lopez, A., Faye, A., Quartier, P., Reguerre, Y., Lutz, P., Carret, A.-S., Dehee, Gilman, P., Lowe, A., Kunkel, L.A. & Fisher, R.I. (2001) Phase II A., Rohrlich, P., Peuchmaur, M., Matthieu-Boue, A., Fischer, A.
study of rituximab in combination with CHOP chemotherapy in & Vilmer, E. (2001) Chimaeric anti-CD20 monoclonal antibody patients with previously untreated, aggressive non-Hodgkin's (rituximab) in post-transplant B-lymphoproliferative disorder lymphoma. Journal of Clinical Oncology, 19, 389-397.
following stem cell transplantation in children. British Journal ofHaematology, 115, 112-118.
Keywords: rituximab, post-transplant lymphoproliferative Teramura, T., Tabata, Y., Yagi, T., Morimoto, A., Hibi, S. & Imashuku, S. (2002) Quantitative analysis of cell-free Epstein-Barr virus ÔGLOVES AND SOCKSÕ PAPULAR PURPURIC SYNDROME FOLLOWING PRIMARY INFECTIONWITH PARVOVIRUS B19: A LINK BETWEEN DERMATOLOGISTS AND HAEMATOLOGISTS ÔGloves and socksÕ papular purpuric syndrome is character- bodies, and platelet-associated immunoglobulins (Ig) were ized by pruritic and painful oedema and erythema localized not detected. Routine blood cultures for the most common to the hands and feet in a Ôgloves and socksÕ distribution. It bacterial, fungal and viral agents and serological and is often associated with oromucosal lesions with vesicular molecular studies for hepatitis, herpes, Coxsackie A and B aphthous lesions localized to the hard and soft palate, and echoviruses were negative. The rise of IgM and IgG pharynx and lips (Ruzicka et al, 1998; Saulsbury, 1998; antibodies against parvovirus B19 was documented by Smith et al, 1998; Grilli et al, 1999; Martinez-Martinez & enzyme-linked immunosorbent assay (ELISA) in serial Maranon, 2000). Fever, asthenia, anorexia, arthralgia and serum samples collected during the acute and convalescent myalgia can be present (Ruzicka et al, 1998; Saulsbury, phases of the disease, proving seroconversion (Smith et al, 1998; Smith et al, 1998; Grilli et al, 1999; Martinez- 1998; Grilli et al, 1999) (Fig 1). The presence of B19 DNA Martinez & Maranon, 2000). The frequent occurrence of sequences was detected in the serum samples from the acute lymph node enlargement and the detection of leucopenia phase, by polymerase chain reaction (Grilli et al, 1999) and thrombocytopenia make this entity of special interest to (Fig 1). The purpuric lesions and lymph node enlargement haematologists. Several infectious agents, especially viruses, disappeared after 12 d, with a concomitant normalization of have been implicated in the pathogenesis of this disease (Ruzicka et al, 1998; Saulsbury, 1998; Smith et al, 1998; The sudden onset of fever, dermatosis, lymphadenitis Grilli et al, 1999; Martinez-Martinez & Maranon, 2000). We and cytopenia suggested the presence of an acute infec- report the occurrence of Ôgloves and socksÕ syndrome tious disease. Seroconversion and high levels of viraemia following a primary parvovirus B19 infection.
were indicative of a recent primary infection with B19, A 38-year-old human immunodeficiency virus-negative whereas extensive microbiological tests failed to identify man presented in February 2001 with a 5-day history of any other agents. Only 30 cases of Ôgloves and socksÕ pruritic oedema and erythema on the dorsum of both hands syndrome have so far been described, but none of these is and feet, which subsequently progressed to involve the in the haematology literature. Adult, often female, patients palms of his hands and the soles of his feet. The cutaneous are affected; only two cases have been reported in lesions were symmetric and marginated on the wrists and children. Four cases have been associated with cytomeg- ankles without mucosal involvement. The patient had alovirus (Smith et al, 1998), Coxsackie B6 (Smith et al, intermittent fever (38Æ5°C) lasting 2 d, and bilateral axillary 1998), measles (Smith et al, 1998) and human herpesvi- and inguinal lymph node enlargement was present. The rus 6 infection (Ruzicka et al, 1998), respectively. A total liver and the spleen were not enlarged. The patient reported of 17 cases has been associated with a B19 infection, no insect bites, medication or travel abroad in the preceding whereas no infectious agents were searched for, or identified, in the remainder (Saulsbury, 1998; Smith et al, (lowest leucocyte count, 3Æ3. 109 ⁄ l), with neutrophilia 1998; Grilli et al, 1999; Martinez-Martinez & Maranon, (neutrophils 71% and lymphocytes 12%) and thrombocy- topenia (lowest platelet count, 75. 109 ⁄ l), a minor reduc- infectiosum, has tropism for erythroid precursors in bone tion in haemoglobin level (from 14 to 12 g ⁄ dl) and a marrow and may cause either transient aplastic crises in reticulocyte count of 1% (Fig 1). Erythrocyte sedimentation immunocompromised hosts or thrombocytopenia in spora- rate was 12 mm ⁄ h. Blood urea nitrogen, serum creatinine, dic cases. B19 infection must be recognized as a common electrolyte concentrations, total bilirubin, alkaline phospha- cause for the Ôgloves and socksÕ syndrome. An atypical tase, serum aspartate-transaminase, serum alanine-transa- aspect of primary B19 infection in this and previously minase, coagulation tests and urinalysis were normal.
reported cases is the almost constant preservation of Rheumatoid factor, antinuclear antibodies, anti-DNA anti- erythroid lineage in the bone marrow.
Ó 2002 Blackwell Science Ltd, British Journal of Haematology 117: 768-774 Fig 1. Changes in the platelet and whitecell counts, haemoglobin level, serum parvo-virus B19 DNA and anti parvovirus B19antibodies during acute and convalescentphases of the disease. Values for IgG and IgMwere considered positive if they were bothabove the cut-off optical density value of 0Æ9.
parvovirus B19 DNA in cutaneous lesions and sera. Journal of theAmerican Academy of Dermatology, 41, 793-796.
This work was supported by a grant from the Associazione Martinez-Martinez, P. & Maranon, A. (2000) Infection by human Italiana per la Ricerca sul Cancro (AIRC) Milan, Italy.
parvovirus B19: Ôgloves and socks papular purpuric syndromeÕ.
Diagnosis of Microbiological Infection and Disease, 36, 209-210.
Ruzicka, T., Kalka, K., Diercks, K. & Schuppe, H.C. (1998) Papular- purpuric Ôgloves and socksÕ syndrome associated with human herpes virus 6 infection. Archives of Dermatology, 134, 242-244.
Saulsbury, F.T. (1998) Petechial gloves and socks syndrome caused by parvovirus B19. Pediatrics Dermatology, 15, 35-37.
Smith, P.T., Landry, M.L., Carey, H., Krasnoff, J. & Cooney, E.
(1998) Papular-purpuric gloves and socks syndrome associatedwith acute parvovirus B19 infection: case report and review.
Clinical Infection and Disease, 27, 164-168.
Grilli, R., Izquierdo, M.J., Farina, M.C., Kutzner, H., Gadea, I., Keywords: B19, cytopenia, erythema, Ôgloves and socksÕ, Martin, L. & Requena, L. (1999) Papular-purpuric Ôgloves and socksÕ syndrome: polymerase chain reaction demonstration of Ó 2002 Blackwell Science Ltd, British Journal of Haematology 117: 768-774

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