LETTERS TO THE EDITOR
TABLE 1. Infectivity of whole blood transferred from Bb syringe-inoculated mice into recipient mice Number of positive urinary bladder or ear skin cultures of: Blood recipients† Infected donors†
Postinfection day that recipients were given transfused blood from infected donors*
Number of donor (recipient) mice 3(3) 3(3) 3(3) 3(3) 3(3) 3(3)
3 4 5 6 7 10
1 1 0 0 0 0
0 0 1 1 3 3
* Donor mice were injected intradermally in the abdominal area with 105 low-passage Bb of strain BL206. Recipient mice were infused with between 0.7 and 1.0 mL of citrated blood within 5 minutes of being collected. † Cultures of urinary bladder and ear skin samples were established in BSK medium as previously described.4 For recipient mice, cultures were established 4 weeks after transfusion from donor mice. Live (motile) Bb were identified after microscopic exam, using phase-contrast microscopy at 400× magnification.
mice evaluated, that had received transfused blood from 10-day post–tick challenge donors, became infected, which is in marked contrast with our findings of short-lived and relatively infrequent spirochetemia in Bb-infected SKH mice. These somewhat discrepant results could be explained partially by the use of syringeinoculated Borrelia and SKH mice in our studies rather than using Bb-infected ticks and the more traditionally preferred C3H mouse strain, as was done by Gabitch and colleagues.5 Another explanation, that we hypothesize, is that Bb is rapidly cleared from the peripheral circulation by splenic and hepatic macrophages or other phagocytic cells, at or about the same time that spirochetes are disseminating to target sites such as the urinary bladder but further testing, including the use of PCR, is needed to prove this possibility. Ginsburg and colleagues1 suggested another series of related experiments be performed in animals for the purpose of evaluating whether or not Bb remains infectious when processed and stored under a variety of blood storage conditions now in use at blood donor facilities in the United States. Our laboratory is in the process of conducting such studies, which will also include PCR analysis and which should provide key additional information on Bb-blood interaction phenomena occurring in the infected host that could be relevant toward a better understanding on why there is a lack of transfusion-associated Lyme disease. CONFLICT OF INTEREST The authors have no conflict of interest.
Charles S. Pavia, PhD e-mail: [email protected] Maria Plummer, MD Department of Biomedical Sciences NYIT College of Osteopathic Medicine Old Westbury, NY
REFERENCES 1. Ginzburg Y, Kessler D, Kang S, Shaz B, Wormser GP. Why has Borrelia burgdorferi not been transmitted by blood transfusion? Transfusion 201353:2822-6. 2. Moody KD, Barthold SW, Terwilliger GA. Lyme borreliosis in laboratory animals: effect of host species and in vitro passage of Borrelia burgdorferi. Am J Trop Med Hyg 1990;43: 87-92. 3. Wang G, Ojaimi C, Iyer R, Saksenberg V, McClain SA, Wormser GP, Schwartz I. Impact of genotypic variation of Borrelia burgdorferi sensu stricto on kinetics of dissemination and severity of disease in C3H/HeJ mice. Infect Immun 2001;69:4303-12. 4. Pavia C, Inchiosa MA Jr, Wormser GP. Efficacy of shortcourse ceftriaxone therapy for Borrelia burgdorferi infection in C3H mice. Antimicrob Agents Chemother 2002;46:132-4. 5. Gabitch ES, Piesman J, Dolan MC, Sykes CM, Zeidner MS. Transfer of Borrelia burgdorferi s.s. infection via blood transfusion in a murine model. J Parasitol 2006;92: 869-70.
Delayed hemolytic transfusion reaction, intravenous immunoglobulin, and rituximab I read with interest “Immunoglobulin-resistant delayed hemolytic transfusion reaction treated with rituximab in an adult sickle cell patient.”1 I would like to make comments regarding intravenous immunoglobulin (IVIG) and rituximab therapy. This case was unusual as an adult sickle cell disease patient presented with hyperhemolysis syndrome (HS) associated with splenic sequestration. The patient did not respond to IVIG therapy and rituximab was prescribed on the day of splenectomy. Pathogenesis of HS is unclear. In some cases (like the reported case),1 red blood cell (RBC) antibodies are not detected in the patient’s samples, direct antiglobulin test is also negative and it has been proposed that activated macrophages play Volume 53, November 2013 TRANSFUSION
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LETTERS TO THE EDITOR
a crucial role in destruction of transfused and patient’s own RBCs.2 IVIG has been used successfully in combination with IV steroids and it has been suggested that there is a synergistic effect in suppressing the activity of macrophages.2 We have previously reported a case of recurrent HS, whereby on the second episode, hemolysis was so severe and Hb levels decreased to 3.2 and 3.6 g/dL. The child received additional transfusion twice, within a 4-day gap, with IVIG and IV methylprednisolone cover for each transfusion.3 Therefore, it is worth considering giving IV steroids or an additional course of IVIG and steroids before labeling as an IVIG-resistant case. In this case,1 cessation of hemolysis immediately after the splenectomy suggests that this was likely to be due to removing the site and source of RBC destruction (spleen). Therefore, it was difficult to prove that the desired response achieved within 24 hours of prescribing rituximab was a direct result of therapeutic outcome. Rituximab had been tried in two patients with HS,4,5 one for prevention of recurrence and another as treatment. In the former case, during the first episode of HS, the patient was treated with steroids and cyclophosphamide and erythropoietin (EPO). Two years later the patient required hip replacement. On admission the patient was stable with no evidence of hemolysis. Rituximab was prescribed as a preventive measure to cover transfusion for surgery and transfusion was uneventful.4 Recurrent HS is extremely rare and there is no way to predict which patient may suffer a recurrence after blood transfusion.3 Therefore, it is impossible to prove or refute that administering rituximab successfully prevented the recurrence. In the latter case,5 the patient developed HS and received transfusion concomitantly with rituximab and steroids and EPO cover. Another dose of rituximab was given 5 days later. The authors have described that rituximab efficiently attracts and bind Fc gamma receptor–expressing macrophages, diminishing the recruitment of these cells. The optimal therapeutic dose in the setting of HS is not known with limited evidence of efficacy.1,4,5 Rituximab is a profound immunosuppressive drug, which might expose sickle cell disease
to the risk of severe infections; therefore, it should only be considered as a last resort in selected cases, if other measures have failed. The decision to prescribe rituximab should be carefully assessed based on the individual patient’s benefit–risk profile and I agree with NoizatPirenne and colleagues4 that informed consent should be obtained from the patient.
CONFLICT OF INTEREST None.
Nay Win, MBBS, FRCP, FRCPath, CTM(Edin) NHS Blood and Transplant London, UK e-mail: [email protected]
REFERENCES 1. Delmonte L, Cantini M, Olivieri O, De Franceschi L. Immunoglobulin-resistant delayed hemolytic transfusion reaction treated with rituximab in an adult sickle cell patient. Transfusion 2013;53:688-9. 2. Win N, Tullie Y, Needs M, Chen FE, Okpala I. Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease. Haematology 2004;9:433-6. 3. Win N, New H, Lee E, de la Fuente J. Hyperhemolysis syndrome in sickle cell disease: case report (recurrent episode) and literature review. Transfusion 2008;48:1231-8. 4. Noizat-Pirenne F, Bachir D, Chadebech P, Michel M, Plonquet A, Lecron JC, Galacteros F, Bierling P. Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease. Haematologica 2007;92:el32-5. 5. Bachmeyer C, Maury J, Parrot A, Bachir D, Stankovic K, Girot R, Lionnet F. Rituximab as an effective treatment of hyperhemolysis syndrome in sickle cell anemia. Am J Hematol 2010;85:91-2.
NEW INSTRUCTIONS FOR SUBMISSION OF LETTERS All Letters to the Editor must be submitted online in the Manuscript Central system: http://mc.manuscriptcentral.com/transfusion Please choose LETTERS as the Manuscript Type. Detailed instructions can be found ONLINE under Instructions and Forms. Copyright Assignment and Conflict of Interest forms should be faxed to the Editorial Office: 443-287-3900. There is no Submission Fee for Letters to the Editor.
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TRANSFUSION Volume 53, November 2013
TABLE 1. Infectivity of whole blood transferred from Bb syringe-inoculated mice into recipient mice Number of positive urinary bladder or ear skin cultures of: Blood recipients† Infected donors†
Postinfection day that recipients were given transfused blood from infected donors*
Number of donor (recipient) mice 3(3) 3(3) 3(3) 3(3) 3(3) 3(3)
3 4 5 6 7 10
1 1 0 0 0 0
0 0 1 1 3 3
* Donor mice were injected intradermally in the abdominal area with 105 low-passage Bb of strain BL206. Recipient mice were infused with between 0.7 and 1.0 mL of citrated blood within 5 minutes of being collected. † Cultures of urinary bladder and ear skin samples were established in BSK medium as previously described.4 For recipient mice, cultures were established 4 weeks after transfusion from donor mice. Live (motile) Bb were identified after microscopic exam, using phase-contrast microscopy at 400× magnification.
mice evaluated, that had received transfused blood from 10-day post–tick challenge donors, became infected, which is in marked contrast with our findings of short-lived and relatively infrequent spirochetemia in Bb-infected SKH mice. These somewhat discrepant results could be explained partially by the use of syringeinoculated Borrelia and SKH mice in our studies rather than using Bb-infected ticks and the more traditionally preferred C3H mouse strain, as was done by Gabitch and colleagues.5 Another explanation, that we hypothesize, is that Bb is rapidly cleared from the peripheral circulation by splenic and hepatic macrophages or other phagocytic cells, at or about the same time that spirochetes are disseminating to target sites such as the urinary bladder but further testing, including the use of PCR, is needed to prove this possibility. Ginsburg and colleagues1 suggested another series of related experiments be performed in animals for the purpose of evaluating whether or not Bb remains infectious when processed and stored under a variety of blood storage conditions now in use at blood donor facilities in the United States. Our laboratory is in the process of conducting such studies, which will also include PCR analysis and which should provide key additional information on Bb-blood interaction phenomena occurring in the infected host that could be relevant toward a better understanding on why there is a lack of transfusion-associated Lyme disease. CONFLICT OF INTEREST The authors have no conflict of interest.
Charles S. Pavia, PhD e-mail: [email protected] Maria Plummer, MD Department of Biomedical Sciences NYIT College of Osteopathic Medicine Old Westbury, NY
REFERENCES 1. Ginzburg Y, Kessler D, Kang S, Shaz B, Wormser GP. Why has Borrelia burgdorferi not been transmitted by blood transfusion? Transfusion 201353:2822-6. 2. Moody KD, Barthold SW, Terwilliger GA. Lyme borreliosis in laboratory animals: effect of host species and in vitro passage of Borrelia burgdorferi. Am J Trop Med Hyg 1990;43: 87-92. 3. Wang G, Ojaimi C, Iyer R, Saksenberg V, McClain SA, Wormser GP, Schwartz I. Impact of genotypic variation of Borrelia burgdorferi sensu stricto on kinetics of dissemination and severity of disease in C3H/HeJ mice. Infect Immun 2001;69:4303-12. 4. Pavia C, Inchiosa MA Jr, Wormser GP. Efficacy of shortcourse ceftriaxone therapy for Borrelia burgdorferi infection in C3H mice. Antimicrob Agents Chemother 2002;46:132-4. 5. Gabitch ES, Piesman J, Dolan MC, Sykes CM, Zeidner MS. Transfer of Borrelia burgdorferi s.s. infection via blood transfusion in a murine model. J Parasitol 2006;92: 869-70.
Delayed hemolytic transfusion reaction, intravenous immunoglobulin, and rituximab I read with interest “Immunoglobulin-resistant delayed hemolytic transfusion reaction treated with rituximab in an adult sickle cell patient.”1 I would like to make comments regarding intravenous immunoglobulin (IVIG) and rituximab therapy. This case was unusual as an adult sickle cell disease patient presented with hyperhemolysis syndrome (HS) associated with splenic sequestration. The patient did not respond to IVIG therapy and rituximab was prescribed on the day of splenectomy. Pathogenesis of HS is unclear. In some cases (like the reported case),1 red blood cell (RBC) antibodies are not detected in the patient’s samples, direct antiglobulin test is also negative and it has been proposed that activated macrophages play Volume 53, November 2013 TRANSFUSION
2829
LETTERS TO THE EDITOR
a crucial role in destruction of transfused and patient’s own RBCs.2 IVIG has been used successfully in combination with IV steroids and it has been suggested that there is a synergistic effect in suppressing the activity of macrophages.2 We have previously reported a case of recurrent HS, whereby on the second episode, hemolysis was so severe and Hb levels decreased to 3.2 and 3.6 g/dL. The child received additional transfusion twice, within a 4-day gap, with IVIG and IV methylprednisolone cover for each transfusion.3 Therefore, it is worth considering giving IV steroids or an additional course of IVIG and steroids before labeling as an IVIG-resistant case. In this case,1 cessation of hemolysis immediately after the splenectomy suggests that this was likely to be due to removing the site and source of RBC destruction (spleen). Therefore, it was difficult to prove that the desired response achieved within 24 hours of prescribing rituximab was a direct result of therapeutic outcome. Rituximab had been tried in two patients with HS,4,5 one for prevention of recurrence and another as treatment. In the former case, during the first episode of HS, the patient was treated with steroids and cyclophosphamide and erythropoietin (EPO). Two years later the patient required hip replacement. On admission the patient was stable with no evidence of hemolysis. Rituximab was prescribed as a preventive measure to cover transfusion for surgery and transfusion was uneventful.4 Recurrent HS is extremely rare and there is no way to predict which patient may suffer a recurrence after blood transfusion.3 Therefore, it is impossible to prove or refute that administering rituximab successfully prevented the recurrence. In the latter case,5 the patient developed HS and received transfusion concomitantly with rituximab and steroids and EPO cover. Another dose of rituximab was given 5 days later. The authors have described that rituximab efficiently attracts and bind Fc gamma receptor–expressing macrophages, diminishing the recruitment of these cells. The optimal therapeutic dose in the setting of HS is not known with limited evidence of efficacy.1,4,5 Rituximab is a profound immunosuppressive drug, which might expose sickle cell disease
to the risk of severe infections; therefore, it should only be considered as a last resort in selected cases, if other measures have failed. The decision to prescribe rituximab should be carefully assessed based on the individual patient’s benefit–risk profile and I agree with NoizatPirenne and colleagues4 that informed consent should be obtained from the patient.
CONFLICT OF INTEREST None.
Nay Win, MBBS, FRCP, FRCPath, CTM(Edin) NHS Blood and Transplant London, UK e-mail: [email protected]
REFERENCES 1. Delmonte L, Cantini M, Olivieri O, De Franceschi L. Immunoglobulin-resistant delayed hemolytic transfusion reaction treated with rituximab in an adult sickle cell patient. Transfusion 2013;53:688-9. 2. Win N, Tullie Y, Needs M, Chen FE, Okpala I. Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease. Haematology 2004;9:433-6. 3. Win N, New H, Lee E, de la Fuente J. Hyperhemolysis syndrome in sickle cell disease: case report (recurrent episode) and literature review. Transfusion 2008;48:1231-8. 4. Noizat-Pirenne F, Bachir D, Chadebech P, Michel M, Plonquet A, Lecron JC, Galacteros F, Bierling P. Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease. Haematologica 2007;92:el32-5. 5. Bachmeyer C, Maury J, Parrot A, Bachir D, Stankovic K, Girot R, Lionnet F. Rituximab as an effective treatment of hyperhemolysis syndrome in sickle cell anemia. Am J Hematol 2010;85:91-2.
NEW INSTRUCTIONS FOR SUBMISSION OF LETTERS All Letters to the Editor must be submitted online in the Manuscript Central system: http://mc.manuscriptcentral.com/transfusion Please choose LETTERS as the Manuscript Type. Detailed instructions can be found ONLINE under Instructions and Forms. Copyright Assignment and Conflict of Interest forms should be faxed to the Editorial Office: 443-287-3900. There is no Submission Fee for Letters to the Editor.
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TRANSFUSION Volume 53, November 2013
