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Ann Thorac Surg 2006;82:889-893
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Low-Dose Prophylactic Intravenous Immunoglobulin Does Not Prevent HLA Sensitization in Left Ventricular Assist Device Recipients

Stavros G. Drakos, MDa,b, Abdallah G. Kfoury, MDa,*, James W. Long, MDa, James C. Stringham, MDb,c, Thomas C. Fuller, PhDb, Karl E. Nelson, RNa, Beverly K. Campbell, RNa, Edward M. Gilbert, MDb,c, Dale G. Renlund, MDa,b

a LDS Hospital, Utah Transplantation Affiliated Hospitals Cardiac Transplant Program, Salt Lake City, Utah
b University of Utah School of Medicine, Utah Transplantation Affiliated Hospitals Cardiac Transplant Program, Salt Lake City, Utah
c George E. Wahlen Veterans Affairs Medical Center, Utah Transplantation Affiliated Hospitals Cardiac Transplant Program, Salt Lake City, Utah

Accepted for publication April 3, 2006.

* Address correspondence to Dr Kfoury, Cardiac Transplant Program, LDS Hospital, 8th Ave and C St, Salt Lake City, UT 84143. (Email: akfoury{at}intermountainmail.org).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: The use of left ventricular assist devices is associated with human leukocyte antigen (HLA) allosensitization. We investigated whether prophylactic treatment with low-dose intravenous immunoglobulin (IVIG), analogous to the use of IgG anti-D (anti-Rh) in preventing Rh immunization, can abrogate HLA allosensitization after left ventricular assist device implantation.

METHODS: We retrospectively reviewed the data from 84 consecutive heart failure patients who underwent implantation of a left ventricular assist device as a bridge to transplantation. After implantation, panel reactive antibody (PRA) was measured biweekly to assess sensitization (defined by PRA > 10%). Patients who were sensitized before left ventricular assist device implantation were excluded from further analysis (n = 12). Patients who either did not require perioperatively transfusions of cellular blood products or received other immunomodifying regimens were also excluded from further analysis (n = 21). The rest of the patients were divided into two groups based on whether they received IVIG, 10 g daily for 3 days (IVIG group, n = 26; non-IVIG group, n = 25). The decision as to whether patients received IVIG was not randomized but was based on surgeon preference.

RESULTS: The sensitization rates (expressed as ratio of sensitized patients to total patients at risk) in the two groups were similar at consecutive time points (2, 4, 6, 8, 12, 20 weeks) after left ventricular assist device implantation. Also, mean PRA at the same time points did not differ between the two groups. Overall, 34.6% (9 of 26) of the IVIG group became sensitized during mechanical support, compared with 32% (8 of 25) of the non-IVIG group (p = 1.0). A PRA of 90% or greater (high-degree sensitization) occurred in 15.3% (4 of 26) of the IVIG group and 12.0% (3 of 25) of the non-IVIG group (p = 0.5).

CONCLUSIONS: The use of low-dose prophylactic IVIG after left ventricular assist device implantation affects neither the incidence nor the severity of HLA allosensitization.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
The advent of temporary mechanical circulatory support for the failing left ventricle has been life saving for selected patients awaiting heart transplantation [1]. Despite the success of mechanical circulatory support bridging to transplant, in many mechanically supported heart transplant candidates, circulating anti–human leukocyte antigen (HLA) antibodies develop with potential donor reactivity, and elevation of the panel reactive antibody (PRA) [2–4]. The existence of preformed antibodies delays cardiac transplantation because of difficulty in identifying a suitable crossmatch-negative donor and has been shown to have a higher risk of posttransplant rejection, morbidity, and mortality [5–8].

The development of sensitization has prompted the deployment of strategies to decrease the level of sensitization and increase the likelihood of finding a suitable donor with a negative crossmatch. These strategies have included the administration of immunoglobulin, immunoadsorption, plasmapheresis, and combination therapies using potent immunosuppression [9]. However, such protocols are neither universally successful nor standardized. An alternative approach is to prevent sensitization in the first place. We investigated whether prophylactic treatment with low-dose intravenous immunoglobulin (IVIG), analogous to the use of IgG anti-D (anti-Rh) in preventing Rh immunization [10, 11], could abrogate HLA allosensitization after left ventricular assist device (LVAD) implantation.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Retrospective data were obtained from the clinical and laboratory records of 84 consecutive heart failure patients who underwent implantation of either the IP (pneumatic) or VE (vented electric) HeartMate LVAS (Thoratec, Pleasanton, California) as a bridge to transplantation from 1993 to 2003. All patients provided informed consent for collection of data used in this study, and the Institutional Review Committee from each institution also approved such data collection for research. Sera from all patients were collected before LVAD implantation and at intervals of 2 to 4 weeks thereafter. The sera were subjected to PRA determination against a panel of donor lymphocytes representing the spectrum of HLA specificities. The PRA assays were performed either by the antiglobulin-augmented, complement-dependent lymphocytotoxicity assay or flow cytometry. All samples were treated with dithiothreitol to remove immunoglobulin M sensitivity. Sensitization was defined as a PRA greater than 10%. Patients who were sensitized before LVAD implantation were excluded from further analysis (n = 12). Patients who either did not require perioperatively transfusions of cellular blood products or received other immunomodifying regimens were also excluded from further analysis (n = 21). The remaining patients were divided in two groups based on whether they received IVIG, 10 g daily for 3 days, after the implantation of the LVAD (IVIG group, n = 26; and non- IVIG group, n = 25). The decision as to whether patients received IVIG was not randomized but based on surgeon preference.

Statistical analysis was performed with the SPSS software (SPSS, Chicago, Illinois). Results of continuous variables are expressed as the mean ± SD. Categorical variables were compared with a {chi}2 test. Continuous variables were compared with a Student's t test. Statistical significance was accepted if the null hypothesis was rejected at p less than 0.05 level.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Sex and cardiac diagnosis did not differ between the two groups. The IVIG group was younger and was mechanically supported longer (Table 1). Transfusion rates of packed red blood cells, platelets, and fresh frozen plasma were not different (Table 1).


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  		Table 1. Patient Characteristics
 
The incidence of allosensitization (expressed as ratio of sensitized patients to total patients at risk) at consecutive time points before transplantation was similar in the two groups (Fig 1). The level of PRA developed at each consecutive time point was also similar. Intravenous immunoglobulin did not prevent the development of sensitization (Fig 2).


Figure 1
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  		Fig 1. Incidence of sensitization. (Gray bars = intravenous immunoglobulin; black bars = no intravenous immunoglobulin; LVAD = left ventricular assist device; NS = not significant.)

 

Figure 2
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  		Fig 2. Panel reactive antibody (PRA). (Gray bars = intravenous immunoglobulin; black bars = no intravenous immunoglobulin; LVAD = left ventricular assist device; NS = not significant.)

 
Overall, 34.6% (9 of 26) of the IVIG group became sensitized during mechanical support, compared with 32% (8 of 25) of the non-IVIG group (p = 1.0; Fig 3). A PRA of 90% or greater (ie, high-degree sensitization) occurred in 15.3% (4 of 26) of the IVIG group and 12.0% (3 of 25) of the non-IVIG group (p = 0.5; Fig 3). There was no difference in the peak PRA reached in the IVIG group when compared with the non-IVIG group (69.7% ± 29.3% versus 57.7% ± 33.8%, respectively; p = 0.44; Fig 4).


Figure 3
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  		Fig 3. Overall sensitization rates during left ventricular assist device support. (Gray bars = intravenous immunoglobulin; black bars = no intravenous immunoglobulin; PRA = panel reactive antibody.)

 

Figure 4
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  		Fig 4. Peak panel reactive antibody (PRA). (Gray bar = intravenous immunoglobulin; black bar = no intravenous immunoglobulin.)

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
The use of LVADs has enjoyed widespread success in bridging patients to cardiac transplantation [1]. However, in many of these patients, circulating antibodies with HLA reactivity eventually develop, creating difficulty in finding a compatible donor. Several investigations have alluded to the strong association of sensitization and mechanical ventricular assist devices [2–4]. Collections of activated inflammatory cells within the pseudoneointima of the HeartMate textured pumping chamber surface with augmented expression of the inflammatory mediator nuclear factor kappa B may give rise to increased production of inflammatory cytokines and B-cell hyperreactivity [12]. The HeartMate interior surface has also been shown to colonize with pluripotent hematopoietic stem cells, which could become immunologically active as well [13]. Schuster and associates [14] suggested that exposure of human mononuclear cells to ventricular assist device–derived biomaterial leads to T-cell–dependent B-cell activation through CD40–CD40 ligand interaction, and that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after ventricular assist device implantation. Ankersmit and associates [15] from the same group have shown that ventricular assist device implantation results in an aberrant state of T cell activation, heightened susceptibility of CD4 T cells to activation induced cell death, progressive defects in cellular immunity, and increased risk of opportunistic infection.

The detection of anti-HLA donor-specific antibodies has been associated with a variety of clinical syndromes that determine short-term and long-term outcomes of cardiac transplant recipients. This form of sensitization has been associated with an increased incidence of early and severe allograft rejection and with the late development of cardiac allograft vasculopathy and decreased survival [16–20]. Furthermore, when an elevated PRA was encountered in the context of a left ventricular assist device, Thompson and associates [21] found that these patients were at very high risk for allograft failure.

Thus, in the sensitized heart transplant candidate, one can reliably assume that if left unmodified, the future donor–host interaction could result in clinically devastating sequelae. Several strategies have been suggested, including administration of immunoglobulin, immunoadsorption, plasmapheresis, and combination therapies using potent immunosuppression to decrease sensitization once it has occurred [9, 22–27]. However, no distinct standardized protocol exists [9].

The principal effects of IVIG are likely predicated by the presence of anti-idiotypic antibodies that are potent inhibitors of HLA-specific alloantibodies in vitro and in vivo. The IVIG preparation contains soluble HLA class I molecules that bind circulating anti-HLA antibodies. Emmi and Chiarini [28] have recently reviewed the immunomodulatory role of IVIG and have proposed several mechanisms responsible for the observed benefits. These include Fc-receptor–mediated effects, modulation of complement, modulation of cytokine production, superantigen neutralization, antibody neutralization by idiotype network, increased catabolism of IgG, and biologic effects of other molecules present in IVIG preparations.

Taking all these in account, we sought to investigate whether prophylactic treatment with low-dose IVIG after transfusions would prevent the subsequent HLA allosensitization of LVAD recipients. Our rational was analogous to the use of IgG anti-D (anti-Rh) in preventing Rh immunization [10, 11], but we found that the use of low-dose prophylactic IVIG affected neither the incidence nor the severity of HLA allosensitization of our LVAD recipients.

In our study, IVIG was used prophylactically in LVAD recipients who received transfusions of cellular blood products perioperatively. We used to follow this strategy because transfusion of cellular blood products has been considered as one major factor giving rise to antibody production in patients who have not been previously sensitized [2, 3, 29, 30]. However, after analyzing data from our program, we reached conclusions somewhat contrary to the popular belief that more transfusions may worsen sensitization among LVAD recipients [4, 31]. Notably, avoiding perioperative transfusion of cellular blood components does not protect and actually may worsen allosensitization before transplantation [4, 31]. Nevertheless, in this study, transfusion was found to be similar in patients receiving or not receiving IVIG and in this way was excluded from being a confounding factor.

The duration of mechanical support was found to be significantly different between the two groups. However, that is not likely to have influenced the sensitization rates of the two groups since the average duration of mechanical support in both groups was longer than the time required for a LVAD recipient to develop sensitization. Notably, no patient included in this study has had sensitization after the 10th week after implantation.

The low dose of IVIG used in our study failed to provide sensitization prevention in our LVAD population, but a higher dose of IVIG does not seem to be an attractive alternative given that LVAD recipients already suffer high rates of infection.

The limitations of this study include those related to a retrospectively performed analysis. Data were obtained by means of chart and electronic database review, which has inherent limitations, such as access and accuracy of the data. In addition to these the decision as to whether patients received IVIG or not was not made in a randomized manner but was based on surgeon preference.

In conclusion, although several strategies for tackling allosensitization have been advocated, no clear consensus exists on the best modality. In this study, we showed that the perioperative prophylactic administration of IVIG in nonsensitized LVAD recipients was not effective in preventing the subsequent allosensitization of these patients after the LVAD implantation. Whether modifications in dose or timing could be helpful remains to be determined.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Frazier OH, Rose EA, Oz MC, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation J Thorac Cardiovasc Surg 2001;122:1189-1195.
  2. Massad MG, Cook DJ, Schmitt SK, et al. Factors influencing HLA sensitization in implantable LVAD recipients Ann Thorac Surg 1997;64:1120-1125.[Abstract/Free Full Text]
  3. McKenna Jr DH, Eastlund T, Segall M, Noreen HJ, Park S. HLA alloimmunization in patients requiring ventricular assist device support J Heart Lung Transplant 2002;21:1218-1224.[Medline]
  4. Stringham JC, Bull DA, Fuller TC, et al. Avoidance of cellular blood product transfusions in LVAD recipients does not prevent HLA allosensitization J Heart Lung Transplant 1999;18:160-165.[Medline]
  5. Smith JD, Danskine AJ, Laylor RM, Rose ML, Yacoub MH. The effect of panel reactive antibodies and the donor specific crossmatch on graft survival after heart and heart-lung transplantation Transpl Immunol 1993;1:60-65.[Medline]
  6. Lavee J, Kormos RL, Duquesnoy RJ, et al. Influence of panel-reactive antibody and lymphocytotoxic crossmatch on survival after heart transplantation J Heart Lung Transplant 1991;10:921-930.[Medline]
  7. Kobashigawa JA, Sabad A, Drinkwater D, et al. Pretransplant panel reactive-antibody screens Are they truly a marker for poor outcome after cardiac transplantation? Circulation 1996;94:II294-II297.
  8. Itescu S, Tung TC, Burke EM, et al. Preformed IgG antibodies against major histocompatibility complex class II antigens are major risk factors for high-grade cellular rejection in recipients of heart transplantation Circulation 1998;98:786-793.[Abstract/Free Full Text]
  9. Mehra MR, Uber PA, Uber WE, Scott RL, Park MH. Allosensitization in heart transplantationimplications and management strategies. Curr Opin Cardiol 2003;18:153-158.[Medline]
  10. Fung Kee Fung K, Eason E, Crane J, et al. Prevention of Rh alloimmunization J Obstet Gynaecol Can 2003;25:765-773.[Medline]
  11. Nester TA, Rumsey DM, Howell CC, et al. Prevention of immunization to D+ red blood cells with red blood cell exchange and intravenous Rh immune globulin Transfusion 2004;44:1720-1723.[Medline]
  12. Itescu S, Ankersmit JH, Kocher AA, Schuster, MD. Immunobiology of left ventricular assist devices Prog Cardiovasc Disa 2000;43:67-80.
  13. Rafii S, Oz MC, Seldomridge JA, et al. Characterization of hematopoietic cells arising on the textured surface of left ventricular assist devices Ann Thorac Surg 1995;60:1627-1632.[Abstract/Free Full Text]
  14. Schuster M, Kocher A, John R, et al. B-cell activation and allosensitization after left ventricular assist device implantation is due to T-cell activation and CD40 ligand expression Hum Immunol 2002;63:211-220.[Medline]
  15. Ankersmit HJ, Tugulea S, Spanier T, et al. Activation-induced T-cell death and immune dysfunction after implantation of left-ventricular assist device Lancet 1999;354:550-555.[Medline]
  16. Zerbe TR, Arena VC, Kormos RL, et al. Histocompatibility and other risk factors for histologic rejection of human cardiac allografts during the first three months following transplantation Transplantation 1991;52:485-490.[Medline]
  17. Rose EA, Pepino P, Barr ML, et al. Relation of HLA antibodies and graft atherosclerosis in human cardiac allograft recipients J Heart Lung Transplant 1992;11:S120-S123.[Medline]
  18. De Mattos AM, Head MA, Everett J, et al. HLA-DR mismatching correlates with early cardiac allograft rejection, incidence, and graft survival when high confidence-level serological DR typing is used Transplantation 1994;57:626-630.[Medline]
  19. Lavee J, Kormos RL, Duquesnoy RJ, et al. Influence of panel-reactive antibody and lymphocytotoxic cross-match on survival after heart transplantation J Heart Lung Transplant 1991;10:921-930.[Medline]
  20. Kobashigawa JA, Sabad A, Drinkwater D, et al. Pretransplant panel reactive antibody screensare they truly a marker for poor outcome after cardiac transplantation?. Circulation 1996;94:II294-II297.[Medline]
  21. Thompson JS, Thacker II LR, Takemoto S. The influence of conventional and cross-reactive group HLA matching on cardiac transplant outcomean analysis from the United Network of Organ Sharing Scientific Registry. Transplantation 2000;69:2178-2186.[Medline]
  22. Jordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients Transplantation 2003;76:631-636.[Medline]
  23. Glotz D, Antoine C, Julia P, et al. Intravenous immunoglobulins and transplantation for patients with anti-HLA antibodies Transpl Int 2004;17:1-8.[Medline]
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  25. Larson DF, Elkund DK, Arabia F, et al. Plasmapheresis during cardiopulmonary bypassa proposed treatment for presensitized cardiac transplantation patients. J Extra Corpor Technol 1999;31:177-183.[Medline]
  26. Pisani BA, Mullen GM, Malinowska K, et al. Plasmapheresis with intravenous immunoglobulin G is effective in patients with elevated panel reactive antibody prior to cardiac transplantation J Heart Lung Transplant 1999;18:701-706.[Medline]
  27. Itescu S, Burke E, Lietz K, et al. Intravenous pulse administration of cyclophosphamide is an effective and safe treatment for sensitized cardiac allograft recipients Circulation 2002;105:1214-1219.[Abstract/Free Full Text]
  28. Emmi L, Chiarini F. The role of intravenous immunoglobulin therapy in autoimmune and inflammatory disorders Neurol Sci 2002;23(Suppl 1):1-8.[Medline]
  29. Moazami N, Itescu S, Williams MR, Argenziano M, Weinberg A, Oz MC. Platelet transfusions are associated with the development of anti-major histocompatibility complex class I antibodies in patients with left ventricular assist support J Heart Lung Transplant 1998;17:876-880.[Medline]
  30. Fauchet R, Genetet B, Gueguen M, Leguerrier A, Rioux C, Logeais Y. Transfusion therapy and HLA antibody response in patients undergoing open heart surgery Transfusion 1982;22:320-322.[Medline]
  31. Drakos SG, Renlund DG, Long JW, et al. The impact of cellular blood product transfusion on allosensitization in LVAD recipients bridged to heart transplantation. Submitted for publication..



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