Infection Watch

Blood transfusions can increase the risk of infection in orthopedic patients

Despite an unknown etiology, transfusion with allogenic blood products predisposes patients to an increased risk of infection.

Javad Parvizi, MD, FRCS
Javad Parvizi

Blood transfusion has always been an integral part of surgical practice. From William Harvey’s discovery of blood circulation in 1628, several practitioners reported success in transfusing animals throughout that century; however, the first successful human blood transfusion was not performed until 1795 by Philadelphian Philip Syng Physick, who never published his findings.

History

In 1818, English obstetrician James Blundell published on successful transfusion for postpartum hemorrhage. Blood transfusion history continued to evolve with Austrian physician Karl Landsteiner’s discovery of the ABO blood grouping system in 1902 and the Rhesus factor in 1939, for which he and his group received, the Nobel Prize.

The field of transfusion medicine was honored with another Nobel Prize in 1912, when French surgeon Alexis Carrel anastomosed a donor vein to the artery of a patient to transfuse the patient. Although this effort proved unsuccessful as a treatment, it paved the way for successful organ transplantation.

The explosion in open heart surgery in the 1950s coupled with two world wars increased demand for blood, and this led to the institution of blood banks around the world. The first reported blood bank was set up in 1932 in a Leningrad hospital. War and conflict during the 20th century has led to a greater understanding of trauma surgery and, hence, transfusion medicine. Isodor Ravidin, another Philadelphia surgeon, first used albumin infusions during the Pearl Harbor conflict as a plasma expander, and the concept of shock management was born.

Blood transfusion has always been controversial, particularly with contaminated products and poor donor screening. Many viruses have been transmitted to donors in the latter part of the 20th century due to inadequate screening techniques; HIV, HTLV, hepatitis B/C and vCJD have all resulted in unnecessary recipient morbidity. Thankfully, screening techniques have improved and the risks of these infections in now minimal.

The two primary transfusion methods used in orthopedic practice today are autologous and allogenic transfusions. Despite their successes, several issues have recently come to light regarding the safety of allogenic blood products, a major one of which in infection.

Risk of infection

Reports from several authors have highlighted the risk of infection associated with the use of allogenic products. The infection risk has been seen in both elective and trauma orthopedic procedures. Koval and colleagues reported an infection rate of 27% as opposed to 15% in transfused vs. nontransfused patients undergoing open reduction and internal fixation for hip fracture, out of a cohort of 687 patients. Similarly, Bierbaum and colleagues, in a multicenter study on 9,482 patients undergoing elective joint arthroplasty, noted an infection rate of 7% in patients who were transfused vs. 3% in nontransfused patients.

Increased postoperative infection associated with blood transfusion has also been seen in other surgical disciplines after cardiac bypass and colorectal surgeries, and the effect was found to be proportional to the number of blood units transfused. Despite the statistical strength, criticisms have been put forth regarding the conclusions of these studies, including their retrospective nature, absence of risk stratification for disease severity and, most importantly, the possibility that blood transfusion may act as a surrogate for other confounding variables such as increased operative time. Their inability to dissociate a predisposition to infection from underlying disease severity acts as a strong confounding factor and must be considered when interpreting these results. Interestingly, the incidence of urinary tract infection is also considerably higher in patients undergoing orthopedic procedures and receiving blood transfusion, pointing to the possible transfusion-induced immunomodulation (TRIM).

TRIM

The term TRIM was coined after observations that patients receiving blood transfusion were at increased risk of any type of infection. The first observations were made when increased renal graft survival was seen in patients receiving allogenic blood transfusion after the transplant. These “immunosuppressive effects” of blood transfusion was fully exploited to maximize the survival of transplant tissues before introduction of immunosuppressive agents such as cyclosporine.

Many other observations such as improvements in autoimmune diseases status such as Crohn’s disease, a decrease in repetitive spontaneous abortions and increase in recurrence of solid tumors, all confirm the adverse effect of allogenic transfusion on cell mediated immunity. The exact mechanism by which allogenic transfusion modulates cell mediated immunity is unknown. Initially, the presence of leukocytes in transfused whole blood was considered as the culprit, and the usage of leuko-depleted products was introduced to abrogate this effect. In recent years, other hypotheses have been proposed.

Part of the cellular immunity involves the maturation of Th0 cells into TH1, 2 and 3 with immune activity. It is believed that release of immunosuppressive cytokines occurs after allogenic blood transfusions that suppress cell mediated immunity. Kirkley and colleagues have shown that the transfusion of allogenic blood in total hip arthroplasty results in release of IL 4 and IL10, which in turn results in suppression of Th1 response.

Cellular anergy theory

T cells when stimulated need co-factors to achieve their final goal, ligands on their surface such as CD40 and CD80 act as accelerators, whereas ligands such as CD152 act as suppressors. It has been suggested that the storage process of allogenic blood releases such suppressors from leukocytes, inducing T cell anergy.

Apoptotic cells are also immunosuppressive in nature. The presence of donor antigen-presenting cells (APC) appears to be a prerequisite for alloimmunization, and they must be both viable and capable of presenting a co-stimulatory signal to induce IL-2 secretion and proliferation of responding CD4 T cells. APCs presenting antigen, but no co-stimulatory signal, can induce non-responsiveness in CD4 T cells, another possible mechanism of TRIM. APCs in refrigerated blood continue to present antigen, but progressively lose their ability to provide co-stimulation. By day 14, co-stimulatory capacity is absent, and transfusion of such blood should not alloimmunize but could induce some degree of immunosuppression. Further refrigerated storage in excess of 2 to 3 weeks leads to induction of apoptosis in contaminating leukocytes and may further debilitate an already compromised transfusion recipient.

The exact mechanism of TRIM has yet to be fully elucidated and certain questions still exist as we try to comprehend its effects on transfused patients.

The immunocompromise that occurs with allogenic transfusion does not explain the increased infection rates seen in trauma patients. Trauma inflicts an immune challenge to patients, and their inflammatory response follows a bimodal pattern with an initial hyperimmune response followed by an immunocompromised state several days post-trauma. A blood transfusion administered during surgery or within 24 hours of trauma should have a minimal effect on blunting this immune response and should not theoretically lead to an increased risk of infection.

Blood groups

There have been reports of patients with certain blood groups having an increased risk of infection. This has been controversially discussed with regard to blood group O and the higher incidence of Helicobacter colonization. Authors have also maintained a link between blood groups B and AB lacking the anti-B isohemagglutinin and, hence, predisposing such patients to infections. Patients lacking the Lewis erythrocyte antigen are known as nonsecretors and have been proven to be at a higher risk of urinary tract infection in a pediatric population. Patients with the Lewis A antigen are at increased risk of bacterial adhesion, particularly at mucosal interfaces.

The Lewis antigen, per se, is not routinely part of the cross matching procedure, as hemolysis is not a recognized feature of a mismatch. Patients negatively expressing such an antigen may be converted to positive expression by transfusion. This facet of transfusion has not been extensively studied and does merit further evaluation. Perhaps the issue may not be immunocompromise due to TRIM but due to other factors such as antigens on transfused erythrocytes inciting susceptibility to infection.

Conclusion

Despite a lack of clarity on its etiology, transfusion with allogenic blood products does predispose patients to an increased risk of infection. With improved handling and screening of blood products, infection now becomes the leading associated risk of transfusing allogenic products. Auto-transfusion, whether through autogenous pre-donation or operative cell salvage, offers a realistic alternative. The practice of hemoglobin trigger levels has reduced the need for transfusion and made liberal transfusion a thing of the past. Alternatives to transfusion such as intravenous iron and erythropoietin analogs are also being investigated, but have yet to gain widespread approval.

For more information:

Eoin Sheehan, MD, FRCS, and Javad Parvizi, MD, FRCS, can be reached at Rothman Institute of Orthopaedics at Jefferson, 925 Chestnut St., 2nd Floor, Philadelphia, PA 19107; 267-399-3617; e-mail: parvj@aol.com.

  • References:

Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg (Am). 1999;81(1):2-10.

Innwehofer P, Klingler A, Klimmer C, et al. Risk for postoperative infection after transfusion of white blood cell-filtered allogeneic or autologous blood components in orthopedic patients undergoing primary arthroplasty. Transfusion. 2005;45(1):103-110

Kirkley SA, Cowles J, Pellegrini VD, et al. Increased T helper 2 (Th2) type cytokine secretion in surgical patients receiving allogeneic transfusions. Transfus Med. 1998;8:195–204.

Koval KJ, Rosenberg AD, Zuckerman JD, et al. Does blood transfusion increase the risk of infection after hip fracture? J Orthop Trauma. 1997;11(4):260-265; discussion 265-266.

Opelz G, Sengar D P S, Mickey M R, Terasaki P I. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc. 1973;5:253–259.

Pulido L, Ghanem E, Joshi A, et al. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res. 2008; 466(7):1710-1715.

Javad Parvizi, MD, FRCS
Javad Parvizi

Blood transfusion has always been an integral part of surgical practice. From William Harvey’s discovery of blood circulation in 1628, several practitioners reported success in transfusing animals throughout that century; however, the first successful human blood transfusion was not performed until 1795 by Philadelphian Philip Syng Physick, who never published his findings.

History

In 1818, English obstetrician James Blundell published on successful transfusion for postpartum hemorrhage. Blood transfusion history continued to evolve with Austrian physician Karl Landsteiner’s discovery of the ABO blood grouping system in 1902 and the Rhesus factor in 1939, for which he and his group received, the Nobel Prize.

The field of transfusion medicine was honored with another Nobel Prize in 1912, when French surgeon Alexis Carrel anastomosed a donor vein to the artery of a patient to transfuse the patient. Although this effort proved unsuccessful as a treatment, it paved the way for successful organ transplantation.

The explosion in open heart surgery in the 1950s coupled with two world wars increased demand for blood, and this led to the institution of blood banks around the world. The first reported blood bank was set up in 1932 in a Leningrad hospital. War and conflict during the 20th century has led to a greater understanding of trauma surgery and, hence, transfusion medicine. Isodor Ravidin, another Philadelphia surgeon, first used albumin infusions during the Pearl Harbor conflict as a plasma expander, and the concept of shock management was born.

Blood transfusion has always been controversial, particularly with contaminated products and poor donor screening. Many viruses have been transmitted to donors in the latter part of the 20th century due to inadequate screening techniques; HIV, HTLV, hepatitis B/C and vCJD have all resulted in unnecessary recipient morbidity. Thankfully, screening techniques have improved and the risks of these infections in now minimal.

The two primary transfusion methods used in orthopedic practice today are autologous and allogenic transfusions. Despite their successes, several issues have recently come to light regarding the safety of allogenic blood products, a major one of which in infection.

Risk of infection

Reports from several authors have highlighted the risk of infection associated with the use of allogenic products. The infection risk has been seen in both elective and trauma orthopedic procedures. Koval and colleagues reported an infection rate of 27% as opposed to 15% in transfused vs. nontransfused patients undergoing open reduction and internal fixation for hip fracture, out of a cohort of 687 patients. Similarly, Bierbaum and colleagues, in a multicenter study on 9,482 patients undergoing elective joint arthroplasty, noted an infection rate of 7% in patients who were transfused vs. 3% in nontransfused patients.

Increased postoperative infection associated with blood transfusion has also been seen in other surgical disciplines after cardiac bypass and colorectal surgeries, and the effect was found to be proportional to the number of blood units transfused. Despite the statistical strength, criticisms have been put forth regarding the conclusions of these studies, including their retrospective nature, absence of risk stratification for disease severity and, most importantly, the possibility that blood transfusion may act as a surrogate for other confounding variables such as increased operative time. Their inability to dissociate a predisposition to infection from underlying disease severity acts as a strong confounding factor and must be considered when interpreting these results. Interestingly, the incidence of urinary tract infection is also considerably higher in patients undergoing orthopedic procedures and receiving blood transfusion, pointing to the possible transfusion-induced immunomodulation (TRIM).

TRIM

The term TRIM was coined after observations that patients receiving blood transfusion were at increased risk of any type of infection. The first observations were made when increased renal graft survival was seen in patients receiving allogenic blood transfusion after the transplant. These “immunosuppressive effects” of blood transfusion was fully exploited to maximize the survival of transplant tissues before introduction of immunosuppressive agents such as cyclosporine.

Many other observations such as improvements in autoimmune diseases status such as Crohn’s disease, a decrease in repetitive spontaneous abortions and increase in recurrence of solid tumors, all confirm the adverse effect of allogenic transfusion on cell mediated immunity. The exact mechanism by which allogenic transfusion modulates cell mediated immunity is unknown. Initially, the presence of leukocytes in transfused whole blood was considered as the culprit, and the usage of leuko-depleted products was introduced to abrogate this effect. In recent years, other hypotheses have been proposed.

Part of the cellular immunity involves the maturation of Th0 cells into TH1, 2 and 3 with immune activity. It is believed that release of immunosuppressive cytokines occurs after allogenic blood transfusions that suppress cell mediated immunity. Kirkley and colleagues have shown that the transfusion of allogenic blood in total hip arthroplasty results in release of IL 4 and IL10, which in turn results in suppression of Th1 response.

Cellular anergy theory

T cells when stimulated need co-factors to achieve their final goal, ligands on their surface such as CD40 and CD80 act as accelerators, whereas ligands such as CD152 act as suppressors. It has been suggested that the storage process of allogenic blood releases such suppressors from leukocytes, inducing T cell anergy.

Apoptotic cells are also immunosuppressive in nature. The presence of donor antigen-presenting cells (APC) appears to be a prerequisite for alloimmunization, and they must be both viable and capable of presenting a co-stimulatory signal to induce IL-2 secretion and proliferation of responding CD4 T cells. APCs presenting antigen, but no co-stimulatory signal, can induce non-responsiveness in CD4 T cells, another possible mechanism of TRIM. APCs in refrigerated blood continue to present antigen, but progressively lose their ability to provide co-stimulation. By day 14, co-stimulatory capacity is absent, and transfusion of such blood should not alloimmunize but could induce some degree of immunosuppression. Further refrigerated storage in excess of 2 to 3 weeks leads to induction of apoptosis in contaminating leukocytes and may further debilitate an already compromised transfusion recipient.

The exact mechanism of TRIM has yet to be fully elucidated and certain questions still exist as we try to comprehend its effects on transfused patients.

The immunocompromise that occurs with allogenic transfusion does not explain the increased infection rates seen in trauma patients. Trauma inflicts an immune challenge to patients, and their inflammatory response follows a bimodal pattern with an initial hyperimmune response followed by an immunocompromised state several days post-trauma. A blood transfusion administered during surgery or within 24 hours of trauma should have a minimal effect on blunting this immune response and should not theoretically lead to an increased risk of infection.

Blood groups

There have been reports of patients with certain blood groups having an increased risk of infection. This has been controversially discussed with regard to blood group O and the higher incidence of Helicobacter colonization. Authors have also maintained a link between blood groups B and AB lacking the anti-B isohemagglutinin and, hence, predisposing such patients to infections. Patients lacking the Lewis erythrocyte antigen are known as nonsecretors and have been proven to be at a higher risk of urinary tract infection in a pediatric population. Patients with the Lewis A antigen are at increased risk of bacterial adhesion, particularly at mucosal interfaces.

The Lewis antigen, per se, is not routinely part of the cross matching procedure, as hemolysis is not a recognized feature of a mismatch. Patients negatively expressing such an antigen may be converted to positive expression by transfusion. This facet of transfusion has not been extensively studied and does merit further evaluation. Perhaps the issue may not be immunocompromise due to TRIM but due to other factors such as antigens on transfused erythrocytes inciting susceptibility to infection.

Conclusion

Despite a lack of clarity on its etiology, transfusion with allogenic blood products does predispose patients to an increased risk of infection. With improved handling and screening of blood products, infection now becomes the leading associated risk of transfusing allogenic products. Auto-transfusion, whether through autogenous pre-donation or operative cell salvage, offers a realistic alternative. The practice of hemoglobin trigger levels has reduced the need for transfusion and made liberal transfusion a thing of the past. Alternatives to transfusion such as intravenous iron and erythropoietin analogs are also being investigated, but have yet to gain widespread approval.

For more information:

Eoin Sheehan, MD, FRCS, and Javad Parvizi, MD, FRCS, can be reached at Rothman Institute of Orthopaedics at Jefferson, 925 Chestnut St., 2nd Floor, Philadelphia, PA 19107; 267-399-3617; e-mail: parvj@aol.com.

  • References:

Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg (Am). 1999;81(1):2-10.

Innwehofer P, Klingler A, Klimmer C, et al. Risk for postoperative infection after transfusion of white blood cell-filtered allogeneic or autologous blood components in orthopedic patients undergoing primary arthroplasty. Transfusion. 2005;45(1):103-110

Kirkley SA, Cowles J, Pellegrini VD, et al. Increased T helper 2 (Th2) type cytokine secretion in surgical patients receiving allogeneic transfusions. Transfus Med. 1998;8:195–204.

Koval KJ, Rosenberg AD, Zuckerman JD, et al. Does blood transfusion increase the risk of infection after hip fracture? J Orthop Trauma. 1997;11(4):260-265; discussion 265-266.

Opelz G, Sengar D P S, Mickey M R, Terasaki P I. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc. 1973;5:253–259.

Pulido L, Ghanem E, Joshi A, et al. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res. 2008; 466(7):1710-1715.