The surgical and immunosuppressive basis for infections in the pediatric solid organ transplant recipient

Balanced immunosuppression is essential to ensure acceptance of a solid organ transplant and an overall successful patient outcome. The fundamental purpose of immunosuppression is to modulate the immune system’s ability to recognize the transplanted organ. However, an overly suppressed immune system increases the risk of certain infections in pediatric solid organ transplant recipients. The goal of balanced immunosuppression is to carefully walk the fine line between too little immunosuppression, which predisposes patients to organ rejection, and too much immunosuppression, which predisposes patients to opportunistic infections.

Although the focus on immunosuppression and its link to infection is warranted, there are other risk factors for infection in pediatric solid organ transplant recipients. Before transplant these may be similar between children and adults. Chronic disease alone is a key risk factor. Potential transplant recipients may undergo multiple rounds of antibiotic treatment for pneumonia, cholangitis, peritonitis, and urinary tract infection, thus increasing their chances of an antibiotic-resistant or opportunistic pathogen. Many potential recipients may also need hospitalization, thus increasing their exposure to multiple types of infections. Transplant candidates are often dependent on the use of central venous catheters, peritoneal dialysis catheters, hemodialysis catheters, ventricular assist devices or extracorporeal membrane oxygenation, all of which increase the risk of systemic invasion by various microorganisms.

Sources of infection after transplant broadly include donor-derived infections, infections acquired perioperatively, reactivation of latent infections, and other infections acquired throughout the patient’s lifetime after transplantation, when there is the added effect of immunosuppressive medications. Postoperatively, poor wound healing is common, and there may be open chests or open abdomens that increase infection risk.

There are also unique issues in pediatric solid organ transplant recipients that contribute to the overall risk of infection. Pediatric recipients are more likely to have malnutrition, which can affect normal immune responses. The actual transplant surgical procedure can involve smaller vascular structures, with higher risk of complications (hematoma, thrombosis). The pediatric solid organ transplant recipient is often naïve to numerous infections, as there is less lifetime exposure to infectious agents. Compounding this is the fact that many children cannot complete the full primary immunization series before transplant. All of these factors contribute to an underdeveloped protective immunity. The following sections review the important surgical and immunologic risk factors for infection in more detail, with a focus on pediatric considerations when appropriate.

Surgical considerations

Surgical infections in the pediatric solid organ transplant recipient are an important source of morbidity, particularly in the early period after transplantation. Surgical infections are broadly classified as either superficial or deep surgical site infections. The risk and nature of these infections differ by organ type.

Superficial surgical site infections

Superficial surgical site infections refer primarily to wound infections in the skin from incisions made during the transplant procedure. Most commonly, these are caused by gram-positive organisms that colonize the skin. Antimicrobial prophylaxis administered before skin incision has been proven to reduce the incidence of these infections and has been adopted for transplant procedures. Treatment of typical superficial surgical site infection includes antibiotic therapy with coverage of gram-positive organisms and local wound care. Local wound care may include exploration of any areas of induration and redness, which may harbor purulent drainage in the subcutaneous space. If such areas are found, treatment consists of reopening the skin and subcutaneous tissue, evacuating the subcutaneous fluid collection, sending any diagnostic samples for microbiologic cultures, and leaving the wound open to heal by secondary intention (granulation from the subcutaneous layer upward). Local wound care thereafter typically includes wet-to-dry dressing changes or the application of a negative-pressure dressing (wound vacuum-assisted closure).

Necrotizing wound infections represent a rare but severe form of wound infection that must be diagnosed and treated expeditiously, particularly in immunosuppressed individuals. These severe necrotizing infections are commonly polymicrobial, but can also be caused by group A Streptococcus and clostridial organisms. Presentation includes severe pain at the surgical site, high fevers, leukocytosis, and electrolyte abnormalities. These infections are characterized by rapid progression along soft tissue planes including fascia. Treatment requires intravenous antibiotic therapy and urgent operative debridement of involved tissues, which typically includes skin, subcutaneous tissue, and deeper fascia.

Deep surgical site infections.

Deep surgical site infections occur in body cavities that are exposed during the surgical procedure. Most commonly, these infections are related to the development of fluid collections in these compartments, which are either primarily or secondarily infected. The causes of deep surgical site infections vary by the type of surgical procedure performed and are discussed by organ type. In many cases, catheter-based drainage of these infected fluid collections combined with antimicrobial therapy allows prompt resolution, but in some cases surgical debridement and drainage is required.

Heart transplantation.

The most common deep space infection after heart transplantation is mediastinitis, which is characterized by a deep infection of the sternum. The incidence after heart transplantation is 2.5% to 7.5%, and risk factors include younger age (<1 year), epicardial pacing wires, and red blood cell transfusion. ^, Mediastinitis is typically a monomicrobial infection, with the most common etiology being both methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus . Treatment generally requires operative debridement of infected tissues, complex chest closure incorporating soft tissue flaps, and prolonged antimicrobial therapy.

Lung transplantation.

After lung transplantation, deep space surgical infections most commonly occur in the pleural space. Fluid and hematoma can accumulate in the pleural space and become secondarily infected, developing into an empyema if the infection progresses. Infected pleural fluid is typically managed with chest tube drainage, but if an empyema develops, surgical debridement and drainage are warranted. The incidence of empyema is approximately 3% to 5% in the lung transplant population and is associated with a significant increase in morbidity and mortality. ^,

Kidney transplantation.

Deep space infection after kidney transplantation arises from infected fluid collections in the surgical bed. Kidney grafts can be implanted in either an intraperitoneal or retroperitoneal location, depending on the size of the recipient. In younger/smaller recipients, the graft is typically placed in an intraperitoneal location, using the distal aorta and inferior vena cava as sites for vascular inflow and outflow, respectively. In this setting, fluid collections that arise thereafter are located in the peritoneal cavity. Fluid collections may consist of hematoma, lymphatic fluid, or, less commonly, urine from a urine leak between the transplanted ureter and recipient bladder. Most common among these are hematomas, which can serve as a rich source of nutrient media for microorganisms.

In older/larger pediatric recipients, the kidney graft is usually placed in a retroperitoneal position, using the external iliac artery and vein for inflow and outflow, respectively. The retroperitoneal space is a more confined, limited space and is thus usually easier to manage if fluid collections develop. The same types of fluid collections (hematoma, lymphocele, and urinoma) can arise in this space and are typically well managed with percutaneous catheter drainage.

Liver transplantation.

Deep space infections after liver transplantation are common and can arise from multiple sources. The formation of a hematoma in the peritoneal cavity is very common after liver transplantation, owing to the coagulopathy that is common in both the pretransplant and early posttransplant period.

Biliary leakage is a primary source of infected fluid collections after liver transplantation. Owing to the relative scarcity of appropriately sized pediatric donors, many pediatric patients receive partial liver grafts consisting of a portion of an adult donor liver, either from a living or deceased donor. The most commonly used partial graft consists of the left-lateral section of an adult donor liver. The biliary drainage from this graft is via the left hepatic duct. Bile leaks can occur from the biliary anastomosis between the graft and a roux-en-Y limb of jejunum. More commonly, bile leaks arise from the cut surface of the liver, where the left-lateral section is divided from the remainder of the donor liver. Fortunately, most of these “cut surface” bile leaks are self-limited and well managed with surgical drains left at the time of transplant.

Multivisceral and intestinal transplantation.

Infections in multivisceral and intestinal transplantation are common owing to the intensive induction immunosuppression administered and the exposure to enteric organisms related to bowel anastomosis. A multivisceral transplant typically consists of the donor liver, pancreas, and small intestine, retrieved from the donor as a single unit (en bloc). The vascular inflow for the graft is provided by an aortic conduit arising from the recipient infrarenal aorta, and the vascular outflow for the graft is via the inferior vena cava. In an isolated intestinal graft, the donor intestine is supplied by the superior mesenteric artery and the vascular outflow by the superior mesenteric vein, which are anastomosed to the aorta and inferior vena cava of the recipient, respectively.

Deep space infections after multivisceral or intestinal transplants may arise from enteric contamination or leakage at the sites of bowel anastomosis, most commonly involving gram-negative and anaerobic organisms. In general, two separate enteric anastomoses are required: one proximal and one distal. The proximal enteric anastomosis is usually constructed between the recipient stomach/proximal intestine and the graft jejunum. The distal enteric anastomosis is constructed between the graft ileum (or colon, if it is included) and the recipient colon. A diverting ileostomy is typically created to allow endoscopic access for the protocol biopsies necessary to monitor the intestinal graft for rejection.

The other primary sources of deep space infection after multivisceral or intestinal transplantation are infected hematomas that arise in the postoperative setting, similar to the other solid organ transplants discussed previously.

Immunologic overview

Components of the immune system

There is a complex interplay within the diverse components of the immune system that helps protect hosts from infectious threats and foreign substances. ^, The first main component consists of the members of the innate immune system: neutrophils, macrophages, dendritic cells, natural killer cells, complement, and various signals such as cytokines and Toll-like receptors. The innate immune system provides constant surveillance against external pathogens. The second component consists of the acquired, or adaptive, immune system, including T cells and B cells, which help the immune system fine-tune the elimination of specific threats, and contribute to memory and tolerance. The acquired immune system helps regulate the overall immune response. The focus of this section is on alloactivation of the acquired immune system, specifically T and B cells, and related processes. The immune system is extremely intricate, and other immune mechanisms fall outside the scope of this chapter.

T cells are activated through a complex pathway of signals ( Fig. 1.1 ), and more than one signal is required for full activation. The major histocompatibility complex (MHC) on the antigen-presenting cell (APC) brings an antigen that binds to the T-cell receptor, known as signal 1. Additionally, a costimulatory signal, between B7 ligands (B7-1, or CD80; and B7-2, or CD86) on the APC and CD28 on the T-cell represents signal 2. Lastly, an interaction between the cytokine IL-2, and its respective receptor on the T cell is represented by signal 3. The IL-2 receptor is made of three subunits, including alpha (CD25), beta (CD122), and gamma chains.

Fig. 1.1, This figure demonstrates the required signals for T-cell activation as well as the mechanistic targets for immunosuppressive agents.

The normal process by which the host learns to recognize self from nonself includes the use of the MHC. There are two specific types of MHC complexes: class I and class II. Class I MHC is expressed by all nucleated cells and is composed of a polymorphic alpha chain, as defined by human leukocyte antigen (HLA) alleles and a highly conserved monomorphic beta-2 microglobulin chain. Nucleated cells constantly have turnover of their proteins, and the proteasome creates peptides, some of which bind to the MHC complex and are translocated across the cell membrane. The extracellular peptide–MHC is then shown to regulatory CD8 T cells, which are normally able to differentiate peptides that bear the intrinsic signature of the host, versus peptides that would indicate a foreign invader, such as a virus, or a malignant cell. Abnormal cells are then targeted for destruction. HLA alleles associated with the MHC class I complex include A, B, and C. In theory, the rise of polymorphisms in the HLA alleles helps with the immune response to a variety of infections and contributes to fitness on an individual and population level.

The class II MHC complex is present only on APCs, macrophages, dendritic cells, and B cells. The class II MHC complex is bound to extracellular protein and is presented to CD4 T cells, which help potentiate the response to foreign invaders. HLA alleles most commonly associated with the MHC class II complex include DR, DQ, and DP.

Matching based on HLA alleles has been one of the primary strategies to ensure optimal clinical outcomes. Although a perfect match may not always be feasible because of the limited number of organs available or the shortened time frame for transplant, HLA mismatch can lead to increased risk of rejection and increased use of immunosuppressive drug regimens, which ultimately lead to increased risk for infection.

Other components of the immune system are worth mentioning here as they represent targets of current immunosuppressive therapies. Regulatory T cells are important in suppressing effector T-cell function through changing the cytokine makeup, competing for the same costimulatory signals, and directing cell-to-cell signals. Cultivating the work of regulatory T cells is necessary in reaching tolerance of the transplanted organ. B cells are also pivotal in their role in both fighting infection and other foreign agents through the secretion of antibodies and facilitation of opsonization. B cells undergo different types of differentiation; a key example is plasma cells that help produce the various immunoglobulin (antibody) types. Immunoglobulins bind to specific foreign antigens and help facilitate phagocytosis and the creation of immune complexes that neutralize pathogens and activate complement. B cells can also function as APCs, in regulatory roles, and as memory cells. They contribute to the development of rejection and are therefore often targets of immunosuppressive regimens.

Lastly, the role of complement cannot be underestimated. The classic complement pathway is activated when C1q binds to the Fc portion of IgM or IgG, either in an antibody–antigen complex or on the surface of cells. Other pathways that lead to activation of complement include when the serum protein lectin binds to mannose, present on bacteria or viral-infected cells; and when complement spontaneously binds to cells recognized as foreign. The downstream target is the generation of C3b, which helps facilitate both opsonization (phagocytosis) and the creation of the terminal complement complex, which effectively punches holes in the cell membranes of pathogens and foreign cells.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here