The Solid Organ Transplant Patient

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Chapter 184

The Solid Organ Transplant Patient

Principles of Disease

Transplanted organs are devoid of their native innervations and thus pain is an unreliable sign of underlying disease. Transplanted organs also have surgical anastomoses to a variety of structures, including vessels, bronchi, ureters, intestines, and even the bladder. Furthermore, the normal inflammatory and immunologic responses to infection and malignant disease are impaired. Subtle symptoms and signs may be the harbingers of serious complications, and each complaint merits careful investigation. Even in the most advanced stages of severe disease, patients may have few specific complaints and physical findings. The baseline physiologic capacity of the allograft will aid in interpretation of chief complaints in the context of possible organ failure. Small changes in allograft function may be a harbinger of an episode of rejection.

Transplant organ complications can generally be classified into one of four categories: anatomy, infection, rejection, and drug toxicity. Each category should be considered in the differential diagnosis for any transplant patient presenting to the ED. Often, the exact etiology is not determined until the patient is admitted to the hospital. In addition, time since transplantation must be considered in the evaluation. Time can help the clinician focus his or her investigative efforts and tailor treatment regimens.

Anatomy

Anatomic complications of solid organ transplants can be categorized into three groups: vascular, nonvascular anastomosis, and complications related to surgery. These are often manifested early in the post-transplantation course, but delayed presentations can occur.

Vascular complications can include both arterial and venous structures. Acute thrombosis of arteries may lead to fulminant organ failure. This is especially true in liver transplant recipients, in whom the hepatic artery is the sole source of blood flow for the biliary system. An ultrasound examination with color flow Doppler study is often performed immediately after liver transplantation to ensure arterial patency and flow. Arterial stenosis may also develop later in the course, with its effects typically determined by the degree of blood flow restriction. Pseudoaneurysms may develop and quickly lead to hemorrhagic shock if they rupture.

Nonvascular organ anastomoses may include bile ducts, bronchi, and ureters. Complications related to these structures include leaks and obstructions that often lead to acute graft dysfunction. Early identification is vital to salvage of the graft. Leaks are often manifested with pain and may lead to abscess formation. Conservative therapy may include antibiotics and percutaneous drainage. Refractory or severe cases may require surgical intervention. Obstructions may be due to scar tissue, migration of stents, or stone development. If the obstruction is not treated, graft dysfunction may lead to infections such as cholangitis and pyelonephritis. Bronchial leaks may cause a pneumothorax or pneumomediastinum. Prolonged leaks may lead to abscess formation in the thorax, requiring antibiotics and surgical drainage.

Complications related to the surgery are directly associated with the procedure but not specific to the transplanted organ. These may include problems related to technique that lead to hematoma or lymphocyte formation. Fever in the acute postoperative period must be evaluated for complications specific to the transplanted organ as well as for other common causes of postoperative fever.

Infection

Lifelong immunosuppression is generally necessary for all recipients of solid organ transplants, and infection is the primary cause of mortality after transplantation. Two thirds of transplant patients have at least one significant infection, most commonly nosocomial during the surgical recovery period or, subsequently, community acquired (Box 184-1).1,2

Signs of infection in this population of patients are often blunted by an impaired inflammatory response. Minor complaints or the chief complaint of a fever in an afebrile patient may herald a severe infection. Aggressive management usually translates into increased patient survival and graft function.1

Primary sources of infection in transplant recipients include pretransplantation, community acquired, transmission from organ donor, and nosocomial. Transplant patients should be vaccinated, but live viral antigens should be avoided. Close family members should not be given live vaccines because of the risk of transmission. The timing of infection can be separated into three periods: first month after transplantation, between 1 and 6 months after transplantation, and more than 6 months after transplantation. These distinctions help predict the etiologic agents of the infection.

1 to 6 Months after Transplantation

Infections occurring 1 to 6 months after transplantation are divided into two general types: immunomodulating viral infections and opportunistic infections. Immunomodulating viruses include cytomegalovirus (CMV), hepatitis B and C viruses, BK polyomavirus, human herpesvirus 6, and Epstein-Barr virus (EBV). Opportunistic pathogens include Pneumocystis, Listeria, and fungal species.

CMV is the most important and prevalent immunomodulating virus 1 to 6 months after transplantation.1 CMV infection may produce disease in multiple systems, but pneumonitis is particularly common and may be manifested insidiously. CMV infection may be primary or due to reactivation from latent viral particles found in lymphocytes. Typically, signs of CMV infection occur at a median of 40 days after transplantation. Survival from CMV infection is improving because of aggressive use of bronchoscopy that leads to earlier diagnosis and treatment with ganciclovir and CMV-specific immune globulin. Prophylaxis with ganciclovir reduces CMV incidence and death due to infection, but routine use of ganciclovir is associated with a number of potential side effects.3 Because the risk of CMV infection is greatest during antilymphocyte therapy, some transplant centers administer ganciclovir only selectively during the treatment period, although CMV infection is still often fatal.4,5

Active CMV infection can trigger or exacerbate organ rejection. CMV is linked to a particular form of glomerulopathy in renal allograft recipients as well as acute hepatic dysfunction and the disappearing bile duct syndrome of chronic hepatic allograft dysfunction.6,7 Furthermore, both acute cardiac dysfunction and accelerated coronary artery atherosclerosis of chronic heart transplant rejection are linked to CMV.8,9

EBV infection causes clinical effects similar to those of CMV infection. EBV contributes to immunosuppression and can cause a mononucleosis-like syndrome associated with lymphadenopathy, weakness, and low-grade fevers. Because CMV and EBV often coexist, both seem to trigger graft rejection. EBV is also implicated in B-cell lymphoproliferative syndrome, which is histologically similar to polymorphic B-cell lymphoma.10

6 Months after Transplantation

Six months after organ transplantation, patients with functioning solid organ allografts receiving immunosuppression therapy can be categorized into three groups relative to infection susceptibility: healthy transplant, chronic viral infection, and chronic rejection.

Chronic Viral Infection.: Progressive disease may develop as a result of the combination of viral immunomodulating infections and long-term immunosuppression. Progressive liver disease due to recurrent or acquired viral hepatitis as well as hepatocellular carcinoma may occur. B-cell lymphoproliferative disorder associated with EBV infection may also develop.1,2

Primary varicella infection may lead to rapid dissemination with pneumonia, pancreatitis, hepatitis, encephalitis, and disseminated intravascular coagulation. Patients who are varicella-zoster virus (VZV) seronegative need high doses of intravenous varicella-zoster immune globulin after any exposure, preferably before the development of the rash. Therapy can be lifesaving if it is administered early before dissemination occurs.1,2

Reactivation of latent VZV infection, manifested as cutaneous herpes zoster, affects at least 10% of solid organ transplant recipients. Fortunately, reactivation of VZV is usually confined to a single dermatome and does not disseminate. Intravenous acyclovir therapy accelerates healing but does not change the incidence of painful neuralgia. Facial zoster involving the cornea and disseminated infections in more than one dermatome are indications for admission.1 In patients who have never contracted VZV, many patients are immunized before transplantation.

Herpes simplex virus (HSV) reactivation is common after solid organ transplantation and can be manifested as oral or anogenital lesions, more often ulcers than vesicles. Some transplant centers prescribe oral acyclovir for 3 to 6 months after transplantation, whereas others choose to treat HSV immediately at the first sign of recurrence.11

Chronic Rejection.: Patients with chronic rejection require ongoing aggressive immunosuppressive treatment to protect the allograft. These patients are at the highest risk for life-threatening opportunistic infections with fungi (e.g., Candida, Cryptococcus, Coccidioides, Blastomyces, and Histoplasma), bacteria (e.g., Listeria and Nocardia), and parasites (e.g., Pneumocystis, Toxoplasma, and Strongyloides).

Fungal infections are distinct to geographic regions and typically are manifested with subacute respiratory complaints associated with fever and focal, disseminated, or miliary infiltrates on the chest radiograph.1 Invasive candidiasis and aspergillosis can also develop in the chronically immunosuppressed group. Primary infections in the lungs, gastrointestinal tract, or nasal sinuses lead to fungemia and contamination of intravenous lines and wounds. Treatment is with antifungal agents such as amphotericin B or agents such as micafungin (Mycamine).

Diverticulitis is the principal bacterial gastrointestinal infection observed in transplant patients with chronic rejection. Inflammation is suppressed with chronic steroid therapy, which leads to an increased incidence of perforation before diagnosis. Patients complain of an insidious onset of pain, change in bowel habits, and sometimes fever, but they typically lack peritoneal signs. Transplant patients are also susceptible to mucosal invasion with salmonellae (nontyphoidal) and Listeria. Infection with both organisms can be manifested as acute diarrheal syndromes that progress to bacteremia or meningitis.1,2

Pulmonary infection with Nocardia asteroides may occur in transplant patients. Primary infection is subacute, with cough, fever, pleurisy, purulent sputum, and subsequent metastatic infection of the brain and skin. Seizures or subcutaneous nodules may be the presenting complaint with a primary Nocardia infection.

Pneumocystis jiroveci (carinii) pneumonia is often found in combination with CMV infection because CMV inhibits alveolar macrophage function (Fig. 184-1). Fortunately, its incidence is reduced with prophylactic low-dose trimethoprim-sulfamethoxazole. Without prophylaxis, infection may develop 1 to 6 months after transplantation and is manifested subacutely with fever, nonproductive cough, progressive dyspnea, and an interstitial infiltrate on the chest radiograph. Differentiation from CMV pneumonia is impossible without bronchoscopic confirmation. Treatment of Pneumocystis pneumonia includes intravenous trimethoprim-sulfamethoxazole and steroids, depending on the degree of hypoxia.

Disseminated toxoplasmosis is a particular concern in heart transplant patients. Toxoplasmosis can lay dormant in the tissues, especially the heart, and be reactivated during immunosuppression, resulting in myocarditis, brain abscesses, or diffuse encephalitis. Typically, treatment of toxoplasmosis is a combination of intravenous sulfadiazine and pyrimethamine.

Strongyloides stercoralis, an intestinal nematode that normally causes minimal symptoms, can become an invasive pathogen during immunosuppression. A hyperinfection syndrome can develop, causing a necrotizing hemorrhagic enterocolitis and hemorrhagic pneumonia. Disseminated strongyloidiasis occurs when the larvae migrate from the gastrointestinal tract. Dissemination and hyperinfection can lead to gram-negative bacteremia and meningitis secondary to impairment of the blood-gut barrier.

Mycobacterial disease can be manifested as opportunistic reactivation or a primary infection. Even disseminated disease can be clinically silent, with invasion of the bowel, skin, and gastrointestinal tract. Pulmonary disease can be absent, miliary, or cavitary (Fig. 184-2). Treatment is difficult because typical agents can cause graft dysfunction.1,2

Rejection

The course of rejection may vary, but each individual typically has a lifelong course of a waxing and waning immune response to the allograft, mandating ongoing surveillance of allograft function. Differentiation of infection and rejection is often difficult in the ED. Determination is often made only after biopsy of the transplanted organ or positive culture results are identified.

Rejection typically occurs in three phases: hyperacute, acute, and chronic. Hyperacute rejection is rare with careful donor-recipient matching. It typically occurs in the immediate perioperative period. Acute rejection occurs within the first months after transplantation. The patient presents with constitutional symptoms and signs of transplant organ insufficiency. Expeditious laboratory assessment, including possible allograft biopsy, can confirm the diagnosis of rejection, and an appropriate adjustment can be made in the immunosuppressant regimen. If immunosuppression is stopped, acute rejection may occur at any time. Chronic rejection has a time course of years and results in the gradual failure of the transplanted organ over time.12

Drug Toxicity of Immunosuppression

Pharmacology of Immunosuppression

Immunosuppressive therapy requires correctly timed drug combinations to establish a delicate balance between immunosuppression, rejection, and susceptibility to infection. Multiple agents are standard. Regimens are typically transplant center specific, but most include a calcineurin inhibitor, an antimetabolite, and varying dosages of steroids. Recognition of the side effects, toxicities, and potential drug interactions of immunosuppressant medications is an important component in the care of any transplant patient.

A new term, operational tolerance, reflects long-term acceptance of transplanted organs without indefinite immunosuppression.13 Allogeneic bone marrow transplantation from the solid organ donor may facilitate operational tolerance. Successful bone marrow transplantation may revolutionize the treatment of solid organ rejection and immunosuppressive therapy.

Accommodation, an acquired resistance of an organ to immune-mediated damage, has been recognized for more than 20 years. Initially, it was identified in blood group–incompatible kidney transplants that survived and functioned normally in recipients with high titers of anti–blood group antibodies directed against antigens in the grafts. Variable sublethal graft injury induces accommodation, and that may be a dynamic condition, eventuating into tolerance on the one hand and chronic graft injury on the other.14

Because of the toxicities of current immunosuppression medications, improvement in long-term transplantation outcomes may depend on new agents with novel mechanisms of action, devoid of the toxicities.15 Inhibitors of pathways in B-cell and plasma cell activation, including belimumab and atacicept, combat the humoral immune response. Biologic agents for maintenance immunosuppression include monoclonal antibodies and fusion receptor proteins that target molecular pathways and enzymes.

Calcineurin Inhibitors:

Cyclosporine.: A variety of immunosuppression strategies are being tested, but the mainstay of transplant immunosuppression is cyclosporine.16,17 Cyclosporine inhibits both cellular and humoral immunity by binding to cyclophilins, which block cytokine transcription and production, thereby inhibiting lymphocyte signal transduction. The result is a potent immunosuppression of helper-inducer T cells, without affecting the suppressor T-cell subset.16,18 The helper-inducer T cells enhance antibody recognition and production by B cells.

Cyclosporine exhibits dose-related nephrotoxicity, which is additive to other nephrotoxic drugs typically used after transplantation, such as amphotericin B, aminoglycosides, and high-dose trimethoprim-sulfamethoxazole. Cyclosporine causes renal tubular injury and direct renal artery vasospasm in a dose-dependent manner, leading to systemic hypertension in many recipients.16

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