Chapter 297: The Transplant Patient

As of the beginning of 2013, there were 76,047 active candidates waiting for solid-organ transplants in the United States, with the kidney transplant waitlist being the largest at 57,903 candidates.¹ The kidney is the most commonly transplanted organ (58%), followed by liver (21%), heart (8%), lung (5%), pancreas (5%), and, less commonly, combined organ transplants and intestine transplants. Annually, there are around 18,000 hematopoietic stem cell transplants in the United States, with about one third of these transplants being allogenic transplants and two thirds being autologous transplants.²

Most transplant patients require lifelong immunosuppression. Transplant patients can develop a number of acute to life-threatening emergencies, including (1) transplant-related infection, (2) medication side effects, (3) rejection, (4) graft-versus-host disease, and (5) postoperative complications or complications of altered physiology secondary to the transplanted organ. Transplant patients may also have common medical problems that require unique management. Adverse outcomes often are directly proportional to increasing age of the recipient and the donor organ.³

The most common acute disorders prompting ED visits are infection (39%) followed by noninfectious GI/GU pathology (15%), dehydration (15%), electrolyte disturbances (10%), cardiopulmonary pathology (10%) or injury (8%), and rejection (6%).^4,5,6,7 Acute graft-versus-host disease is an important complication, especially in those with hematopoietic stem cell transplantation.⁸ Coronary artery disease, sudden cardiac death, and heart failure are results of premature cardiovascular disease in solid-organ recipients, due to underlying comorbidities and metabolic effects of immunosuppression.⁹ Preoperative and regular postoperative cardiovascular assessment identifies risk factors and enables treatment to mitigate risk effects.¹⁰

HISTORY AND COMORBIDITIES

Key historical elements for the management of transplant patients are listed in Table 297-1.

PHYSICAL EXAMINATION

Direct the physical examination to the chief complaint, present illness, and evidence of complications of the transplant or immunosuppressive medications (Table 297-2).^{4,5,6,7,8,11,12}

Consider complications of immunosuppressive medication, infection, solid-organ rejection, and graft-versus-host disease (Tables 297-3 and 297-4). Chronic immunosuppressant medications, including corticosteroids, cause a wide range of physical changes evident on physical examination. Medication changes should be made by, or in consultation with, the patient's transplant team. Outpatient or inpatient management depends on the severity of illness; the need for ongoing immunosuppression often requires admission when symptoms interrupt maintenance of medication.

Solid-organ rejection and graft-versus-host disease are immune-medicated inflammatory reactions that may present with fever, signs and symptoms, and laboratory and radiographic findings that resemble infection. Infection and rejection (or an exacerbation of graft-versus-host disease) can occur simultaneously, and treatment should be started for both. When suspecting acute rejection or acute graft-versus-host disease, consult the transplant team about treatment. Typically, high-dose corticosteroids are given, but the steroid, the dose, and the duration of therapy should be confirmed.

Infections account for a large number of deaths in transplant patients, with many undiagnosed until autopsy. Viral and bacterial illnesses may occur concurrently. Febrile episodes in the early phase after allogenic stem cell transplantation are likely related to infections secondary to neutropenia. Immunosuppression-induced blunting of the inflammatory response may mask the classic signs, symptoms, and laboratory markers of infection if the patient presents early in the course of the illness. Later in the course of infection, patients may present with more advanced ominous signs such as seizure, obtundation, coma, and cardiac arrest.

CLINICAL FEATURES

The most common reason for an ED visit by a transplant recipient is fever.^4,5,6,7 Fever may be masked by immunosuppressive agents and other factors such as steroids, uremia, and hyperglycemia, and may be absent in half of those with infection.⁵ Fever may be due to factors other than infection, such as drug effects, hypersensitivity reaction, rejection, or malignancy. Fever in a transplant patient should prompt an aggressive workup, even if low grade.

Signs and symptoms of infection depend on the type of infection and can, in part, be predicted by the time frame since the transplant (Table 297-5).¹³ Combining all posttransplant period groups, urinary tract infections (43%) and pneumonia (23%) are likely to be the most common infections.¹¹ In contrast, a study of 238 ED presentations of febrile pediatric heart transplant patients found pneumonia in 24%, bacteremia in 3%, cellulitis in 2%, and urinary tract infection in 1%; the majority had a negative workup.¹²

DIAGNOSIS AND TREATMENT

The evaluation should include routine testing as well as additional tests based on complaint, history, and physical examination (Table 297-6).¹⁴

Leukopenia can represent acute bacterial infection,⁵ and leukopenia with an increase in atypical lymphocytes is commonly seen with viral infections, especially cytomegalovirus. Pulmonary infections that are encountered frequently include Pneumocystis jiroveci, Nocardia, Legionella pneumophila, and Aspergillus; these require special stains and studies for accurate diagnosis.

Treatment recommendations should be determined by careful analysis of each individual patient for potential atypical infections requiring specific coverage. Empiric antimicrobial therapy for transplant patients is outlined in Table 297-7.^15,16,17 Empiric treatment prior to confirmatory studies centers first on antibacterial agents, and then, especially if there is concern for meningitis/encephalitis, on antiviral agents such as acyclovir. Discuss treatment of suspected fungal infections or atypical infections with the transplant team.

Graft-versus-host disease is a major cause of morbidity and mortality affecting approximately 50% of allogeneic hematopoietic stem cell transplantation patients,¹⁸ but it also occurs after small bowel or liver transplantation.¹⁹ Hyperacute graft-versus-host disease is an unusual and severe form of acute graft-versus-host disease. Onset occurs in the first week after hematopoietic stem cell transplantation and is characterized by fever, generalized erythroderma, severe hepatitis, fluid retention, widespread inflammation, and shock.²⁰

Acute graft-versus-host disease is classified as appearance of the disease up to 100 days after transplant. A well-appearing hematopoietic stem cell transplantation recipient with a nonspecific rash (most common symptom) or diarrhea (second most common symptom) should be suspected of having new-onset or an exacerbation of graft-versus-host disease.²⁰ The most widely used graft-versus-host prophylaxis includes a combination of a calcineurin inhibitor (e.g., cyclosporine, tacrolimus) with methotrexate.²⁰ In patients who recover from acute graft-versus-host disease, later long-term complications from chronic graft-versus-host disease are common.

Chronic graft-versus-host disease is a late complication characterized by immune dysregulation.²¹ It results in severe morbidity, with complications affecting skin (sclerodermatous contractures), muscles (myopathy), bone (osteoporosis), nerves (peripheral neuropathy), and the cardiopulmonary system (physical deconditioning).²²

ACUTE GRAFT-VERSUS-HOST DISEASE

Consider graft-versus-host disease in any patient with a rash. Rash is often misattributed as a drug reaction. The typical rash is maculopapular, frequently demonstrating a brownish hue and slight scaling (Figure 297-1). The rash can be pruritic and painful. The distribution varies greatly but often affects palms and soles initially, and later progresses to cheek, ears, neck, trunk, chest, and upper back. In the more severe forms, erythroderma or bullae develop.⁸ Mucositis has been reported to occur in 35% to 70% of patients.

Diarrhea, GI bleeding, or hepatic dysfunction can occur. Diarrhea, with or without upper GI symptoms such as anorexia, nausea, and emesis, is common. Symptoms include painful cramping, ileus, and, sometimes, life-threatening hemorrhage from the colon. Hepatic involvement is characterized by increase in liver function studies. GI hemorrhage in the early posttransplant period may be a result of coagulation abnormalities, especially thrombocytopenia. The differential diagnosis of GI bleeding in this setting includes all the usual causes of GI bleeding in addition to bleeding due to acute graft-versus-host disease–related damage to colonic tissues and infection (viral, fungal, or bacterial).^18,23 Diagnosis requires endoscopy.

Treatment is directed by the transplant team, typically PO prednisone or IV methylprednisolone, at 1 to 2 milligrams/kg daily, and possibly adjustment of other immunosuppressant doses.⁸

Disposition and interval for follow-up are also determined by the transplant team.

TRANSFUSION-ASSOCIATED GRAFT-VERSUS-HOST DISEASE

Most living cells that are in transfused blood survive for no more than a few days or weeks. However, in some patients, transfused cells engraft, expand, and circulate. When immunocompetent T lymphocytes engraft in an immune-suppressed patient, transfusion-associated graft-versus-host disease may occur and is almost always fatal.^24,25 It is possible to avoid transfusion-associated graft-versus-host disease by irradiating blood products before transfusion. Patients with immunocompromise or other risk factors (Table 297-8) should receive irradiated blood products.

RENAL TRANSPLANTATION

Renal transplantation is the preferred treatment for end-stage renal disease. Vascular complications that occur following renal transplantation include renal artery stenosis, allograft infarction, arteriovenous fistulas, pseudoaneurysm, and renal vein thrombosis. Nonvascular complications include ureteral obstruction, urine leak, periallograft fluid collections (hematomas, lymphoceles, and abscesses), neoplasms, GI complications, and posttransplant lymphoproliferative disease.²⁶ The major causes of renal transplant loss are death from vascular, malignant, or infectious disease, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Medication changes, as well as imaging contrast agent use that may affect renal function (including gadolinium-based contrast agents), should be discussed with the patient's transplant team.

DIAGNOSTIC TESTING

Table 297-6 lists recommendations on diagnostic testing in transplant patients, including renal transplant patients. The serum creatinine level is the most valuable prognostic marker of graft function at all times after transplantation and should be obtained whenever renal failure or infection is suspected. The urinalysis provides important clues to acute changes in graft viability. Red blood cell casts and proteinuria are commonly seen in recurrent or de novo glomerulonephritis. The presence of WBCs, bacteria, and nitrites is helpful in diagnosing urinary tract infections. Proteinuria may signal rejection, drug toxicity, glomerular disease, or other graft nephropathy, although proteinuria from a remaining native kidney should also be considered. Obtain cyclosporine or tacrolimus blood levels for all patients on these medications. Contact the patient's transplant team regarding abnormal drug levels, because low drug levels are sometimes deliberately used to reduce side effects.

IMAGING

Ultrasonography is the best test to detect urinary obstruction. Renal graft ultrasonography can also be useful in patients suspected of having pyelonephritis, vascular abnormalities (stenosis, thrombosis, pseudoaneurysm, and arteriovenous fistula), perinephric abscess, urine leak, wound infection, or an episode of rejection.

MRI can be helpful in evaluating hematomas and other fluid collections, vascular abnormalities, and small infarcts caused by medication-induced vasculitis. Magnetic resonance angiography has the advantage of requiring either no contrast material or a gadolinium chelate that is less nephrotoxic than other agents. However, gadolinium-based contrast agents can cause acute renal failure in up to 3.5% of patients with underlying chronic renal insufficiency.²⁷ Therefore, the patient's transplant team should be consulted before using gadolinium-based contrast agents.

GRAFT DYSFUNCTION AND FAILURE

Chronic renal dysfunction precedes the majority of graft failures. Acute renal failure in transplant patients is defined as a 20% rise from baseline serum creatinine levels, as opposed to a 50% rise in other patients with acute renal failure. Consider the conditions described in Table 297-9 when evaluating possible graft dysfunction or even a small increase in serum creatinine.^28,29

LIVER TRANSPLANTATION

The most common reasons for ED visits are fever and abdominal pain.⁶ Complications include bleeding, rejection, and infection, as well as biliary, vascular, and wound complications. Bacterial infection may accompany acute rejection.³⁰ Specific complications of liver transplantation are listed in Table 297-10. Obtain a CBC with platelet count and differential; serum chemistries, including electrolytes, BUN, creatinine, basic coagulation studies, liver function tests, amylase, and lipase levels; and cultures of blood, urine, bile, and ascites. Radiographic testing as indicated may include chest x-ray and abdominal ultrasonography with Doppler flow studies. US with Doppler can identify fluid collections, thrombosis of the hepatic artery or portal vein, and dilatation of the biliary tree (although the absence of biliary dilatation does not exclude obstruction or other posttransplantation pathology). With partial obstruction, the intrahepatic ductal system often does not appear to be dilated appreciably by US. With complete obstruction, duct dilation is usually seen. Patients often require cholangiography for complete evaluation. Patients with choledochocholedochostomy may be best evaluated by endoscopic retrograde cholangiopancreatography because it permits both a radiographic diagnosis and the potential for nonoperative intervention. Patients with a Roux-en-Y hepaticojejunostomy or those who cannot have endoscopic retrograde cholangiopancreatography must undergo percutaneous cholangiography. Early, broad-spectrum prophylactic antibiotics should be administered before any biliary tract manipulation. Discuss treatment and disposition with the transplant team.

LUNG TRANSPLANTATION

Fever, cough, and increasing dyspnea are common reasons for ED visits in lung transplant patients. Important clinical features to note are the respiratory rate, pulse oximetry measurement, and physical findings of cyanosis, diaphoresis, use of accessory muscles, signs of congestive heart failure, and adequacy of peripheral perfusion. Obtain a chest radiograph and arterial blood gas analysis when adequacy of ventilation is in question. Give β₂-agonists and anticholinergics as indicated. Signs of infection often overlap with the signs and symptoms of rejection, and the management of infection is quite different from that of rejection. A drop in the forced expiratory volume in 1 second of >10% warrants clinical investigation, but pulmonary function testing cannot distinguish between acute rejection, infection, and nonimmunologic causes of respiratory dysfunction such as airway stenosis.³¹ Therefore, bronchoscopy is required for specific diagnosis. Lung transplant patients can deteriorate very quickly in the absence of the proper therapy. Thus, it is common practice to cover both infection and rejection until additional histopathologic and culture results are obtained.³²

COMPLICATIONS OF LUNG TRANSPLANTATION

Complications occur most frequently in the first year but can occur at any time starting from the first few weeks after transplant and continue throughout the lifetime of the patient (Table 297-11).^32,33 Indications for hospital admission are listed in Table 297-12.

Acute rejection is common and may occur three to six times in the first postoperative year. After the first year, the frequency of acute rejection decreases, but it can occur for several years after transplant. Signs of rejection include cough, chest tightness, increase or decrease in temperature from baseline of >0.28°C (0.5°F), hypoxemia, decline in forced expiratory volume in 1 second (10% or more), and infiltrates on the chest radiograph. Radiographic abnormalities are less common >6 weeks after transplant, and an acute rejection episode actually may be "radiographically silent" after this. Discuss treatment with the transplant team. If the maintenance immunosuppressant regimen has been tapered, it can be very helpful to return to pretaper dosages. In addition, high-dose corticosteroids are often used to treat acute rejection. The usual dosing regimen is 15 milligrams/kg of IV methylprednisolone each day for 3 consecutive days. After the corticosteroid bolus, if the maintenance prednisone had been tapered, increasing the prednisone to 1 milligram/kg/d and tapering over the next 10 days may be helpful.³¹ Clinical response to treatment is gauged by improvements in oxygenation, spirometry, and radiographic appearance and typically occurs within 24 to 48 hours after treatment is initiated. Failure to improve should suggest infection as an alternative diagnosis. After clinical improvement, the maintenance dose of prednisone is increased, with a slow taper back to baseline.

Pulmonary infections from bacteria, fungi, or viruses are the most common causes of morbidity and mortality in lung transplant patients^34,35 (Tables 297-5 and 297-11). Lung transplant patients are at risk for pneumonia because of colonization of the recipient's airway in the setting of transplantation for bronchiectasis and cystic fibrosis and at risk of aspiration in the presence of gastroesophageal reflux disease.³³ Antibiotic selection is best left to the lung transplant specialist.

CARDIAC TRANSPLANTATION

Cardiac transplantation has been applied successfully to patients of all ages, from newborns through persons in their late 60s. Heart transplantation is indicated for patients with end-stage heart failure not remediable by standard medical or surgical therapy. Many in the latter group will have undergone previous coronary artery bypass or valve surgery or been bridged on mechanical assist devices. The leading causes of death in those age 60 to 69 are graft failure and infection.³⁶

The success of a heart transplantation operation depends on the ability of the denervated heart to support the normal circulation. The lack of sympathetic and parasympathetic innervation does, however, induce an altered physiologic state. The denervated heart has a normal sinus rhythm with a heart rate between 90 and 100 beats/min. Denervation results in the absence of the initial centrally mediated tachycardia in response to stress or exercise, but the heart remains responsive to circulating catecholamines. Thus, the cardiac response to stress or exertion is blunted. With proper conditioning, patients are able to resume normal activity levels, including vigorous exercise, following transplantation.

The donor heart is implanted with its own sinus node intact to preserve normal atrioventricular conduction. The technique of cardiac transplantation also results in preservation of the recipient's sinus node at the superior cavoatrial junction, and the two sinus nodes remain electrically isolated from each other. Thus, ECGs frequently will have two distinct P waves (Figure 297-2). The sinus node of the donor heart is easily identified by its constant 1:1 relationship to the QRS complex, whereas the native P wave marches through the donor heart rhythm independently. The presence of the two separate P waves may lead to confusion about the patient's rhythm, mistakenly interpreting sinus rhythm as second-degree heart block. The ECGs may also be interpreted erroneously as showing atrial fibrillation, atrial flutter, or frequent premature atrial complexes. Some patients may have evidence of "cardiomegaly" related to the transplantation of a heart from a donor who was larger than the recipient (Figure 297-3). Clinical evaluation is based on the reason for the ED visit. Chest x-ray, ECG, and further evaluation are based on complications of cardiac transplantation (Table 297-13) and underlying patient comorbidities, especially in elderly transplant recipients.

CORNEAL TRANSPLANTATION

Corneal transplantation (penetrating keratoplasty) is the most common form of human solid tissue transplantation. Unlike other tissue and organ transplants, corneal allotransplantation usually does not require systemic or permanent immunosuppression. Reasons for graft failure include corneal graft rejection (30.9%), corneal endothelial cell failure (21.0%), glaucoma (8.5%), and other causes (26.2%).^37,38 Ophthalmology consultation is required for any change in visual acuity or other ocular signs or symptoms in a patient with a corneal transplant.

Corneal graft rejection is a specific process in which a graft that has been clear suddenly develops graft edema with anterior segment inflammatory signs. Rejection can occur at any time starting at 10 days after transplant. The inflammatory process starts at the graft margin nearest to the most proximal blood vessels and then moves toward the center to involve the entire graft.³⁷ Signs and symptoms include eye pain, photophobia, corneal or scleral injection, or decreased visual acuity. Examination may reveal unilateral anterior chamber reaction with keratic precipitate or corneal edema in a previously clear graft. Late graft failure can present with gradual onset of graft edema with no associated inflammation or keratic precipitates. Treatment includes topical or systemic steroids, cycloplegics, and immunosuppressive drugs such as local and systemic cyclosporine A and tacrolimus.

Wound dehiscence can occur early or late after corneal transplantation, as a result of infection or after eye trauma. Trauma may be unrecognized or be a result of events such as motor vehicle airbag deployment or a fall with the patient's glasses impacting the eye. There may be globe rupture, slight separation of part of the suture line, or just broken sutures.

Viral,³⁷ bacterial,³⁹ or fungal⁴⁰ infection can threaten the transplanted cornea. In patients with a history of herpetic keratitis, consider recurrence and examine with fluorescein for characteristic corneal staining and signs of anterior chamber inflammation.³⁷ Ophthalmology consultation is needed for diagnosis and treatment.