Chapter 99. The Transplant Patient

Management of the transplant patient in the emergency department can be divided into 3 general areas: disorders specific to the transplanted organ; disorders common to all transplant patients due to their immunosuppressed state or antirejection medication; and disorders unrelated to their transplant, yet special care is required due to their medications or altered physiology. Disorders specific to the transplanted organ are manifestations of acute rejection, surgical complications specific to the procedure performed, and altered physiology (most important in cardiac transplantation). The most common presentations of transplant patients to the emergency are: infection (39%) followed by noninfectious GI/GU pathology (15%), dehydration (15%), electrolyte disturbances (10%), cardiopulmonary pathology (10%) or injury (8%), and rejection (6%). Before prescribing any new drug for a transplant recipient, the treatment plan should be discussed with a representative from the transplant team.

Predisposing factors to infections posttransplant include ongoing immunosuppression in all patients and the presence of diabetes mellitus, advanced age, obesity, and other host factors. Table 99-1 lists the broad array of potential infections and the time after transplant they are most likely to occur.

Clinical Features

The initial presentation of a potentially life-threatening infectious illness may be quite subtle in transplant recipients. As many as 50% of transplant patients, with serious infections, will not have fever. A nonproductive cough with little or no findings on physical examination may be the only clue to emerging Pneumocystis jiroveci pneumonia or cytomegalovirus (CMV) pneumonia. Urinary tract infections are a very common cause of fever in this group of patients.

Diagnosis and Differential

Blood counts, inflammatory markers, baseline tests of renal and liver function may be helpful in this group of complex patients. The threshold for obtaining chest radiographs for these patients should be low. Cultures of all appropriate fluids, including blood, are essential before (or simultaneous with) initiating antimicrobial therapy. Central nervous system infections such as meningitis (Listeria monocytogenes and cryptococci) should be considered. Complaints of recurrent headaches, therefore, with or without fever, should be investigated vigorously, first with a structural study to exclude a mass lesion (central nervous system lymphomas occur with increased frequency, too) and then with a lumbar puncture. Liver transplant patients are especially susceptible to intraabdominal infections during the first postoperative month. Lung transplant patients are especially prone to pneumonia. Cardiac transplant patients may develop mediastinitis during the first postoperative month.

Emergency Department Care and Disposition

1. Drug choice, dose, and ultimate management should be accomplished in consultation with the transplant team. The following recommended drugs are listed for the event of urgent patient need due to instability or delay in reaching the transplant team.

2. For skin and superficial wounds, a broad spectrum antibiotic plus an agent specific to MRSA is recommended. Therefore, imipenem 500 milligrams IV every 6 hours, or meropenem 1 gram IV every 8 hours, or piperacillin/ tazobactam 3.375 IV every 6 hours can be initiated plus vancomycin 1 gram IV every 12 hours or linezolid 600 milligrams IV every 12 hours are recommended.

3. Pneumonia may be caused by a wide variety of organisms from common to atypical to opportunistic. Treatment options include imipenem 500 milligrams IV every 6 hours, meropenem 1 gram IV every 8 hours, cefotaxime 1 to 2 grams IV every 6 to 8 hours plus gentamicin 1 to 2 milligrams/kilogram IV every 8 hours, or piperacillin/tazobactam 3.375 grams IV every 6 hours. Add MRSA specific therapy, listed above, and fungal therapy, listed below, if suspected.

4. Intraabdominal infection may be due to enteric gram-negative aerobic, obligate anaerobic bacilli and facultative bacilli, and enteric gram-positive streptococci. Recommended coverage is to combine metronidazole 500 milligrams IV every 12 hours plus one of the following agents: imipenem 500 milligrams IV every 6 hours, meropenem 1 gram IV every 8 hours, doripenem 500 milligrams IV every 8 hours, piperacillin/tazobactam 3.375 grams IV every 6 hours. Ampicillin-sulbactam is not recommended for use because of high rates of resistance to this agent among community-acquired E coli.

5. Meningitis is frequently due to L monocytogenes, and patients with suspected meningitis should be treated cefotaxime 2 grams IV every 4 to 6 hours plus vancomycin 1 gram IV every 12 hours. The addition of vancomycin should be considered.

6. The initial treatment of suspected fungal disease is fluconazole 400 milligrams daily IV; amphotericin B 0.7 milligram/kilogram/d IV, has been a mainstay of treatment, but has more toxicity than fluconazole. Oral or esophageal Candida, treat with fluconazole 200 milligrams day 1, then 100 milligrams PO daily.

7. Suspected CMV disease is treated with ganciclovir, with a dose of 5 milligrams/kilogram IV twice daily; in bone marrow transplant patients, add immunoglobulin.

8. Varicella and herpes simplex virus are typically treated with acyclovir 800 milligrams IV 5 times a day for dissemination or ocular involvement. Acyclovir has renal excretion, and the dose must be adjusted for renal insufficiency. Alternatives include valacyclovir 1000 milligrams every 8 hours, and famciclovir 500 milligrams every 8 hours.

9. Epstein-Barr virus is typically treated with a reduction in the immunosuppression regimen. Both acyclovir and ganciclovir have also been used, but not routinely.

10. Treatment of choice for Pneumocystis jiroveci pneumonia starts with prednisone 80 milligrams/day followed immediately by antimicrobial therapy. First choice is trimethoprim/sulfamethoxazole (TMP-SMX), TMP 15 milligrams/kilogram/d IV divided every 8 hours while critically ill. Oral therapy is TMP-SMX double strength (DS) 2 tablets PO every 8 hours for 3 weeks of total therapy. Pentamidine 4 milligrams/kilogram/d IV or IM for 3 weeks, or clindamycin 600 milligrams IV plus primaquine 30 milligrams orally daily are reserved as alternative therapies if TMP-SMX is not tolerated.

11. Toxoplasmosis can be treated initially with pyrimethamine 200 milligrams PO initially then 50 to 75 milligrams PO daily plus sulfadiazine 1 to 4 grams PO daily plus folinic acid 10 milligrams PO daily.

12. Urinary tract infections (see Chapter 54), invasive gastroenteritis (due to Salmonella, Campylobacter, and Listeria, see Chapter 37 and Chapter 96), and diverticulitis (see Chapter 44) can be treated with the usual antimicrobial agents.

Therapeutic immunosuppression is accompanied by a number of adverse effects and complications. These adverse effects are typically gradual in onset, but may be life threatening such as pancreatitis, bleeding, hypoglycemia or hyperglycemia, bradycardia or tachycardia, hyperkalemia, hypertension or hypotension, cardiotoxicity, pulmonary edema, seizures, thromboembolic events, and thrombocytopenia. Side effects such as fever or rigors may also be confused for life-threatening infections. A headache syndrome often indistinguishable from migraine is common in transplant recipients and usually develops within the first 2 months of immunosuppression. An important differential must include infectious causes and malignancy when headache first presents and usually requires computed tomography of the head with subsequent biochemical analysis of cerebrospinal fluid. As the number of immunosuppressive drugs has increased dramatically, a complete listing of adverse effects is beyond the scope of this manual. The reader is referred to the parent textbook, referenced at the end of this manual chapter, or to web resources, or a personal digital assistant, for a more complete listing of side effects of these medications.

Any illness that prevents transplant patients from taking or retaining their immunosuppressive therapy warrants hospital admission for IV therapy, preferably at a transplant center. Starting even simple medications can precipitate complications. For example, nonsteroidal anti-inflammatory drugs may increase nephrotoxicity. In general, any new medications should be discussed with a representative of the patient's transplant team.

Transplantation results in a denervated heart that does not respond with centrally medicated tachycardia in response to stress or exercise but does respond to circulating catecholamines and increased preload. Patients may complain of fatigue or shortness of breath with the onset of exercise, which resolves with continued exertion as an appropriate tachycardia develops.

The donor heart is implanted with its sinus node intact to preserve normal atrioventricular conduction. The normal heart rate for a transplanted heart is 90 to 100 beats/min. The technique of cardiac transplantation also results in the preservation of the recipient's sinus node at the superior cavoatrial junction. The atrial suture line renders the 2 sinus nodes electrically isolated from each other. Thus, electrocardiograms frequently will have 2 distinct P waves. The sinus node of the donor heart is easily identified by its constant 1:1 relation to the QRS complex, whereas the native P wave marches independently through the donor heart rhythm.

Clinical Features

Because the heart is denervated, myocardial ischemia does not present with angina. Instead, recipients present with heart failure secondary to silent myocardial infarctions or with sudden death. Transplant recipients who have new onset shortness of breath, chest fullness, or symptoms of congestive heart failure should be evaluated, in routine fashion with an electrocardiogram and serial cardiac enzymes levels, for the presence of myocardial ischemia or infarction.

Although most episodes of acute rejection are asymptomatic, symptoms can occur. The most common presenting symptoms are dysrhythmias and generalized fatigue. The development of atrial or ventricular dysrhythmia in a cardiac transplant recipient (or congestive heart failure) must be assumed to be due to acute rejection until proven otherwise. In children, rejection may present with low-grade fever, fussiness, and poor feeding.

Emergency Department Care and Disposition

1. Rejection: Management of acute rejection is methylprednisolone 1 gram IV after consultation with a representative from the transplant center. Treatment for rejection without biopsy confirmation is contraindicated except when patients are hemodynamically unstable.

2. Dysrhythmias: If patients are hemodynamically compromised by dysrhythmias, empiric therapy for rejection with methylprednisolone 1 gram IV may be given after consultation. Atropine has no effect on the denervated heart; isoproterenol is the drug of choice for bradydysrhythmia in these patients. Patients who present in extremis should be treated with standard cardiopulmonary resuscitation measures.

3. Hypotension: Low-output syndrome, or hypotension, should be treated with inotropic agents such as dopamine or dobutamine when specific treatment for rejection is instituted.

4. Hospitalization: Transplant patients suspected of having rejection or acute illness should be hospitalized, preferably at the transplant center, if stable for transfer.

Clinical Features

Clinically, the patient suffering rejection may have a cough, chest tightness, fatigue, and fever (> 0.5°C above baseline). Acute rejection may manifest with frightening rapidity, causing a severe decline in patient status in only 1 day. Isolated fever may be the only finding. Spirometry may show a 15% drop in forced expiratory volume in 1 second, the patient may be newly hypoxic, and examination may show rales and adventitious sounds. Chest radiograph may demonstrate bilateral interstitial infiltrates or effusions but may be normal when rejection occurs late in the course. The longer a patient is from transplant, the less classic a chest radiograph may appear for acute rejection. Infection, such as interstitial pneumonia, may present with a clinical picture similar to acute rejection. Diagnostically, bronchoscopy with transbronchial biopsy is usually needed not only to confirm rejection but also to exclude infection.

Two late complications of lung transplant are obliterative bronchiolitis and posttransplant lymphoproliferative disease (PTLD). Obliterative bronchiolitis presents with episodes of recurrent bronchitis, small airway obliteration, wheezing, and eventually respiratory failure. PTLD is associated with Epstein-Barr virus and presents with painful lymphadenopathy and otitis media (due to tonsillar involvement) or may present with malaise, fever, and myalgia.

Diagnosis and Differential

Evaluation of the lung transplant patient should include chest radiograph, pulse oximetry, arterial blood gas analysis (if CO2 retention is suspected), spirometry, complete blood cell count, serum electrolytes, creatinine and magnesium levels, and appropriate drug levels.

Emergency Department Care and Disposition

1. Rejection: After consultation with the transplant center representative, and infection is excluded, methylprednisolone 500 to 1000 milligrams IV should be given for acute rejection. Patients who have a history of seizures associated with the administration of high-dose glucocorticoids also will need concurrent benzodiazepines to prevent further seizure episodes.

2. Late complications: Obliterative bronchiolitis is treated with increased immunosuppression including high-dose steroids, whereas PTLD is treated with reduced immunosuppression and other therapy such as rituximab. These decisions should be made in consultation with specialists from the transplant center.

Clinical Features

Diagnosis and treatment of acute rejection is most critical. Without timely recognition and intervention, allograft function may deteriorate irreversibly in a few days.

Renal transplant recipients, when symptomatic from acute rejection, complain of vague tenderness over the allograft (in the left or right iliac fossa). Patients also may describe decreased urine output, rapid weight gain (from fluid retention), low-grade fever, and generalized malaise. Physical examination may disclose worsening hypertension, allograft tenderness, and peripheral edema. The absence of these symptoms and signs, however, does not exclude the possibility of acute rejection. With improved methods of maintenance immunosuppression, the only clue may be an asymptomatic decline in renal function.

Diagnosis and Differential

Even a change in creatinine levels from 1.0 milligrams/dL to 1.2 or 1.3 milligrams/dL may be important. When such changes in creatinine levels are reproducible, a careful workup consists of complete urinalysis, possibly renal ultrasonography, and levels of immunosuppressive drugs if available, in addition to a careful history and examination. It is critical to interpret changes in renal function in the context of prior data (eg, trends of recent serum creatinine levels, recent history of rejection, or other causes of allograft dysfunction). Evaluation should consider the multiple etiologies of decreased renal function in the renal transplant recipient. The 2 most common causes, apart from acute rejection causing an increase in creatinine, are volume contraction and cyclosporine-induced nephrotoxicity.

Emergency Department Care and Disposition

1. Rejection: After consultation with the transplant center representative, treatment of allograft rejection consists of high-dose glucocorticoids, typically methylprednisolone 500 milligrams IV.

Clinical Features

Although frequently subtle in presentation, a syndrome of acute rejection includes fever, liver tenderness, lymphocytosis, eosinophilia, liver enzyme elevation, and a change in bile color or production. In the perioperative period, the differential diagnosis must include infection, acute biliary obstruction, or vascular insufficiency. Diagnosis can be made with certainty only by hepatic ultrasound and biopsy, which usually requires referral back to the transplant center for management and follow up.

Two possible surgical complications in liver transplant patients are biliary obstruction or leakage and hepatic artery thrombosis. Biliary obstruction follows 3 typical presentations. The most common is intermittent episodes of fever and fluctuating liver function tests. The second is a gradual worsening of liver function tests without symptoms. Third, obstruction may present as acute bacterial cholangitis with fever, chills, abdominal pain, jaundice, and bacteremia. It can be difficult to distinguish clinically from rejection, hepatic artery thrombosis, CMV infection, or a recurrence of a preexisting disease, especially hepatitis.

If a biliary complication is suspected, all patients should have a complete blood count; serum chemistry levels; liver function tests; basic coagulation studies; and lipase levels; cultures of blood, urine, bile, and ascites, if present; chest radiograph; and abdominal ultrasound. Ultrasound looks for the presence of fluid collections, screens for the presence of thrombosis of the hepatic artery or portal vein, and identifies any dilatation of the biliary tree. Alternatively, abdominal computed tomography can be used.

Biliary leakage is associated with 50% mortality. It occurs most frequently in the third or fourth postoperative week. The high mortality may be related to a high incidence of concomitant hepatic artery thrombosis, infection of leaked bile, or difficult bile repair when the tissue is inflamed. Patients most often have peritoneal signs and fever, but these signs may be masked by concomitant use of steroids and immunosuppressive agents. Presentation is signaled by elevated prothrombin time and transaminase levels and little or no bile production, but this complication also may present as acute graft failure, liver abscess, unexplained sepsis, or a biliary tract problem (leak, obstruction, abscess, or breakdown of the anastomosis).

Emergency Department Care and Disposition

1. Rejection: After consultation with the transplant center representative, acute rejection is managed with a high-dose glucocorticoid bolus of methylprednisolone 500 to 1000 milligrams IV.

2. Surgical complications are best managed at the transplant center. Biliary obstruction is managed with balloon dilatation, and all patients should receive broad spectrum antibiotics against gram-negative and gram-positive enteric organisms, such as metronidazole 500 milligrams IV every 12 hours plus one of the following agents: imipenem 500 milligrams IV every 6 hours, or piperacillin/tazobactam 3.375 grams IV every 6 hours. Biliary leakage is treated with reoperation, and hepatic artery thrombosis is treated with retransplantation.

Hematopoietic stem cell transplant (HSCT) is performed for a variety of conditions, include hematopoietic malignancies, severe anemia, and other conditions. The most common complication of HSCT is graft-versus-host disease, affecting approximately 50% of HSCT patients.

Clinical Features (Graft‐versus-Host Disease)

A HSCT recipient presenting to the ED with nonspecific rash (see Fig. 99-1) should be suspected of having graft-versus-host disease. The rash may be pruritic or painful, frequently demonstrating a brownish hue and slight scaling. 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, skin involvement is erythrodermic or may show bullae formation. Mucositis has been reported to occur in 35% to 70% of patients. As many as 90% of patients undergoing combined chemotherapy and radiotherapy develop severe skin disease.

The second most common presentation is gastrointestinal with diarrhea. Upper GI symptoms such as anorexia, nausea, and emesis are common. The patient may develop painful cramping, ileus, and, sometimes, life-threatening hemorrhage from the colon.

Diagnosis and Differential (Graft‐versus-Host Disease)

The diagnosis of graft-versus-host disease is made on clinical grounds initially. The patient with serious GI hemorrhage in the early posttransplant period may have coagulation deficits, especially thrombocytopenia. The differential diagnosis of GI bleeding in this setting includes all the usual causes of GI bleeding in addition to infection (viral, fungal, or bacterial). Liver involvement presents with hyperbilirubinemia and increases in alkaline phosphatase and transaminase levels.

Emergency Department Care and Disposition

1. Most patients with graft-versus-host disease will need supportive care in consultation with the patient's transplant team for management including possible admission or transfer to the transplant center.

2. Initiation of prednisone 60 milligrams PO daily, or methylprednisolone at 1 to 2 milligrams/kilogram IV daily until clinical improvement is seen is the usual management.

3. If other immunosuppressants that have recently been tapered or discontinued are, generally, increased or reinstituted.