Fear of Rejection: Managing the Transplant Patient in the ED

A 52-year-old male with a history of chronic renal failure presents with fever and abdominal pain for one day. He has no appetite, with one episode of non-bloody, non-bilious vomiting. His vital signs reveal HR 118, BP 90/52, RR 22, T 100.8F, and O2 saturation 97% on room air. As you look at his abdomen, you notice a scar in the right lower quadrant. “Oh yeah, I had a transplant about 3 years ago, and I take this medication for my immune system. I think it’s called Prograf.” 

Introduction
Organ transplantation can significantly improve quality of life and longevity for patients with end-organ failure. The first transplant involved a human kidney in the early 1950’s. Today’s medical technology allows combination organ transplant, with improved survival rates [^1]. In 2013, over 75,000 candidates were listed on the transplant wait list. The most commonly transplanted organ is the kidney (58% of all transplantations), followed by the liver (21%), heart (8%), and lung (5%) [^2-5].

These patients can be challenging to manage, as they are on immunosuppressive medications and have significant anatomic and physiologic variations [^3-6]. Due to these factors, transplant patients may develop a number of complications including infection, medication effects, rejection, and specific complications related to the organ transplant [^3-6].

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The 52-year-old male appears sick with cool extremities. You begin a fluid bolus and obtain laboratory studies including CBC, renal function, urinalysis, Xray, ECG, lactate, and blood cultures. 

Transplant Infection
Several factors increase the risk of infection, with an incidence within the first year post-transplant ranging from 25% to 80% [^4-8]. The primary factor of increased infection risk includes immunosuppression, though the efficacy of immunosuppressive medications has reduced transplant organ rejection [^4-7]. Bacteremia is more common in solid organ transplant patients, usually in association with urinary tract infection (UTI). Fever is the most common sign or symptom, though this is seen in approximately half of patients [^4-6,8-13].

Pearl #1: Fever is present in 50% of transplant infections.

Emergency physicians should consider several aspects in the management of suspected infection, shown in Table 1 below [^4-6,13-19]. Multiple factors determine the net state of immunosuppression including past and current treatments, underlying comorbidities, presence of necrotic tissue or fluid collection, presence of invasive device such as central venous catheter, metabolic disease, and concomitant infection with viruses that possess immunomodulating effects (EBV, CMV, and HIV) [^13-19].

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The timeline from transplantation affects the risk and type of infection, shown in Table 2 below. Infections within one month of transplant are defined as early infections. These are usually nosocomial, due to a surgical site infection, or from the donor organ [^4,5,18-22]. Infection from 1 to 6 months post-transplant, or intermediate, are most commonly due to opportunistic infection. This is the period when immunosuppressive medications alter the patient’s intrinsic immune system [^4-8]. Transplant physicians often maintain the patient on prophylactic antimicrobials during this period to reduce infection [^5-9]. Late infections are those greater than 6 months from transplant, and these are more commonly community infections [^4-10]. Though the timeline affects risk of infection, the etiology of infection is diverse and includes a variety of infections [^4-10].

Pearl #2: Time from transplant predicts the type of infection.

Providers should take several factors into account during the evaluation and management of these patients. Fever is the most common presentation of infection, though it may be absent in half of patients with infection [^4,10-12]. These patients may demonstrate lower temperatures and WBC counts lower than normal patients [^23,24]. However, transplant patients still show a response to infection with an increase in temperature and WBC count, just not to the degree of normal patients’ physiologic response to infection. Patients taking mycophenylate mofetil and azathioprine in particular demonstrate decreased temperatures and WBC counts, with temperatures approximately 37^oC with confirmed infection [^23,24].

Pearl #3: Providers should consider using a lower temperature threshold for fever.

These patients require consultation with their transplant physician as soon as possible. Rapid evaluation and management of the patient is paramount, with careful evaluation for sepsis. Resuscitation with intravenous fluids and broad-spectrum antimicrobials should be started if the patient is in shock, followed by imaging of the transplanted organ (ultrasound, Xray, or CT) [^4-10]. Infectious Disease consultation has been demonstrated to improve mortality [^{4-8, 25].} Testing varies based on the suspected infection, though the gold standard for diagnosis is often biopsy [^4-6]. Table 3 below shows diagnostic testing.

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Pearl #4: Speak with the patient’s transplant physician as soon as possible and begin resuscitation in sick patients. 

The patient has an elevated creatinine with signs of urinary tract infection. You are able to speak with the patient’s transplant physician, who asks for an ultrasound of the graft and renal vasculature. The transplant specialist requests cefepime and vancomycin, which you have already ordered. The patient is admitted to transplant service.

Your next patient is a 32-year-old female with a known cardiac transplant. She presents with dyspnea on exertion and worsening lower extremity edema. Her respiratory rate is mildly elevated at 22/min, though the rest of her vital signs are normal.

Rejection
One of the most feared transplant complications includes rejection, which is a major cause of allograft dysfunction. Patients often do not fully recover from an episode of rejection [^2-5]. Immunosuppressive medications have reduced rejection, though this must be balanced with the risk of infection. Rejection includes several phases, shown in Table 4 below [^26-29].

Several factors affect signs and symptoms including the transplant type and time from operation, shown in Table 5 below. Rejection occurs in 17% in live donor and 20% of deceased-donor renal transplant recipients [^30,31]. Approximately 64% of patients with liver transplant experience rejection within the first 6 weeks, with 23% experiencing rejection after this period [^32]. Cardiac transplant rejection affects 30% [^33]. One third of lung transplant recipients experience rejection in the first year, which may be asymptomatic [^34-36]. All patients require transplant consult, and high dose steroids (methylprednisolone 500 mg to 1000 mg IV) [^4,37,38]. Other medications may be required, as 10% of cases are steroid-resistant [^4,37,38]. The table above displays organ-specific rejection. Testing is specific to the organ, though imaging and biopsy will be required.

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Pearl #5: Rejection depends on the organ type and time from transplant operation. Patients require high dose steroids, with biopsy during admission.

The patient with cardiac transplant is not in respiratory distress. Her BNP returns at 2,542, the ECG shows sinus tachycardia with two p waves per QRS signal, and the chest Xray shows cardiomegaly with pulmonary edema. You order methylprednisolone 1 g IV and admit to the medical ICU after discussion with the patient’s transplant physician and surgeon. 

Medication Effects
Transplant recipients require lifelong immunosuppression to decrease risk of rejection. Regimens consisted of corticosteroids and azathioprine before the 1980’s, after which several other important medications were introduced [^2,4,5]. Optimal regimens vary based on the patient, specific organ transplanted, and time from transplant [^41-44].

Immunosuppression regimens are broken into induction, occurring right after the transplant with the highest rejection rate, and maintenance, which usually occurs after three months from transplant [^43,44]. Many maintenance regimens involve triple therapy up to one year after transplant, with one medication withdrawn after this period (commonly the steroid) [^43,44].

Most patients will present to the ED during the maintenance phase. These medications may have numerous side effects, shown in Table 6 below. Any suspected adverse effect requires transplant consult. Drug levels may be obtained for cyclosporine, tacrolimus, and sirolimus, though these levels may not return while the patient is in the ED [^4,5].

Other effects contribute to significant morbidity and even mortality including metabolic syndrome, coronary artery disease, new malignancy, gout, tendinopathy, and metabolic bone disease [^4,5,48-56]. P-450 effects are also common with certain medications. Any new medication should be discussed with the transplant team, as there are significant interactions with many medications, shown in Table 7 below (click to enlarge) [^4,5,56-58].

Pearl #6: Immunosuppressive medications affect multiple organ systems and possess complex mechanisms and interactions. Before making medication changes, speak with the pharmacist and transplant physician.

Organ-Specific Complications
Each transplanted organ possesses its own anatomic and physiologic intricacies. These organs have specific complications related to the surgical procedure, immunosuppressive medications, and infections. Renal complications post-transplant include infection, vascular obstruction, hematoma, ureteral obstruction, and lymphocele [^59-66]. Patients often present with edema, decreased urine output, and increased serum creatinine. Infection, specifically urinary tract infection, affects close to 80% of patients [^4-7,59-61]. At least two antibiotics should be used for treatment [^5,59,60]. Liver transplant complications include vascular obstruction, biliary conditions (stricture, leak, biliary stone, fluid collection), biloma, and stricture [^4,61,66-69]. Ultrasound can be helpful in evaluating for fluid collections, though ERCP may be needed for stricture evaluation [^61,66-70]. Cardiac transplant is associated with denervation, thus patients often do not present with chest pain in the setting of rejection [^61,70,71]. Edema is more common [^61,70]. Common complications include vasculopathy with accelerated atherosclerosis and cardiac dysrhythmia, with atrial and ventricular dysrhythmias occurring in almost all patients [^72-80]. Direct cardioversion is usually needed for these patients. Atropine will not work in the patient with cardiac transplant, thus necessitating epinephrine, isoproterenol, or norepinephrine [^78-80]. Lung transplant requires the formation of three anastomotic connections [^{61,70,81,82].} Patients may experience obstruction, vascular complications, phrenic nerve dysfunction, and pleural lining complications [^61,80-87]. Airway intervention and bronchoscopy are often needed [^61,82,83].

Pearl #7: Each transplant has specific complications related to anatomy and physiology. Imaging and laboratory studies targeted at the specific organ are a must, along with consultation with the transplant physician and surgeon.

Summary
Transplant patients possess significant variation in anatomy and physiology based on the surgical procedure and medications. Infection is the most frequent complication, classified by several different periods: within one month of transplant, one to six months, and after six months. Rejection occurs in several phases including hyperacute, acute, and chronic. Patient symptoms differ based on the specific organ. Immunosuppressive medication effects are common and have significant interactions with other medications commonly used in the ED. Each organ transplanted has several different complications that may occur. All transplant patients require consultation with the transplant team. Surgical consultation may also be required.

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