INTRODUCTION
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
GENERAL APPROACH TO EVALUATION
Key historical elements for the management of transplant patients are listed in Table 297-1.
| Historical Item | Significance |
|---|---|
| Recent temperature increase or decrease from baseline | Potential clue to onset of infection or rejection. |
| Changes from baseline function | Decreased urine may signify rejection in renal transplant patients or acute dehydration. Decreased exercise tolerance may signify rejection in heart transplant patients. Change in skin color (jaundice specifically) may signify rejection in liver transplant patients or graft-versus-host disease. |
| Date of transplant surgery | The date from transplant helps to predict typical infections and types of posttransplant complications (i.e., graft-versus-host disease). |
| Graft source for solid-organ transplant, special features of graft if any, prior infections; donor living related vs cadaveric | These details predict the potential for certain infections and rejection. |
| Graft source for hematopoietic stem cell transplant: autologous, degree of match, related donor | These details predict potential graft-versus-host disease. |
| Rejection history | May predict current rejection if similar presentation and difficulty in controlling a current episode of rejection. |
| Recent changes in dosages of antirejection and other medications | Although a planned part of transplant management, rejection is very common when immunosuppression doses are reduced. |
| Chronic infections (CMV, Epstein-Barr virus, hepatitis B and C, other viruses) | History of chronic infections increases the chances that current presentation is an exacerbation. |
| Recent exposure to infections (chickenpox, CMV, tuberculosis) | Increases the chance of current infection. |
| Recent history of compliance with immunosuppressive medications | Noncompliance increases chance of rejection. |
| Recent travel, exposure to persons arriving from countries with endemic infections, exposure to potential foodborne illness or insect vectors | Exposure may predict unusual infections not commonly considered. |
| Complete list of all medications, including over-the-counter medication | Complex drug interactions are common causes of symptoms in transplant patients and must be evaluated. |
| Baseline: blood pressure, body weight, serum creatinine (for renal transplants), and expected levels of immunosuppressive medication | Changes in these parameters may predict rejection or acute illness. |
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
| Examination | Comments |
|---|---|
| Volume status | Check static vital signs, orthostatic blood pressures, and pulse. Use US to assess inferior vena cava diameter as a measure of intravascular volume status. |
| Head, ears, eyes, nose, and throat | Periorbital edema (glomerulonephritis), retina (CMV or toxoplasmic chorioretinitis, Listeria endophthalmitis), sinuses (Staphylococcus aureus, mucormycosis, and invasive fungal disease), mouth (Candida, HSV), neck (meningismus, retropharyngeal abscess), lymphadenopathy (CMV, EBV, hepatitis, posttransplant lymphoproliferative disorder). |
| Lungs | Pneumonia is a common source of infections in transplant patients. Streptococcus pneumoniae and other community-acquired agents are still common sources, but opportunistic infections, such as Pneumocystis jiroveci pneumonia, Aspergillus, tuberculosis, coccidioidomycosis, and viral pneumonias should be suspected. Noninfectious pulmonary infiltrates may also cause dyspnea. |
| Heart | Pericardial friction rubs as a complication of uremia and a wide range of viral infections. New heart murmur can represent infection. |
| Abdomen | Peritonitis without a defined source is one of the most common sites for infection in transplant patients. Right upper quadrant tenderness associated with hepatitis B and C, CMV, and EBV. Varicella-zoster virus causes pancreatitis. If left in place, peritoneal dialysis catheters can be sources of infection. |
| Flank and suprapubic area | The urinary tract was the most common site of infection identified. |
| Graft | Renal graft usually placed in abdominal flap; inspect (look for signs of wound infection), palpate (graft tenderness and swelling are often seen in acute rejection, outflow obstruction, and pyelonephritis), and auscultate (bruits suggest renal artery stenosis and AV malformation or AV fistula). Deep tenderness over liver graft could indicate abscess. |
| Rectal | Perirectal abscess is a common, yet often overlooked, source of infection in transplant patients. |
| Extremities | Access sites for hemodialysis can be sources of infection. Peripheral edema in the transplant patient can represent a number of different etiologies: recurrent versus de novo glomerulonephritis, renal graft failure, liver graft failure, cirrhosis, nephrotic syndrome (from native kidneys), renal vein thrombosis, malnutrition, hypoalbuminemia, and heart failure. |
| Skin | Rashes are commonly seen in graft-versus-host disease, viral syndromes (hepatitis B and EBV), cellulitis from indwelling catheter sites, nocardial cutaneous lesions, and drug reactions. |
| Mental status/neurologic examination | Cyclosporine/tacrolimus neurotoxicity, steroid psychosis, HSV encephalitis, Listeria meningitis/encephalitis, and cryptococcal meningitis. |
DIFFERENTIAL DIAGNOSIS
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.
| Body System | Adverse Effects |
|---|---|
| Constitutional | Fever, rigors, malaise, dizziness, anorexia |
| Ophthalmologic | Blurred vision, conjunctivitis, cataracts, papilledema, blindness |
| Mouth/ears | Gingival hyperplasia, stomatitis, hearing loss, tinnitus |
| Respiratory | Cough, dyspnea, interstitial lung disease, pneumonitis, pleural effusion, noncardiogenic pulmonary edema |
| Cardiovascular | Hypertension, tachycardia, bradycardia, cardiomyopathy, congestive heart failure, hypotension, syncope |
| GI | Nausea, vomiting, diarrhea, epigastric pain, esophagitis, gastritis, hiccups, constipation, hepatotoxicity, ascites, pancreatitis, colonic necrosis, bleeding |
| Musculoskeletal | Myopathy, osteoporosis, tendon rupture |
| Hematologic | Neutropenia, lymphopenia, anemia, thrombocytopenia, bleeding, thrombosis |
| Renal | Nephrotoxicity, oliguria, dysuria, renal failure |
| Neurologic | Headache, vertigo, paresthesias, tremors, convulsions, agitation, neuropathy, confusion, generalized weakness, leukoencephalopathy, encephalopathy, cerebral edema |
| Skin | Alopecia, hirsutism, thickening, thinning, necrosis, edema |
| Metabolic | Electrolyte disturbances (sodium, potassium, calcium, magnesium, phosphorus), fluid retention, hypercholesterolemia, hyperlipidemia, hyperglycemia, hypoglycemia |
| Endocrine | Adrenal suppression |
| Immunogenic | Susceptibility to infection, acute allergic reactions, anaphylaxis |
| Concern | Signs and Symptoms |
|---|---|
| Edema and other swelling | Assess symmetry, pain, color, temperature, and active range of motion. Suspect infection, orthopedic conditions, deep vein thrombosis (due to immobility). |
| Skin breakdown | The back, pressure points, heels, elbows, and leg ulcers (due to corticosteroid-induced weakness). |
| Joint range of motion | Shoulders, elbows, fingers, wrists, and knees (may be limited due to steroid-induced weakness or sclerodermatous skin changes). |
| Thoracic constriction | Relatively noncompliant edema like swelling on the chest wall. If present, ask about associated dyspnea on exertion. |
| Abdominal constriction | Firm skin. History of bloating, gas, constipation, diarrhea, nonspecific pains. |
| Sclerodermatous skin | Sclerodermatous skin changes can affect joint mobility and GI and respiratory function. Note the firmness of edema and skin, especially on the thorax and around joints. A firm, soft leather consistency of swelling, tougher than cardiogenic pitting edema, can be a serious problem. Assess for recent-onset dyspnea on exertion. |
| Dehydration | Increased thirst, loss of appetite, chills, fatigue, weakness, skin flushing, dark or decrease volume of urine, dry mouth, tachycardia, weight loss. |
| Electrolyte disturbance | Signs and symptoms of dehydration above, hypotension, headache, bradycardia or tachycardia, irregular heartbeat, tremor, muscle weakness, increased urination, constipation, altered tendon reflexes, mood changes, abdominal pain, weight loss, muscle cramping. |
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.
POSTTRANSPLANT INFECTIONS
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.
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
| Period after Transplant/Conditions | Infection | Comments |
|---|---|---|
| <1 mo: resistant organisms | MRSA Vancomycin-resistant Enterococcus faecalis Candida species (including non-albicans) | Opportunistic infections are generally absent during this period as full effect of immunosuppression not complete. MRSA important in HSCT patients. |
| <1 mo: complications of surgery and hospitalization | Aspiration Catheter infection Wound infection Anastomotic leaks and ischemia C. difficile colitis | Clostridium difficile common during this period. Early graft injuries may abscess. Unexplained early signs of infection such as hepatitis, encephalitis, pneumonitis, or rash may be donor derived. |
| <1 mo: colonization of transplanted organ or HSCT neutropenia | Aspergillus Pseudomonas Klebsiella Legionella | Microbiologic analysis of aspirates or biopsy from surgery essential for therapeutic decisions. |
| <1 mo: HSCT-specific infections | Additional bacterial pathogens: Streptococcus viridans and enterococci Viral infections include respiratory syncytial virus and HSV | Neutropenia and mucocutaneous injury increase risk for HSCT patients. Lungs, bloodstream, and GI tract most commonly affected sites. |
| 1–6 mo: in patients with Pneumocystis jiroveci pneumonia and antiviral (CMV, HBV) prophylaxis | Polyomavirus BK infection, nephropathy C. difficile colitis HCV infection Adenovirus infection, influenza Cryptococcus neoformans infection Mycobacterium tuberculosis infection Anastomotic complications | Activation of latent infections, relapse, residual, and opportunistic infections occur during this period. Viral pathogens and allograft rejection cause the majority of febrile episodes during this period. Polyomavirus BK, adenovirus infections, and recurrent HCV are becoming more common. |
| 1–6 mo: in patients without prophylaxis | Pneumocystis Infection with herpesviruses (HSV, varicella-zoster virus, CMV, Epstein-Barr virus) HBV infection Infection with Listeria, Nocardia, Toxoplasma, Strongyloides, Leishmania, Trypanosoma cruzi | Discontinuation of prophylaxis at the end of this period may prompt active infection, especially CMV. Graft-versus-host disease and mucocutaneous injury increase risk for HSCT patients. |
| >6 mo: general | Community-acquired pneumonia and urinary tract infections Infection with Aspergillus, atypical molds, Mucor species Infection with Nocardia, Rhodococcus species | Community-acquired organisms dominate during this period. Transplant recipients have a persistently increased risk of infection due to community-acquired pathogens. |
| >6 mo: late viral infections | CMV infection (colitis and retinitis) Hepatitis (HBV, HCV) HSV encephalitis Community-acquired viral infections (severe acute respiratory syndrome, West Nile) JC polyomavirus infection (progressive multifocal leukoencephalopathy) Skin cancer, lymphoma (PTLD) | In some patients, chronic viral infections may cause allograft injury (e.g., cirrhosis from HCV infection in liver transplant recipients, bronchiolitis obliterans in lung transplant recipients, accelerated vasculopathy in heart transplant recipients with CMV infection) or a malignant condition such as PTLD or skin or anogenital cancers. |
The evaluation should include routine testing as well as additional tests based on complaint, history, and physical examination (Table 297-6).14
| Test | Comments |
|---|---|
| CBC | Leukocytosis or left shift of the WBC count may be blunted by immunosuppressive agents. |
| Renal function tests: BUN, creatinine | Essential in the evaluation of renal transplant patients, may help determine dosing of antibiotics in all transplant patients. |
| Liver function tests | May show mild transaminase elevations with cytomegalovirus and Epstein-Barr virus infections, and much higher elevations with hepatotropic viruses such as hepatitis B and C viruses. May be elevated in Legionella infections. |
| C-reactive protein | Significant elevations more likely in infections versus noninfectious infiltrates. |
| Procalcitonin level | Significant elevations more likely in infections versus noninfectious infiltrates. |
| CT of the brain | Focal infections in the brain are much more common in this population, but CT should be used only as clinically indicated. |
