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1984 SECTION 26: Special Situations hepatitis C is associated with more deaths in the United States than combined deaths from 60 other infectious diseases.35 For evaluation of a clinical syndrome suggestive of acute hepatitis (e.g., weakness, nausea, fever, abdominal pain, or jaundice), obtain laboratory tests that include serum transaminase levels, bilirubin level, alkaline phosphatase level, prothrombin time, and serologic testing. Many patients can receive an outpatient care plan. Admission criteria include inability to tolerate oral intake, toxicity, and significantly pro longed prothrombin time. Counsel patients about sexual transmission and needle exposure, and encourage informing all sexual and needlesharing partners and household contacts of their exposure. Long-term sequelae of infection include chronic active hepatitis, decompensated cirrhosis, and primary liver cancer. Unfortunately, drug treatment programs often lack adequate fund ing to offer optimal hepatitis B and C prevention, diagnosis, and care. Current hepatitis B virus vaccination rates among injection drug users remain low at 30%. The short- and long-term benefit and cost of antiviral treatment for hepatitis C for both the individual patient who continues to intravenously inject drugs (increasing reexposure or reinfection) and any partners are unclear. 36 Both partners are key in appropriately framed therapeutic discussions.37 OPHTHALMOLOGIC INFECTIONS Ophthalmologic infections in injection drug users are usually the result of hematogenous seeding from a primary source of infection or from opportunistic infections associated with HIV disease. Bacterial endo phthalmitis often presents acutely, with pain, redness, lid swelling, and decrease in visual acuity. Inflammation is usually present in both the anterior and posterior chambers. White-centered, flame-shaped embolic hemorrhages (Roth spots), cotton-wool exudates, and macular holes may be present. S. aureus is the most commonly isolated organism, followed by Streptococcus species. Treatment involves subconjunctival, intravitreal, and systemic antibiotic therapy. Surgical intervention, such as vitrectomy, may be needed. Fungal organisms, often Candida or Aspergillosis , but sometimes rarer organisms such as Torulopsis, Helminthosporium, and Penicillium species, are causes of endophthalmitis among injection drug users, notably from Mexican black tar heroin injection. In injection drug users coinfected with HIV , cytomegalovirus infection, toxoplasmosis retinitis, and choroidal Cryptococcus and Mycobacterium avium-intracellulare complex infections must also be considered. Symptoms include blurred vision, pain, poorly reactive pupil, and decreased visual acuity and can progress over days to weeks. White cotton-like lesions are seen on the choroid retina, with vitreous haziness. Uveitis, papillitis, and vitreitis also have been reported. Microbiologic diagnosis is made from the results of blood and vitreous culture. Treatment includes amphotericin B, amphotericin lipid complex, and fluconazole, with or without intravitreous antifungal therapy and early vitrectomy. 39,40 REFERENCES The complete reference list is available online at www.TintinalliEM.com.

Microbiologic diagnosis is made from the results of blood and vitreous culture. Treatment includes amphotericin B, amphotericin lipid complex, and fluconazole, with or without intravitreous antifungal therapy and early vitrectomy. 39,40 REFERENCES The complete reference list is available online at www.TintinalliEM.com. CHAPTER The Transplant Patient Brit Long Alex Koyfman INTRODUCTION Organ transplantation is growing in frequency, with the first successful kidney transplant in the early 1950s.1,2 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. 3 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 approximately 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. 4 The recent opioid epidemic has produced several chal lenges for the transplant-awaiting population. The increase in opioidrelated deaths has led to an increase in the number of available organs; however, the risk of infection from opioid-related donor organs is slightly higher than from non–opioid substance user donors. The U.S. Public Health Service states that organs obtained from opioid abusers are at slightly increased risk of infection, although recent data suggest these organs can be safely used for transplant. Potential recipients also may suffer from addiction, which is associated with worse outcomes with transplantation. Most transplant patients require lifelong immunosuppression. Transplant patients can develop a number of acute to life-threatening emergencies, including (1) transplant-related infection, (2) medica tion 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. 6 Patients with transplanted organs may present significant challenges due to anatomic and physiologic variations, immunosuppression, complications from transplantation, and comorbidities. 2,6-8 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%). 9-12 Acute graft-versus-host disease is an important complication, especially in those with hema topoietic stem cell transplantation. 13 Coronary artery disease, sudden cardiac death, and heart failure are the result of premature cardiovas cular disease in solid-organ recipients, due to underlying comorbidities and metabolic effects of immunosuppression. 14 Preoperative and regular postoperative cardiovascular assessment identifies risk factors and enables treatment to mitigate risks.  GENERAL APPROACH TO EVALUATION 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). 9-13,16,17 DIFFERENTIAL DIAGNOSIS Consider complications of immunosuppressive medication, infection, solid-organ rejection, and graft-versus-host disease (Tables 297-3 and 297-4).

ion to the chief complaint, present illness, and evidence of complications of the transplant or immunosuppressive medications (Table 297-2). 9-13,16,17 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 cortico steroids, 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 immunosup pression often requires admission when symptoms interrupt mainte nance of medication. Solid-organ rejection and graft-versus-host disease are immunemedicated inflammatory reactions that may present with fever, signs and symptoms, and laboratory and radiographic findings that resemble Tintinalli_Sec26_p1979-2024.indd 1984 8/1/19 1:33 PM

quires admission when symptoms interrupt mainte nance of medication. Solid-organ rejection and graft-versus-host disease are immunemedicated inflammatory reactions that may present with fever, signs and symptoms, and laboratory and radiographic findings that resemble Tintinalli_Sec26_p1979-2024.indd 1984 8/1/19 1:33 PM CHAPTER 297: The Transplant Patient 1985 infection (see later discussions). Infection and rejection (or an exac erbation 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 infections undiagnosed until autopsy. Patients are at increased risk of infection, with an incidence of infection within the first year after transplant of 25% to 80%. 7,18-21 Although immunosuppressive regimens can reduce the risk of rejection, they can also increase risk of infection. The level of immunosuppression depends on current regimen, underlying diseases, presence of necrotic fluid/fluid collection, presence of an indwelling device, metabolic disease, and concomitant viral infection. The time from transplant also affects risk of infection and type of infection. 20-25 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. Solid-organ transplant recipients have risk of bacteremia, often in the setting of urinary tract infection. 10,12,19,21,26,27 CLINICAL FEATURES The most common reason for an ED visit by a transplant recipient is fever. 9-12 Fever may be masked by immunosuppressive agents and TABLE 297-1 Key Historical Elements Specific to Transplant Patients 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-versushost 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.

ase. 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. Abbreviation: CMV = cytomegalovirus. TABLE 297-2 Physical Examination in Transplant Patients 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.

es 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. Abbreviations: AV = arteriovenous; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HSV = herpes simplex virus. Tintinalli_Sec26_p1979-2024.indd 1985 8/1/19 1:33 PM

ogic examination Cyclosporine/tacrolimus neurotoxicity, steroid psychosis, HSV encephalitis, Listeria meningitis/encephalitis, and cryptococcal meningitis. Abbreviations: AV = arteriovenous; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HSV = herpes simplex virus. Tintinalli_Sec26_p1979-2024.indd 1985 8/1/19 1:33 PM 1986 SECTION 26: Special Situations TABLE 297-3 Adverse Reactions to Immunosuppressant Medications 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 TABLE 297-4 Physical Examination Clues to Complications of Medications and Graft-Versus-Host Disease 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 decreased 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. other factors, such as steroids, uremia, and hyperglycemia, and may be absent in half of those with infection. 10 Fever may be due to factors other than infection, such as drug effects, hypersensitivity reaction, rejection, or malignancy. Even a low-grade fever in a transplant patient should prompt an aggressive workup.

ther factors, such as steroids, uremia, and hyperglycemia, and may be absent in half of those with infection. 10 Fever may be due to factors other than infection, such as drug effects, hypersensitivity reaction, rejection, or malignancy. Even a low-grade fever in a transplant patient should prompt an aggressive workup. Although in the setting of infec tion transplant patients demonstrate temperatures lower than those of nontransplant patients,10-12,28 those with transplant still demonstrate a physiologic response to infection (temperature of 37.9°C vs. 38.2°C for transplant vs. nontransplant patients, respectively). Specifically, patients on regimens including mycophenolate mofetil and azathioprine demonstrate decreased temperatures. 28-30 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). 7 The specific site of infection also depends on the trans planted organ. Combining all posttransplant period groups, urinary tract infections (43%) and pneumonia (23%) are likely to be the most common infections. 16 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. DIAGNOSIS AND TREATMENT The evaluation should include routine testing as well as additional tests based on complaint, history, and physical examination (Table 297-6). Leukopenia can represent acute bacterial infection, 10 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. Resuscitation with intravenous fluids and broadspectrum antimicrobials is recommended in patients with sepsis or septic shock. Empiric antimicrobial therapy for transplant patients is outlined in Table 297-7. 32-34 Empiric treatment prior to confirmatory studies should first involve antibacterial agents and then, especially if there is concern for meningitis or encephalitis, antiviral agents such as acyclovir. Discuss treatment of suspected fungal infections or atypical infections with the transplant team. The emergency provider should discuss the case with the patient’s transplant physician, and consultation with infectious disease specialist may improve outcomes and reduce mortality. 2,7,18,19,35  GRAFT-VERSUS-HOST DISEASE Graft-versus-host disease is a major cause of morbidity and mortal ity, affecting approximately 50% of allogeneic hematopoietic stem cell transplantation patients, and is caused by donated T cells attacking antigens on host cells, 36 but it also occurs after small bowel or liver transplantation, as well as transfusion of unirradiated blood products in high-risk groups. 37 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. 38-41 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 com mon symptom) or diarrhea (second most common symptom) should be suspected of having new-onset or an exacerbation of 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 com mon symptom) or diarrhea (second most common symptom) should be suspected of having new-onset or an exacerbation of graft-versus-host disease. 38 The most widely used graft-versus-host prophylaxis includes a combination of a calcineurin inhibitor (e.g., cyclosporine, tacrolimus) with methotrexate. 38 In patients who recover from acute graft-versushost disease, later long-term complications from chronic graft-versushost disease are common. Chronic graft-versus-host disease is a late complication character ized by immune dysregulation (>100 days after transplantation) and is a distinct clinical syndrome from the acute form. 42 It results in severe morbidity, with complications affecting skin (sclerodermatous contractures), muscles (myopathy), bone (osteoporosis), eyes (keratoconjunctivitis sicca), nerves (peripheral neuropathy), and the cardiopulmonary system (physical deconditioning), resembling autoimmune disorders. Risk factors include older age, CMV seropositivity, and a male who received a Tintinalli_Sec26_p1979-2024.indd 1986 8/1/19 1:33 PM

myopathy), bone (osteoporosis), eyes (keratoconjunctivitis sicca), nerves (peripheral neuropathy), and the cardiopulmonary system (physical deconditioning), resembling autoimmune disorders. Risk factors include older age, CMV seropositivity, and a male who received a Tintinalli_Sec26_p1979-2024.indd 1986 8/1/19 1:33 PM CHAPTER 297: The Transplant Patient 1987 TABLE 297-5 Infections Stratified by Post-transplant Period Period After Transplant/Conditions Infection Comments <1 mo: resistant organisms MRSA Opportunistic infections are generally absent during this period as full effect of immunosuppression not complete. MRSA important in HSCT patients. Vancomycin-resistant Enterococcus faecalis Candida species (including non-albicans) <1 mo: complications of surgery and hospitalization Aspiration C. 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. Catheter infection Wound infection Anastomotic leaks and ischemia Clostridium difficile colitis <1 mo: colonization of transplanted organ or HSCT neutropenia Aspergillus Microbiologic analysis of aspirates or biopsy from surgery essential for therapeutic decisions.Pseudomonas Klebsiella Legionella <1 mo: HSCT-specific infections Additional bacterial pathogens: Streptococcus viridans and enterococci Neutropenia and mucocutaneous injury increase risk for HSCT patients. Lungs, bloodstream, and GI tract most commonly affected sites.Viral infections include respiratory syncytial virus and HSV 1–6 mo: in patients with Pneumocystis jiroveci pneumonia and antiviral (CMV, HBV) prophylaxis Polyomavirus BK infection, nephropathy 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. C. difficile colitis HCV infection Adenovirus infection, influenza Cryptococcus neoformans infection Mycobacterium tuberculosis infection Anastomotic complications 1–6 mo: in patients without prophylaxis Pneumocystis 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. Infection with herpesviruses (HSV, varicella-zoster virus, CMV, Epstein-Barr virus) HBV infection Infection with Listeria, Nocardia, Toxoplasma, Strongyloides, Leishmania, Trypanosoma cruzi >6 mo: general Community-acquired pneumonia and urinary tract infections Community-acquired organisms dominate during this period. Transplant recipients have a persistently increased risk of infection due to community-acquired pathogens. Infection with Aspergillus, atypical molds, Mucor species Infection with Nocardia, Rhodococcus species >6 mo: late viral infections CMV infection (colitis and retinitis) 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.

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. 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) Abbreviations: CMV = cytomegalovirus; HBV = hepatitis B virus; HCV = hepatitis C virus; HSCT = hematopoietic stem cell transplant; HSV = herpes simplex virus; MRSA = methicillin-resistant Staphylococcus aureus; PTLD = posttransplantation lymphoproliferative disorder. stem cell transplant from a multiparous woman.43 Management is similar to the acute form with prolonged immunosuppression.44 ACUTE GRAFT-VERSUS-HOST DISEASE The disease is typically characterized by involvement of three dif ferent systems: skin (rash), gastrointestinal, and liver (jaundice, hepatitis). Consider graft-versus-host disease in any patient with a rash. Rash is often misattributed as a drug reaction. 45 The typical rash is maculopapular, frequently demonstrating a brownish hue and slight scaling (Figure 297-1). The rash can be pruritic and painful. The dis tribution 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. 13 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 and may appear green, mucoid, and watery. 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 thrombocyto penia. 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). 36,46 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. 13 Patients may require resuscitation with balanced crystalloids, blood product resuscitation Tintinalli_Sec26_p1979-2024.indd 1987 8/1/19 1:33 PM

s 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. 13 Patients may require resuscitation with balanced crystalloids, blood product resuscitation Tintinalli_Sec26_p1979-2024.indd 1987 8/1/19 1:33 PM 1988 SECTION 26: Special Situations TABLE 297-6 Diagnostic Tests to Consider in the Evaluation of Infections in the Transplant Patient 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. Cyclosporine or tacrolimus level or other levels of immunosuppressants These levels may be deliberately low depending on the desired level of immunosuppression. Bioavailability may be variable. Cultures of mouth, sputum, urine, blood, stool, vascular access, and wound sites Collect as indicated by history and physical. Urine Legionella antigen should be considered before treatment of patients with pneumonia with GI complaints. Bacterial and fungal cultures of blood and urine should be obtained on all patients. Cerebrospinal fluid cultures and antigen tests Collect as indicated by history and physical. Serology: cytomegalovirus, Epstein- Barr virus, hepatitis, toxoplasmosis, cryptococcosis Because viral and fungal cultures are not very sensitive, clinicians should rely on their acumen to order organism-specific antigen assays and antibody titers. When contemplating viral or parasitic infections, these tests should be obtained to allow identification of bacterial, fungal, and viral pathogens. May be useful in patients with diffuse lymphadenopathy. Chest radiograph Infiltrates on chest radiograph may reflect infectious or noninfectious complications of hematopoietic stem cell transplant or organ transplant. Obtain in posttransplant fever to evaluate for source. CT of the chest Patients with evidence of pulmonary infiltrates on chest radiograph or high-resolution CT, but without productive sputum, may ultimately require bronchoscopy with bronchoalveolar lavage and transbronchial biopsy for definitive diagnosis. CT or US to include the graft These scans can be used to identify likely abscess formation or possible anastomotic leaks. Tests after admission Beyond the scope of this chapter, but may include biopsy of the transplanted organ, bronchoalveolar lavage on bronchoscopy, and focused imaging of suspected sites of infection. Creatine kinase May have increased levels in infections with certain organisms, such as Legionella. Urinalysis As dictated by history and examination. Recommended in patients with renal transplant. Lactate Evaluate for severity of illness (sepsis and septic shock). Biopsy Typical standard diagnosis requires biopsy of graft, which is not obtainable in ED but should be discussed with admitting physician. (leukocyte-depleted and irradiated red blood cells), electrolyte replace ment, and broad-spectrum antibiotics.47 Disposition and interval for follow-up are also determined by the transplant team.

standard diagnosis requires biopsy of graft, which is not obtainable in ED but should be discussed with admitting physician. (leukocyte-depleted and irradiated red blood cells), electrolyte replace ment, and broad-spectrum antibiotics.47 Disposition and interval for follow-up are also determined by the transplant team. Survival approaches 50% at 1 year with intensive corticosteroid therapy, with 50% developing chronic disease.41,44,45 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. 48,49 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. POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER Posttransplantation lymphoproliferative disorders consist of lympho mas occurring after organ transplantation, particularly solid-organ and allogeneic hematopoietic stem cell transplants. Posttransplantation lymphoproliferative disorders are associated with poor outcomes and are not uncommon, accounting for up to 21% of all cancers in patients receiving solid-organ transplants. 50,51 The incidence is increasing due to older age of transplant donors and recipients, increasing number of transplants, new immunosuppressive agents, newer types of stem cell transplantation, greater awareness of the disease, and improved diagnosis. 52 Primary risk factors depend on the organ transplanted (kidney transplant has the lowest risk). Specific T-cell depletion procedures display higher risk of posttransplantation lymphoproliferative disorders in the setting of haploidentical allogeneic hematopoietic stem cell transplantation, as does the specific immunosuppressive regimen used. Age greater than 50 years and Epstein-Barr virus seronegative status before transplantation elevate the risk of posttransplantation lymphoproliferative disorders. 52-55 The incidence of posttransplantation lymphoproliferative disorders follows a bimodal curve, with an initial spike during the first and second year and a second spike 5 to 15 years after transplantation. The presentation varies, ranging from asymptomatic to fulminant organ failure or tumor lysis syndrome. Posttransplantation lymphoproliferative disorders dis play a high incidence of extranodal involvement often involving the GI tract (up to 30% of cases), solid allografts (15%), and the CNS (5% to 20%). 51,56,57 Diagnosis typically includes histopathologic examination based on six subclasses. However, this is not available in the ED. Treat ment varies but typically involves reduction of immunosuppression, surgical extirpation, local radiation, rituximab, chemotherapy, cellular immunotherapy, and/or stem cell transplantation. TRANSPLANTATION MEDICATION EFFECTS Transplant patients are typically on extensive medication regimens including immunosuppression. In the 1980s, this consisted of cortico steroids and azathioprine, but current regimens are more extensive, with many options dependent on the patient, specific organ transplant, and time from transplant (Table 297-9). TRANSPLANTATION REJECTION A feared complication other than infection includes graft rejection, as many do not fully recover from an episode of rejection. Immunosup pressive regimens have reduced the risk of rejection, although this is balanced with the risk of infection.

nsplant, and time from transplant (Table 297-9). TRANSPLANTATION REJECTION A feared complication other than infection includes graft rejection, as many do not fully recover from an episode of rejection. Immunosup pressive regimens have reduced the risk of rejection, although this is balanced with the risk of infection. Several phases of rejection are present including hyperacute (minutes to hours after transplant due to preexisting antibodies), acute (within the first 6 months due to acute cellular rejection or humoral rejection), and chronic (months to years after transplant due to antibody and cell-mediated rejection). Presentations of rejection are demonstrated in Table 297-10. Tintinalli_Sec26_p1979-2024.indd 1988 8/1/19 1:33 PM

o preexisting antibodies), acute (within the first 6 months due to acute cellular rejection or humoral rejection), and chronic (months to years after transplant due to antibody and cell-mediated rejection). Presentations of rejection are demonstrated in Table 297-10. Tintinalli_Sec26_p1979-2024.indd 1988 8/1/19 1:33 PM CHAPTER 297: The Transplant Patient 1989 TABLE 297-7 Empiric Antimicrobial Therapy Condition Antimicrobial Agent Comments* All patients Discuss agent(s) with transplant team. The transplant team caring for the patient should always be consulted as soon as possible; however, in certain life-threatening situations, empiric broad-coverage therapy may be indicated immediately. Suspected infection site based on history and physical examination Site-specific agents are preferable if predicted by initial findings, balanced by known pathogens as listed in Table 297-5. The urgency for treatment should be based on the patient’s presenting condition; bacterial infections are the most aggressive organisms requiring coverage, but some fungal infections may yield sepsis. In general, broad coverage for any suspected site infection is recommended initially pending cultures and further workup to define noninfectious causes of fever. Neutropenia in the absence of symptoms suggesting site-specific infection Third-generation cephalosporin such as ceftazidime or a carbapenem plus coverage for MRSA below. Multiple alternative agents used, including an aminopenicillin plus a β-lactam inhibitor such as piperacillin-tazobactam or cefepime. Monotherapy has fewer complications, but concern for MRSA remains high. Addition of antiviral and antifungal agents should be at the discretion of the transplant team. Suspected MRSA Vancomycin In the majority of patients, MRSA infection should be seriously considered as a potential cause of infection, pending cultures. Linezolid is an alternative antibiotic. Parasitic infections Trimethoprim-sulfamethoxazole after discussion with transplant team Consider Toxoplasma gondii, Pneumocystis jiroveci. Viral infections Ganciclovir or valganciclovir for CMV, acyclovir for herpes simplex and varicella-zoster Consider treatment for CMV pneumonia, CMV chorioretinitis, CNS or disseminated herpes simplex or varicella-zoster. Fungal infections Discuss with transplant team; agent depends on site and severity of illness Consider Aspergillus, Candida albicans, Cryptococcus neoformans. Abbreviations: CMV = cytomegalovirus; MRSA = methicillin-resistant Staphylococcus aureus. *Standard doses apply but may be altered by transplant team recommendations.  SPECIFIC TYPES OF TRANSPLANTATION RENAL TRANSPLANTATION Renal transplantation is the preferred treatment for end-stage renal disease. Kidneys obtained from deceased or living donors are most commonly placed in the recipient’s pelvis, with the ureters anasto mosed to the bladder. 3,6,8,58 Vascular complications that occur following renal transplantation include renal artery stenosis, allograft infarction, arteriovenous fistulas, pseudoaneurysm, graft hematoma, and renal artery or vein thrombosis. Nonvascular complications include ureteral obstruction, urine leak, periallograft fluid collections (hematomas, lymphoceles, and abscesses), neoplasms, GI complications, and post transplant lymphoproliferative disease. 8 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 and use of an imaging contrast agent that may affect renal function (including gadolinium-based contrast agents) should be discussed with the patient’s transplant team.

, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Medication changes and use of an imaging contrast agent 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, which is often elevated in the setting of trans plant infection or rejection. 59 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, which is one of the most common complications with renal transplant. 60,61 However, pyuria may present with rejection. 2,60,61 FIGURE 297-1. Rash of acute cutaneous graft-versus-host disease. The maculopapular lesions have acquired a brownish hue, and there is slight scaling. [Reproduced with permission from Wolff KL, Johnson R, Suurmond R: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 6th ed. © 2009, McGraw-Hill, Inc., New York.] TABLE 297-8 Significant Risk Factors for the Development of Transfusion- Associated Graft-Versus-Host Disease •   Congenital and acquired immunodeficiency syndromes •   History of bone marrow (stem cell) transplantation, whether allogeneic or autologous •   Transfusions from blood relatives (“directed donation”) •   Transfusions with fresh whole blood •   Premature infants receiving any sort of transfusion •   Human leukocyte antigen–matched platelet transfusions •   Hodgkin’s disease, even when in remission •   Leukemia not in remission •   Patients treated with purine analogues; the effects of fludarabine and cladribine (2-CdA) persist for a year Tintinalli_Sec26_p1979-2024.indd 1989 8/1/19 1:33 PM

sort of transfusion •   Human leukocyte antigen–matched platelet transfusions •   Hodgkin’s disease, even when in remission •   Leukemia not in remission •   Patients treated with purine analogues; the effects of fludarabine and cladribine (2-CdA) persist for a year Tintinalli_Sec26_p1979-2024.indd 1989 8/1/19 1:33 PM 1990 SECTION 26: Special Situations TABLE 297-9 Transplantation Medications Medication Mechanism Adverse Effect Cyclosporine (Sandimmune , generic) Calcineurin inhibitor; decreases T lymphocyte activity and IL-2 function Acute/chronic nephrotoxicity, electrolyte derangements (hyperkalemia, hypomagnesemia), gout, hemolytic-uremic syndrome, gingival hyperplasia, hirsutism, hypertension, hyperlipidemia Tacrolimus (Prograf  ) Calcineurin inhibitor; inhibits T lymphocyte activity and IL-2 function Similar to cyclosporine Neurotoxicity (headache, tremor, paresthesias, seizures), hair loss instead of hirsutism, less hypertension/hyperlipidemia Azathioprine (Imuran ) Blocks nucleotide production for immune cell replication Bone marrow suppression, macrocytosis, anemia, hepatotoxicity, pancreatitis Mycophenolate mofetil (CellCept  ) Cytostatic effect on B and T cells; decreases proliferation by inhibiting nucleotide synthesis Abdominal pain, decreased oral intake, nausea/vomiting, diarrhea, anemia, leukopenia, thrombocytopenia Corticosteroids Impairs phagocyte function Attenuates production of proinflammatory mediator Decreases T-cell activity Decreases cell signal transduction Weight gain, cataracts, acne, skin thinning, bruising, osteoporosis, GI bleeding, hyperglycemia, hyperlipidemia, psychologic effects, cushingoid appearance Sirolimus (Rapamune  ) Blocks mTOR receptor and immune cell signal transduction, reducing B- and T-cell activity Thrombocytopenia, leukopenia/anemia (less common), diarrhea, mucosal irritation, buccal ulceration, interstitial pneumonitis, hyperlipidemia Polyclonal antibodies (antithymocyte γ-globulin) Antilymphocyte antibody Used for immunosuppression when nephrotoxic agent is held Used for treatment of corticosteroid resistant rejection Fever, serum sickness, anaphylaxis, anemia, thrombocytopenia Monoclonal antibodies (OKT3, IL-2 receptor antibody) Antilymphocyte antibody Used for prophylaxis against rejection in early period Used for immunosuppression when nephrotoxic agent is held Used for treatment of corticosteroid resistant rejection OKT3: During first 3 days of therapy, may have headache, aseptic meningitis, encephalopathy, seizures, nausea, vomiting, diarrhea, pulmonary edema, nephrotoxicity IL-2 receptor antibodies have rare adverse effects such as anaphylaxis Abbreviations: IL-2 = interleukin-2; mTOR = mammalian target of rapamycin. TABLE 297-10 Presentations of Transplant Rejection Transplant Organ Symptoms/Signs Management Renal Many asymptomatic Symptoms: •  Hypertension •  Fever,  malaise, oliguria, graft pain, and tenderness over site •   Worsening renal function with decreased urine output and rising serum creatinine Acute rise in serum creatinine; electrolyte abnormalities. US may demonstrate increased graft size, loss of corticomedullary junction, prominent hypoechoic pyramids. Renal Doppler studies may demonstrate elevated vascular resistance indices. Biopsy needed during admission. Liver Fever, malaise, abdominal pain, hepatosplenomegaly, ascites

creatinine; electrolyte abnormalities. US may demonstrate increased graft size, loss of corticomedullary junction, prominent hypoechoic pyramids. Renal Doppler studies may demonstrate elevated vascular resistance indices. Biopsy needed during admission. Liver Fever, malaise, abdominal pain, hepatosplenomegaly, ascites Laboratory abnormalities: elevated liver function tests and bilirubin. US of graft and vasculature may find focal lesion or vascular abnormality. Biopsy needed during admission. Cardiac Dyspnea at rest/exertion, orthopnea, palpitations, near-syncope/syncope, peripheral edema, or GI symptoms with right heart involvement Chest pain is absent due to denervation during surgery Dysrhythmias common Cardiac troponin and B-type natriuretic peptide often elevated. ECG may demonstrate T-wave/ST-segment changes. Echocardiogram with systolic/diastolic dysfunction. Chest radiograph may demonstrate findings of congestive heart failure. Biopsy needed during admission. Lung Shortness of breath and cough most common Lung examination variable: clear lung fields, crackles, or decreased breath sounds May demonstrate stridor or wheezes May present with respiratory distress or failure Eosinophilia suggestive on CBC with differential. Normal chest radiograph is not reliable to rule out disease. Chest CT often required. Pulmonary function testing not helpful in differentiating infection and rejection. Effusion requires thoracentesis. Bronchoscopy and biopsy needed during admission. 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 US is the best test to detect urinary obstruction. Renal graft US can also be useful in patients suspected of having pyelonephritis, vascular abnormalities (stenosis, thrombosis, pseudoaneurysm, hematoma, and arteriovenous fistula), perinephric abscess, urine leak, wound infection, or an episode of rejection. Tintinalli_Sec26_p1979-2024.indd 1990 8/1/19 1:33 PM

uction. Renal graft US can also be useful in patients suspected of having pyelonephritis, vascular abnormalities (stenosis, thrombosis, pseudoaneurysm, hematoma, and arteriovenous fistula), perinephric abscess, urine leak, wound infection, or an episode of rejection. Tintinalli_Sec26_p1979-2024.indd 1990 8/1/19 1:33 PM CHAPTER 297: The Transplant Patient 1991 CT angiography may be used to diagnose vascular complication such as hematoma, artery stenosis, and vascular thrombosis.62-64 MRI can be helpful in evaluating hematomas and other fluid collec tions, vascular abnormalities, and small infarcts caused by medicationinduced vasculitis. Magnetic resonance angiography has the advantage of requiring either no contrast material or a gadolinium chelate that is less nephrotoxic than other agents. 2 However, gadolinium-based contrast agents can cause acute renal failure in up to 3.5% of patients with underlying chronic renal insufficiency. 65 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 297-11 when evaluating possible graft dysfunction or even a small increase in serum creatinine. 66,67 LIVER TRANSPLANTATION The most common reasons for ED visits are fever and abdominal pain.11 Hepatosplenomegaly, ascites, and malaise may also occur, specifically with rejection. 2 Complications include bleeding, rejection, and infection, as well as biliary, vascular, and wound complications. Bacterial infection may accompany acute rejection. 68 Specific complications of liver trans plantation are listed in Table 297-12. Obtain a CBC with platelet count and differential; serum chemistries, including electrolytes, BUN, creati nine, 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 radiograph and abdominal US 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). 69-73 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. CT with contrast may be required for diagnosis of vascular complica tion or biliary stricture. 2,69,70 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 hepaticoje junostomy or those who cannot have endoscopic retrograde cholan giopancreatography must undergo percutaneous cholangiography. 72-75 Early, broad-spectrum prophylactic antibiotics should be administered before any biliary tract manipulation. Discuss treatment and disposition with the transplant team. LUNG TRANSPLANTATION Lung transplantation involves three anastomoses: airway (the most vulnerable to complication, 2% to 33%), pulmonary arterial, and pulmonary vein to the left atrium. 3,6,76-78 Fever, cough, and increasing dyspnea are common reasons for ED visits in lung transplant patients.

with the transplant team. LUNG TRANSPLANTATION Lung transplantation involves three anastomoses: airway (the most vulnerable to complication, 2% to 33%), pulmonary arterial, and pulmonary vein to the left atrium. 3,6,76-78 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 β 2-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. 79 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. TABLE 297- 11 Differential Diagnosis of Renal Allograft Dysfunction Differential Disorder Comments Mechanical Presents with decreased urine output. At US, a urine leak (i.e., urinoma) appears as a well-defined, anechoic fluid collec tion with no septations that increases in size rapidly. Requires consultation with urology and transplant physician. Obstruction typically requires Foley catheter placement, followed by stent placement. Complications of surgery Ureteral obstruction Urine leak: urinoma, ascites, or abscess Lymphocele Results from perivascular lymphatic vessel leakage, which forms a collection of lym phatic fluid in up to 15% of patients within the first 3 months of transplant. Vascular The transplanted kidney is usually placed extraperitoneally in the right iliac fossa. End-to-side anastomosis to the external iliac vasculature provides circulation. Color duplex imaging of the renal artery and vein is helpful in assessing renal vascular stenosis or thrombosis. CT angiography can be utilized as well. Treatment often includes thrombolysis for vascular stenosis/ thrombosis and surgery for peritransplant hematoma. Renal artery stenosis or thrombosis (12%) Renal vein thrombosis Renal artery and renal vein thromboses are uncommon; they usually occur in the first month after transplant. Peritransplant hematoma Glomerulonephritis Infection Urinary tract infections are the most com mon source of bacteremia in renal trans plant recipients, and infectious diseases are the second leading cause of death in this population. See “Posttransplant Infections” section. At least two antibiotics should be used for treatment of urinary tract infection. Urinary tract infection Interstitial nephritis from polyoma BK virus, cytomegalovirus, herpes viruses 1 and 2, and adenovirus Rejection Most common presentation of rejection in renal transplant patients is hypertension and falling urine output, but rejection may be asymptomatic. Fever, pain, malaise, oliguria, and site tenderness may occur. Comparison of creatinine at the time of presentation to prior levels is critical, as creatinine elevation is common. Fever may be a presentation of rejection.

l transplant patients is hypertension and falling urine output, but rejection may be asymptomatic. Fever, pain, malaise, oliguria, and site tenderness may occur. Comparison of creatinine at the time of presentation to prior levels is critical, as creatinine elevation is common. Fever may be a presentation of rejection. Hyperacute Acute Late (recurrent acute) Chronic cellular Chronic humoral Recurrent pyelonephritis/vesicoureteral reflux Common problem threatening graft and patient survival Nephrotoxic agents Drug serum levels do not correlate well with the degree of renal damage. NSAIDs are contraindicated in this group. Avoid contrast agents if possible. Aminoglycosides, fluoroquinolones, cidofovir, foscarnet, sulfonamides, calcineurin inhibitors (cyclosporin A and tacrolimus), NSAIDs, gadolinium-based and some other contrast agents, herbal preparations Noncompliance with Diabetes often follows transplantation; marked exacerbations in hypertension are frequently associated with graft failure. Medications Management of risk factors such as diabetes and hypertension Chronic allograft nephropathy Common cause of graft dysfunction Tintinalli_Sec26_p1979-2024.indd 1991 8/1/19 1:33 PM

ce with Diabetes often follows transplantation; marked exacerbations in hypertension are frequently associated with graft failure. Medications Management of risk factors such as diabetes and hypertension Chronic allograft nephropathy Common cause of graft dysfunction Tintinalli_Sec26_p1979-2024.indd 1991 8/1/19 1:33 PM 1992 SECTION 26: Special Situations TABLE 297-12 Complications of Liver Transplantation Complication Comments Bleeding complications GI bleeding should be managed in the usual fashion but may signal graft dysfunction. Biliary complications Bile leaks present early, and biliary strictures present late (>2 mo from transplant). In both cases, cholestatic liver enzymes are elevated, typically with right upper quadrant pain (more pronounced with bile leak). Jaundice and fever may also be present. US with Doppler of hepatic vessels displays sensitivity of 38%–66%. If US is negative, cholangiogram may be needed, with patients often requiring endoscopic retrograde cholangiography (ERC). Strictures come in two forms, with anastomotic strictures occurring within the first year after surgery. Imaging includes CT, US, and MRI, with treatment including ERC and stent placement. Bile leaks occur in up to 25% of patients, with ERC needed for diagnosis and treatment (stent). Bilomas can be diagnosed with US and managed with drainage and antibiotics. Bile leak Biliary stricture (anastomotic and nonanastomotic) Biloma Hepatic artery complications Vascular complications affect the hepatic artery or portal vein most commonly. CT with contrast (if renal function adequate) or US is helpful in the evaluation of these conditions. CT with IV contrast has greater sensitivity for arterial stenosis, but US displays a sensitivity up to 90% for venous thrombosis. Mortality reaches 80% for portal vein thrombosis if not diagnosed. For thrombosis, thrombolysis may be required. Pseudoaneurysms are typically treated with transcatheter embolization. Hepatic artery thrombosis Hepatic vein thrombosis Portal vein complications Pseudoaneurysm Rejection Early alkaline phosphatase and bilirubin levels rise, followed by a rise in aspartate aminotransferase and alanine aminotransferase. US may reveal focal lesion or vascular abnormality. Biopsy is needed during admission. Neurologic complications Causes include hemorrhage, cerebrovascular infarct, cerebral abscess, hypertensive encephalopathy, osmotic demyelination syndrome, and sinus thrombosis. MRI is best for evaluation. Malignancy Increased risk for squamous cell carcinoma, lymphomas, and posttransplant lymphoproliferative disorder. present in respiratory distress or failure. Eosinophilia may be present with rejection. Radiographic abnormalities are less common >6 weeks after transplant, and an acute rejection episode actually may be “radio graphically 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. 79,95,96 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.

ments 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 TABLE 297-13 Time Course of Lung Transplant Complications Days After Transplant Complications Most Commonly Seen in Each Time Period 0–3 d Hemorrhage from technical/mechanical problems Reperfusion injury Dysrhythmia 3 d–1 mo Infection: bacterial, Mycoplasma, community respiratory viruses Rejection Anastomotic failure Pulmonary embolism Muscle weakness Dysrhythmia Starting at 1 mo Rejection Obliterative bronchiolitis Infection Bacterial, fungal, community respiratory viral (can occur at any later time) Mycoplasma 0–4 mo Mycobacteria after 4 mo Other Cytomegalovirus infection and Pneumocystis jiroveci pneumonia may occur any time, but are more common when prophylaxis is not being given, especially when such treatment has been recently discontinued. TABLE 297-14 Indications for Hospital Admission for Lung Transplant Patients Pretransplant patients •  Respiratory  failure •  Infiltrate •  Systemic  infection •  Decompensated  congestive heart failure or pulmonary edema •  Pneumothorax Posttransplant patients •  Respiratory  failure •   Acute rejection •   Rapidly progressive airflow limitation (forced expiratory volume in 1 second decreases >10% over 48 h) •   Infiltrate •   Systemic infection •   Febrile neutropenia •   Pneumothorax  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 can continue throughout the lifetime of the patient ( Table 297-13). 80,81 Airway complications often occur with dyspnea, wheezing, or stridor or postobstructive pneumonia. A variety of mechanisms of airway obstruction may occur, such as bronchial stenosis, tracheobronchomalacia, hyperplastic granulation tissue, and bronchial necrosis. Diag nosis typically includes chest CT and bronchoscopy. 76-78,82-84 Vascular complications (stenosis, kinking, and thrombus formation) are not as frequent but have poor outcomes and can present with hypoxemia, dyspnea, hypotension, and edema. 85-87 US may reveal right-sided cardiac dysfunction with vascular complications, although definitive diagnosis includes CT angiography. Phrenic nerve dysfunction is more common in heart-lung transplant (40% of cases) as compared to lungonly transplant (3% to 9%). 88-91 Indications for hospital admission are listed in Table 297-14. 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, although the chest radiograph may be nor mal. Lung auscultation is often variable, with examination revealing clear lung fields, crackles, or decreased breath sounds. 92-95 Patients may Tintinalli_Sec26_p1979-2024.indd 1992 8/1/19 1:33 PM

ratory volume in 1 second (10% or more), and infiltrates on the chest radiograph, although the chest radiograph may be nor mal. Lung auscultation is often variable, with examination revealing clear lung fields, crackles, or decreased breath sounds. 92-95 Patients may Tintinalli_Sec26_p1979-2024.indd 1992 8/1/19 1:33 PM CHAPTER 297: The Transplant Patient 1993 patients97,98 (Tables 297-5 and 297-13). 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. 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 lead ing causes of death in those age 60 to 69 years are graft failure and infection. 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. 100-103 The donor heart is implanted with its own sinus node intact to pre serve 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 indepen dently. 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 errone ously 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. Patients may present with a variety of symptoms in the setting of rejection including dyspnea, orthopnea, syncope, and edema, but chest pain is typically absent due to denervation during surgery. 92 Chest radiograph, ECG, and further evaluation are based on complications of cardiac transplantation (Table 297-15) and underlying patient comorbidities, especially in elderly transplant recipients. Cardiac biomarkers are typically elevated in rejection, with findings consistent with heart failure on echocardiogram and chest radiograph. CORNEAL TRANSPLANTATION Corneal transplantation (penetrating keratoplasty) is the most com mon form of human solid-tissue transplantation and is a key element in vision restoration.

ardiac biomarkers are typically elevated in rejection, with findings consistent with heart failure on echocardiogram and chest radiograph. CORNEAL TRANSPLANTATION Corneal transplantation (penetrating keratoplasty) is the most com mon form of human solid-tissue transplantation and is a key element in vision restoration. Unlike other tissue and organ transplants, corneal allotransplantation usually does not require systemic or permanent FIGURE 297-2. ECG in a heart transplant patient. ECG demonstrates donor and recipient P waves ( arrowhead = donor P wave; arrow = recipient P wave). FIGURE 297-3. Chest radiograph of healthy post–heart transplant patient with typical postoperative changes, including “cardiomegaly” due to transplantation of a heart from a donor who was larger than the recipient. Tintinalli_Sec26_p1979-2024.indd 1993 8/1/19 1:33 PM