PRACTICE UPDATES.  TRANSPLANT EMERGENCIES PART I: INFECTION, REJECTION, AND MEDICATION EFFECTS. SEPTEMBER 5, 2016 BRIT LONG Tomado de Emdocs

Case
A 42-year-old male with a history of chronic renal failure presents with fever and abdominal pain for one day. He states he has felt nauseous and has had no appetite. His vital signs reveal HR 108, BP 110/72, RR 22, T 100.8F, and O2 97% on RA. As you look at his abdomen before palpating, you notice a scar in the right lower quadrant. “Oh yeah, I had a transplant about 3 years ago, and I take a medication for my immune system. I think it’s called Prograf.”
 Introduction
Organ transplantation is becoming more common, as it 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, and today’s medical technology allows combination organ transplant, with improved survival rates.1 In 2013, over 75,000 candidates were placed on the wait list. The kidney is the most common transplanted organ (58%), followed by the liver (21%), heart (8%), and lung (5%).2-4
These patients can be challenging to manage, as they are on immunosuppressive medications and have significant anatomic and physiologic variations.3-5 Transplant patients may develop a significant number of complications including infection, medication effects, rejection, and specific complications related to the transplanted organ.3-5 This is the first of a 2-part series detailing transplant complications. This post will discuss infection, rejection, and medication side effects. Part II will discuss several organ-specific complications.
Transplant Infection
The incidence of infection within the first year post-transplant is between 25% and 80%.5-10 Although the increasing efficacy of immunosuppressive medications has dramatically reduced rejection, these medications directly increase the risk for infection.8-10 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, seen in approximately half of patients.7,10-14
Several key considerations for transplant patients include the need for increased suspicion of infection, especially with immunosuppression, shown in table 1.5,8,16-22 Multiple factors determine the net state of immunosuppression including past and current treatments, underlying diseases, presence of necrotic tissue or fluid collections, invasive device presence, metabolic disease, and concomitant infection with viruses that possess immunomodulating effects.16-22
 
Transplant Infection Considerations

– Diverse etiology of organisms

– Inflammatory responses associated with infection are often impaired by immunosuppressive therapy, resulting in decreased symptoms and atypical clinical and radiologic results
– Serologic testing cannot be relied on in the ED
– Altered anatomy may modify signs of infection, necessitating imaging of involved organ
– Antimicrobial regimen must be broad and is more complex due to medication interactions
– Increased antimicrobial resistance may be present
– Surgical consultation may be needed for intervention of localized infection where antimicrobial agents alone are not effective
Table 1– Considerations for infections in transplant patients
 
The timeline from transplantation affects the risk and type of infection, shown in Table 2. The etiology of infection is diverse and may include community-acquired infections, opportunistic infections, donor-derived infections, and nosocomial infections.5-7,10 Early infections, defined as within 1 month of transplant, are usually nosocomial, surgical site infection, or from the donor organ.5,23-26 Infection from 1 to 6 months post-transplant, also called intermediate, are most commonly due to opportunistic organisms, as immunosuppressive medications begin to take action.5-7 Transplant physicians often maintain the patient on prophylactic antimicrobials during this time.5-7,10 Late infections are those greater than 6 months from transplant and are commonly community-acquired infections.5-10
 
Transplant Period Infection

Early: First month after transplantation – Donor derived: Donor-derived bacteria (MRSA, VRE, tuberculosis), fungi (Candida), and parasite (toxoplasmosis, Chagas disease)

– Nosocomial/Surgery-related: Aspiration pneumonia, surgical site infection, urinary tract infection, superinfection of graft tissue, vascular access infection, C. difficile colitis
Intermediate: One to six months after transplantation

 
– Opportunistic organisms: Pneumocystis jirovecii, Histoplasma, Coccidioides, Cryptococcus, Hepatitis B/C, BK polyomavirus, Kaposi’s sarcoma, Cytomegalovirus, Tuberculosis, Epstein-Barr virus (EBV)

– Surgical site infections may also arise in this period
– Reactivation of dormant host infections (CMV, HZV, HSV, EBV)
Late: Greater than 6 months after transplantation – Community-acquired infections: Respiratory viruses, Pneumococcus, Legionella, Listeria, Influenza, EBV

Table 2 – Infection based on transplant period
 
During evaluation, providers must consider the immunosuppressed nature of these patients. Inquiring about patient exposures with a detailed history is essential. Fever is the most common symptom of infection, though it may not be present in half of patients with infection.12-14 Two studies find that transplant patients demonstrate temperatures and WBC counts lower than patients without transplant in the setting of infection.27,28 However, transplant patients still appear to mount some physiologic response to infection. In one study, temperature for transplant versus non-transplant patients during infection was 37.9oC versus 38.2oC, while WBC was 12.1 versus 14.0. Patients taking mycophenylate mofetil and azathioprine demonstrate decreased temperatures and WBC counts as compared to other regimens.27,28 In these patients, providers should consider using a lower temperature as a marker for fever.
Resuscitation with intravenous fluids and broad-spectrum antimicrobials must be started rapidly if the patient is in shock. This should be promptly followed by imaging of the suspected site.5-7,10 The emergency provider should speak with the patient’s transplant physician. Infectious Disease consultation should be considered as this is associated with improved mortality for transplant patients.5-7,29 For some infections, the typical gold standard for diagnosis requires biopsy, which is not obtainable in the ED. Serologic tests may allow the inpatient team to target therapy, though results will not return while the patient is in the ED.5,10 Likewise, culture results will not be available to the ED provider. Suggested testing is shown below in Table 3.
 
Suspected Source Diagnostic Testing

No suspected source – Urinalysis with culture, chest radiograph, blood cultures, lactate, CBC with differential, CMV PCR, PPD or QuantiFERON test

Pulmonary – Chest radiograph

– CT chest if concern present for pneumonia with negative plain radiograph
– CBC with differential
– Blood cultures
– Urine Legionella and pneumococcal antigens
– PPD
– CMV PCR, Coccidioides serology
– Biopsy may be warranted
Diarrhea – Stool for WBC count, culture, C. difficile testing, ova and parasites, CMV PCR

Central nervous system (CNS) – Head CT noncontrast, MRI if initial CT unrevealing

– Lumbar puncture with CSF studies: cell count, glucose, protein, AFB culture, cryptococcal antigen, viral PCR
– Biopsy may be warranted for focal lesion(s)
Diffuse lymphadenopathy – EBV PCR, CMV PCR, Bartonella serology, PPD, node biopsy, CT neck/chest/abdomen/pelvis

Urinary tract – Urinalysis and culture

– Renal function panel and CBC
– If criteria for sepsis met, obtain CBC, renal function panel, medication levels specific to patient, lactate, blood cultures
Table 3 – Infectious Source Testing
 
Rejection
Transplant rejection is a major cause of allograft dysfunction, and patients often do not fully recover from an episode of rejection.2-4 Immunosuppressive medications have dramatically reduced rejection, though optimizing drug levels with infection risk remains challenging.
Rejection occurs due to several mechanisms in discrete phases. The first stage is sensitization, where intrinsic CD4 and CD8 recognize cells on the foreign graft and stimulate a host response. The direct pathway is due to host T-cells recognizing foreign donor cells, while the indirect pathway occurs via T-cell stimulation of other immune cells.30-34 Ultimately, both pathways lead to cell death.34 Stages of rejection are shown below in table 4.
 
Rejection Stage Time Course Pathogenesis

Hyperacute Minutes to hours – Antibody mediated due to preexisting antibodies in host, resulting in complement activation and thrombosis

Acute First 6 months – Acute cellular rejection due to activated lymphocytes

– Humoral rejection due to antidonor antibodies produced after transplant
Chronic Months to years – Antibody and cell-mediated rejection

Table 4 – Stages of Rejection
 
The type of transplant, as well as the time from operation determines each presentation of graft rejection. Rejection occurs in 17% in live donor and 20% of deceased-donor renal transplant recipients.35,36 Approximately 64% of patients with liver transplant experience rejection within the first 6 weeks. Late rejection can occur in 23%.37,38 Cardiac transplant rejection is most commonly acute, affecting 30%.39 One third of lung transplant recipients experience rejection in the first year.40-42 Frighteningly, these patients may be asymptomatic, with rejection found on biopsy only. All patients require transplant consult, along with high dose steroids, methylprednisolone 500 mg to 1000 mg IV loading dose.43-45 Close to 10% of patients will be steroid resistant, requiring other medications such as mycophenolate, tacrolimus, sirolimus, thymoglobulin, or antibodies.43-45 Table 5 below displays organ-specific rejection findings.
 
Transplant Organ Symptoms/Signs Labs/Imaging findings

Renal46 – Many asymptomatic

– Fever, malaise, oliguria, graft pain and tenderness over site
– Hypertension
– Worsening renal function
– Acute rise in serum creatinine common

– Electrolyte abnormalities may be present
– Ultrasound typically demonstrates increased graft size, loss of corticomedullary junction, prominent hypoechoic pyramids
– Renal Doppler studies may demonstrate elevated resistance indices
– Biopsy typically needed during admission
Liver – Fever, malaise, abdominal pain, hepatosplenomegaly, ascites

 
– Laboratory abnormalities common: elevated LFT, GGT, bilirubin

– Obtain US of graft and vasculature
– Biopsy is required during admission
Cardiac – Dyspnea at rest/exertion, orthopnea, palpitations, near-syncope/syncope, peripheral edema, gastrointestinal symptoms with right heart involvement

– Chest pain is absent
– Dysrhythmias common
– Cardiac troponin and BNP often elevated

– ECG changes may demonstrate T wave/ST segment changes
– Echocardiogram often demonstrates systolic/diastolic dysfunction
– Chest radiograph may demonstrate findings of congestive heart failure
– Biopsy often needed during admission
Lung47 – Shortness of breath and cough most common

– Lung examination variable: clear lung fields, crackles or decreased breath sounds
– May present with respiratory distress or obstructive lung disease
 
– CBC with eosinophilia on differential is suggestive

– Pulmonary function testing not helpful differentiating infection and rejection
– Chest radiograph has low sensitivity and specificity
– Chest CT often required
– Effusion requires thoracentesis
– Bronchoscopy and biopsy needed during admission
Table 5 – Transplant Rejection Presentation and Laboratory/Imaging Findings
 
Medication Side Effects
Transplant recipients require lifelong immunosuppression to decrease risk of rejection. Before the 1980’s, regimens consisted of corticosteroids and azathioprine.2,4 The introduction of other medications has revolutionized transplant management. Optimal regimens vary based on the patient, specific organ transplanted, and time from transplant.48-50
Immunosuppression regimens are broken into induction, occurring right after the transplant when the rate of rejection is highest, and maintenance, which usually occurs after three months from transplant.50 Many maintenance regimens involve triple therapy for 3 months to 12 months after transplant, after which one medication may be withdrawn (commonly the steroid).50,51
The majority of patients presenting to the ED will be in the maintenance phase. Due to a wide variety of mechanisms, immunosuppressive medications may have numerous adverse effects. Any suspected adverse effect requires a 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.
 
Medication Mechanism Adverse Effect

Cyclosporine (Sandimmune, generic) – Calcineurin inhibitor, decreasing T lymphocyte activity and IL2 – Acute or chronic nephrotoxicity, electrolyte derangements (hyperkalemia, hypomagnesemia), gout, hemolytic-uremic syndrome, hirsutism, gingival hyperplasia, hypertension, hyperlipidemia

Tacrolimus (Prograf) – Calcineurin inhibitor, inhibiting T lymphocyte activity and IL2 -Similar to cyclosporine above.

– Includes neurotoxicity (headache, tremor, paresthesias, seizures), hair loss instead of hirsutism, less hypertension/hyperlipidemia, no gingival hyperplasia
Azathioprine (Imuran) – Block nucleotide production for immune cell replication – Bone marrow suppression, macrocytosis, anemia, hepatotoxicity, pancreatitis

Mycophenolate mofetil (CellCept) – Cytostatic effect on B and T cells, decreasing proliferation through inhibiting nucleotide synthesis – Abdominal pain, decreased oral intake, nausea/vomiting, diarrhea, anemia, leukopenia, thrombocytopenia

Corticosteroids – Impairs phagocyte function

– Attenuates production of pro-inflammatory 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), hyperlipidemia, buccal ulceration, diarrhea, interstitial pneumonitis

Polyclonal antibodies (antithymocyte gamma-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, IL2-receptor antibody)52,53 – 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: First 3 days of therapy may have headache, aseptic meningitis, encephalopathy, seizures, nausea, vomiting, diarrhea, pulmonary edema, nephrotoxicity. After 3 days low risk of adverse effects

– IL2-receptor antibodies rare adverse effects
Table 6 – Immunosuppressive Medications and Common Side Effects
 
Other effects contribute to significant morbidity and even mortality. Metabolic syndrome is common in transplant recipients, most commonly due to steroids and cyclosporine.2-4,54,55 This condition affects liver transplant recipients up to 52% post-transplant. Coronary artery disease is a leading cause of death.54,55 These medications also increase the risk of new malignancy, and most are routinely followed for regular evaluation.2-4,56-58 Metabolic bone disease occurs with significant bone loss, and fractures most commonly occur within the first 6 months after transplant.59,60 Joint disease, gout, tendon disease, and avascular necrosis may occur due to medication use and interactions.59-63 Central nervous system complications include vascular damage and leukoencephalopathy.64,65
Immunosuppressive agents possess many medication interactions due to P-450 system effects. Calcineurin inhibitors (cyclosporine and tacrolimus) and sirolimus interact with calcium channel blockers, amiodarone, antifungal agents (itraconazole), aminoglycosides, and macrolide antibiotics, resulting in nephrotoxicity due to increased drug levels.66-68 These medications must be dosed carefully with phenobarbital, phenytoin, carbamazepine, rifampin, or isoniazid, as they increase drug metabolism and clearance, resulting in acute rejection. Calcineurin inhibitors also can produce rhabdomyolysis when combined with statins. Azathioprine may interact with allopurinol to produce bone marrow suppression through xanthine oxidase inhibition.66-68 Any new medication should be discussed with the transplant team.
Case Conclusion
The 42-year-old male’s presentation is suspicious for infection, and he is started on IV fluids, with cefepime and vancomycin. His transplant physician requests other labs including medication levels. The patient’s labs return with WBC 13,000/microliter, with a lactate of 3.4. His urinalysis displays bacteria, WBC, positive LE, and positive nitrates. His Cr is also elevated at 2.4, from baseline 1.5. Fortunately, his VS improve with the IV fluids and antibiotics, and he is admitted.
 
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.
– Each time period is associated with different infections.
– 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.
– All transplant patients require consultation with the transplant team. Surgical consultation may also be required.
 
 
References/Further Reading
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2012 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 2012. Department of Health Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI.

Abecassis M, Bridges ND, Clancy CJ, et al. Solid Organ Transplantation in Older Adults: Current Status and Future Research. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012;12(10):2608-2622.

Venkat KK, Venkat A. Care of the renal transplant recipient in the emergency department. Ann Emerg Med 2004 Oct;44(4):330-41.

Fishman JA. Infection in Solid-Organ Transplant Recipients. N Engl J Med 2007;357:2601-14.

Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-29.

Wilck M, Fishman J. The challenges of infection in transplantation: donor-derived infections. Curr Opin Organ Trans- plant 2005;10:301-6.

Fishman JA, Rubin RH. Medical progress: infection in organ transplant recipients. N Engl J Med. 1998;338:1741-

Sia IG, Paya CV. Infectious complications following renal transplantation. Surg Clin North Am. 1998;78:95-112.

Tanphaichitr NT, Brennan DC. Infectious complications in renal transplant recipients. Adv Renal Replac Ther. 2000;7:131-146.

Savitsky EA1, Votey SR, Mebust DP, Schwartz E, Uner AB, McCain S. A descriptive analysis of 290 liver transplant patient visits to an emergency department. Emerg Med. 2000 Aug;7(8):898-905.

Turtay MG1, Oguzturk H, Aydin C, Colak C, Isik B, Yilmaz S. A descriptive analysis of 188 liver transplant patient visits to an emergency department. Eur Rev Med Pharmacol Sci. 2012 Mar;16 Suppl 1:3-7.

Tokalak I1, Başaran O, Emiroğlu R, Karakayali H, Bilgin N, Haberal M. Problems in postoperative renal transplant recipients who present to the emergency unit: experience at one center. Transplant Proc. 2004 Jan-Feb;36(1):184-6.

Green M. Introduction: Infections in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:3.

van den Berg AP, Klompmaker IJ, Haagsma EB, et al. Evidence for an increased rate of bacterial infections in liver transplant patients with cytomegalovirus infection. Clin Transplant 1996; 10:224.

George MJ, Snydman DR, Werner BG, et al. The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland. Am J Med 1997; 103:106.

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Green M, Covington S, Taranto S, et al. Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee. Transplantation 2015; 99:282.

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Fishman JA, Greenwald MA, Grossi PA. Transmission of infection with human allografts: essential considerations in donor screening. Clin Infect Dis 2012; 55:720.

Chong PP, Razonable RR. Diagnostic and management strategies for donor-derived infections. Infect Dis Clin North Am 2013; 27:253.

Pelletier SJ, Crabtree TD, Gleason TG, Raymond DP, Oh CK, Pruett TL, Sawyer RG. Characteristics of infectious complications associated with mortality after solid organ transplantation. Clin Transplant. 2000 Aug;14(4 Pt 2):401-8.

Sawyer RG, Crabtree TD, Gleason TG, Antevil JL, Pruett TL. Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections. Clin Transplant. 1999 Jun;13(3):260-5.

Hamandi B, Husain S, Humar A, Papadimitropoulos EA. Impact of infectious disease consultation on the clinical and economic outcomes of solid organ transplant recipients admitted for infectious complications. Clin Infect Dis 2014; 59:1074.

Baldwin WM 3rd, Valujskikh A, Fairchild RL. Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. Curr Opin Organ Transplant. 2015 Nov 14.

Lin CM, Gill RG. Direct and indirect allograft recognition: pathways dictating graft rejection mechanisms. Curr Opin Organ Transplant. 2015 Nov 14.

Boix F, Millan O, San Segundo D, Mancebo E, Miras M, Rimola A, et al. Activated Regulatory T Cells Expressing CD4(+)CD25(high)CD45RO(+)CD62L(+) Biomarkers Could Be a Risk Factor in Liver Allograft Rejection. Transplant Proc. 2015 Oct. 47 (8):2380-1.

Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation. 2005 Sep 15;80(5):555-63.

Kitchens WH, Uehara S, Chase CM, Colvin RB, Russell PS, Madsen JC. The changing role of natural killer cells in solid organ rejection and tolerance. Transplantation. March 2006;81(6):811-7.

http://srtr.transplant.hrsa.gov/annual_reports/2011/default.aspx (Accessed on May 17, 2016).

Cecka, JM, Terasaki, PI. Early rejection episodes. In: Clinical Transplants, Terasaki, PI (Eds), UCLA Tissue Typing Laboratory, Los Angeles 1989. p.425.

Ramji A, Yoshida EM, Bain VG, et al. Late acute rejection after liver transplantation: the Western Canada experience. Liver Transpl 2002; 8:945.

Soin AS, Rasmussen A, Jamieson NV, et al. CsA levels in the early posttransplant period–predictive of chronic rejection in liver transplantation? Transplantation 1995; 59:1119.

Hertz MI, Aurora P, Christie JD, et al. Scientific Registry of the International Society for Heart and Lung Transplantation: introduction to the 2009 Annual Reports. J Heart Lung Transplant 2009; 28:989.

Martinu T, Chen DF, Palmer SM. Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc 2009; 6:54.

Martinu T, Pavlisko EN, Chen DF, Palmer SM. Acute allograft rejection: cellular and humoral processes. Clin Chest Med 2011; 32:295.

Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report–2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant 2015; 34:1264.

Volpin R, Angeli P, Galioto A, et al. Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: a controlled clinical trial. Liver Transpl 2002; 8:527.

Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270:283.

Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by anti-inflammatory steroids. J Immunol 1984; 132:266.

Pham, PTT, Nast, et al. Diagnosis and therapy of graft dysfunction. In: Chronic kidney disease, dialysis and transplantation, 2, Periera, BJG, Sayegh, et al. (Eds), Elsevier Saunders, Philadelphia 2005. p.641.

Kasiske BL. Cardiovascular disease after renal transplantation. Semin Nephrol 2000;20:176-187.

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