Transplant Emergencies Part I: Infection, Rejection, and Medication Effects

Authors: Brit Long, MD (@long_brit, EM Physician at SAUSHEC, USAF) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) // Edited by: Jamie Santistevan, MD (@Jamie_Rae_EMdoc)

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

  1. NPR. Transplant pioneers recall medical milestone. http://www.npr.org/templates/story/story.php?storyId=4233669. Accessed 28 Jun 2016.
  2. 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.
  3. 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.
  4. Venkat KK, Venkat A. Care of the renal transplant recipient in the emergency department. Ann Emerg Med 2004 Oct;44(4):330-41.
  5. Fishman JA. Infection in Solid-Organ Transplant Recipients. N Engl J Med 2007;357:2601-14.
  6. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-29.
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  8. Fishman JA, Rubin RH. Medical progress: infection in organ transplant recipients. N Engl J Med. 1998;338:1741-
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  10. Tanphaichitr NT, Brennan DC. Infectious complications in renal transplant recipients. Adv Renal Replac Ther. 2000;7:131-146
  11. Kalil AC, Syed A, Rupp ME et al. Is bacteremic sepsis associated with  higher mortality in transplant recipients than in nontransplant patients? A matched case-control propensity-adjusted study. Clin Infect Dis 2015; 60:216.
  12. 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.
  13. 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.
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  32. 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.
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  47. Kasiske BL. Cardiovascular disease after renal transplantation. Semin Nephrol 2000;20:176-187.
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  49. Johnson RWG. Sirolimus (rapamune) in renal transplantation. Curr Opin Nephrol Hypert. 2002;11:603-607.
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  65. Goldstein LS, Haug MT 3rd., Pearl J 2nd et al. Central nervous system colplications after lung transplantation. J Heart Lung Transplant 1998;17:185-191.
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  67. Mignat C. Clinically significant drug interactions with new immunosuppresive agents. Drug safety. 1997;16:267-278.
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