Key words: Solid organ transplant, Immunosuppression, Opportunistic infection With the introduction of immunosuppressive drugs, solid organ transplant (SOT) has progressed such that potential recipients significantly outnumber available organs. In 2007, there were 14,394 donors of 28,353 organs, but 98,645 persons were on a waiting list as of March 2008.1 Improved graft survival following transplant and an escalation in transplant rates increase the likelihood that physicians of all specialties will encounter transplant recipients and will need to treat them as a special population group. To adequately serve the transplant-recipient patient population, physicians need to be familiar with the types of immunosuppression that commonly occur, the basic principles of diagnosis and management of infections in these patients, and measures to prevent infection. IMMUNOSUPPRESSIVE AGENTS AND INFECTION RISKS The most common immunosuppressive agents used in transplant recipients are corticosteroids, immunophilin inhibitors (eg, calcineurin inhibitors and sirolimus), inhibitors of DNA and RNA synthesis, and antibodies. Different regimens impose different infection risks and pose different potentials for adverse interactions. This can affect the treatment choices for a broad range of conditions. Corticosteroids Corticosteroids remain the backbone of antirejection medication regimens. They exert multiple effects on both the immune response and the inflammatory response. Corticosteroids decrease the concentration and activity of lymphocytes, monocytes, and basophils in the vascular circulation, and redistribution to lymphoid compartments occurs.2-4 Absolute neutrophil counts increase as these cells become restricted to the vascular compartment and are unable to migrate to areas of inflammation.5 Corticosteroids also inhibit interleukins (ILs), especially IL-1, which stimulates production of prostaglandins,6 and IL-2, which promotes further T-cell proliferation.7 Adverse effects are myriad and commonly include agitation, insomnia, gastroesophageal reflux, hirsutism, acne, weight gain, glucose intolerance, aseptic necrosis of the femoral head, osteoporosis, cataract formation, and hyperlipidemia. Largely because of these adverse events, corticosteroid-sparing regimens increasingly have been adopted, especially as maintenance therapy. Immunophilin inhibitors Introduced in the early 1980s, cyclosporine was the first major advance in therapeutic immunosuppression following the introduction of corticosteroids 3 decades earlier. Both cyclosporine and the newer agent, tacrolimus, are calcineurin inhibitors, which interfere with cytokine transcription in response to T-cell receptor signaling 002E.5 Cyclosporine decreases production of IL-2, while tacrolimus decreases IL-1 and IL-2, interferon-γ, IL-2 receptors, and T-cell proliferation. Calcineurin inhibitors may cause nephrotoxicity, neurotoxicity, hyperglycemia, and hypertension. Cyclosporine causes gingival hyperplasia and hirsutism and a greater degree of hyperlipidemia and hypertension than tacrolimus, which has a greater propensity to provoke development of diabetes mellitus.The use of cyclosporine increased 1-year renal allograft survival by 15% but did not increase long-term graft survival.8 However, tacrolimus is far more potent than cyclosporine by weight and appears to be more effective in preventing rejection.9 In contrast to cyclosporine, tacrolimus is generally not associated with increased risk of infectious complications. Because cyclosporine is less potent than tacrolimus, its use results in increased need for adjunctive immunosuppressant therapy.9 The cyclosporine-based regimens have been associated with a higher risk of Cytomegalovirus (CMV) infection and poorer outcomes in patients with hepatitis C in some studies.10 In addition, a recent increase in BK virus nephropathy among kidney transplant recipients has been attributed to potent immunosuppression with tacrolimus.11 Sirolimus is a newer immunosuppressive agent. Although it binds to the same receptor as tacrolimus, the resulting complex inhibits the mammalian target of rapamycin (mTOR). Inhibition of mTOR disrupts cytokine signaling that would otherwise result in T- and B-cell proliferation. Elevated cholesterol and triglyceride levels, hypertension, nephrotoxicity, and pancytopenia may occur. Because sirolimus interferes with proliferation of fibroblasts, wound healing may be delayed.12 Sirolimus can be used synergistically with the calcineurin inhibitors,13 and it has replaced tacrolimus in some regimens. In a retrospective case-control study, sirolimus exposure following renal transplant was associated with a lower risk of CMV infection relative to tacrolimus.14 A randomized trial found that a sirolimus-containing regimen was associated with significantly lower risk of CMV infection than a cyclosporine-containing regimen (6% vs 23%; P < .01). Both sirolimus and the calcineurin inhibitors are often used in combination with the antiproliferative agents azathioprine and mycophenolate mofetil (MMF). RNA and DNA synthesis inhibitors Azathioprine and MMF inhibit RNA and DNA synthesis, thus blocking proliferation of T and B cells during clonal expansion.5 The primary adverse effect of these drugs is leukopenia; however, GI effects, such as abdominal pain, nausea, vomiting, and diarrhea are also commonly associated with MMF use. Drug interactions are a major consideration in patients who receive cyclosporine, tacrolimus, or sirolimus. These drugs are all metabolized by the cytochrome P-450 3A enzyme; therefore, drugs that inhibit this enzyme, such as azole antifungals, will increase drug levels a nd potential toxicity, whereas drugs that induce the cytochrome P-450 3A enzyme, such as rifampin, will lower drug levels, leading to possible organ transplant rejection. Clinically significant interactions between anti-infectives and immunosuppressants are summarized in Table 1.15 In the setting of azole antifungal therapy, the dose of the immunosuppressant agent often must be decreased. Furthermore, coadministration of sirolimus and ketoconazole or voriconazole is contraindicated. When cyclosporine is coadministered with voriconazole, the dose of the immunosuppressant should be reduced by half. When tacrolimus is administered, the tacrolimus dose should be reduced by two-thirds. Fluconazole, however, often can be used with immunosuppressants without dose adjustments. Coadministration of rifampin and azole antifungals with immunosuppressants is especially problematic. With the exception of itraconazole, use of an alternative drug is recommended whenever possible. Immunosuppressant levels need to be closely monitored, patients have to be watched for signs of toxicity, and dosage adjustments must be made as needed. Rifampin-type interactions also can be expected to occur with rifabutin and rifapentine, but the severity may be less with rifabutin. The effect of rifampin is usually apparent in 2 days-1 week at maximum. A cyclosporine dose increase of 2-fold or more may be required to maintain stable cyclosporine levels. Antibodies Some of the most potent (and toxic) immunosuppressant therapies are antilymphocyte antibody-based regimens. These are used as salvage therapy or sometimes as induction therapy. They have no role in maintenance immunosuppression. Because these agents can contribute to immunosuppression long after administration, physicians need to be aware of their previous use by a transplant recipient. Polyclonal antibody formulations are prepared from the hyperimmune serum of rabbits (Thymoglobulin) or horses (Atgam) that have been injected with human thymocytes. Mechanisms of action include elimination of circulating T cells, apoptosis of activated T cells, changes in cell surface receptors, and institution of anergy.5 In kidney transplant recipients who received a 3-day course of Thymoglobulin, T-cell counts remained depressed at 1 year.16 Meanwhile, the monoclonal antibody preparation Orthoclone OKT3 targets the T-cell receptor CD3, causing apoptosis, anergy, or antigenic modulation involving loss of CD3 expression.17 T-cell depletion by Orthoclone OKT3 is not as severe or long-lasting as it is with polyclonal antibodies. Instead, the long-term effectiveness of Orthoclone OKT3 seems to involve promotion of CD4+CD25+ regulatory cells, which actively induce immune tolerance. Both polyclonal and monoclonal antibody treatments can reduce the requirement for maintenance therapy, but physicians should not mistake a relatively mild maintenance regimen for a low degree of immunosuppression in these patients. IL-2 receptor antagonists (daclizumab, basiliximab) are newer monoclonal antibody agents that disrupt T-cell proliferation. These are approved for use in combination with other immunosuppressant induction drugs, and their use is associated with decreased risk of rejection without an increased risk of opportunistic infection or lymphoproliferative disease.18,19 Thus, IL-2 receptor antagonist therapies are unlike other antibody-based therapies; previous exposure by itself may not further increase immunocompromise. INFECTION RISK IN SOT RECIPIENTS Physicians should be vigilant for infection in SOT recipients. The risk is determined by epidemiological exposure, the net state of immunosuppression, and the consequences of the invasive procedures to which the recipient has been subjected.20,21 Serious infection is common in this population. In one follow-up study that averaged 54 months posttransplant, infection requiring hospital admission or prolonged hospitalization developed in 55% of 259 heart transplant recipients.22 The early work of Rubin and colleagues2 demonstrated that the type of infectious complication correlates with the time line following transplant. Table 2 provides a summary of infections to look out for in relation to the time line after organ transplant. During the first postoperative month, most infections are related to hospitalization and surgery. During the 1- to 6-month posttransplant period, the effects of immunosuppression become more apparent. At this time, opportunistic infections manifest. Patients also are at risk for activation of latent infection associated with the donor organ. For example, CMV is the most frequent cause of opportunistic infection in transplant recipients at this stage in the time line despite use of prophylactic antiviral therapy. Acute rejection may cause fever and malaise and be mistaken for infection. Recipients of heart transplants may present with jugulovenous distention, an S3, or dyspnea, whereas kidney transplant recipients exhibit tenderness over the graft, decreased urinary output, and a rise in baseline serum creatinine level. Hepatitis occurs with acute rejection in liver transplant recipients. Lung transplant recipients often have dyspnea and fail pulmonary function tests. Acute rejection is a medical emergency, and rapid referral to a transplant physician is critically important to preserve graft function and the patient’s life. After about 6 months, the infection profile in transplant recipients who do not experience complications resembles that of the general population. However, in those patients who require repeated treatment for acute rejection episodes, return to relatively normal immune function may be delayed. Indeed, return to normal immune function for transplant recipients in whom chronic organ rejection occurs may be delayed indefinitely.23 Even common infections may be more difficult to diagnose in transplant recipients. Because an immunosuppressive agent decreases the host’s inflammatory response, infections may have an attenuated presentation. For example, pain, fever, pulmonary infiltrates, and leukocytosis may be absent. Patients with a surgical abdomen may not demonstrate rebound tenderness or guarding on physical examination.24 Therefore, maintaining a high index of suspicion for infection after SOT is vital. During the first 6 months following transplant, evaluation for infection should be performed even when signs and symptoms are subtle. Fever (eg, a temperature of 38°C [100.5°F]), malaise, weight loss, and failure to thrive are signs and symptoms that should lead the physician to pursue a workup for differential diagnoses of an infectious process. As mentioned, CMV is the most common cause of infection in transplant recipients. CMV infection in SOT recipients exhibits a wide range of clinical manifestations, from asymptomatic infection to severe, lethal CMV disease.23 Urinary tract infections (UTIs) are predictably common in kidney transplant recipients.25 UTIs in this patient population are more frequent and may be more severe during the first 4 to 6 months following transplant.2 Because UTIs in transplant recipients may be asymptomatic, with the exception of fever, and occur in the absence of pyuria, a high index of suspicion and routine surveillance with urine cultures is needed to detect and treat them appropriately.23 Muoz26 has recommended a 10-day course of antibiotics for bacterial infections that occur more than 6 months after transplant. Community-acquired infections such as sinusitis, bronchitis, pneumonia, and viral upper respiratory tract infections also are common after transplant and tend to occur 6 months posttransplant. Opportunistic pathogens must be included in the differential diagnosis, and the clinician should keep in mind that a normal radiograph does not rule out infection in transplant recipients. Unless patients have had problems with rejection, they should be treated in the same way that immunocompetent patients with respiratory infections are treated. Empiric therapeutic regimens for respiratory infections should include those that are effective against pneumonia. Quinolones are a good option because they are associated with fewer drug interactions than macrolide antibiotics. Interventions to identify the cause of a respiratory infection in patients who fail to respond to empiric therapy are essential. Diagnostic interventions should include bronchoscopy with bronchoalveolar lavage, and thoracoscopic lung biopsy should be performed if less invasive procedures do not aid in establishing a diagnosis. The microbiology laboratory should be instructed to perform studies for identification of unusual pathogens, such as viruses, fungi, Pneumocystis jiroveci, and Legionella. Cutaneous manifestations of opportunistic infections also develop in transplant recipients. Herpes zoster is frequently seen. Whereas the overall incidence of herpes zoster was 8.6% in a recently published review, incidence was nearly double this figure in lung and heart transplant recipients (15.1% and 16.8%, respectively).27 Postherpetic neuralgia was seen in 42.7% of the transplant recipients. If antiviral therapy in the form of acyclovir, valacyclovir, or famciclovir is given within 72 hours of rash onset, the likelihood of postherpetic neuralgia is decreased.28-30 Systemic fungal infections also may manifest as skin lesions. If a fungal organism is identified through histological examination of a skin lesion biopsy specimen, evaluation for systemic fungal involvement should be pursued. CT of the chest and MRI of the brain are sensitive methods of detecting the presence of invasive fungal disease in transplant recipients. PRETRANSPLANT EVALUATION AND POSTTRANSPLANT COUNSELING Before transplant, all potential SOT candidates should be evaluated for active infection that may require treatment or preclude transplant and its risk factors for infection. A thorough history, including information on exposure to infection, colonization, anatomical risk factors, and immunizations, is important. Pretransplant serological testing should be done to screen for underlying infections, such as hepatitis B and C, toxoplasmosis, and syphilis, and infections caused by herpes simplex virus, varicella-zoster virus, Epstein Barr virus, and HIV. Although few data show the efficacy of vaccination after transplant, it is recommended that SOT candidates be current on vaccinations against tetanus, diphtheria, pertussis; measles, mumps, rubella; influenza; pneumococcal infection; hepatitis B (and A if they travel frequently); Haemophilus influenzae type B infection (in children); and varicella-zoster virus infection (if seronegative for the virus).31,32 Live virus vaccines are contraindicated posttransplant.33 Influenza vaccine, pneumococcal vaccine, and tetanus toxoid vaccines should be given according to recommended dosing schedules after transplant. Immune responses to influenza vaccine are diminished in transplant recipients; therefore, a useful strategy is to vaccinate all members of the recipient’s household. However, the intranasal vaccine is not recommended for transplant recipients or members of their household because it is a live, attenuated virus vaccine. The varicella vaccine also is a live virus vaccine and should not be given to transplant patients, but it may be given to household members. This guideline takes into account the fact that an inactivated chickenpox vaccine is not available.33 Hand hygiene should be stressed for all members of the recipient’s household. Safe food preparation with thorough cooking is important, and although drinking bottled water is popular, partially consumed bottles should be refrigerated promptly after opening or else they should be discarded. Exposure to animals may pose a risk. Birds are associated with Chlamydia psittaci infection, cats with toxoplasmosis, puppies with Cryptosporidium parvum infection, and reptiles with salmonellosis. Travel may pose special infectious risks to transplant recipients, and those who wish to travel should be referred to their transplant center for specific recommendations. In addition, transplant recipients should be counseled about the potential for increased vulnerability to sexually transmitted infections. In one 12-year study of 166 female lung transplant recipients, the incidence of cervical intraepithelial neoplasia of grades 1 and 3 was 42.2 and 30 per 1000, respectively, compared with 8.3 and 6.2 per 1000 in a large reference population of women aged 20 to 69 years.34 Sexual health counseling and screening may be particularly relevant for the growing number of adolescents and young adults who had received transplants during childhood.35 Vaccination against human papillomavirus infection may be useful, but specific recommendations for use in transplant recipients are not available. Substance abuse also should be addressed, especially in patients with a positive history of substance abuse or dependence, before undergoing an SOT procedure. References: REFERENCES 1. 2003 OPTN/SRTR Annual Report. www.ustransplant.org/annual_reports/archives/2003/default.htm. Accessed November 6, 2008. 2. Rubin RH, Wolfson JS, Cosimi AB, Tolkoff-Rubin NE. Infection in the renal transplant recipient. 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Sirolimus exposure during the early post-transplant period reduces the risk of CMV infection relative to tacrolimus in renal allograft recipients. Clin Transplant. 2007;21:466-471. 15. Immunosuppressive drug interactions with anti-infective agents. Am J Transplant. 2004;4(suppl 10):164-166. 16. Agha IA, Rueda J, Alvarez A, et al. Short course induction immunosuppression with thymoglobulin for renal transplant recipients. Transplantation. 2002;73:473-475. 17. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7:622-632. 18. Zenapax [package insert]. Nutley, NJ: Roche Pharmaceuticals; 2005. 19. Simulect [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2005. 20. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338:1741-1751. 21. Infectious Disease Community of Practice. American Society of Transplantation, Infectious Disease Guidelines for Transplantation. Am J Transplant. 2004;4(suppl 10):6-9. 22. Agüero J, Almenar L, Martinez-Dolz L, et al. Variations in the frequency and type of infections in heart transplantation according to the immunosuppression regimen. Transplant Proc. 2006;38:2558-2559. 23. Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev. 1997;10:86-124. 24. Auchincloss H, Rubin RH. Clinical management of the critically ill renal transplant patient. In: Parillo JE, Masur H, eds. The Critically Ill Immunosuppressed Patient. Rockville, MD: Aspen; 1987:347-376. 25. Tolkoff-Rubin NE, Rubin RH. Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am. 1997;11:707-717. 26. Muñoz P. Management of urinary tract infections and lymphocele in renal transplant recipients. Clin Infect Dis. 2001;33(suppl 1):S53-S57. 27. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. Am J Transplant. 2004;4:108-115. 28. Huff JC, Drucker JL, Clemmer A, et al. Effect of oral acyclovir on pain resolution in herpes zoster: a reanalysis. J Med Virol. 1993;(suppl 1):S93-S96. 29. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med. 1995;123:89-96. 30. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain. 2002;18:350-354. 31. Kotton CN, Ryan ET, Fishman JA. Prevention of infection in adult travelers after solid organ transplantation. Am J Transplant. 2005;5:8-14. 32. Centers for Disease Control and Prevention. Recommended Adult Immunization Schedule: United States, October 2006-September 2007. www.cdc.gov/vaccines/recs/schedules/downloads/adult/06-07/adult-schedule.pdf. Accessed November 6, 2008. 33. Guidelines for vaccination of solid organ transplant candidates and recipients. Am J Transplant. 2004;4(suppl 10): 160-163. 34. Malouf MA, Hopkins PM, Singleton L, et al. Sexual health issues after lung transplantation: importance of cervical screening. J Heart Lung Transplant. 2004;23:894-897. 35. Sucato GS, Murray PJ. Developmental and reproductive health issues in adolescent solid organ transplant recipients. Semin Pediatr Surg. 2006;15:170-178.
