FEVER AND THE RENAL TRANSPLANT RECIPIENT
Infection is the primary cause of death (41%) following renal transplantation (the other causes being cardiovascular problems, 20%; suicide, 15%; gastrointestinal problems, 13%; neoplasms, 4%; and various other disorders, 7%). Nevertheless, there has been a substantial decrease in the frequency of infection, which can be attributed to improved surgical techniques, more precise immunosuppressive regimens, better matching of donor and recipient organs, improved harvesting and preservation of donor organs, and prompt diagnosis and treatment of infections. Since the introduction of cyclosporine, an 11-amino acid, cyclic polypeptide antirejection agent, the incidence of infection has decreased even further. In a randomized, prospective trial of cyclosporine versus azathioprine for immunosuppression in renal allograft recipients, the incidence of all infections in the cyclosporine-treated patients was approximately half that in the azathioprine-treated patients. The number of bacterial infections was similar in the two groups, but viral infections, particularly cytomegalovirus (CMV) infections, occurred in a significantly greater number of azathioprine-treated than cyclosporine-treated patients. There was no significant difference, however, between the two treatment groups in the actuarial patient and graft survival rates.
Other drugs for immunosuppression to decrease the dosage of corticosteroids used include a monoclonal pan-T-cell antibody (OKT3), tacrolimus (FK506), and mycophenolate. With improved immunosuppression, the rate of fungal infections has decreased from 45% to 5% in recent years.
Rubin and associates categorized the most common types of infection in renal transplant recipients according to time of onset in the period after transplantation. During the first month after transplantation, the chief considerations are wound, pulmonary, urinary tract, and IV line-related infections caused by the usual bacterial pathogens. Hepatitis B and herpes simplex virus infections are also common during this period. Opportunistic infections are rare during the first month after transplantation, and their occurrence suggests either an unusual nosocomial exposure or an infection that was present but unrecognized in the period before transplantation, with symptomatic disease resulting from immunosuppressive therapy, surgical manipulation, or both.
Opportunistic infections become manifest 1 to 6 months after transplantation. Infections caused by CMV, Epstein-Barr virus, varicella-zoster virus, hepatitis C and other hepatitis virus agents, Nocardia, Listeria, fungi, Toxoplasma, and Pneumocystis carinii, and serious bacterial infections related to the surgical procedure are common at this time. Among these pathogens, CMV predominates. During this period, the infections are probably a consequence of the intensive immunosuppressant therapy; CMV itself is immunosuppressive.
In the late post-transplantation period, 6 months or more after the transplantation, cryptococcal meningitis is seen. Cryptococcal infections usually begin more than 1 year after transplantation. Other infections observed in the late period are CMV infection, chorioretinitis, urinary tract infection, chronic viral hepatitis, and the usual community-acquired infections, such as pneumococcal pneumonia.
Fever in a renal transplant recipient may indicate an infectious or noninfectious cause. Important noninfectious causes of fever are allograft rejection, malignancy, drug fever, and pulmonary emboli. When a renal transplant patient has a fever, the clinician should initiate an exhaustive evaluation to determine any clues to its cause. Symptoms and signs other than fever help to localize the site of infection. Clues to the presence of infection are often subtle in a renal transplant recipient. Headache, even without a stiff neck, indicates the possibility of meningitis. Travel history and place of residence are important factors if coccidioidomycosis, histoplasmosis, or parasitic disease is suspected and diagnosed. The possibility of drug fever must always be considered. The clinician should order blood, urine, and other cultures based on the clinical clues. Signs of rejection should be assessed by measuring changes in renal function. Other useful studies include urinalysis, chest roentgenography, CBC count, acute and convalescent serologies, and cultures of the urine and buffy coat for CMV. Computed tomography and ultrasound examinations are useful to evaluate the transplant site and detect any other occult intraabdominal disease.
Infection is responsible for approximately 75% of fevers. Of these infections, viruses are the most frequent cause, responsible for more than half (55%) of all febrile episodes. Of the viral agents, CMV is by far the most frequent and can be found alone or in combination with other viruses. Most CMV disease occurs between 14 days and 4 months after transplantation, and only 17% of the febrile episodes observed more than 1 year after transplantation are associated with CMV infection. Bacterial and fungal infections are responsible for 14% and 5% of febrile episodes, respectively. The other important cause of fever is rejection, which accounts for 13% of post-transplantation fever. Infection with HIV can occur, and screening for this agent should be carried out in donors as well as recipients.
Bacterial wound and urinary tract infections occur frequently in renal transplant recipients. Immunosuppressive drugs often obscure the usual symptoms and signs of a wound infection and may make the diagnosis difficult. In recent years, the incidence of wound infections has decreased dramatically because of increased technical and surgical expertise and, possibly, the use of antimicrobial prophylaxis. The diagnosis of a wound infection can be established by aspiration of the wound or by ultrasonic or computed tomographic examination of the site. Ultrasonography may not differentiate an abscess from a lymphocele or seroma. Lymphoceles can become secondarily infected, and the collection must be drained.
Urinary tract infections are the most common bacterial infections in renal transplant recipients. The incidence varies from 35% to 79% in some reports, and approximately 60% of the bacteremias originate from the transplant. Urinary tract infections in the first 3 months after the transplantation are often associated with pyelonephritis and bacteremia. Infections that occur after months are generally benign and respond to conventional 10- to 14-day courses of antimicrobials. Trimethoprim-sulfamethoxazole (TMP- SMX), given as one double-strength tablet at bedtime for 4 months, significantly decreased the incidence of urinary tract infection in one test group compared with a control group that received placebo. In another study in which TMP-SMX was used twice daily for 1 year, the incidence of bacterial infections was reduced, especially infections of the urinary tract and bacteremias. Use of TMP-SMX may also prevent P. carinii pneumonia, listeriosis, and nocardiosis.
Infection with CMV occurs in most (60% to 96%) patients after renal transplantation. Three patterns of disease are described: primary disease, reactivation disease, and superinfection. Primary disease occurs in a seronegative renal transplant recipient who receives an allograft from a seropositive donor. The virus is transmitted with the donor kidney, and immunosuppressive therapy activates the latent virus. In reactivation disease, endogenous latent virus is reactivated during immunosuppressive therapy in an already seropositive transplant recipient. Superinfection occurs in a seropositive renal transplant recipient and involves acquisition of another CMV strain from the donor kidney. Patients with superinfection are usually symptomatic.
Most infections begin 1 to 4 months after transplantation, and approximately 25% of the infections are symptomatic. The effects of the virus can be categorized as follows: (a) clinical symptoms and signs, (b) depression of host defenses leading to superinfection by other pathogens, and (c) allograft rejection. The clinical manifestations of CMV infection are fever, malaise, arthralgias, pneumonitis, hepatitis, abdominal pain, diarrhea, gastrointestinal bleeding, and leukopenia. Splenomegaly and lymphadenopathy are generally absent. Chorioretinitis is an important, late-occurring symptom of CMV infection. Infection with CMV is rarely fatal when it occurs alone, but when it is complicated by another infection, the outcome is often fatal. The virus can have devastating effects on the renal transplant recipient. Various strategies have been used to prevent CMV infection in transplant recipients, including use of acyclovir, ganciclovir, and high-titer anti-CMV immunoglobulin. The results are encouraging, but further studies are needed to define the optimal prophylactic regimen for renal transplant recipients.
CNS infections occur in about 10% of renal transplant recipients. The CNS is second only to the lungs as a site of infection by opportunistic pathogens. Three pathogens are responsible for about 90% of the infections: Listeria monocytogenes, Cryptococcus neoformans, and Aspergillus fumigatus. Fever and headache are the most common symptoms and are often the only clues present. A minority of cases have nuchal rigidity. All renal transplant recipients with fever and headache should have a lumbar puncture analysis. Computed tomography should precede the lumbar puncture if papilledema or any focal neurologic finding is present. The use of OKT3 to reverse graft rejection following renal transplantation has been associated with an aseptic meningitis syndrome characterized by fever, headache, and an altered mental status. In this syndrome, patients have a cerebrospinal fluid pleocytosis with negative cultures.
Fever and pulmonary infiltrates in a renal transplant recipient, as in any other immunocompromised host, suggest many diagnoses, both infectious and noninfectious, and an organized approach to establish a causative diagnosis is imperative. Pulmonary infection is a major cause of mortality in renal transplant recipients. Noninfectious causes, such as pulmonary emboli and pulmonary edema, account for about 25% of the cases in one report. Clues to the cause can be obtained from assessing the course of illness and the chest roentgenographic pattern. For example, fungi and Nocardia produce cavitation, and the infiltrates generally develop over several weeks. Common infecting pathogens, such as Streptococcus pneumoniae and influenza virus, are still seen more often than opportunistic pathogens, except for CMV, and must always be considered in a patient with community-acquired pneumonia. CMV infection occurs during the 1- to 4-month interval after transplantation. In one report, mixed infections were noted in 40% of patients. If the expectorated sputum fails to yield a diagnosis, more invasive techniques are required. Treatment should be based on the specific cause. (N.M.G.)
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Review. Consider extrapulmonary tuberculosis in a renal transplant patient with fever.
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Lung involvement predominates. Drug interaction between cyclosporine and TMP-SMX may require use of another agent for therapy of Nocardia infection (e.g., imipenem, amikacin, minocycline, or amoxicillin-clavulanic acid).
Bencini PL, et al. Cutaneous manifestations in renal transplant recipients. Nephron 1983;34:79.
Twelve percent of the skin lesions were precancerous or cancerous.
Brayman KL, et al. Analysis of infectious complications occurring after solid-organ transplantation. Arch Surg 1992;127:38.
Infection remains the most frequent cause of death after renal transplantation. Most life-threatening infections were noted in the first 4 months after transplantation.
Case records of the Massachusetts General Hospital (case 24-1984). N Engl J Med 1984;310:1584.
Fever and pancytopenia in a renal transplant recipient from Venezuela. Diagnosis is disseminated histoplasmosis.
Dowling JN, et al. Infections caused by Legionella micdadei and Legionella pneumophila among renal transplant recipients. J Infect Dis 1984;149:703.
Renal transplant recipients are at increased risk for Legionella infection at certain transplant centers.
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Farrugia E, Schwab TR. Management and prevention of cytomegalovirus infection after renal transplantation. Mayo Clin Proc 1992;67:879.
CMV disease usually occurs within 2 to 6 months after transplantation.
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An unusual cutaneous complication.
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Review. CMV is the most important pathogen affecting transplant recipients. Diagnosis is made with tests for antigenemia, polymerase chain reaction assays, or tissue biopsy.
Fox BC, et al. A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost- benefit of prophylaxis. Am J Med 1990;89:255.
After removal of the catheters, long-term prophylaxis, for at least 1 year, was effective in reducing infections in renal transplant patients.
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An unusual outbreak. Therapy for meningitis should be given for 3 weeks to prevent relapse.
Green M, et al. Comparison of intravenous ganciclovir followed by oral acyclovir with intravenous ganciclovir alone for prevention of cytomegalovirus and Epstein-Barr virus disease after liver transplantation in children. Clin Infect Dis 1997;25: 1344–1349.
Two weeks of IV ganciclovir alone was effective CMV prophylaxis in liver transplant recipients.
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Review. Infection, particularly fungal infection, is the major cause of mortality in patients undergoing a solid-organ transplant.
Hooper DC, Pruitt AA, Rubin RH. Central nervous system infection in the chronically immunosuppressed. Medicine (Baltimore) 1982;61:166.
Three major pathogens accounted for more than 75% of CNS infections: Cryptococcus neoformans, Listeria monocytogenes, and Aspergillus fumigatus.
John GT, et al. A timetable for infections after renal transplantation in the tropics. Transplantation 1996;61:970–972.
In the tropics (India), the infections noted were similar to those seen outside the tropics except for an increase in cases of tuberculosis.
Kontoyiannis DP, Rubin RH. Infection in the organ transplant recipient. An overview. Infect Dis Clin North Am 1995;9:811–822.
Review. Infections result from technical problems (e.g., wound hematoma), epidemiologic exposures (e.g., Aspergillus species), and net state of immunosuppression (e.g., CMV infection, drugs to prevent rejection).
Lichtenstein IH, MacGregor RR. Mycobacterial infections in renal transplant recipients: report of five cases and review of the literature. Rev Infect Dis 1983;5:216.
Review. Almost half of the patients had disseminated infections.
Lloveras J, et al. Mycobacterial infections in renal transplant recipients. Seven cases and a review of the literature. Arch Intern Med 1982;142:888.
Tuberculosis occurred in fewer than 1% of renal transplant recipients. Joint and subcutaneous tissue infections predominated.
Martin MA, et al. Nosocomial aseptic meningitis associated with administration of OKT3. JAMA 1988;259:2002.
The pathogenesis of this syndrome is unknown. No meningeal signs or focal defects were noted.
Martinez-Marcos F, et al. Prospective study of renal transplant infections in 50 consecutive patients. Eur J Clin Microbiol Infect Dis 1994;13:1023–1028.
During the first year after transplantation, urinary tract infections, especially asymptomatic bacteriuria, were most common.
Mayoral JL, et al. Diagnosis and treatment of cytomegalovirus disease in transplant patients based on gastrointestinal tract manifestations. Arch Surg 1991;126:202.
Clinical symptoms in patients with invasive CMV disease involving the gastrointestinal tract included abdominal pain (79%), fever (36%), diarrhea (21%), and gastrointestinal bleeding (21%).
Paterson DL, Singh N. Interactions between tacrolimus and antimicrobial agents. Clin Infect Dis 1997;25:1430–1440.
Tacrolimus (FK506) is metabolized by the cytochrome P-450 3A system, and any antimicrobial drug that inhibits or induces these enzymes can alter levels of tacrolimus. Tacrolimus can cause nephrotoxicity.
Peterson PK, et al. Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine (Baltimore) 1980;59:283.
Review of CMV. Fever was present in 95% of patients.
Peterson PK, et al. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med 1981; 71:345.
Viral infections, primarily CMV infections, were responsible for more than 50% of the episodes.
Peterson PK, et al. Infectious diseases in hospitalized renal transplant recipients: a prospective study of a complex and evolving problem. Medicine (Baltimore) 1982; 61:360.
Ponticelli C, et al. Randomized study with cyclosporine in kidney transplantation: 10-year follow-up. J Am Soc Nephrol 1996;7:792–797.
Cyclosporine allows better graft survival than azathioprine at a 10-year follow-up.
Ramsey PG, et al. The renal transplant patient with fever and pulmonary infiltrates: etiology, clinical manifestations, and management. Medicine (Baltimore) 1980;59:206.
Mortality of 50% reported.
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Symptoms and causes were similar to those found in normal hosts.
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Review. Single or multiple nodular chest lesions, along with a pleural effusion (33%), occur commonly.
Rubin RH. Infection in the organ transplant recipient. In: Rubin RH, Young LS, eds. Clinical approach to infection in the compromised host, 3rd ed. New York: Plenum Publishing, 1994.
A comprehensive review.
Rubin RH, Tolkoff-Rubin NE. Antimicrobial strategies in the care of organ transplant recipients. Minireview. Antimicrob Agents Chemother 1993;37:619–624.
Review of prophylaxis. Use fluconazole for asymptomatic candiduria in diabetic renal transplant patients.
Rubin RH, et al. Infection in the renal transplant recipient. Am J Med 1981;70:405.
Infections categorized according to time of onset in this classic article.
Scroggs MW, et al. Causes of death in renal transplant recipients. Arch Pathol Lab Med 1987;111:983.
Infection remains the leading cause of death, but the rates have diminished because of more selective immunosuppression.
Stamm AM. Listeriosis in renal transplant recipients: report of an outbreak and review of 102 cases. Rev Infect Dis 1982;4:665.
The major manifestations of the disease are meningitis (50%) and primary bacteremia (30%).
Stephan RN, Munschauer CE, Kumar A. Surgical wound infection in renal transplantation: outcome data in 102 consecutive patients without perioperative systemic antibiotic coverage. Arch Surg 1997;132:1315–1319.
Incidence of wound infection was only 2%.
Stevens DA, et al. Laboratory evaluation of an outbreak of nocardiosis in immunocompromised hosts. Am J Med 1981;71:928.
Air and dust samples were positive for Nocardia. This is a common problem in Aspergillus infection but extremely unusual with Nocardia.
Stone RM. Case records of the Massachusetts General Hospital (case 31-1997). N Engl J Med 1997;337:1065–1074.
Fever and diffuse pulmonary infiltrates 5 months after renal transplantation. Diagnosis was lymphoma.
Tolkoff-Rubin NE, Rubin RH. The infectious disease problems of the diabetic renal transplant recipient. Infect Dis Clin North Am 1995;9:117–130.
Diabetic renal transplant recipients have the same infections as nondiabetic patients, plus infections resulting from vascular compromise (e.g., foot infections).
Tolkoff-Rubin NE, et al. A controlled study of trimethoprim-sulfamethoxazole prophylaxis of urinary tract infection in renal transplant recipients. Rev Infect Dis 1982;4:614.
TMP-SMX is effective for prophylaxis of urinary tract infection.
Toogood GJ, Roake JA, Morris PJ. The relationship between fever and acute rejection or infection following renal transplantation in the cyclosporin era. Clin Transplant 1994;8:373–377.
Fever in the first 2 weeks is more likely caused by rejection rather than infection.
Wagener MM, Yu VL. Bacteremia in transplant recipients: a prospective study of demographics, etiologic agents, risk factors, and outcomes. Am J Infect Control 1992;20:239.
The urinary tract (58%) was the most frequent source for a bacteremia in renal transplant recipients. Mortality was 11%.
Weiland D, et al. Aspergillosis in 25 renal transplant patients. Ann Surg 1983;622:198.
Sputum culture failed to yield the organism in 60% of patients.
Wheat, LJ et al. Histoplasmosis in renal allograft recipients. Two large urban outbreaks. Arch Intern Med 1983;143:703.
A diagnosis of histoplasmosis is suspected in renal transplant recipients with prolonged unexplained fever in endemic areas. Results of chest roentgenography are often negative.
Wilson JP, et al. Nocardial infections in renal transplant recipients. Medicine (Baltimore) 1989;68:38.
Review. Overall mortality was 25% but 42% in patients with CNS disease.