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The close linkage of infection with the nature and intensity of the transplant immunosuppressive program has led to the concept of the therapeutic prescription. This has two components: an immunosuppressive one to prevent or treat rejection and graft-versus-host disease and an antimicrobial one to make it safe. This review provides a conceptual framework to approach the risk and risk periods for infection in solid organ and hematopoietic stem cell transplant recipients as well as an approach to antimicrobial use in this population.

Background. Invasive fungal infections (IFI), particularly those caused by Aspergillus and other angioinvasive molds, are associated with an excessive mortality despite therapy. Methods. Voriconazole was prescribed on a compassionate basis to patients with IFI who were intolerant to or who had progressed despite standard therapy. Outcome was determined by protocol-based criteria as established by the consensus definitions (complete response [CR], partial response [PR], stable disease, failure, and intolerance). Results. Forty-five patients were enrolled in a compassionate release program (29 [64%] because of failure of response to standard therapy), between 1998 and 2002. Of the 45 patients enrolled, 35 (78%) had invasive Aspergillus, 3 (7%) had Fusarium, and 2 (4%) had Scedosporium infections. Underlying illnesses were as follows: 13 (29%) solid-organ transplant (SOT), 11 (24%) BMT, and 7 (13%) hematologic malignancy. Site of infection was as follows: 26 (58%) pulmonary, 9 (20%) disseminated, 5 (11%) central nervous system (CNS), and 3 (7%) sinus. Overall response rates were as follows: 9 (20%) CR, 17 (38%) PR, 15 (33%) failure, and 4 (9%) intolerant. Seven of the eight (88%) patients with sinus or CNS disease demonstrated stabilization of the IFI. The median duration of voriconazole therapy was 79 days with 9 (20%) patients receiving over 1 year of therapy. Nine thousand one hundred twenty-eight days of therapy were given with only four serious adverse events in two cases considered possibly or probably drug related. Conclusions. In this population of severely immuno-compromised patients with life-threatening IFI who have failed or were intolerant to standard antifungal therapy, voriconazole demonstrated substantial efficacy and an acceptable level of toxicity.

Background. The efficacy of trimethoprim-sulfamethoxazole (TMP/SMX) in the prevention of toxoplasmosis after orthotopic cardiac transplantation has been the subject of some controversy, with many transplant groups preferring to use the combination of pyrimethamine and sulfadiazine. Although effective, this latter regimen does not offer equal protection against other pathogens, such as Nocardia or Listeria. To assess the value of TMP/SMX, we reviewed the experience in our heart transplant patients, all of whom received TMP/SMX (160/800 mg) three times weekly for approximately 8 months after transplantation. Methods. We report on 417 orthotopic cardiac transplants during a 17-year period. We have 100% one-year patient follow-up after transplantation. Data was collected on pretransplantation donor and recipient anti-Toxoplasma serology, immunosuppression, allograft rejection, survival, yearly posttransplantation anti-Toxoplasma serology, development of acute toxoplasmosis, and the occurrence of other infections. Results. In this cohort, acute toxoplasmosis developed after transplantation in one case (0.2%). Among the highest risk patients (D+R-) who were treated for at least one episode of rejection, the risk of acute toxoplasmosis was 5% (1 of 22 patients). No change in survival was found between the different anti-Toxoplasma IgG serogroups (D-R-, D-R+, D+R-, or D+R+). Anti-Toxoplasma IgG seroconversion occurred in eight Toxoplasma-seronegative recipients after transplantation; all patients, except the case already noted, were asymptomatic and required no specific anti-Toxoplasma therapy. No cases of Listeria, Nocardia, or Salmonella infections were identified. Five proven and two suspected cases of Pneumocystis carinii pneumonia were found (only 2 of these 7 patients were receiving TMP/SMX at the time of Pneumocystis carinii pneumonia diagnosis). Conclusions. These data demonstrate that TMP/SMX prophylaxis (160/800 mg) three times per week is effective Toxoplasma prophylaxis after orthotopic cardiac transplantation and has prophylactic benefits against other posttransplantation opportunistic pathogens.

Background. Pseudomonas aeruginosa is an uncommon cause of infection in the female genital tract. We report a case of postmenopausal tubo-ovarian abscess (TOA) due to P. aeruginosa in a renal transplant recipient. The presentation included mild abdominal symptoms with rapid progression of peritonitis and surgical abscess drainage. This is the first such case in an organ transplant recipient described in the English literature. Methods and Results. Published reports of 1040 cases of TOA were reviewed. The most common features were a history of sexually transmitted disease or pelvic inflammatory disease, and symptoms including abdominal pain and fever. Escherichia coli, Bacteroides spp., and Klebsiella pneumoniae were the most frequently encountered pathogens. Neisseria gonorrhoeae and Chlamydia trachomatis, which are frequently isolated from cervical cultures, are uncommonly isolated from tubo-ovarian abscesses. Forty percent of patients were treated with antibiotics alone, 18.8% with abdominal surgery, and 32% with surgery and antimicrobial therapy. Conclusion. This report illustrates the muted presentation and atypical microbiology of gynecologic infection in an organ transplant recipient.

It is often very difficult to distinguish between infection-related and immunosuppression-related gastrointestinal (GI) complications after transplantation. The risk of infection itself is determined by the patient's net state of immunosuppression as well as the presence of anatomic or technical abnormalities and the patient's epidemiological exposures. Of the anatomic abnormalities, diverticulitis is a particular problem in transplant patients, with a high rate of perforation and abscess formation. The causes of infectious disease syndromes are very different immediately after, early after, and late after transplantation. Infection during the first month may result from a pre-existing infection in the donor or recipient, or from the surgical wound, endotracheal tube, vascular access or drainage. During 1-6 months after transplantation, viruses attack and, with sustained immunosuppression, make opportunistic infections possible. Beyond 6 months after transplantation, the 80% of patients with good result from the transplant are at risk primarily for community-acquired microbes, including such enteric pathogens as Salmonella. Of the remaining patients, 10% have chronic viral infections and the 10% who have poor allograft function are at greatest risk for opportunistic infection. This time line is helpful in determining whether a GI complication is likely to be related to infection rather than a specific effect of an immunosuppressant drug. Fever, inflammatory cells in the stool, abnormalities on endoscopy or computed tomography and leukocytosis can be useful in the diagnosis but are inconsistent markers for an infectious cause.

Infectious complications are still a significant cause of morbidity and death in solid-organ transplant patients, with significant infection being found in up to two-thirds of these individuals. The risk of infection in the organ transplant patient, particularly of opportunistic infection, is largely determined by 3 factors: the net state of immunosuppression, the epidemiologic exposures the patient encounters, and the consequences of the invasive procedures to which the patient is subjected. The most important principles of patient treatment are prevention, early diagnosis, and specific therapy. This issue is designed as a position paper by a group of experts on epidemiology, prevention, diagnosis, and management of infections in solid-organ transplant patients. We feel that our efforts may serve as an important first step in the development of guidelines in this area.

This review presents evidence-based guidelines for the prevention of infection after blood and marrow transplantation. Recommendations apply to all myeloablative transplants regardless of recipient (adult or child), type (allogeneic or autologous) or source (peripheral blood, marrow or cord blood) of transplant.In Section I, Dr. Dykewicz describes the methods used to rate the strength and quality of published evidence supporting these recommendations and details the two dozen scholarly societies and federal agencies involved in the genesis and review of the guidelines.In Section II, Dr. Longworth presents recommendations for hospital infection control. Hand hygiene, room ventilation, health care worker and visitor policies are detailed along with guidelines for control of specific nosocomial and community-acquired pathogens.In Section III, Dr. Boeckh details effective practices to prevent viral diseases. Leukocyte-depleted blood is recommended for cytomegalovirus (CMV) seronegative allografts, while ganciclovir given as prophylaxis or preemptive therapy based on pp65 antigenemia or DNA assays is advised for individuals at risk for CMV. Guidelines for preventing varicella-zoster virus (VZV), herpes simplex virus (HSV) and community respiratory virus infections are also presented.In Section IV, Drs. Baden and Rubin review means to prevent invasive fungal infections. Hospital design and policy can reduce exposure to air contaminated with fungal spores and fluconazole prophylaxis at 400 mg/day reduces invasive yeast infection.In Section V, Dr. Sepkowitz details effective clinical practices to reduce or prevent bacterial or protozoal disease after transplantation. In Section VI, Dr. Sullivan reviews vaccine-preventable infections and guidelines for active and passive immunizations for stem cell transplant recipients, family members and health care workers.

Background: Optimal prophylaxis against cytomegalovirus (CMV) disease for organ transplant patients at risk for primary infection (donor seropositive, recipient seronegative, D+R−) remains to be determined. We hypothesized that prolonged oral ganciclovir therapy following intravenous therapy would provide increased protection. Methods: A total of 155 evaluable D+R− organ transplant recipients from 13 transplant centers were entered into the study: all received intravenous ganciclovir (5 mg/kg/day) for 5–10 days and then either oral acyclovir (400 mg tid) or oral ganciclovir (1 g tid) for an additional 12 weeks. Patients were assigned to their treatment groups at a central randomization site, with a separate randomization scheme for each of the organs transplanted (kidney, heart, or liver). In the case of kidney transplants, the patients were stratified according to source of the kidney (living related vs. cadaveric donor). The primary endpoint was the incidence of CMV disease in the first six months post-transplant. Results: Treatment with oral ganciclovir was associated with a significant decrease in the incidence of symptomatic disease or viremia when compared with the oral acyclovir group (32% vs. 50%, P

Cytomegalovirus (CMV) remains the most important infection affecting heart-transplant recipients. Treatment of clinical disease is with a two to three-week course of intravenous ganciclovir, which is effective in more than 90% of individuals. However, relapsing disease, particularly in those with primary infection, is an increasing problem, occasionally with the development of ganciclovir-resistant infection. In those instances, foscarnet is needed, despite its nephro- and neurotoxicities. Increasingly, in order to prevent relapse, more prolonged oral courses of anti-viral therapy are being added to the standard two to three-week course of intravenous treatment. In the prevention of CMV disease, those at risk of primary disease (donor seropositive, recipient seronegative) should receive prophylaxis; for seropositive transplant patients, preemptive strategies linked to immunosuppression or viremia monitoring are becoming increasingly prevalent. In the future, as new drugs become available, the essential question will be whether chronic allograft injury (i.e., accelerated coronary artery atherosclerosis) can be prevented with an anti-viral strategy.

Background: Although the primary treatment of symptomatic cytomegalovirus (CMV) disease in organ transplant recipients is successful in >90% of individuals, relapsing disease, particularly in those with primary infection, remains an important problem. Previously, we had observed that the rate of symptomatic recurrence was >60% in those with primary disease (seronegative for CMV prior to transplant), and approximately 20% in those who were seropositive prior to transplant. The present study was undertaken to determine whether a maintenance regimen of oral ganciclovir for 2–3 months added to the routine 14–21 days of intravenous ganciclovir would further prevent symptomatic CMV recurrence. Methods: From May 1995 until June 1998, all kidney and liver transplant recipients with confirmed tissue-invasive CMV disease or CMV syndrome were treated with 14–21 days of intravenous ganciclovir (5 mg/kg b.i.d. with dose adjusted for renal dysfunction) followed by 2–3 months of oral ganciclovir (2 g daily). The incidence of recurrence of CMV disease and/or viremia during and after oral therapy was then determined over a mean follow-up of 530.6 days. Results: Thirty-seven patients, 19 kidney and 18 liver transplant recipients, were studied; 5 had biopsy-proven tissue-invasive disease (13.5) and 32 suffered a CMV syndrome (86.5). Twenty-one of these patients (58.6) were seronegative for CMV prior to transplant and received an allograft from a seropositive donor (D+/R−). Overall, 10 patients (27.0) developed CMV recurrence. Eight of 21 patients who were D+/R− for CMV (38.1) developed recurrence as opposed to 2 of 16 patients with other serologic status (12.5) (P=0.14). Patients with recurrent CMV disease and/or viremia had a peak antigenemia assay titer during their initial CMV event of 319.2 positive cells/2 slides compared with 109.8 positive cells/2 slides for patients without recurrent CMV infection (P=0.14); the trend of having a higher peak antigenemia assay titer among patients who recurred occurred both in patients who were at risk of primary CMV infection (D+/R− for CMV) and in those who were not. Two patients developed recurrent infection with strains of CMV that were resistant to ganciclovir. Conclusions: This new therapeutic regimen of oral ganciclovir following intravenous ganciclovir slightly reduced the overall rate of recurrent CMV disease and/or viremia, but it still did not adequately prevent CMV recurrence in patients who are at risk of primary infection prior to transplant. Of particular concern, 2 patients with primary infection treated with this regimen developed ganciclovir-resistant recurrent disease ( Note).

BACKGROUND Leukopenia is not infrequently encountered following solid organ transplantation, most often in the setting of cytomegalovirus (CMV) disease and/or its treatment with ganciclovir. The present study was undertaken to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) in renal and liver transplant recipients with leukopenia. METHODS Between 1 June 1991 and 1 June 1998, patients received G-CSF for 2 indications: 1) white blood cell count (WBC) < 3000/mm3, with a decline from baseline; 2) to shorten the duration of leukopenia associated with chemotherapy. A retrospective review of the outcome of such therapy was undertaken. RESULTS 50 patients were given 100 courses of treatment with G-CSF; 35 of 168 liver transplant recipients (20.8%), 14 of 391 kidney transplant recipients (3.6%), and 1 of 4 recipients of combined liver-kidney transplants (25.0%) received from 1 to 9 courses of G-CSF. Presumed causes of leukopenia were identified as ganciclovir in 28 cases (28.0%), CMV in 21 (21.0%), chemotherapy in 12 (12.0%), sepsis in 11 (11.0%), azathioprine in 5 (5.0%), interferon in 3 (3.0%) and other causes in 20 cases (20.0%). The median length of therapy was 10.0 days (range 1-154 days) and the average dose of daily G-CSF received was 3.9+/-1.5 microg/kg/day. The average WBC was (2.4+/-1.3 )x 10(3)/microl at the beginning of therapy, and (13.8+/-9.1) x 10(3)/microl at the end of therapy. In 7 of 100 treatments (7.0%) a WBC of 5.0 x 10(3)/microl was not reached during G-CSF therapy; in 6 of these 7 cases, G-CSF therapy lasted fewer than 4 days. The mean time needed to reach a WBC count of 5 x 10(3)/microl was 3.7+/-3.3 days among 71 patients who had daily WBC counts sent. Eight G-CSF treatments (8.0%) were followed by episodes of rejection appearing during or within 2 months of treatment; 5 of them were biopsy-documented. No relation was found between the highest WBC obtained during G-CSF therapy and the risk of rejection. Eight patients (16.0%) died while receiving G-CSF, all from infection. Six of these 8 patients were receiving G-CSF for leukopenia secondary to sepsis. Overall, 25 patients (50.0%) received 49 courses of G-CSF secondary to CMV and/or ganciclovir therapy. In 40 of 49 courses (81.6%), ganciclovir could be continued at recommended doses. Twenty-one of 22 patients (95.5%) with symptomatic CMV infection had a clinical response to ganciclovir. Sixteen of 18 patients (88.9%) treated for a CMV infection and followed with serial antigenemia assays attained microbiological cure; both patients who did not were infected with ganciclovir resistant CMV. CONCLUSION G-CSF was well tolerated in solid organ transplant recipients. It was particularly useful in patients with CMV disease, allowing optimal ganciclovir therapy.

Background. The optimal regimen for the prevention and treatment of cytomegalovirus (CMV) disease in solid organ transplant recipients remains to be defined, particularly for patients with abnormal or changing renal function. Methods. A prospective trial was conducted in patients receiving i.v. ganciclovir using a standardized dosing nomogram that corrects for renal function. Steady state peak (P) and trough (T) serum levels were determined by high-performance liquid chromatography and correlated with therapeutic outcomes and toxicities attributable to ganciclovir. Results. Over the study period, 44 individuals received ganciclovir prophylaxis (5 mg/kg/day) and 25 patients were treated (5 mg/kd q12 hr) for symptomatic CMV disease. Ganciclovir levels (mg/ml6SD) achieved in prophylaxis were P: 7.9863.34, T: 3.0362.63; and in treatment were P: 9.0063.72, T: 2.6561.82. Despite corrections for renal dysfunction, undialyzed patients with serum creatinine >3.0 mg/dl had trough levels in excess of the population mean (T: range 3‐ 8 mg/ml). Failure of prophylaxis (disease) or therapy (relapse) occurred in 14 patients; 8 of these were at risk for primary infection (donor CMV seropositive, recipient seronegative, P 3.0, 1.25 mg/kg QOD for Cr >5.0). Some groups of transplant recipients may require more intensive anti-CMV regimens. Cytomegalovirus (CMV*) is a major cause of morbidity in solid organ transplant recipients (1‐9). In various series, between 20 and 70% of organ transplant recipients are affected by CMV infection (2, 10 ‐12). Ganciclovir, in both i.v. and oral formulations, is commonly used to prevent and to treat CMV infection, although the optimal dose and duration of therapy have not yet been completely defined (13‐21). In clinical practice, patients requiring prophylaxis or treatment for CMV infection often have abnormal or fluctuating renal function. This is particularly relevant in the setting of recent organ transplantation or during acute renal allograft rejection. However, few data are available on which to base decisions about the dosing of ganciclovir in such patients (22‐23). In the attempt to optimize antiviral therapy in solid organ transplant recipients with variable renal function, a prospective study was performed to study blood levels and clinical outcomes associated with the routine administration of i.v. ganciclovir based on a standardized nomogram. Peak and trough serum ganciclovir levels were measured by highpressure liquid chromatography. An attempt was made to assess the dosing of ganciclovir and to assess the impact of dosage and serum levels on the efficacy and toxicities of antiviral therapy and any impact that might be detected with the use of prophylactic or therapeutic ganciclovir on the development of or recurrence of symptomatic CMV infection.

Infection and rejection, the two major barriers to successful organ transplantation, are closely linked, with immunosuppressive therapy being central to the pathogenesis of both. After almost two decades when azathioprine and prednisone, supplemented by antilymphocyte antibody therapy, were the cornerstones of post-transplant immunosuppressive programs, there has been a major increase in the therapeutic armamentarium available to treat rejection: cyclosporine, tacrolimus, mycophenolate mofetil, rapamycin, and antibodies directed against the interleukin-2 receptor. These agents are potent inhibitors of microbial specific T cell function, thus potentiating opportunistic infection with herpes group viruses, fungal and mycobacterial species, Strongyloides stercoralis, and a variety of intracellular pathogens. The mechanisms by which each of these drugs exerts its effects are an important determinant of the antimicrobial strategies that will be necessary to combat infection. Indeed, strategies to limit these infections are being linked to the nature of the immunosuppressive therapy required in a particular patient. Thus, the therapeutic prescription for the transplant patient is said to have two components: an immunosuppressive component to prevent and treat rejection, and an antimicrobial one to make it safe. In addition to using antimicrobial agents therapeutically, in the transplant patient prevention is stressed in which antibiotics are deployed prophylactically or preemptively ( Note).

Background. Due to the limited supply and increased demand for donor livers, waiting times are progressively lengthening, which may lead to transplantation at more advanced and less cost-effective stages of disease. The purpose of this study was to evaluate the outcomes and hospital charges of liver transplantation during two recent eras to identify areas for providing more cost-effective care. Methods. A total of 144 primary liver allografts were performed from 1991 to 1996. Patient characteristics, outcome measures, and hospital charges were compared for patients receiving allografts between 1991 and 1993 (group A) versus those receiving grafts between 1994 and 1996 (group B) using unpaired Student t tests for continuous data and chi-squared tests for categorical data. Results. In comparing groups A and B, no significant differences in patient demographics, relative contraindications, or indication for transplantation existed; median waiting time from date of listing until transplant increased from 88 days to 159 days; and a shift in UNOS priority status at time of transplantation occurred, as the percentage of patients requiring inpatient care increased from 58% to 75% (P=0.034). Despite this, patient hospital and 1-year survival significantly improved from 75.0% to 90.3% (P=0.016), and from 68.1% to 88.9% (P=0.002), respectively. Total hospital charges, without correction for inflation, were $174,908

Background, Organ transplant recipients who are seropositive for cytomegalovirus (CMV) and who are treated with antilymphocyte antibody (ALA) therapy have a high rate of symptomatic CMV disease. The intravenous administration of ganciclovir therapy once daily during ALA therapy decreased the incidence from 24% to 10% in patients receiving ALA as an induction therapy and from 64% to 22% in those treated for rejection. The present study was undertaken to determine whether a more intensive and sustained antiviral regimen could be more effective. Methods. From April 1995 to December 1997, all CMV seropositive renal and liver transplant recipients who received ALA therapy were treated with intravenously administered ganciclovir (5 mg/kg/day with dose adjusted for renal dysfunction) for the length of ALA therapy and then with orally administered acyclovir (400 mg three times/day) or ganciclovir (1 gm twice/day) for 3 to 4 months. The incidence of CMV viremia and of CMV disease was determined during the 6 months after completion of ALA therapy. Results. Forty-one patients (35 renal and 6 liver transplant recipients) were studied. CMV disease occurred in 2 patients (4.9%), both of whom were treated for rejection; it occurred in 1 of 21 patients (4.8%) treated with orally administered acyclovir, and in 1 of 20 patients (5%) treated with orally administered ganciclovir. The only patient who developed CMV disease in the ganciclovir group had received only 26 days of oral antiviral therapy. No CMV disease was documented in the group of patients receiving ALA therapy as induction therapy. CMV viremia occurred in three patients in the acyclovir group (14.3%) and in one patient in the ganciclovir group (5%). Among renal transplant recipients only, 1 of 35 patients developed CMV disease (2.9%) and no case of CMV disease was documented in patients treated with orally administered ganciclovir. All six patients receiving two courses of ALA therapy each were free of CMV disease. Toxicity of the regimen was minimal, and antiviral resistance did not develop. Conclusions. Preemptive antiviral therapy with intravenously administered ganciclovir during ALA therapy and then orally administered ganciclovir for 3 to 4 months provides virtually complete protection against the excessive rate of CMV disease that occurs in CMV seropositive allograft recipients receiving ALA therapy.

A primary goal in organ transplantation is the prevention or effective treatment of infection, the most common life-threatening complication of long-term immunosuppressive therapy. The challenges involved in achieving this goal are several: a broad range of potential sources of infection ranging from latent viruses to pathogens of both community and hospital origin; immunosuppression-induced impairment of the inflammatory response, which attenuates the signs and symptoms of invasive infection; and the adverse effects of the antimicrobial drugs used for prophylaxis and therapy, which result both from the duration of therapy required and from interactions with the immunosuppressive drugs cyclosporine and tacrolimus. Our . . .

SUMMARY Considerable progress has been made in elucidating the factors involved in the pathogenesis of infection in the organ transplant patient. One of the general principles that has emerged is that the risk of clinical infection, particularly opportunistic infection, is determined largely by the interaction between the patient's net state of immunosuppression and the epidemiologic exposures the patient encounters. The two major factors that determine the net state of immunosuppression are the nature of the exogenous immunosuppressive therapy that is administered and whether or not infection is present with one or more of the immunomodulating viruses (particularly cytomegalovirus, Epstein-Barr virus, and the hepatitis viruses). Finally, the therapeutic prescription for the transplant patient has two components—an immunosuppressive component to prevent and treat rejection and an antimicrobial component, which is linked to the intensity of the immunosuppressive therapy required, to make this safe. This reflects the recognition that the two major barriers to successful transplantation, rejection and infection, are closely tied together by the current requirement for lifelong immunosuppressive therapy. Progress in one area will have beneficial effects on the other.

Approximately 30% of patients with end stage renal disease who undergo transplantation develop renal failure as a result of their long-standing diabetes mellitus. Therefore, diabetics warrant special attention in considering the infectious disease problems associated with transplantation. The three categories that should be considered in infections affecting the diabetic renal transplant recipient are discussed in this article.

Fungal infections following solid organ transplantation remain a major cause of morbidity and mortality. Candida species and Aspergillus fumigatus continue to account for the majority of these infections, although the attack rate is higher among recipients of organs other than kidneys because those patients receive more immunosuppressive therapy. Although amphotericin B remains the drug of choice for treatment of invasive aspergillosis, its toxicity profile limits its widespread use. Recent experience suggests that fluconazole may be a safe and effective alternative for the treatment of fungal infections caused by Candida species or Cryptococcus neoformans. Prevention of fungal infections remains one of the most important goals in the field of transplantation. New approaches--such as the use of "preemptive therapy," or prophylaxis, for patients at greatest risk of developing infection--may assist in attainment of this goal.

Patient 1. A 24-year-old woman with chronic renal failure secondary to membranoproliferative glomerulonephritis underwent living-related renal transplantation from her 56-year-old mother. Other than her renal disease, she had no significant medical problems. She received cyclosporine, prednisone, and azathioprine as immunosuppressive therapy post transplant. The allograft functioned immediately, and the serum creatinine concentration fell to I . I mg/dl 3 days after transplantation. Because the donor was seropositive for cytomegalovirus (CMV), the patient received CMV hyperimmune globin, 150 mg/kg intravenously every 2 weeks, beginning on the first post-transplant day and continuing until she presented with CMV infection on the 38th post-transplant day. On the 10th day post transplant, the patient's temperature rose to 100.6° F and she felt sick. Physical examination revealed no site of infection, a chest radiograph was normal, and all cultures were negative; the serum creatinine, however, had risen to 1.6 mg/dl. Ultrasound examination of the allograft revealed no fluid collection or evidence of hydronephrosis. A clinical diagnosis of allograft rejection was made, and 500 mg of methylprednisolone was administered intravenously on 2 consecutive days. Although the patient became afebrile, she became increasingly oliguric, and her serum creatinine continued to rise (to 3.2 mg/dl). A percutaneous renal biopsy revealed acute allograft rejection without evidence of cyclosporine toxicity; anti-rejection therapy with OKT3 was initiated at a dose of 5 mg/kg for a total of 14 days. By the end of this course of OKT3, the serum creatinine had returned to normal. The therapeutic program then consisted of cyclosporine, 450 mg/day; prednisone, 20 mg/day; azathioprine, 100 mg/day; one single

Since the early days of transplantation, infection has been a major consequence of antirejection immunosuppressive therapy. Increasingly effective prophylactic and preemptive strategies are being developed to prevent the infectious consequences of immunosuppressive therapy. Although the data base is incomplete and there remains a compelling need for well-designed, randomized, comparative trials, the potential for controlling life-threatening viral, bacterial, fungal, and protozoal infections exists. The cornerstone of this effort is the recognition that effective immunosuppressive strategies require an antimicrobial program to make them safe and that such an antimicrobial program needs to be individualized in order to be appropriately matched with the needs of the antirejection program. Thus, escalation and de-escalation of the antimicrobial program should be carried out to match the immunosuppressive program. Infection and rejection remain closely intertwined, linked by the immunosuppressive program that is prescribed.

As of November 1991, 8 of 83 children who had received renal transplants at Massachusetts General Hospital since January 1979 required admission for primary variceila. All 8 had cutaneous manifestations of disease, and 4 had evidence of visceral disease. Three of these 8 children received varicella zoster immune globulin (VZIG) after exposure to varicella; in the remaining children, exposure was not revealed until symptoms were present. All 8 children were treated with high-dose intravenous acyclovir. Two children died of complications of varicella infecfion, including 1 child who received VZIG on the day of exposure to varicella. Neither VZIG prophylaxis nor treatment with intravenous acyclovir offers complete protection against severe varicella infection to immunosuppressed children who have received organ transplants. A high priority should be given to the evaluation of alternative treatments, such as vaccination to the varicella virus, which could be administered to susceptible transplant candidates, preferably prior to transplantation.

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for greater than 3 days with viremia or unexplained fever for greater than 3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4-17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P less than 0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.

The infectious disease clinician and microbiologist have critical roles in assisting the transplant surgeon with decisions regarding safety and appropriate timing of transplantation from an infectious disease standpoint. Following transplantation, the emphasis shifts to rapidly determine the microbiology of specimens obtained from the transplant recipient, and looking for the routine and unusual organisms that may cause classic or unusual presentations of disease. As the number and range of organs being transplanted increase, new infectious disease problems will arise and careful evaluation of specimens, with particular attention to unusual opportunistic pathogens, will continue to allow the infectious disease physician to prescribe effective therapy as promptly as possible.

Cytomegalovirus infection is initiated when tumor necrosis factor binds to the cytomegalovirus receptors of latently infected cells, resulting in the reactivation of the virus and the production of clinical disease of two types: direct infection causing pneumonia, mononucleosis, colitis and other viral-related syndromes, and indirect infection in which an array of cytokines are released by the host that produce much the same effect as does the rejection process.These effects fall into three categories: allograft injury, an increase in superinfection with opportunistic pathogens and an increase in the incidence of B cell lymphoproliferative disease. Other factors that modulate the clinical impact of reactivated cytomegalovirus in the transplant patient include the past experience of the host with the virus (primary infection, donor seropositive and recipient seronegative), the degree of major histocompatibility complex mismatch, the viral burden and the amount of calcineurin inhibitor the patient receives.Optimal therapy for diagnosing, treating and preventing these indirect effects still remains to be defined; the direct effects, in contrast, are well managed with valganciclovir.

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Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation. Significant progress has been made in the prevention of CMV disease over the past decade, but prevention of late CMV disease continues to be a challenge in selected high-risk populations. The pretransplantation CMV serostatus of the donor and/or recipient remains an important risk factor for posttransplantation outcome despite the use of antiviral prophylaxis and preemptive therapy; CMV-seropositive recipients of T cell-depleted grafts in particular continue to have a survival disadvantage compared with seronegative recipients with seronegative donors. The risk of developing antiviral drug resistance remains low in most patients; however, in a setting of intense immunosuppression (eg, after transplantation from a haploidentical donor), the incidence may be as high as 8%. Primary CMV infection via blood transfusion can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1% to 2% of CMV disease remains. Surveillance and preemptive therapy are effective in preventing the sequelae of transfusion-related CMV infection. Indirect immunomodulatory effects of CMV are increasingly recognized in hematopoietic stem cell transplant recipients. Strategies currently being investigated include long-term suppression of CMV with valganciclovir for the prevention of late CMV infection and disease, adoptive transfer of CMV-specific T cells, and donor and recipient vaccination strategies.

Despite substantial advances made in controlling the effects of cytomegalovirus (CMV) infection, it remains the single most important pathogen in solid organ transplantation (SOT). Because CMV shares some characteristics with other human herpesviruses, it is also an important model system for understanding the actions of herpesviruses 6 and 7, Epstein-Barr virus (EBV) and, potentially, hepatitis C and B. As the lessons learned from HIV influenced our thinking about other viral infections (e.g. importance of viral load), so too what is learned about CMV will be applied to other herpesviruses. The pervasive nature of CMV and the common problems posed by this virus prompted the convening of a panel of experts in the field of SOT to discuss issues associated with CMV in transplant recipients. This supplement reflects the presentations and discussions at this symposium, including the clinical implications of CMV drug resistance, economic impact of CMV on transplant programs, the rationale for CMV hyperimmune globulin (CMW-IGIV, CytoGam) in SOT, antibody inhibition of CMV, hypogammaglobulinemia, role of CMV in allograft vasculopathy, and the clinical use of CytoGam therapy in a variety of SOT patients. A number of questions during the general discussion prompted the addition of other material to this Supplement, including the development of CMV-IGIV for clinical use in SOT recipients and resource utilization associated with CMV-related hospital readmissions.

BK virus is a human polyomavirus associated with a range of clinical presentations from asymptomatic viruria with pyuria to ureteral ulceration with ureteral stenosis in renal transplant patients or hemorrhagic cystitis in bone marrow transplant recipients. Infection of renal allografts has been associated with diminished graft function in some individuals. Fortunately, however, the majority of patients with BK virus infections are asymptomatic. The type, duration, and intensity of immunosuppression are major contributors to susceptibility to the activation of BK virus infection. Histopathology is required for the demonstration of renal parenchymal involvement; urine cytology and viral polymerase chain reaction methods are useful adjunctive diagnostic tools. Current, treatment of immunosuppressed patients with polyomavirus viruria is largely supportive and directed toward minimizing immunosuppression. Improved diagnostic tools and antiviral therapies are needed for polyomavirus infections.

TRANSPLANTATION, of both bone marrow and solid organs, must be regarded as one of the great success stories of 20th-century biomedical science. At the same time, it must be recognized that the mani...

Hepatitis C virus (HCV) is both the leading cause of cirrhosis and hepatic failure leading to liver transplantation and a cause of chronic hepatitis in approximately 10% of all transplant recipients. Beginning 5-10 years or more posttransplant, HCV causes progressive liver disease in a significant fraction of infected individuals and contributes to an increased incidence of opportunistic infection and hepatocellular carcinoma. The existence of multiple genotypes of HCV with differing biologic behaviors and the generation of antigenic diversity of the virus (quasispecies) during the course of infection, limit the capacity of the immune system to generate protective immunity. Antiviral therapy with interferon-alpha is effective in only a minority of transplant patients, and since allografts from HCV infected donors are quite efficient in transmitting the virus, great attention is paid to the appropriate use of organs from HCV-positive donors. At present, these organs should be particularly targeted for patients in emergent need of lifesaving heart, liver, or lung transplants. Issues requiring further investigation include the impact of viral superinfection on HCV-infected recipients of organs from HCV-infected donors and the use of such organs in seronegative patients who are older, diabetic, or highly sensitized, for whom quality of life issues may outweigh the long-term impact of HCV infection.

The risk of opportunistic infection in the cardiac transplant patient is determined by the interaction between the epidemiologic exposures that the patient encounters and the patient's net state of immunosuppression. The epidemiologic exposures include those encountered in both the community and the hospital, with the latter being more important as they usually occur at a point in time when the patient's net state of immunosuppression is at its highest. The net state of immunosuppression is a complex function whose major determinants are the immunosuppressive program and the presence or absence of infection with a group of immunomodulating viruses, particularly cytomegalovirus. Strategies for preventing opportunistic infection in this patient population are based on the following factors: technically impeccable surgery, precisely managed immunosuppression, environmental protection (particularly in the hospital), and the use of preventative antimicrobial strategies. These last are of two types, prophylactic and preemptive. The key point in both these approaches is to link the preventative strategy to the intensity of the immunosuppressive program and to target the antimicrobial program to the time period and patient group at greatest risk. For most opportunistic infections this is the time period 1 to 6 months after transplantation (when viral infections are prevalent), and the small group of patients more than 6 months after transplantation who are chronically overimmunosuppressed because of rejection.