J. Stephen Dummer

THE FREQUENCY OF EPSTEIN-BARR VIRUS INFECTION AND ASSOCIATED LYMPHOPROLIFERATIVE SYNDROME AFTER TRANSPLANTATION AND ITS MANIFESTATIONS IN CHILDREN

Twenty cases of Epstein-Barr virus (EBV)-associated lymphoproliferative syndrome (LPS), defined by the presence of EBV nuclear antigen and/or EBV DNA in tissues, were diagnosed in 1467 transplant recipients in Pittsburgh from 1981–1985. The frequency of occurrence in pediatric transplant recipients was 4% (10/253), while in adults it was 0.8% (10/1214) (P < .0005). The frequency of LPS in adults declined after 1983 coincidental with the introduction of cyclosporine monitoring. However there was no apparent decline of LPS in children. We describe these ten pediatric cases and one additional case of LPS in a child who received her transplant before 1981. The frequency of EBV infection in 92 pediatric liver recipients was 63%. Of these subjects, 49% were seronegative and 77% of those acquired primary infection. Of 11 cases of pediatric EBV-associated LPS, 10 were in children who had primary infection shortly before or after transplantation. These results reinforce the importance of primary EBV infection in producing LPS, which was previously shown in adults. Children are at greater risk because they are more likely to be seronegative for EBV and to acquire primary infection. Three clinical types of LPS were recognized in children. The first (5 cases) was a self-limited mononucleo-sislike syndrome. The second syndrome (4 cases) began similarly, but then progressed over the next two months to widespread lymphoproliferation in internal organs and death. The third type (2 cases) was an extranodal intestinal monoclonal B cell lymphoma, occurring late after primary infection.

FUNGAL INFECTIONS IN LIVER TRANSPLANT RECIPIENTS

Sixty-two adults who underwent orthotopic liver transplantations between February 1981 and June 1983 were followed for a mean of 170 days after the operation. Twenty-six patients developed 30 episodes of significant fungal infection. Candida species and Torulopsis glabrata were responsible for 22 episodes and Aspergillus species for 6. Most fungal infections occurred in the first month after transplantation. In the first 8 weeks after transplantation, death occurred in 69% (18/26) of patients with fungal infection but in only 8% (3/36) of patients without fungal infection (P<0.0005). The cause of death, however, was usually multifactorial, and not solely due to the fungal infection. Fungal infections were associated with the following clinical factors: administration of preoperative steroids (P<0.05) and antibiotics (P<0.05), longer transplant operative time (P<0.02), longer posttransplant operative time (P<0.01), duration of antibiotic use after transplant surgery (P<0.001), and the number of steroid boluses administered to control rejection in the first 2 posttransplant months (P<0.01). Patients with primary biliary cirrhosis had fewer fungal infections than patients with other underlying liver diseases (P<0.05). A total of 41% (9/22) of Candida infections resolved, but all Aspergillus infections ended in death.A retrospective analysis of 462 consecutive orthotopic liver transplantations was undertaken to evaluate incidence, risk factors, clinical course, and outcome of fungal infections. Infections involving Aspergillus (6 cases), Candida (5 cases), Mucor (1 case), and Cryptococcus (1 case) were observed in 2.8% (13/462) of our patients. Twelve of the 13 episodes developed during the first 2 postoperative months. None of the potential risk factors for fungal infections described by other authors (i.e., age, rejection treatment, dialysis, mechanical ventilation, graft failure, long operation time, second transplant, serious nonfungal infection) correlated significantly with the episodes in our patients. However, in patients who exhibited three or more of these potential risk factors the incidence of fungal infections was elevated (P<0.001). Six of seven exogenous infections (Aspergillus, Mucor) began before July 1991 when our department moved from Charlottenburg to Wedding, thus indicating that the incidence of these infections is highly influenced by exposure (P=0.01). Exposure prophylaxis should therefore by meticulously followed, particularly when severely compromised patients are involved, in order to prevent exogenous infections (i.e., Aspergillus/Mucor). Infections involving such patients are combined with a very high mortality (57%). We observed Candida infection as a pathological overgrowth of physiological oropharynx flora into the esophagus and/or trachea in five patients. In each case treatment led to full recovery.

Heart-Lung Transplantation: Lessons Learned and Future Hopes

Since March, 1982, 33 patients have undergone cardiopulmonary transplantation. Nineteen were discharged from the hospital following the operation, and 16 continue to do well. Eight patients have survived 1 year, 5 patients 2 years, and 1 patient 3 years. Often survival has been influenced most by the selection of candidates, as no patient who had undergone a previous sternotomy survived (3 of 3). All 7 early (between 30 and 72 days) and 3 late (145 to 466 days) deaths were related to infection. Methods for ex vivo preservation of the heart-lung bloc have included storage at 4 degrees C, cardiopulmonary bypass and profound hypothermia, and autoperfusion of the heart-lung bloc. The last technique is original and currently is preferred for distant procurement. Because dehiscence of the tracheal anastomosis has occurred in 3 patients, a sutured line is now encircled with a wrap of omentum. Isolated rejection of the lung is frequent in the first three weeks following operation and has been controlled with methylprednisolone. Late survivors have shown a mild restrictive lung disorder that has not progressed between 6 and 24 months. Bronchoalveolar lavage has been useful for diagnosing infection and providing insight into the immunobiology of the transplanted lung. Although mortality and morbidity have been high, the experiences gained through this series will likely result in an improved outlook for future recipients.

INFECTION WITH HUMAN IMMUNODEFICIENCY VIRUS IN THE PITTSBURGH TRANSPLANT POPULATION: A Study of 583 Donors and 1043 Recipients, 1981–1986

We performed a retrospective serologic survey of 583 organ donors and 1043 transplant recipients for antibodies to human immunodeficiency virus type 1 (HIV-1). Two (0.34%) of the 583 donors and 18 (1.7%) of the 1043 recipients had HIV-1 antibodies by enzyme immunoassay and by Western blot. Two of 5 seropositive recipients tested also had blood cultures positive for HIV-1. Seven (0.7%) of the 1043 transplant recipients had antibodies to HIV-1 before transplantation; 2 of these had hemophilia A, and 5 had previous transfusions. Eleven (1.3%) of 860 recipients followed for 45 days or more seroconverted to HIV-1 a mean of 96 days after transplantation. Likely sources of HIV-1 infection for 3 of these 11 recipients included a seropositive organ donor in 1 patient and high-risk blood donors in 2 patients. A definite source of HIV-1 infection was not found for the other 8 recipients, 3 of whom seroconverted to HIV-1 after institution of blood donor screening for HIV-1 antibodies. Seroconversion to HIV-1 was less common in kidney recipients than in liver, heart, or multiple-organ recipients (P less than 0.02). Nine (50%) of the 18 HIV-1 seropositive transplant recipients died a mean of 6 months after transplant surgery, and 9 (50%) are still alive a mean of 43 months after transplantation. AIDS-like illnesses occurred in 3 of the dead and 1 of the living patients and included pneumocystis pneumonia (3 cases), miliary tuberculosis (1 case), and recurrent cytomegalovirus infection (1 case). These data suggest that the course of HIV-1 infection is not more severe in transplant recipients receiving cyclosporine than in other hosts and that, despite screening of blood and organ donors, a small number of transplant recipients will become infected with HIV-1.

Extragenital Mycoplasma hominis infections in adults

PURPOSE To heighten awareness of the role of Mycoplasma hominis as an extragenital pathogen in adults. PATIENTS AND METHODS AND RESULTS Patients ranged in age from 14 to 76 years. Thirteen patients were immunosuppressed, including nine organ transplant recipients; three were receiving steroids, and two had an underlying malignancy. The remainder were immunocompetent. Thirteen patients had prior surgery at or near the site of infection. M. hominis was isolated from normally sterile sites such as blood or cerebrospinal, pleural, abdominal and joint fluids, and bone. Non-sterile sites of isolation included surgical wounds and pulmonary secretions. The organism was detected in anaerobic cultures of clinical specimens sent to the laboratory for routine bacteriologic culture. Gram stains of fluids or wound drainage revealed neutrophils but no bacteria. Anti-mycoplasmal therapy was effective in eradicating the organism in 13 of 15 patients who were treated. Of those in whom treatment failed, one patient had an antibiotic-resistant isolate and the other had M. hominis isolated from the lung at postmortem after just 2 days of therapy. CONCLUSION Our experience suggests that significant infections due to M. hominis, although uncommon, are not rare, and methods to isolate and identify this organism should be available for general adult medical and surgical populations.

The artificial heart: Infection-related morbidity and its effect on transplantation

Between October, 1985, and September, 1987, a total of 195 patients received cardiac allografts and 15 candidates required mechanical support with the Jarvik-7 total artificial heart. Seven of the 15 died within 60 days of total artificial heart implant. There have been no late deaths, and survivors are unrestricted. Six of 7 deaths were related to infection (mediastinitis, 5; pneumonia and sepsis, 1), and the remaining 1 was due to failure of the transplanted heart. Respiratory tract infection occurred in each of the recipients who died with infection, and the same organisms appeared to be related to subsequent mediastinitis in 3 patients (Serratia marcescens, 2; Pseudomonas, 1) and caused fatal sepsis in another (Enterobacter aerogenes, Candida albicans). One patient died with pneumonia and sepsis prior to transplantation, and another succumbed with mediastinal infection known to be present before transplantation.

Successful management of an abo-mismatched lung allograft using antigen-specific immunoadsorption, complement inhibition, and immunomodulatory therapy

Background. Successful management of an ABO-mismatched lung allograft recipient has not previously been described. Methods. Because of a clerical error, a 67-year-old blood type B patient with idiopathic pulmonary fibrosis received a left single-lung allograft from a blood type A donor. Cyclophosphamide was added to immunosuppression with anti-thymocyte globulin induction, cyclosporine, mycophenolate mofetil, and prednisone. When increasing anti-A antibody titers were detected, antigen-specific immunoadsorption, anti-CD20 monoclonal antibody, and recombinant sol-uble complement receptor type 1 (TP10) were administered. Results. Rising anti-A antibody titers were reduced acutely by immunoadsorption, and remained low during long-term follow-up. Humoral injury to the graft was not detected. Acute cellular rejection and multiple complications were successfully managed. Three years after transplantation the patient is clinically well on stable maintenance immunosuppression and prophylactic photochemotherapy. Conclusions. Modulation of anti-A antibody, preserved graft function, and a favorable patient outcome can be achieved for an ABO-mismatched lung allograft.

Organ procurement for pulmonary transplantation

Selection of suitable donors is critical to the success of clinical pulmonary transplantation. Requirements for lung donors, management before explantation, and methods of preservation were reviewed for the 70 heart-lung, eight double-lung, and two single-lung transplantations performed at the University of Pittsburgh since 1982. Careful observation of trends of hyperoxygenation studies, chest roentgenograms, and Gram stain and culture results of tracheal secretions, as well as findings on bronchoscopy, can help identify which lungs not only have adequate function but are acceptable for transplantation. In spite of the rigid criteria used, 76% of tracheal cultures from donors deemed acceptable grew organisms. The presence of oropharyngeal flora has been shown to correlate with the development of early intrathoracic infections in the recipient. Prophylactic broad-spectrum antibiotic treatment of the donor is desirable to treat microbial contamination that could cause focal injury to the donor lung and predispose to infection in the recipient. Acceptance of less than ideal donors is ill-advised even though rejection of such donors conflicts with the current shortage of organs.

Disruption of the aortic anastomosis after heart-lung transplantation

Disruption of the aorta at the anastomotic site occurred in 4 of 66 consecutive heart-lung transplant recipients and was associated with a 100% mortality. In 3 of these patients, Candida either was cultured from the suture line or was seen in the wall of the aorta at postmortem examination. In 2 of these 3 patients, cultures of material from the donor trachea taken at the time of explanation grew Candida species. Two patients were seen with sudden massive hemorrhage on postoperative day 26 and postoperative day 28. One patient experienced acute decompensation due to right ventricular outflow tract obstruction on postoperative day 30, and the remaining patient was seen 7 months postoperatively with obstruction of both the left main bronchus and the right pulmonary artery caused by extrinsic compression by an aortic pseudoaneurysm. A high index of suspicion should be maintained when transplanting lungs containing Candida species, as we believe there is substantial evidence of donor transmission of the fungal agents. We now include amphotericin B in our antibiotic prophylactic regimen in an attempt to prevent fungal infection because previous treatment has been uniformly unsuccessful. Furthermore, we wrap both the trachea and the aorta with omentum to lessen the likelihood of mediastinal spread of infection to the aortic suture line.

Epstein-barr virus-induced lymphoma in a cardiac transplant recipient

A monoclonal diffuse histiocytic lymphoma developed during the course of a serologically documented primary Epstein-Barr virus infection in a 22-year-old cardiac transplant recipient taking cyclosporine and prednisone. Throat washings revealed the virus at tumor presentation, and the tumor was shown to contain Epstein-Barr nuclear antigen-positive cells and the viral genome. Prolonged inversion of the T cell helper/suppressor ratio was demonstrated. A brief course of acyclovir appeared to halt viral shedding in the throat but had no apparent effect on the tumor.