Cytomegalovirus infection in renal transplant recipients

We have retrospectively analyzed the incidence of cytomegalovirus (CMV) infection in 250 consecutive renal allograft transplants performed in 244 recipients. The mean follow-up was 35.1+/-25.4 months. Immunosuppression was cyclosporine- or tacrolimus-based triple therapy. CMV infection prophylaxis with ganciclovir for 3 months post transplant was prescribed in CMV-seronegative recipients of allografts from seropositive donors (D+R-) and in all recipients treated with OKT3. CMV antigenemia was monitored by the pp65-antigen assay. Thirteen of 57 D+R- recipients (22.8%) developed CMV antigenemia. One recipient had a breakthrough of CMV antigenemia during ganciclovir prophylaxis; 12 D+R- recipients developed CMV antigenemia 147.5+/-173.8 days after transplantation. Four of 13 (30.7%) D+R- recipients had asymptomatic CMV infection, 8 (61.6%) had CMV infection with non-specific symptoms including fever, and 1 (7.7%) developed CMV pneumonia. Six of 13 (46.1%) D+R- patients had been treated with intensified immunosuppressive therapy before CMV infection. In the low-risk CMV groups (D+R+; D-R+; D-R-), 28 recipients (14.5%) developed CMV antigenemia 42.5+/-15.2 days post transplantation. Ten of the 28 (35.7%) recipients had asymptomatic CMV infection, 17 (60.7%) developed CMV infection with non-specific symptoms, and 1 (3.6%) developed CMV pneumonia. Twenty-one of 28 (75.0%) had intensified immunosuppressive therapy before CMV infection. In conclusion, ganciclovir prophylaxis diminished and delayed the onset of CMV infection but did not totally prevent it from occurring in D+R- renal transplant recipients. Clinicians should be vigilant to the possibility of CMV infection in both seronegative and seropositive recipients, especially after anti-rejection therapy.     

Prevention and treatment of cytomegalovirus infection in organ transplant recipients

Cytomegalovirus (CMV) is the most common viral pathogen in organ transplant recipients. The patients at highest risk of developing CMV disease are seronegative recipients of seropositive donors, and seropositive recipients who receive antilymphocyte agents such as OKT3 and antithymocyte globulin (ATG) for induction or for rejection. There have been many trials of CMV prevention, but they are difficult to compare with one another because of variability in definitions and end points. Two modalities that have been used to prevent CMV disease are prophylaxis and preemptive therapy. In prophylaxis all patients are given an antiviral agent in order to prevent CMV disease, while in preemptive therapy (also called targeted prophylaxis) only patients who are identified as ‘high risk’ are selected for treatment. Selected trials of prophylaxis and preemptive therapy in solid-organ recipients are reviewed. The factors to be considered in using one modality or the other are side effects from antivirals, cost of monitoring and antivirals, efficacy of the two modalities, and potential emergence of drug resistance. Sensitive tests that have been used for early diagnosis and monitoring of CMV are antigenemia and the polymerase chain reaction (PCR). Antigen pp65 is a lower matrix protein and can be detected in peripheral blood leukocytes. The sensitivity and specificity are high and vary from 89% to 100% and 92% to 96%, respectively. Currently, many authors believe that the antigenemia test is more useful than the PCR test. The antigenemia test is useful for viral monitoring as a guide for preemptive therapy after organ transplantation. Persistence of high counts of antigenemia may indicate inadequate antiviral therapy or emergence of resistance. Recurrence of positive antigenemia after treatment of CMV disease can be a sign of relapse. Transplant patients who develop resistance to antiviral drugs are usually seronegative recipients who receive an organ from a seropositive donor and have several courses of antivirals for CMV disease. Ganciclovir is the most frequent antiviral agent used in transplant recipients and is usually well tolerated. Resistance to ganciclovir may occur and is usually secondary to virus mutation in the UL97 gene. The availability of sensitive diagnostic tests such as pp65 antigenemia has made the early diagnosis of CMV possible in organ transplant recipients. CMV is being treated much earlier now, and progression to disseminated disease is uncommon. Prudent use of antiviral drugs will hopefully limit the problem of drug resistance.     

Epstein-Barr virus infection in renal transplant recipients. Effects of antithymocyte globulin and interferon

We studied Epstein-Barr (EB) virus excretion and antibody in 41 renal transplant recipients enrolled in a placebo-controlled trial of human leukocyte interferon. Half the patients were also treated with antithymocyte globulin. Epstein-Barr virus excretion occurred more often in recipients of cadaver kidneys (P = 0.03) and those receiving antithymocyte globulin (P = 0.04) and less often in patients given interferon (P = 0.08). Antibody to viral capsid antigen increased fourfold or more in 12 of 22 patients treated with antithymocyte globulin and in none of the non-antithymocyte globulin-treated group (P = 0.0002). Antibody to the restricted component of early antigen rose fourfold or more in eight patients and appeared related to the occurrence of syndromes similar to those attributed to cytomegalovirus in transplant recipients. We conclude that increasing immunosuppression augments the rate of EB virus reactivation and that EB virus may be an important pathogen in heretofore ill-defined syndromes.     

Polymerase chain reaction in detection of CMV DNA in renal allograft recipients

This study investigates the w of polymerase chain reaction (PCR) in comparison with viral culture and serology for monitoring of cytomegalovirus (CMV) infection in 21 consecutive renal allograft recipients mated with a quadruple immunosuppression protocol. In addition, an attempt is made to explore the significance of quantitation of CMV signals obtained from peripheral blood leucocytes.
CMV infection developed in 16 patients with seven of the patients having organ involve mat. All of these 16 patients bad a fourfold rise in antibody as well as positive identification of CMV DNA in peripheral blood leucocytes by PCR. Blood viral cultures were negative in two of these patients. All five patients who remained PCR negative also remained culture negative with no antibody change. PCR detected CMV infection on average 15 days and 20 days earlier than viral culture and serology respectively. All except one of the patients with CMV organ involvement had an initial peak of CMV DNA followed by prolonged carriage of detectable CMV. The majority of patients with fever only or asymptomatic CMV infection had a transient peak of CMV DNA.
A high incidence of CMV disease with organ involvement occurred in seronegative recipients of kidneys from seropositive donors (3/5) and in seropositive recipients Of kidneys from seronegative donors (3/7). OKT3 was associated with a higher incidence of CMV organ involvement compared to Antilymphocytic globulin (3/5 v 4/16) but there was a higher incidence of CMV mismatched patients in the OKT3 created group.
This study confirmed the high incidence of CMV infection in renal allograft recipients on an aggressive immunosuppression regimen. The detection of CMV DNA in peripheral blood leucocytes by PCR is a sensitive and specific marker of CMV infection. It enables an earlier diagnosis of CMV infection. The precise role for monitoring of CMV DNA levels is yet to be fully defined.     

Failure of prophylactic ganciclovir to prevent cytomegalovirus disease in recipients of lung transplants.

In an effort to prevent cytomegalovirus (CMV) pneumonitis, seven consecutive CMV-seronegative lung transplant recipients of organs from seropositive donors (D+/R-) were given ganciclovir, 2.5-5 mg/kg intravenously twice daily for the first 10-21 days after transplantation, and commercial polyvalent immune globulin, 200-400 mg/kg every 7-14 days intravenously, for the first 2-3 weeks after transplantation. This regimen was followed by oral acyclovir. Six patients developed CMV viremia and all developed CMV pneumonitis. Viremia occurred later in these patients compared with D+/R- patients who received alternative forms of CMV prophylaxis or CMV-seropositive recipients who received no specific prophylaxis (P = .023 and P = .021, respectively). There was no statistical difference in incidence or time to onset of CMV pneumonitis. When given as described, prophylactic ganciclovir and immune globulin followed by oral acyclovir may have delayed CMV viremia but did not prevent it or pneumonitis in high-risk lung transplant recipients.     

Hyperimmune globulin therapy of clinical cytomegalovirus infection in renal allograft recipients

Intravenous cytomegalovirus (CMV) hyperimmune globulin therapy was used in 24 episodes of proven CMV disease in 22 renal allograft recipients. All patients had fever up to 39-40 degrees C for at least 3 days. Many patients had thrombocytopenia, leukopenia, and/or elevation of serum transaminase levels. Five had pneumonitis. The diagnosis of CMV infection was confirmed by isolation of virus from urine or bronchoalveolar lavage fluid using a rapid culture method based on the demonstration of CMV early nuclear protein in cell culture monolayers and/or by the demonstration of CMV specific IgM antibodies. The hyperimmune globulin was given until fever disappeared. The infusions were well tolerated and no side effects were recorded. A clinical response defined as normalization of body temperature, occurred in 23/24 cases. One patient with septic fever and a fatal outcome had a superinfection with tuberculosis. Two other fatal complications were caused by invasive pulmonary aspergillosis and by multiple penetrating duodenal ulcers. Two reversible acute rejections and one recurrence of the original renal disease were recorded. 19/22 patients are alive, 18 with normal renal function. We conclude that hyperimmune globulin therapy is well tolerated and may help to control sever CMV infections in renal transplant recipients.     

Prevention of CMV infection by screening for CMV antibodies in renal allograft recipients and their blood and kidney donors

The influence of the cytomegalovirus (CMV) serostatus of blood and kidney donors on patient and graft survival was studied prospectively in 73 cadaveric renal graft recipients. Six out of 12 (50%) CMV seronegative recipients receiving a kidney from a CMV seropositive donor developed CMV disease, in contrast to none of 7 CMV seronegative donor/recipient combinations. Transmission of CMV with blood products to seronegative recipients was not observed in this study. A poor graft survival of 41% 3 years after transplantation was found in CMV seronegative recipients with CMV seropositive allograft donors, compared with an actuarial 3 year graft survival of 72% in the 7 CMV seronegative donor/recipient combinations. Six patients with graft failure had a CMV infection. This study, in accordance with other studies, suggests that selection of CMV seronegative renal allograft donors for CMV seronegative recipients will improve graft survival.     

Cytomegalovirus infections and toxoplasmosis in heart transplant recipients in Sweden.

The morbidity of cytomegalovirus (CMV) infection and toxoplasmosis was evaluated in 75 heart transplant recipients. Among the 73 patients who survived more than one week after transplantation, 16 (22%) acquired primary CMV infection and 30 (41%) had evidence of secondary infection. All CMV seronegative recipients receiving hearts from seropositive donors developed CMV infection. The majority of infections (42/46) occurred during the first 4 months after transplantation. Overall, the incidence of symptomatic CMV disease was 44%. The infections were generally mild and only 1 death was attributed to primary CMV disease complicated by bacterial septicaemia and multiple organ failure. The severity of CMV disease was greatest among those with primary infection. There were 3 cases of toxoplasmosis. Two patients were toxoplasma seronegative before transplantation and developed clinical and serological signs of infection 2-3 months after transplantation despite receiving organs from seronegative donors. Of toxoplasma seronegative recipients receiving allografts from seropositive donors 3/4 were prophylactically treated with pyrimethamine for 6 weeks. None developed clinical or serological signs of toxoplasmosis while one patient who received trimethoprim-sulfamethoxazole had a subclinical infection.     

Cytomegalovirus infection in heart-lung transplant recipients: risk factors, clinical associations, and response to treatment.

The risk factors, clinical associations, and response to treatment of cytomegalovirus (CMV) pneumonia and infection were studied in 65 recipients of heart-lung transplantation. There were 29 episodes of CMV pneumonia in 22 patients. In 80% (20/25) of episodes of CMV pneumonia treated with intravenous ganciclovir, the histologic changes resolved and the patient survived. Among seronegative recipients, a seropositive donor was a significant risk factor for CMV pneumonia and infection in the first 90 days after heart-lung transplantation (P = .004 and .002, respectively). Among seropositive recipients, there was no additional risk associated with a sero-positive donor. Rates of CMV pneumonia and infection were significantly increased when treatment with augmented immunosuppression had been given in the preceding 30 days (P less than .001). A significant association was found between CMV pneumonia or infection and pulmonary bacterial infections occurring 30 days before or after such an episode (P less than .001).     

Primary and reactivated toxoplasma infection in patients with cardiac transplants. Clinical spectrum and problems in diagnosis in a defined population

We have attempted to define the serologic criteria for diagnosis of toxoplasmosis in heart transplant recipients. Of 31 patients who were seronegative before transplantation, 4 received a heart from a seropositive donor, and 3 of these 4 had seroconversion and developed life-threatening toxoplasmosis; the remaining 27 did not have seroconversion or develop clinical toxoplasmosis. Of 19 patients who had antibodies to Toxoplasma before transplantation, 10 developed significant increases in test titers of the dye test or double-sandwich IgM enzyme-linked immunosorbent assay but did not develop a clinical illness that could be attributed to toxoplasma infection. Significant serologic changes occurred more often in patients who received azathioprine, corticosteroids, and antithymocyte globulin than in those who received cyclosporine, corticosteroids, and antithymocyte globulin (p less than 0.05). These data show the wide clinical spectrum and differences in kinetics of antibody response of patients who develop toxoplasma infection after transplantation, and suggest that clinical disease occurs in those who have seroconversion but is rare in patients with preexisting antibody who have serologic evidence of recrudescence.     

Preemptive therapy is not adequate for prevention of cytomegalovirus disease in pancreas–kidney transplant recipients

Background. Cytomegalovirus (CMV) remains the most common viral infection after pancreas–kidney transplantation (PKT). Comparative studies about CMV prophylaxis in PKT have not been developed.
Methods. We analyzed CMV disease in a cohort of 84 PKT recipients. All received intravenous ganciclovir during treatment with anti-thymocyte globulin and later one of the following options for pre-transplant CMV-seropositive recipients: (a) no prophylaxis ( n =10 patients), (b) preemptive therapy (PT) ( n =13), or (c) continuous prophylaxis (CP) for 12 weeks ( n =29). Pre-transplant CMV-seronegative recipients received CP ( n =21).
Results. Eleven patients were excluded because of organ explantation in the first 15 days. Incidence of CMV disease in seropositive recipients was 30% under no prophylaxis, 23% under PT, and 6.9% under CP. Incidence of CMV disease under CP was 33.3% in seronegative recipients. Six of 9 episodes of CMV disease under CP occurred after finishing prophylaxis. Under CP, the incidence of CMV disease was significantly higher in seronegative than in seropositive recipients ( P <0.05).
Conclusion. According to the results of our study, for CMV-seropositive PKT recipients, CP is a better strategy than PT. For CMV-seronegative recipients, 3 months of CP is an inadequate strategy.     

Cytolytic IgM antibody to cytomegalovirus in primary cytomegalovirus infection in humans

Suspensions of cytomegalovirus (CMV)-infected human foreskin fibroblasts were used to measure cytolytic antibody (CyA) to CMV in serum by a 51Cr release assay. CyA was associated with IgM but not with IgG antibody to CMV, required rabbit or human complement, and was directed at a surface antigen. CyA was detectable for one to three months in the sera of 16 patients with community-acquired CMV infection and in the sera of 20 of 22 renal transplant recipients with primary CMV infection. CyA was found less frequently in the sera of renal transplant recipients with reactivated CMV infection and occurred almost exclusively when the donor was seropositive for CMV. One individual, unlike many patients with CyA, was free of symptoms. Sera from patients with either rheumatoid factor-positive arthritis or heterophil-positive infectious mononucleosis and from 70 of 71 control patients with other types of antibody to CMV yielded no 51Cr release.     

Influence of antithymocyte globulin dose on outcome in cytomegalovirus-seropositive recipients of partially T cell-depleted stem cell grafts from matched-unrelated donors

The adverse impact of positive-recipient Cytomegalovirus (CMV) serostatus on the outcome of matched-unrelated donor (MUD) grafts has been stressed. We evaluated whether CMV-seropositive MUD recipients transplanted after 1999 still showed inferior outcome compared with CMV-seronegative recipients. Two important changes in transplantation procedure were introduced in 1999: (1) reduction of antithymocyte globulin dose, (2) introduction of sequence-based typing of HLA-DRB1. Thirty-six patients received partial T cell-depleted grafts before 1999, and 44 after 1999. CMV-seropositive patients transplanted before 1999 showed a highly significant inferior outcome compared with seronegative recipients. In contrast, no difference in outcome was observed between the two groups of patients transplanted after 1999.     

Late cytomegalovirus infection after oral ganciclovir prophylaxis in renal transplant recipients

The purpose of this study was to retrospectively review our experience with a consecutive group of 41 renal transplant recipients (R) who received a kidney from a cytomegalovirus (CMV) seropositive donor (D(+)) and had 3 months of prophylaxis with oral ganciclovir. Patients were prospectively monitored clinically and with determinations of CMV antigenemia for at least 6 months. Patients were followed for a mean period of 247+/-16 days. CMV antigenemia developed in 51% of patients (53% D(+)R(-), 47% D(+)R(+)) after the transplant, but in no case was antigenemia seen during the period of oral ganciclovir therapy. Antigenemia developed at a median of 167 days post transplant (range 99-522 days) and peak antigen counts ranged from <1-3940, and tended to be higher in D(+)R(-) recipients. Infection was symptomatic in 67% of the antigenemic patients and symptoms tended to be more marked in the D(+)/R(-) than in the D(+)/R(+) group. All symptomatic patients were treated with intravenous ganciclovir (21 days) followed by 9 weeks of oral ganciclovir and responded with resolution of symptoms and antigenemia. No evidence of tissue-invasive disease was seen. Recurrence of antigenemia was observed exclusively in the D(+)R(-) group, occurred with less severe manifestations of CMV infection, and invariably responded to retreatment with ganciclovir. Our results suggest that oral ganciclovir prophylaxis is effective in preventing CMV infection during the 3-month period of prophylaxis, that a 3-month period of prophylaxis appears to be sufficient for D(+)R(+) recipients, but a longer period of oral ganciclovir prophylaxis may be needed in D(+)R(-) recipients. Clinicians caring for renal transplant recipients should be vigilant to the possibility of late CMV infection, especially in D(+)R(-) recipients.     

Cytomegalovirus pneumonia in adult autologous blood and marrow transplant recipients

CMV pneumonia is a major cause of morbidity and mortality among allogeneic BMT recipients. To assess the frequency, timing, risk factors and response to therapy of CMV pneumonia among autologous BMT recipients, we reviewed our experience with 795 patients. Sixteen (2%) patients were diagnosed with CMV pneumonia. The frequency was higher among patients who were seropositive than those who were seronegative (3.3% vs 0%, P = 0.008). Among seropositive patients, the frequency was higher among patients with hematological malignancies than patients with solid tumors (5.0 % vs 1.0%, P = 0.019). Eleven cases occurred <30 days, and five cases occurred >100 days post transplant. The overall CMV pneumonia-related mortality rate was 31%. Seven (78%) of nine patients treated with ganciclovir and IVIG prior to respiratory failure survived; neither of two patients treated after respiratory failure survived. Four of five (80%) untreated patients survived. In conclusion, CMV is a not infrequent cause of pneumonia among autologous BMT recipients. Risk factors include CMV seropositivity and an underlying hematological malignancy. A favorable response hinges on the prompt initiation of therapy. The survival of 25% of the patients without antiviral therapy suggests that the isolation of CMV from a BAL specimen occasionally reflects oropharyngeal contamination or that CMV pneumonia may sometimes be self-limited in more immunocompetent autologous BMT recipients.     

Failure to prevent cytomegalovirus infection by cytomegalovirus hyperimmune plasma: a randomized trial by the Nordic Bone Marrow Transplantation Group

Bone marrow transplantation recipients who were cytomegalovirus (CMV) seropositive and/or had a CMV seropositive donor were randomized for treatment with CMV hyperimmune plasma (n = 27) or no treatment at all (n = 27). The CMV hyperimmune plasma had neutralization titers greater than 250 and enzyme-linked immunosorbent assay titers greater than 18,000. Plasma (200 mg/kg body weight) was given on four occasions (during 2 days) from day 3 to day 76 after transplantation. Patient characteristics were similar in the two groups. After transplantation, the median CMV titers increased with greater than 100% in the group receiving the CMV plasma and decreased to less than 50% in the controls (p less than 0.01). Asymptomatic CMV infections occurred in 26% of the patients in the plasma group and 33% of the controls. The frequency of patients with symptomatic CMV infections was also the same in the two groups (51% vs 33%). Three patients each in the two groups developed CMV-associated interstitial pneumonitis. Patient survival and causes of death were similar in the two groups. To conclude, no beneficial effect of CMV hyperimmune plasma was seen in patients at high risk of developing CMV infections.     

Clinical characteristics of 13 solid organ transplant recipients with ganciclovir-resistant cytomegalovirus infection

Abstract: Background. Ganciclovir-resistant (GCV-R) cytomegalovirus (CMV) is now being reported with increasing frequency in solid organ transplant recipients. Objective . To describe the clinical characteristics and outcomes of all solid organ transplant patients with GCV-R CMV seen between 1990 and 2000 at a single center. Methods . Patients with clinically suspected GCV resistance had viral isolates subjected to phenotypic analysis by plaque reduction assay, and also genotypic analysis. Medical records of the 13 patients with GCV-R CMV were reviewed for demographic, microbiologic, clinical, and pathologic data. Results . Thirteen patients were identified, including 5 kidney, 1 heart, and 7 lung transplant recipients. All but one patient (92%) were CMV donor seropositive, recipient negative (D+/R–), and 11/13 (85%) had tissue-invasive CMV. CMV viremia was recurrent in 9/13 (69%); in 2 others, the first CMV episode was fatal. Overall, 9/13 (69%) of patients have died, all of CMV or its complications. Of the 10 who received foscarnet, only one survived. All patients had received GCV-based prophylactic regimens; 8/13 patients (62%) had received CMV hyperimmune globulin (CMVIG) as part of prophylaxis, 6/13 (46%) had received oral ganciclovir, and 5/13 (38%) had received intermittent (3×/week) IV ganciclovir for prophylaxis. Conclusions . GCV-R CMV is associated with CMV D+/R– status, tissue-invasive disease, and high mortality even with foscarnet therapy. Exposure to less than fully therapeutic levels of GCV, in the form of oral or intermittent IV GCV, is common. The use of CMVIG in prophylaxis does not appear to prevent resistance. Further work remains to be done to elucidate the risk factors and optimal mode of prophylaxis and treatment for GCV-R CMV.     

Prevention dof recurrent cytomegalovirus disease in renal and liver transplant recipients: effect of oral ganciclovir

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 Presented in part at the American Society of Transplant Physicians Meeting, May 1999, Chicago, Illinois.
).     

The importance of cytomegalovirus in heart-lung transplant recipients

The first 33 heart-lung transplant recipients in our series were studied for evidence of CMV infection. CMV infection was diagnosed by a change in the serologic status, viral culture, or histology of lung tissue. Of 18 patients who were preoperatively negative for CMV antibody, eight received organs from CMV antibody-positive donors. Five developed pneumonitis (fatal in three)l; one survived primary CMV of the GI tract. Those who recovered from CMV pneumonitis received IV ganciclovir with CMV hyperimmune globulin given prophylactically from the time of transplantation. Only three of ten antibody-negative patients receiving organs from antibody-negative donors developed primary CMV, characterized by only fever in two but associated with rejection, and repeated infection was fatal in a third. CMV reactivation/reinfection occurred in seven of 15 (47 percent) without clinical disease in all but one case. Following heart-lung transplantation, CMV is the cause of considerable mortality and morbidity. We recommend that CMV antibody-negative recipients should receive organs only from antibody-negative donors. If a donor/recipient mismatch occurs, hyperimmune globulin and ganciclovir may improve survival.     

Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem-cell disorder in which the affected cells are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins. Paroxysmal nocturnal hemoglobinuria is frequently associated with aplastic anemia, although the basis of this relation is unknown. OBJECTIVE: To assess the PNH status of patients with diverse marrow failure syndromes. DESIGN: Correlation of cytofluorometric data with clinical features. SETTING: Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. PATIENTS: 115 patients with aplastic anemia, 39 patients with myelodysplasia, 28 patients who had recently undergone bone marrow transplantation, 18 patients with cancer that was treated with chemotherapy, 13 patients with large granular lymphocytosis, 20 controls who had received renal allografts, and 21 healthy participants. INTERVENTION: Patients with aplastic anemia, myelodysplasia, or renal allografts received antithymocyte globulin. MEASUREMENTS: Flow cytometry was used to assess expression of GPI-anchored proteins on granulocytes. RESULTS: Evidence of PNH was found in 25 of 115 (22%) patients with aplastic anemia. No patient with normal GPI-anchored protein expression at presentation developed PNH after therapy (n = 16). Nine of 39 (23%) patients with myelodysplasia had GPI-anchored protein-deficient cells. Abnormal cells were not detected in patients with constitutional or other forms of bone marrow failure or in renal allograft recipients who had received antithymocyte globulin. Aplastic anemia is known to respond to immunosuppressive therapy; in myelodysplasia, the presence of a PNH population was strongly correlated with hematologic improvement after administration of antithymocyte globulin (P = 0.0015). CONCLUSIONS: Flow cytometric analysis is superior to the Ham test and permits concomitant diagnosis of PNH in about 20% of patients with myelodysplasia (a rate similar to that seen in patients with aplastic anemia). The presence of GPI-anchored protein-deficient cells in myelodysplasia predicts responsiveness to immunosuppressive therapy. Early emergence of GPI-anchored protein-deficient hematopoiesis in a patient with marrow failure may point to an underlying immune pathogenesis.