Developed Cytomegalovirus Infection Research Articles

Gastric mucosal nodules due to cytomegalovirus infection

We report a patient who developed cytomegalovirus infection after receiving a heart transplant. Nodular gastric lesions were noted on radiologic and endoscopic examinations. Endoscopic biopsy provided early evidence of cytomegalovirus infection.

FDA's newly designated treatment INDs

WE HEREIN describe two new investigational drugs, cytomegalovirus immune globulin and trimetrexate glucuronate, that physicians may obtain under treatment protocols for certain patients with the serious or life-threatening conditions for which the drugs are indicated. The drugs have been approved for early availability under special "Treatment IND" procedures by the commissioner of the Food and Drug Administration. <h3>CYTOMEGALOVIRUS IMMUNE GLOBULIN</h3><h3>Background</h3> Cytomegalovirus immune globulin (CMVIG), the subject of a Treatment IND, is sponsored by the Massachusetts Public Health Biologic Laboratories, Division of the State Laboratory Institute, Department of Public Health, The Commonwealth of Massachusetts, Boston. The product is indicated for the attenuation of primary cytomegalovirus (CMV) disease associated with kidney transplantation in seronegative recipients of kidneys from seropositive donors. Approximately 75% of untreated seronegative recipients would be expected to develop CMV infection.¹Clinical studies have shown a 50% reduction in primary CMV disease in renal transplant recipients given CMVIG.

FDA's Newly Designated Treatment INDs

WE HEREIN describe two new investigational drugs, cytomegalovirus immune globulin and trimetrexate glucuronate, that physicians may obtain under treatment protocols for certain patients with the serious or life-threatening conditions for which the drugs are indicated. The drugs have been approved for early availability under special IND procedures by the commissioner of the Food and Drug Administration. CYTOMEGALOVIRUS IMMUNE GLOBULIN Background Cytomegalovirus immune globulin (CMVIG), the subject of a Treatment IND, is sponsored by the Massachusetts Public Health Biologic Laboratories, Division of the State Laboratory Institute, Department of Public Health, The Commonwealth of Massachusetts, Boston. The product is indicated for the attenuation of primary cytomegalovirus (CMV) disease associated with kidney transplantation in seronegative recipients of kidneys from seropositive donors. Approximately 75% of untreated seronegative recipients would be expected to develop CMV infection. 1 Clinical studies have shown a 50% reduction in primary CMV disease in renal transplant recipients given CMVIG.

Cytomegalovirus infections in heart and heart and lung transplant recipients.

Of the first 166 heart and 15 heart and lung transplant recipients at Papworth Hospital, Cambridge, who survived for more than one month after transplantation, 162 were investigated for cytomegalovirus (CMV) infection by serological methods. Altogether, 73 (45%) developed CMV infection after transplantation: 30 (18.5%) had acquired primary infection and 43 (26.5%) reactivation or reinfection. Six patients died of primary infection, probably acquired from the donor organ. Recipients negative for CMV antibody who received an organ from an antibody positive donor had the most severe disease. Heart and lung transplant recipients experienced more severe primary CMV infection than those in whom the heart alone was transplanted. The most sensitive and rapid serological method was a mu-capture enzyme linked immunosorbent assay (ELISA) for detecting CMV specific IgM, the amount of which was often of prognostic value and influenced the management of patients.

Transfusion-acquired cytomegalovirus infection in neonates. A prospective study.

The incidence of cytomegalovirus (CMV) infection was determined in 114 transfused neonates of any birthweight born to CMV antibody-negative mothers. In a second phase of this study, an additional 28 transfused infants weighing less than 1250 g, born to both CMV antibody-negative and antibody-positive mothers, were followed. All infants underwent weekly virus culture and monthly serology during hospitalization and at 6 to 12 weeks after their last transfusion. Only one of 126 (0.8%) seronegative infants and one of 16 (6.3%) seropositive infants developed CMV infection. If the assumption is made that the CMV-infected infant received only 1 unit of infectious blood, the risk of transfusion-acquired CMV infection to seronegative infants is 0.16 percent per cellular unit transfused or 0.37 percent per seropositive cellular unit transfused. Despite similarities in the prevalence of CMV antibody in the donor population, the age of blood products used, and the mean number of donor exposures, a significantly lower incidence of CMV infection was found in the seronegative transfused infants than that in two previously published studies (p less than 0.01, p less than 0.001). Because no mortality and very little morbidity could be attributed to transfusion-acquired CMV infection in the nurseries, the authors can see no justification for the provision of specialized blood components for the prevention of CMV infection in this patient population.

The Risk of Cytomegalovirus Infection in Seronegative Transfusion Recipients Not Receiving Exogenous Immunosuppression

We studied 637 transfusion recipients seronegative for cytomegalovirus (CMV) in the following categories: neonates; pregnant women; and patients experiencing trauma, burns, cardiovascular surgery (adult or pediatric), major surgery, or gastrointestinal hemorrhages. Cultures and serological tests were used to follow up subjects for evidence of CMV infection for a period of three months after their last transfusion. Six (0.9%) developed CMV infection. No significant differences in risk among patient categories were observed. Infected patients received a significantly larger mean number of units of cellular blood products (CBP; 50.0 +/- 38.9 vs. 6.2 +/- 8.5; P less than .001) and plasma (23.7 +/- 15.3 vs. 2.6 +/- 4.6, P less than .001) than did uninfected patients. This result represents a risk per unit of CBP transfused of 0.14%, or approximately 0.38% per unit of seropositive CBP transfused. We observed, however, that patients exposed to CBP from greater than 30 donors had a higher risk of acquiring CMV infection than would be predicted if infectious units were randomly distributed among all donors (P less than .01).

Cytomegalovirus as a risk factor in living-related renal transplantation. A prospective study.

Forty-four living-related donor kidney (LRD) recipients (19 HLA-identical and 25 haploidentical) were followed prospectively to determine the posttransplant incidence and sequelae of cytomegalovirus (CMV) infection as they relate to the CMV status of recipients and donors. CMV titers were measured in all patients before transplantation by an immunofluorescent assay (IFA). Recipients similarly had CMV titers measured at selected intervals after transplant and during febrile episodes. Appropriate viral cultures were simultaneously performed. Laboratory evidence of infection was correlated with symptoms and signs of active CMV disease. Mean follow-up period was 20 +/- 12 months with a range of 3-51 months. Three patients were excluded due to early acute rejection resulting in graft loss. Twenty-eight of 41 donors (68%) and 22 of 41 recipients (54%) had positive CMV titers before transplantation. Six of 41 recipients (15%) subsequently developed clinical and laboratory evidence of CMV infection: three of 19 seronegative recipients and three of 22 seropositive recipients. All six patients received kidneys from seropositive donors. Four patients had severe CMV disease (2 seronegative, 2 seropositive), whereas two patients had leukopenia and fever only. Two patients with severe CMV infections subsequently lost their grafts due to unrelated causes. Overall, actual patient and graft survival of the entire group is 95% and 82%, respectively. In conclusion, individuals who receive LRD kidneys from seronegative individuals are unlikely to develop CMV infection, and transplantation of seropositive LRD kidneys may be associated with transmission of CMV in susceptible recipients regardless of their serologic status. With appropriate management of CMV illness in the posttransplant period, LRD kidney donation is safe and efficacious and should not be discouraged on the basis of pretransplant CMV serology in any donor-recipient pairing.

Cytomegalovirus Infection After Bone Marrow Transplantation: An Association With Acute Graft-v-Host Disease

Abstract Among 181 patients undergoing allogeneic bone marrow transplantation over a five-year period (1978 through 1982), cytomegalovirus (CMV) infection was a frequent and often lethal complication. Recipient pretransplant serology was the most important predictor of posttransplant CMV infection. CMV infection occurred in 26/137 seronegative recipients and in 28/44 seropositive recipients (P less than .001). Among patients who developed CMV infection, the time to infection was identical in seronegative and seropositive patients (median, 71 days post transplant). Bone marrow donor CMV serology did not significantly influence CMV infection rate. CMV infection was strongly associated with acute graft-v-host disease (AGVHD), occurring in 34/81 patients with AGVHD and 20/100 without GVHD (P less than .001). AGVHD preceded CMV infection by 33.7 days (mean) in patients developing both complications. Patients who developed CMV infections had also received more cellular blood products post transplant. These data suggest that CMV infection may occur through reactivation of latent virus (in seropositive recipients) or through exogenous exposure, possibly through transfused blood products, but that duration of immunoincompetence may be more critical than route of exposure in timing of clinically evident CMV infection. Prophylaxis tailored to the likely infectious source and more effective GVHD prevention both may be critical in preventing CMV infection after bone marrow transplantation.

Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease

Among 181 patients undergoing allogeneic bone marrow transplantation over a five-year period (1978 through 1982), cytomegalovirus (CMV) infection was a frequent and often lethal complication. Recipient pretransplant serology was the most important predictor of posttransplant CMV infection. CMV infection occurred in 26/137 seronegative recipients and in 28/44 seropositive recipients (P less than .001). Among patients who developed CMV infection, the time to infection was identical in seronegative and seropositive patients (median, 71 days post transplant). Bone marrow donor CMV serology did not significantly influence CMV infection rate. CMV infection was strongly associated with acute graft-v-host disease (AGVHD), occurring in 34/81 patients with AGVHD and 20/100 without GVHD (P less than .001). AGVHD preceded CMV infection by 33.7 days (mean) in patients developing both complications. Patients who developed CMV infections had also received more cellular blood products post transplant. These data suggest that CMV infection may occur through reactivation of latent virus (in seropositive recipients) or through exogenous exposure, possibly through transfused blood products, but that duration of immunoincompetence may be more critical than route of exposure in timing of clinically evident CMV infection. Prophylaxis tailored to the likely infectious source and more effective GVHD prevention both may be critical in preventing CMV infection after bone marrow transplantation.

Lymphocyte responses after cytomegalovirus infection in bone marrow transplant recipients--a one-year follow-up.

A group of 46 bone marrow transplant (BMT) recipients were studied by lymphocyte stimulation with cytomegalovirus (CMV) antigen before, and repeatedly in the first year after, BMT. Of these, 25 patients developed CMV infection and 68% of these got a positive lymphocyte response to CMV. The recipients with an early response (up to 3 months) to CMV antigen after the CMV infection were less prone to develop chronic graft-versus-host disease (GVHD) than those who responded later or not at all (P = 0.002). After the CMV infection, the increased lymphocyte CMV reactivity remained in recipients without chronic GVHD, but recipients with chronic GVHD usually lost their reactivity. The results suggest that it may be possible to predict patients who are not going to develop chronic GVHD by studying lymphocyte responses to CMV infections.

HLA-restricted cytotoxic T lymphocytes are an early immune response and important defense mechanism in cytomegalovirus infections.

Eighty-eight bone marrow transplant recipients were studied for development of cytomegalovirus (CMV) infections and associated cytotoxic lymphocyte responses. Sixty-one patients developed CMV infection that was diagnosed by virus isolation (18 patients), fourfold rises in serum antibodies (13), or both (30). Interstitial pneumonitis developed in 27 patients. Among patients tested during infection, HLA-restricted, CMV-specific cytotoxic T cell responses occurred in 25 patients, and non-restricted, non-T cell cytotoxic responses, or responses of undetermined cell type, occurred in 10 patients. Levels of CMV-specific cytotoxicity in infected and uninfected patients were compared in two ways. Eighty-nine percent of patients (32 of 36) with cytotoxicity greater than or equal to 15% lysis (50:1 effector-to-target-cell ratio) and 100% of patients (21 of 21) with sequential increases in cytotoxicity of greater than or equal to 15% lysis were infected. The median time of occurrence of CMV-specific cytotoxic responses preceded the median onset of viral shedding by 1.4 weeks, or rises in titers of serum antibody by 1.7 weeks, and of interstitial pneumonitis by 2.5 weeks. Immune competence, as demonstrated by survival from infection, was always associated with a CMV-specific cytotoxic response. The HLA-restricted cytotoxic T cell response appears to be important as an early host-defense mechanism and an early diagnostic evidence of infection.

The Effects of Viral Infections on Renal Transplants and Their Recipients

A prospective study of viral infections occurring after 188 renal transplants in 167 patients showed active cytomegalovirus (CMV) infection after 52 per cent of transplantations. All 37 CMV seronegative cases who received grafts from seronegative donors remained free of infection, while 24 (70.6 per cent) of 34 seronegative recipients whose donors were seropositive developed primary CMV infection (p less than 0.001). The diagnosis of 92 per cent of these primary infections was made between one and two months after grafting. Secondary CMV infection was found in 71 (62 per cent) of 114 seropositive cases, and the frequency of infection was not affected by the CMV status of the renal donor. Neither acute rejection episodes nor total graft rejections were associated with primary or secondary infections. CMV was isolated from a colonic abscess and the relationship of the virus to the intestinal disease is discussed. Herpes simplex virus was isolated from 47 per cent of cases and 32 per cent had an increase in antibody titre. Zoster was seen in nine patients, representing an incidence of 3.4 per cent per year. Other viral or mycoplasmal infections diagnosed included 71 due to respiratory tract pathogens, and a single case of hepatitis B. None of these infections was particularly severe or frequent and no association with graft rejection was detected.

Cellular Immune Response to Cytomegalovirus Infection After Renal Transplantation

A prospective study of 15 patients who received renal transplants defined the effect of renal transplantation on the cellular immune response to cytomegalovirus infection. Of 15 patients, 14 developed cytomegalovirus infection, usually in the first 2 months after transplantation, and all infections were accompanied by a normal humoral immune response. After the initiation of immunosuppressive therapy and transplantation, there was a general depression of lymphocyte transformation, as reflected in the response to phytohemagglutinin, accompanied by a specific defect in cellular immunity, as indicated by lymphocyte transformation to cytomegalovirus antigen. Eleven patients had cellular immunity to cytomegalovirus before transplantation, and all of these became negative in the first month after transplantation. In subsequent months, only 6 of the 14 study patients with cytomegalovirus infection developed specific cellular immune responses to cytomegalovirus. This occurred most often in patients who had severe febrile illnesses in association with infection. The specific cellular immune response which developed in the posttransplant period did not persist in three of the patients. This study demonstrates the dissociation of the humoral and cellular immune response to cytomegalovirus infection in renal transplant patients and indicates the importance of the loss of cellular immunity in the appearance of infection. Previously infected patients lost their cell-mediated immunity and had reactivation infections despite the presence of serum antibody.

Reactivation of murine cytomegalovirus by cyclophosphamide

THE high prevalence of cytomegalovirus (CMV) infection in transplant recipients is well known but our understanding of the risk factors involved is incomplete. It is thought that the role of immunosuppression is probably paramount. In a series of rheumatologic patients followed prospectively after initiation of cyclophosphamide therapy, a significant proportion (43%) developed CMV infection as evidenced by viruria and serologic response1. Since most of these infections were seen in initially seropositive patients, we believe that they represent reactivations of latent (herein defined as an infection in which no virus can be detected by standard plaque assays) or inapparent infection. Presumably, reactivation by immunosuppression also occurs in transplant recipients. Another risk factor for CMV infection in renal transplant recipients is the transfer of kidneys from donors seropositive for CMV into seronegative recipients2,3. We are using the mouse cytomegalovirus (MCMV) model for better understanding of the factors involved in latency and reactivation of this group of herpeslike viruses and have shown that allografting will enhance chronic MCMV infection in the recipients4. We present here further observations on the mouse model, showing that latent MCMV infection can be reactivated by treatment with cyclophosphamide and that the transfer of latently infected spleen cells can lead to infections in recipients. We also show a role for immunosuppression in the latter situation.

Cytomegalovirus (CMV) in the Compromised Host(s)

Cytomegalovirus infection in compromised hosts occurs most frequently as asymptomatic shedding of a reactivated virus. Reactivation occurs when cellular immunity is compromised owing to either immune-deficiency disease or iatrogenic intervention. When intervention is modest, most antibody-positive patients do not shed virus (19); when the group is treated with a higher mean dose of cytotoxic agents, almost all antibody-positive patients shed virus (6). In the instance where the chemotherapeutic program includes massive doses of these agents, as in heart or marrow transplantation, or when dysfunction of all cellular activity is extreme, as in the case of severe combined immune deficiency and far-advanced neoplasia, dissemination of infection with multiple-organ involvement ensues (17, 20-22). Primary infection may occur in some patients with neoplasia or in marrow-transplant recipients from either blood transfusions or from marrow, although data are insufficient to be certain (22). It has been conclusively shown, however, that seronegative renal-allograft recipients usually develop primary infection when they acquire a kidney from a seropositive donor. Clinical illness related to virus infection in the first few months after transplantation occurs in almost all patients with primary infection and seldom in those with reactivation infection (6, 25, 26). Three very intriguing observations have been made that should suggest avenues for future research: (a) Since illness occurs more closely related to development of antibody than it does to onset of virus shedding, this suggests that host response plays an important role in the disease that is obviously caused by a virus; a definition of the mechanism of this interaction could lead to an understanding of host-induced disease processes in man; (b) Graft-versus-host disease in marrow transplantation; and (c) allograft rejection in renal-graft recipients correlate with development of CMV infection (16, 22, 24, 26). Taken together, these observations are consistent with the hypothesis that virus antigens interrelate with most antigens in such a way as to lead to immune response to both antigens. Exploration of this clinical observation could lead to a greater understanding of the function of the HL-A system in man.

Cytomegalovirus Infections With Viremia Following Renal Transplantation

Six patients developing cytomegalovirus infection following renal transplantation were studied to evaluate the type of infection that might occur. All developed virological or serological evidence of infection, while two developed symptomatic illness. A syndrome resembling mononucleosis was evident in one, while a hepatitis was seen in the other. Both patients were viremic during their illness and from two weeks to two months after they returned to normal health. A third patient showing no evidence of a viral illness was viremic. Cytomegalovirus was isolated from the erythrocyte layer of all three patients, but less regularly from the leukocytes, plasma, and serum. High-titer complement-fixing antibody was present during the viremic periods, and immunosuppression appeared to have no effect on the specific antibody response and little on semiquantitatively measured lgM, lgG, and lgA levels.

Cytomegalovirus infections with viremia following renal transplantation

Six patients developing cytomegalovirus infection following renal transplantation were studied to evaluate the type of infection that might occur. All developed virological or serological evidence of infection, while two developed symptomatic illness. A syndrome resembling mononucleosis was evident in one, while a hepatitis was seen in the other. Both patients were viremic during their illness and from two weeks to two months after they returned to normal health. A third patient showing no evidence of a viral illness was viremic. Cytomegalovirus was isolated from the erythrocyte layer of all three patients, but less regularly from the leukocytes, plasma, and serum. High-titer complement-fixing antibody was present during the viremic periods, and immunosuppression appeared to have no effect on the specific antibody response and little on semiquantitatively measured lgM, lgG, and lgA levels.

IMMUNOLOGIC RESPONSE TO CYTOMEGALOVIRUS INFECTION IN RENAL ALLOGRAFT RECIPIENTS1

Craighead, J. E. (College of Medicine, Univ. of Vermont, Burlington, Vt.). Immunologic response to cytomegalovirus infection in renal a I log raft recipients. Amer. J. Epid., 1969, 90: 506–513.—Cytomegalovirus (CMV) infection was established by serologic means in 60% of renal allograft recipients undergoing transplantation at the Peter Bent Brig ham Hospital over a four-year period. Evidence of infection was not found during the month immediately following surgery; it usually appeared during the subsequent five months. More than half of the patients who possessed no serologic evidence of CMV infection before transplantation developed significant levels of antibody after the procedure. The data suggest that infection may have occurred as a result of environmental exposure to CMV in the hospital or clinic. Substantial increases in CF titer were demonstrated in the majority of allograft recipients having serum antibody at the time of transplantation. It is assumed that these patients experienced an exacerbation of “latent” virus. Evidence is presented which suggests that the antibody response is altered in some patients developing CMV infection during periods of immunosup-pressive treatment. Falling levels of CF or neutralization antibody or both were demonstrated in all but one of 11 patients who died with generalized CMV infection. Neutralization tests showed that most patients developed antibody which was reactive with three established strains of CMV.