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Introduction: Opportunistic infection with multiple pathogens currently has become less uncommon since the application of immunosuppressant or corticosteroid in non- Human immunodeficiency virus patients. However, the clinical diagnosis of the co-infection remains difficult since the uncertainty and deficiency of the microbiologic testing methods., Patient Concerns: A 66-year-old male patient was admitted to our hospital with chest stuffiness, shortness of breath and elevated body temperature., Diagnosis: He was diagnosed with the co-infection of Pneumocystis jiroveci and cytomegalovirus by metagenomic next-generation sequencing of bronchoalveolar lavage fluid after bronchoscopy., Interventions: The patient was empirically treated with broad-spectrum antibiotics, trimethoprim/ sulfamethoxazole and ganciclovir in the beginning of the admission., Outcomes: The condition of this patient was not improved even with the intervention at the early stage of the disease. His family requested discharge after 24 inpatient days., Lessons: This case highlights the application of metagenomic next-generation sequencing in the clinical diagnosis of pulmonary co-infection. Suitable prophylaxis, necessary clinical awareness and accurate diagnosis are indispensable for immunocompromised patients with pulmonary infection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Understanding the relationship between infection and stroke has taken on new urgency in the era of the coronavirus disease 2019 (COVID-19) pandemic. This association is not a new concept, as several infections have long been recognized to contribute to stroke risk. The association of infection and stroke is also bidirectional. Although infection can lead to stroke, stroke also induces immune suppression which increases risk of infection. Apart from their short-term effects, emerging evidence suggests that poststroke immune changes may also adversely affect long-term cognitive outcomes in patients with stroke, increasing the risk of poststroke neurodegeneration and dementia. Infections at the time of stroke may also increase immune dysregulation after the stroke, further exacerbating the risk of cognitive decline. This review will cover the role of acute infections, including respiratory infections such as COVID-19, as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; immune dysregulation after stroke and its effect on the risk of stroke-associated infection; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes. Finally, we will present a model to conceptualize the many relationships among chronic and acute infections and their short- and long-term neurological consequences. This model will suggest several directions for future research.

Purpose of Review: Cytomegalovirus (CMV) keratitis, albeit an uncommon manifestation of this ubiquitous pathogen, can lead to devastating ocular morbidity. Timely diagnosis and appropriate treatment are also unfortunately uncommon. The purpose of this review is to discuss recently published literature regarding the epidemiology, pathophysiology, diagnosis, and therapy of CMV keratitis., Recent Findings: Classic clinical presentations of CMV keratitis are known; however, current investigations further elucidate characteristics of typical versus atypical disease. Ongoing research stems beyond utilizing PCR analysis towards targeted diagnostic studies with advanced imaging modalities as well as modern genotyping techniques. Strong clinical acumen combined with appropriate handling of these modern technologies are proving invaluable for rapid diagnosis and treatment of this virulent pathogen., Summary: The current recommended treatment for CMV keratitis is systemic ganciclovir. Astute clinicians must consider this diagnosis in any patient with keratitis, anterior uveitis, and intraocular hypertension. Novel diagnostic techniques should be combined with clinical exam findings to accurately and efficiently diagnose, treat, and monitor progression.

Purpose: To report the long-term outcomes of topical ganciclovir (GCV) and corticosteroids as a maintenance therapy for cytomegalovirus (CMV) corneal endotheliitis., Methods: This retrospective study included 10 eyes of 9 patients diagnosed with CMV corneal endotheliitis with a minimum 1-year follow-up at a tertiary referral hospital between 2008 and 2014. CMV corneal endotheliitis was defined by corneal edema associated with typical keratic precipitates (KPs) and a positive CMV polymerase chain reaction from aqueous humor taps. Patients receiving long-term topical 0.5% GCV and topical corticosteroids without discontinuation were included. The final corneal condition and endothelial cell density (ECD) were reported., Results: The mean age was 45.6 ± 11.7 years. The mean follow-up duration was 48 ± 25 months. All patients exhibited typical coin-shaped and/or linear KPs. A significant resolution of corneal edema and decreased KPs were achieved within 1 month in all patients after initiating topical 0.5% GCV every 2 hours and topical corticosteroids twice a day. The dose frequency was gradually tapered to GCV 4 times and corticosteroids once or twice a day as a maintenance therapy. All 10 eyes had a clear graft or corneas at the end of this study. The mean ECD was 1630 ± 699 cells per millimeter square before treatment and 1776 ± 834 cells per millimeter square at the end of the study period., Conclusions: Topical 0.5% GCV and corticosteroids as a maintenance regimen without interruption effectively preserved long-term corneal endothelial function.

Background: Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV., Methods: We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study., Results: Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants., Conclusion: Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.

We report a rare case of congenital cytomegalovirus (CMV) in a patient who was subsequently diagnosed as leukocyte adhesion defect type 1 with natural killer cell deficiency. The clinical course was complicated by severe CMV pneumonitis during the newborn period. Thereafter the infant suffered from recurrent skin infections without pus formation, otitis media, and bronchopneumonia since 3 months of age. The patient had congenital CMV infection as urine and blood plasma was positive for CMV from day 12 onward. Neutrophil chemotaxis studies showed a decrease in directed chemotaxis. Neutrophils were dyspoetic and nonfunctional lacking HLA DR, CD11c, and CD18. Lymphocytes were polyclonal but lacked CD56, CD16, and surface membrane immunoglobulin.

Purpose: The purpose of this study was to report long-term visual outcome of acute retinal necrosis., Methods: Medical records of patients with acute retinal necrosis were reviewed., Results: Thirty-two patients were diagnosed with acute retinal necrosis from 1998 to 2007. Twenty patients (25 eyes) had at least 1 follow-up and available medical records. Intravitreal injections of ganciclovir and/or foscarnet were administered in 11 of 25 eyes. Intravenous and oral antiviral medications were used in 14 of 20 and 19 of 20 patients, respectively. Eleven of 25 eyes had <25% of retina affected, 8 of 25 had 25% to 50% of retina affected, and 6 of 25 had >50% of retina affected. Mean visual acuity at all time points was best when retinitis involved <25% and decreased as area increased. All but 1 eye with >50% involvement experienced decreased vision regardless of treatment. Three of 4 eyes with 25% to 50% involvement that received intravitreal antivirals had an improvement in visual acuity of > or =2 Snellen lines. Five of 25 eyes developed retinal detachment. None of the six eyes treated with prophylactic laser detached., Conclusion: Greater extent of retinitis portends a worse visual prognosis. Although intravitreal treatment did not prevent visual acuity loss in patients with severe disease, patients with moderate disease (25-50% retina involved) did well with intravitreal therapy with most having stable or improved visual acuity. Prophylactic laser decreased the rate of detachment.

Purpose: The purpose was to study the congenital cytomegalovirus (CMV), which is the most common cause for congenital infection in the United States, affecting nearly 40,000 infants per year. There is no widely accepted treatment protocol for congenital CMV infection despite recent clinical trials with antiviral medications ganciclovir and valganciclovir., Methods: We present a case report of an infant with severe congenital CMV infection with presentation of chorioretinitis in both eyes at 5 months of age., Results: The child did not receive treatment with ganciclovir during hospitalization after birth despite severe manifestations of CMV infection. Treatment was again withheld after diagnosis of retinitis because of immunocompetent status, potential side effects of ganciclovir treatment, and location of retinitis in the retinal periphery of both eyes. The retinitis resolved during a period of 3 months., Conclusion: This case shows that CMV retinitis in infants with congenital CMV infection can be delayed in presentation and can resolve without treatment. It shows the need for more consistent monitoring for chorioretinitis in infants with congenital CMV infection.

A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.

Background: Potential xenozoonosis is a concern for the clinical application of xenotransplantation. Human cytomegalovirus (HCMV) is one of the most important pathogens in allotransplantation, but the consequences of HCMV cross-species infection of porcine xenografts are unknown. Therefore, we investigated the effects of HCMV infection of porcine endothelial cells (pEC) on cell surface molecule expression and human leukocyte recruitment., Methods: Infection of pEC inoculated with untreated, UV-inactivated, or heparin-treated HCMV at a multiplicity of infection (MOI) of 1 was analyzed by immediate early (IE) antigen expression. Cell surface receptor expression was studied by flow cytometry on pEC bulk cultures and differentially on IE-positive and -negative pEC. Adhesion of human leukocytes was tested on pEC monolayers. pEC supernatants were analyzed for cytokine content, chemotactic activity, and stimulatory effect on resting secondary pEC cultures., Results: At day 2 postinfection, IE staining was evident in 10% to 20% of HCMV-infected cells. Cell-surface expression of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) was upregulated in both IE-negative and -positive fractions of HCMV-infected pEC. In contrast, porcine major histocompatibility complex class I expression was upregulated in IE-negative cells, but reduced in IE-positive cells. The receptor alterations in the IE-negative fraction were mediated by pEC-derived soluble factors. The increased adhesion receptor expression was paralleled by enhanced human leukocyte chemotaxis and adhesion to infected pEC cultures. Pretreatment of HCMV with heparin, but not UV-inactivation, prevented adhesion-receptor modulation and reversed the increased adhesion and chemotaxis., Conclusions: After pig-to-human solid organ transplantation HCMV may infect and activate the porcine endothelium, rendering the xenograft more susceptible to human leukocyte recruitment and rejection.

Purpose of Review: To review existing data regarding late cytomegalovirus disease occurring after antiviral prophylaxis., Recent Findings: There is a continued debate as to the respective merits of the preemptive and the prophylactic approach to prevent cytomegalovirus disease after transplantation. Arguably, by allowing some infection, the preemptive approach helps build immunity in contrast to prophylaxis, explaining the occurrence of late cytomegalovirus disease in the latter approach. No study comparing directly both approaches is large enough to definitely determine whether the preemptive approach leads to a faster development of immune response protective from late disease nor whether late disease is clinically different after prophylaxis compared to early cytomegalovirus diseases. While risk factors for late cytomegalovirus disease all point to a delay in mounting immune responses, there are no identified markers that would help predict the risk for late disease at the time of prophylaxis discontinuation. Various approaches to prevent late cytomegalovirus disease have been developed: prolonged prophylaxis, microbiological surveillance and preemptive treatment after prophylaxis discontinuation. Considering the identifying risk factors for late disease, it would also make sense to envision vaccinating cytomegalovirus-seronegative recipients., Summary: The best approach to prevent or manage late cytomegalovirus disease associated with cytomegalovirus prophylaxis remains to be defined.

A series of prospective studies of a large cohort population of renal transplant recipients who did not receive cytomegalovirus (CMV) prophylaxis or preemptive therapy examined the effects of CMV infection and disease on renal allograft rejection, long-term recipient and graft survival, and new-onset diabetes mellitus. CMV infection and disease were found to be independent risk factors for allograft rejection and new-onset diabetes mellitus within 100 days posttransplantation, and for recipient mortality and uncensored graft loss beyond 100 days posttransplantation. Additional studies are needed to determine whether CMV prophylaxis or preemptive therapy may be of benefit in preventing these complications.

Objective: Inflammatory processes play an important role in atherosclerosis, and increasing evidence implies that microbial pathogens and proinflammatory cytokines are involved in the development and activation of atherosclerotic lesions. To find new inflammatory genes, we explored the vascular transcriptional response to an activator of innate immunity bacterial lipopolysaccharides (LPSs)., Methods and Results: Gene arrays identified the cytomegalovirus-inducible gene 5 (cig5)/viperin among the genes most potently induced by LPS in human vascular biopsies. Viperin was expressed by endothelial cells in atherosclerotic arteries and significantly elevated in atherosclerotic compared with normal arteries. In culture, cytomegalovirus infection, interferon-gamma, and LPS induced viperin expression., Conclusions: Viperin is expressed in atherosclerosis and induced in vascular cells by inflammatory stimuli and cytomegalovirus infection. The putative functions of viperin in atherosclerosis may relate to disease-associated microbes.

Background: Cardiac allograft vasculopathy (CAV) is initiated by allograft endothelial injury. We hypothesized that a major mechanism by which cytomegalovirus (CMV) could contribute to CAV is by dysregulation of the endothelial vasomotor response., Methods: Coronary endothelial vasomotor function was determined in 183 consecutive patients (24+/-33 months after transplantation), and was correlated with recipient and donor CMV serological status before transplantation and with documented CMV infection episodes (CMVpp65Ag+). Serial endothelial function measurements were performed in a subgroup of 53 transplant recipients (1 month and 12 months after transplantation). The composite endpoint of cardiovascular related events and death during a follow-up of 66+/-41 months was analyzed based on the CMV serological status before transplantation., Results: The medium event-free time for CMV-negative recipients of CMV-positive hearts was 8.1 years compared with 13.3 years for the other groups (P<0.05). Distal epicardial but not microvascular endothelial function was significantly impaired in CMV seronegative recipients of seropositive donor hearts (n=48) compared with all other groups (P<0.01 versus seronegative recipient/seronegative donor; P<0.05 versus seropositive recipient/seronegative donor; P<0.05 versus seropositive recipient/seropositive donor). Distal epicardial endothelial dysfunction was more pronounced in heart transplant recipients with a history of documented CMV infection compared with patients without any documented CMV infection (P<0.01). In a longitudinal subgroup analysis, distal epicardial and microcirculatory endothelial vasomotor response deteriorated significantly in recipients with documented CMV infection (P<0.05 versus baseline) but not in patients without previous CMV infection., Conclusions: Documented CMV infection episodes in heart transplant recipients are associated with impaired coronary endothelial function. CMV-negative recipients of CMV-positive donor hearts have an impaired distal epicardial endothelial function and an increased incidence of cardiovascular-related events and death during follow-up. CMV infection may contribute to allograft failure by accelerating coronary endothelial dysfunction.

Background: Herpesvirus infection is a possible risk factor for atherogenesis, and diabetics may be at particular risk. Endothelial dysfunction is an early marker for atherosclerosis, and the present study tests the hypotheses that (1) prior infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) is associated with endothelial dysfunction and (2) this may be more marked in diabetics., Methods and Results: Serum samples were tested for anti-IgG antibodies to CMV and HSV from 400 subjects (mean age for diabetics and nondiabetics, 37.8+/-4.3 and 37.9+/-3.7 [SD]). We also assessed Helicobacter pylori and Chlamydia pneumoniae serology. Coronary atheroma was quantified by means of electron beam computed tomography. Subjects (n=157) underwent venous occlusion plethysmography with acetylcholine, bradykinin, glyceryl trinitrate, norepinephrine, and l-NG-monomethyl-l-arginine. Individuals who were seropositive for CMV had reduced responses to bradykinin (P=0.005) and glyceryl trinitrate (P=0.006). The reduced response to bradykinin remained significant (P=0.045) after adjusting for the response to glyceryl trinitrate and was independent of conventional risk factors. Positive serology for the other organisms did not have an independent effect on reactivity. There was a weaker association between CMV and coronary artery calcification (P=0.09). Positive serology for each of the other pathogens did not affect reactivity, but there was a relation between total pathogen burden and impaired vascular reactivity. No significant differences were found between diabetics and nondiabetics., Conclusions: This study shows that CMV-seropositive individuals have endothelial dysfunction and impaired responses to NO. This association was independent of conventional risk factors and may be associated with increased atherosclerosis burden.

Background: A rapidly progressive disorder termed consumptive coagulopathy (CC) has been observed frequently in pig-to-baboon renal xenotransplantation. CC may be initiated by endothelial activation and induction of procoagulant factors after immunologic injury or infection, or by molecular incompatibilities between porcine coagulation proteins and primate clotting factors. The activation of porcine (P) cytomegalovirus (PCMV) and baboon (B) CMV infections has been documented in pig-to-primate xenotransplantation. The purpose of this study was to determine the contribution of PCMV and BCMV to CC., Methods: Endothelial activation was assessed by means of measurement of porcine tissue factor (pTF) in a functional assay in primary porcine aortic endothelial cells (PAEC) in vitro. Renal xenografts and native kidneys were studied by immunohistochemistry in immunosuppressed swine and baboons. BCMV and PCMV DNA was measured by quantitative molecular assays using real-time polymerase chain reaction., Results: In vitro, infection of PAEC with PCMV resulted in a significant increase of pTF expression. In vivo, pTF increase occurred without the activation of PCMV in two xenografts, and in four grafts no pTF was detected despite PCMV activation. All animals with graft pTF increase developed CC. BCMV activation in the baboon xenograft recipients did not correlate with CC or pTF increase. Control pigs and baboons had activation of PCMV and BCMV, respectively, but without coagulation abnormalities., Conclusions: PCMV induces endothelial cell activation in vitro with procoagulant expression. However, in vivo, CC and pTF induction has an uncertain relationship to increased replication of PCMV within a xenograft. Although the data do not exclude a contributory role of PCMV in CC, other mechanisms are also likely to contribute to coagulopathies observed in pig-to-primate xenotransplantation.

Background: Preemptive therapy of human cytomegalovirus (HCMV) infections has gained popularity in transplantation centers. However, standardized protocols are not available. In particular, whether a qualitative molecular assay for detection of a late (pp67) HCMV mRNA represents a valuable alternative to quantitative antigenemia remains to be defined., Methods: Overall, 82 heart (HTR) and lung (LTR) transplant recipients were randomized into two arms, where therapy was guided by qualitative pp67 mRNA NASBA (40 patients) or quantitative antigenemia (42 patients). In the NASBA arm, both primary and recurrent infections were treated upon first confirmed positive NASBA result. In the antigenemia arm, primary infections were treated upon first confirmed positive result, while recurrent infections were treated upon cutoff of 100 pp65-positive leukocytes. In both arms, therapy was stopped upon virus disappearance. Primary endpoint was duration of therapy., Results: The number of treated/infected patients was significantly higher in the NASBA arm (25/30 vs. 15/39; P=0.015), as was the number of treated/relapsing patients (5/8 vs. 1/11; P=0.040), whereas the number of HCMV-infected/total number of patients was significantly higher in the antigenemia arm (39/42 vs. 30/40; P=0.026). Thus, in the NASBA arm, although the median duration of therapy was shorter compared to antigenemia (17 vs. 21 days, P>0.05), the overall number of days of therapy was significantly higher. No patient developed HCMV disease., Conclusion: pp67 mRNA NASBA can safely replace antigenemia, with some apparent advantages (semiautomation and objectivity of test results) and disadvantages (overtreatment of patients and greater duration of overall treatment).

Background: The long-term effect of viral infections on graft dysfunction and rejection after renal transplantation is uncertain., Methods: A cohort of 37 renal transplant recipients was followed prospectively for 3 years. Creatinine clearance rate at 6 months and 3 years and chronic allograft nephropathy were correlated with the detection of cytomegalovirus (CMV), human herpesvirus 6 and human herpesvirus 7 and BK virus DNA, CMV disease, and acute rejection., Results: CMV disease was significantly associated with poor graft function at 6 months, whereas chronic allograft nephropathy was associated with graft dysfunction at 3 years. Both CMV disease and detection of human herpesvirus 6 DNA were associated with chronic allograft nephropathy., Conclusions: CMV disease was a significant cause of early graft dysfunction, whereas the presence of chronic allograft nephropathy was the main determinant of poor long-term graft function. The role of viral infections in chronic allograft nephropathy deserves further investigation.

Objective: To study the impact of cytomegalovirus (CMV) seroconversion on HIV-1 disease progression., Design: Follow-up of CMV-seronegative subjects enrolled in the French SEROCO/HEMOCO cohorts of HIV-infected subjects., Methods: A total of 290 subjects were CMV-seronegative at enrolment in the cohort. Serological testing for CMV infection was done at enrolment and then every 6 months in CMV-seronegative subjects. The person-years method was used to calculate the incidence of CMV seroconversion. After adjustment for age, the CD4+ cell count at enrolment and the HIV exposure group in a Cox model, we studied CMV seroconversion as a time-dependent variable in progression to a CD4+ cell count below 200 x 10(6) cells/l and to clinical AIDS., Results: Overall, 61 CMV seroconversions were observed. The overall incidence rate was 4.4 per 100 person-years [95% confidence interval (CI), 3.3-5.5]. The risk of progression to a CD4+ cell count below 200 x 10(6) cells/l was not increased in CMV seroconverters. However, the risk of progression to AIDS was increased two-fold in CMV seroconverters compared with subjects who remained CMV-seronegative [relative risk (RR) = 2.09; 95% CI, 1.16-3.74; P = 0.01]., Conclusion: This analysis of 61 CMV seroconversions, the largest study in the literature, confirms the impact of recent CMV infection on progression to AIDS.

Cytomegalovirus ventriculoencephalitis (CMV-VE) is a devastating opportunistic infection seen most frequently in patients with AIDS. The authors describe eight patients with AIDS and CMV-VE, who developed the clinical features of the Wernicke-Korsakoff syndrome, including impaired memory, confabulation, nystagmus, ophthalmoplegia, and ataxia. CMV-VE is perhaps a more frequent cause of the Wernicke-Korsakoff syndrome than traditional associations.

Objective: Many patients feel exhausted or depressed before the onset of an acute coronary event, but little is known about the origin of these feelings. We tested the hypothesis that the depressive symptomatology is associated with a reactivation of latent viruses and inflammation of a coronary vessel., Methods: A blood sample was drawn and a biopsy sample was obtained from the coronary lesion of 15 exhausted and 15 nonexhausted patients treated with directional coronary angioplasty because of severe angina. Blood samples were analyzed to measure antibody titers against Chlamydia pneumoniae, cytomegalovirus, and the cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. The biopsy sample was analyzed for the presence of IL-1beta and TNF-alpha., Results: Exhausted/depressed patients had higher antibody titers against cytomegalovirus, higher levels of C. pneumoniae immunoglobulin G, and higher levels of IL-1beta and TNF-alpha. No associations between the mental state of a patient and cytokine mRNA in the biopsy sample were found., Conclusions: The findings indicate that the mental state of angioplasty patients is positively associated with serological markers of inflammation. It remains to be seen whether the inflammation causes feelings of exhaustion, whether exhaustion and depression set the stage for inflammation, or whether existing feelings of exhaustion are amplified by the inflammation.

Objective: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients., Design: An open pilot non-comparative multicentre study., Methods: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase., Results: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]., Conclusion: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.

Background: Infection with human cytomegalovirus (HCMV) has been associated with vascular disease processes such as vascular allograft rejection, transplantation vasculopathy, restenosis after angioplasty, and native atherosclerosis. To elucidate underlying pathomechanisms, the effect of acute HCMV infection on the expression of pro-inflammatory adhesion molecules on human umbilical vein endothelial cells (HUVEC) and human vascular smooth muscle cells (hvSMC) was examined., Methods and Results: Cells were infected in vitro with clinical strains of HCMV and the resulting changes in adhesion molecule expression were quantified by histology and flow cytometric analysis. On HUVEC, surface expression of vascular cell adhesion molecule-1 and E-selectin was induced de novo on HCMV infection and intercellular adhesion molecule-1 expression was increased by >200%. On hvSMC, intercellular adhesion molecule-1 surface expression induced de novo, although vascular cell adhesion molecule-1 and E-selectin were not changed. Expression of major histocompatibility complex (MHC) class II, lymphocyte-function associated antigen 3 (LFA-3; CD58), and CD40 was not altered by HCMV infection in either cell type. In partially infected cultures, up-regulation of surface molecules also occurred on noninfected cells, suggesting a paracrine mechanism via a soluble factor. Expression of surface molecules could be enhanced in noninfected HUVEC and hvSMC by incubation with virus-free conditioned supernatant from HCMV-infected cells or by coincubation in transwells with infected cells. The responsible agent could be identified as IL- interleukin- (IL) 1beta by detection of de novo secretion of IL-1beta by HCMV-infected cells and by prevention of adhesion molecule up-regulation after addition of an IL-1-converting enzyme inhibitor or IL-1 receptor antagonist. Surface molecule up-regulation could be suppressed by UV inactivation of virus, but not by treatment of cell cultures with inhibitors of viral replication (ganciclovir)., Conclusion: We propose that HCMV infection induces IL-1beta release and subsequent up-regulation of pro-inflammatory adhesion molecules on noninfected neighboring cells through a paracrine mechanism. This may lead to local potentiation of the inflammatory effects of HCMV infection, not amenable to current therapeutic antiviral strategies.

Interferon-gamma stimulates major histocompatibility complex (MHC) class I antigen processing and presentation by inducing the expression of major histocompatibility complex class I heavy chains, beta2-microglobulin, the transporter associated with antigen processing, and components of the proteasome complex. We demonstrate that this effect of interferon-gamma on the major histocompatibility complex class I pathway is inhibited in human cytomegalovirus-infected fibroblasts and endothelial cells. This is the result of a direct human cytomegalovirus/cell interaction leading to a block in interferon-gamma signal transduction beginning at early times after infection and peaking at 72 hr after infection. These observations suggest a novel level of herpesvirus interference with antigen processing: protection of infected cells from the immunoregulatory effects of interferon-gamma. Thus protected, human cytomegalovirus persists and may exacerbate graft rejection or lead to fulminant infection in the immunocompromised transplant recipient.

Objectives: To use follow-up on untreated HIV-positive men to assess the prognostic information provided by baseline data on plasma HIV RNA, CD4 cell count, age, and HIV-related symptom status, separately for three specific AIDS-defining illnesses: Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV), and Mycobacterium avium complex (MAC)., Methods: The study population were 734 HIV-positive homosexual men enrolled in the Multicenter AIDS Cohort Study, with follow-up (1984-1985 through mid-1988) restricted to the antiretroviral treatment-free and prophylaxis-free era. Baseline marker values were categorized and assessed as predictor variables in separate time-to-event analyses for each of the three specific outcomes., Results: A total of 138 cases of PCP, 25 cases of CMV, and 25 cases of MAC were observed. For PCP and CMV, higher categories of HIV RNA and lower categories of CD4 cell count were associated with increased risk relative to the respective reference groups. For MAC, oral candidiasis or fever and elevated HIV RNA at baseline were the primary risk factors. Further analysis highlighted the importance of monitoring HIV RNA levels in addition to CD4 cell counts when evaluating patients' risk of developing PCP., Conclusions: In the absence of treatment, plasma HIV RNA levels provide prognostic information about the risk of these three specific AIDS-defining illnesses, independently of the CD4 cell count. These data provide a useful reference as researchers investigate changing patterns in the incidence and predictors of opportunistic infections in the era of increasingly active antiretroviral therapies.

Background: Cytomegalovirus (CMV) infection and disease has been found to be associated with decreased graft and patient survival among heart transplant recipients. We sought to explore the effect of CMV infection and disease on long-term survival in orthotopic liver transplant (OLT) recipients using a derivation and validation cohort., Methods: For derivation-validation modeling, we used data collected from two prospectively followed cohorts as the basis for multivariate analyses: 167 OLT recipients from the Boston Center for Liver Transplantation (the derivation set; median follow-up: 5.5 years, mortality: 40%) and an independent cohort of 294 OLT recipients from the Mayo Clinic (the validation set; median follow-up: 4.8 years, mortality: 27%)., Results: Underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis, number of units of red blood cells administered during transplantation, and donor CMV seropositivity were the pre- and intratransplant variables independently associated (P<0.01) with decreased long-term survival in the derivation cohort. For variables collected up to 1 year after transplantation, the need for retransplan. tation, CMV pneumonia, invasive fungal disease, and underlying liver disease other than primary biliary cirrhosis or sclerosing cholangitis were independently associated (P<0.01) with decreased long-term survival in the derivation cohort. The magnitude of the relationship of each pre-, intra-, and posttransplant factor with survival, as measured by the relative risk, did not significantly differ between the derivation and validation cohorts. The derivation model, incorporating pre-, intra-, and posttransplant factors, had receiver operating characteristic areas of 73% and 74% for 5-year mortality in the derivation and validation cohorts, respectively., Conclusions: Data from a derivation and an independent validation cohort demonstrate that CMV factors (reflected by either donor CMV seropositivity at transplantation, CMV pneumonia, or CMV disease within the first posttransplant year) are independently associated with decreased long-term survival in OLT recipients.

Background: Cytomegalovirus (CMV) has been implicated as an exacerbating agent in the development of transplant vascular sclerosis; however, specific etiologic mechanisms remain unresolved. Based upon our previous observations that CMV-infected endothelial cells (ECs) stimulate proliferation and cytokine production by allogeneic T cells, we now test the hypothesis that CMV-driven cytolytic activity may contribute to graft endothelial injury., Methods: Limiting dilutions of CMV-seropositive or -seronegative donor-derived T cells were stimulated with CMV-infected or uninfected allogeneic ECs in the presence of interleukin-2. T-cell proliferation was monitored by assay of [3H]thymidine incorporation and stimulated T cells were tested for lytic activity against CMV-infected or uninfected radiolabeled EC targets by 51Cr release assay. Natural killer (NK) cell activity was examined by incubating freshly isolated peripheral blood mononuclear cells with 51Cr-labeled targets, followed by assay of radiolabel release., Results: CMV-infected ECs were resistant to T cell- and NK-mediated cytolysis regardless of donor serostatus, nature of stimulation, or level of T-cell proliferation. In contrast, although uninfected ECs were unharmed by NK cells, these targets experienced significant lysis by T cells stimulated with either uninfected or CMV-infected ECs., Conclusions: These results implicate CMV-infected graft endothelium as a persistent source of infectious virus, a chronic stimulus for potentially destructive host inflammatory activity, and a potential trigger for the generation of lytic injury to uninfected bystander endothelia, suggesting multiple mechanisms by which this virus might perturb equilibrium at the graft/host interface.

Background: In the last few years, human cytomegalovirus (HCMV) viremia, pp65 antigenemia, and leuko- and plasma-DNAemia have been developed to quantitate virus in blood of immunocompromised patients with HCMV infection. However, thus far, no conclusive studies have been performed to define the correlation of each of the different assays with clinical symptoms in primary HCMV infections., Methods: This correlation was investigated in a population of 20 heart and heart-lung transplant recipients with primary HCMV infection using standardized virological methods., Results: Median peak HCMV viremia, antigenemia, and leukoDNAemia levels were 110 (0-2,000) p72-positive fibroblasts, 450 (27-2,000) pp65-positive leukocytes, and >10,000 (1,358-10,000) genome equivalents (GE) in the 14 symptomatic patients and 18 (1-130) p72-positive fibroblasts, 86.5 (5-350) pp65-positive leukocytes, and 248 (10-863) GE in the six asymptomatic patients, respectively. The difference was statistically significant for antigenemia (P=0.009) and leukoDNAemia (P<0.0001). However, on an individual basis, unlike viremia and antigenemia, all DNA peaks of the 6 asymptomatic patients were below the DNA range of the 14 symptomatic patients (<1,000 GE), while all the 14 symptomatic patients had DNA peaks higher than those of asymptomatic patients (>1,000 GE). Follow-up confirmed these results, showing that 1,000-2,000 GE was the threshold zone for emergence of clinical symptoms. Symptoms were never observed in patients with secondary DNA peaks, except for one patient suffering from an HCMV organ localization (HCMV gastritis)., Conclusions: LeukoDNAemia is the viral parameter of choice for monitoring of primary HCMV infections and antiviral treatment in heart and heart-lung transplant recipients. In this patient population, antigenemia-guided preemptive therapy could be replaced by leukoDNAemia-based antiviral therapy.

Objectives: To document viral and 'atypical' infections in HIV-positive patients and association with influenza-like symptoms., Patients and Methods: Monthly culture of urine, faeces and throat swabs in 63 HIV-positive patients (30 asymptomatic and 33 with AIDS-related complex/AIDS) over 5-27 months (with 1125 patient-months of follow-up), with further sample collections during influenza-like episodes. Standard viral detection methods were used. Throat swabs were assessed for Chlamydia sp. by culture and immunoblotting, and for Mycoplasma pneumoniae by polymerase chain reaction., Results: Viruses were detected in 15 (50%) and M. pneumoniae in nine (30%) out of 30 HIV-positive patients during an influenza-like illness. A close temporal relationship with symptoms was observed in 12 (40%) patients: cytomegalovirus in six (20%), M. pneumoniae in three (10%), herpes simplex virus in three (10%), and enterovirus in one (4%). Influenza-like symptoms were more frequent in asymptomatic HIV infection than in AIDS-related complex/AIDS patients (actuarial risk at 1 year, 63 versus 26%; P=0.002), particularly in those with CD4 cell counts >300 x 10(6)/l at enrolment (P=0.002). At least 44% (four out of nine) M. pneumoniae infections were asymptomatic and 78% (seven out of nine) were associated with prolonged excretion (2-17 months). Chlamydia sp. were not detected., Conclusions: Influenza-like symptoms were more likely to be reported by HIV-positive patients at early stages of disease, possibly as a result of differences in immune responses to viral infection. There was a close association in 40% of cases between the development of symptoms and detection of cytomegalovirus, herpes simplex virus, enterovirus and M. pneumoniae (a previously unrecognized association).

Background: A wealth of clinical and experimental evidence exists for cytomegalovirus (CMV) infection as an accelerating factor in the development of cardiac allograft vasculopathy. In this study, the impact of 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) on rat CMV infection-enhanced cardiac allograft vasculopathy is investigated., Methods and Results: Heterotopic rat cardiac allografts were performed from the DA to the WF rat strain, and the recipients were immunosuppressed with cyclosporine A 2 mg.kg-1.d-1 s.c. for a period of 90 days until the end of experiment. Two groups of recipients were infected intraperitoneally with 10(5) plaque-forming units of rat CMV, whereas one group was left noninfected and used as controls. One group of rat CMV-infected rats was treated with DHPG with an initial dose of 20 mg/kg i.p. and a maintenance dose of 10 mg/kg i.p. twice a day from 1 day before transplantation to 30 days after transplantation. Compared with noninfected rats, rat CMV infection was associated with a significant increase in intimal thickening, from 0.68 +/- 0.10 to 1.30 +/- 0.12 score units (P < .01), and double the number of vessels affected (P < .01). DHPG treatment significantly reduced intimal thickening in rat CMV-infected rats, from 1.30 +/- 0.12 to 0.68 +/- 0.13 score units (P < .01), and halved the number of vessels affected (P < .01)., Conclusions: The present results demonstrate that DHPG prophylaxis entirely abolishes the accelerating effect of rat CMV infection on cardiac allograft vasculopathy in immunosuppressed rat recipients, which is consistent with our earlier findings demonstrating a similar effect in nonimmunosuppressed rat aortic allografts. Taken together, these results suggest that DHPG might be useful in the prevention of CMV-accelerated cardiac allograft vasculopathy among heart transplant recipients.

Guillain-Barré syndrome (GBS) is usually preceded by infections, in particular cytomegalovirus (CMV) and Campylobacter jejuni infection. We studied the clinical and electrophysiologic features of 20 CMV-associated GBS patients and compared the findings with earlier established data of C. jejuni-related GBS patients (n = 43) and of GBS patients without these infections (n = 71). The patients all participated in the Dutch GBS trial in which we compared the effect of intravenous immune globulins and plasma exchange. We demonstrate that CMV-related GBS patients have a different clinical pattern in comparison with the other two GBS groups. They are significantly younger, initially have a severe course indicated by a high frequency of respiratory insufficiency, and often develop cranial nerve involvement and severe sensory loss. This is in contrast to C. jejuni infection, which is associated with motor GBS. Both infections are associated with delayed recovery compared with the GBS patients without these infections.

Background: Major risk factors for accelerated allograft arteriosclerosis include humoral and cellular immune response, hyperlipidemia, and viral infections. We demonstrated earlier that rat cytomegalovirus (RCMV) infection doubles smooth muscle cell proliferation and intimal thickening of rat aortic allografts. In this study, the effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograft arteriosclerosis are investigated., Methods and Results: Aortic allografts from the DA to the WF rat strain were used. The recipients were inoculated with 10(5) plaque-forming units of RCMV 1 day after transplantation. Two groups of RCMV-infected rats were treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day for a period of 14 days. In the DHPG prophylaxis group (n = 22), the drug administration started 1 day before infection, and in the DHPG treatment group (n = 17), 7 days after infection. One group of infected rats was left untreated (n = 21). The grafts were removed 7 and 14 days and 1, 3, and 6 months after transplantation. In the DHPG prophylaxis group, no virus could be recovered by plaque assays. In the treatment group, 50% of rats were virus-positive at 1 month and 40% at 3 months. DHPG prophylaxis prevented the infiltration of inflammatory cells and their proliferation in the adventitia of RCMV-infected recipients (P < .01), with a 60% reduction in the interleukin-2 receptor expression (P < .05) and a 30% decrease in major histocompatibility complex class II expression (P = NS). DHPG prophylaxis did not significantly alter the levels of insulin-like growth factor-1, epidermal growth factor, platelet-derived growth factor-BB, transforming growth factor-beta 1, acidic fibroblast growth factor, and basic fibroblast growth factor messages in the allograft vascular wall. Early media necrosis was reduced. Arteriosclerotic alterations and proliferation of smooth muscle cells were both reduced 50% to 70% by DHPG prophylaxis (P < .05 at 3 months). The responses in the DHPG treatment group were quite similar but less impressive and statistically nonsignificant., Conclusions: We consider it likely that DHPG inhibits arteriosclerotic alterations primarily by reducing the infectious virus and thereby the inflammatory response in the allograft vascular wall; another possibility is a direct antiproliferative effect on smooth muscle cell replication. A dose-dependent inhibitory effect of DHPG on smooth muscle cell replication was recorded in an in vitro study.

A total of 30-50% of all renal transplant recipients undergo infections caused by human cytomegalovirus. With the introduction of ganciclovir and foscarnet for specific antiviral therapy there is an increasing demand for diagnostic tools that allow the early and rapid identification of CMV as the causative agent of the observed disease. We and others previously showed the direct detection of pp65 antigen in peripheral blood leukocytes to be an excellent marker for active cytomegalovirus infection. In order to establish whether the detection of CMV DNA by the polymerase chain reaction (PCR) supplies further information in this regard, we compared both methods. In 41 renal transplant patients the PCR assay yielded a sensitivity of 100% compared with 87.5% of the antigenemia assay. Specificities reached 67% and 92.5%, respectively. In 5 patients without both serological signs of infection and antigenemia, CMV DNA was also found. The duration of CMV DNA detection in PBL during active infection was significantly longer than antigenemia. Even after successful treatment of symptomatic CMV disease, DNA was present for a period of weeks without any relapse of disease. In contrast, antigenemia disappeared after antiviral therapy and reappeared only in one patient with relapse of CMV disease. We conclude that PCR offers no advantages over antigen detection in monitoring for CMV infections after renal transplantation.

Gastrointestinal infection due to cytomegalovirus occurs frequently in liver transplant recipients. Upper gastrointestinal cytomegalovirus infection is associated with subjective complaints of nausea, a sense of abdominal fullness, and occasionally emesis and/or dysphagia. In order to determine whether these symptoms reflect a disruption of the normal motility of the stomach, the following study was performed. Eleven individuals who were evaluated for liver transplantation were prospectively recruited and studied as follows: (1) upper gastrointestinal endoscopy with biopsy of the gastric antral mucosa; (2) viral culture of the gastric mucosa; (3) a histologic examination of the gastric mucosa; and (4) a radionuclide gastric emptying study was obtained before and 4-8 weeks following successful liver transplantation. Prior to liver transplantation, none had symptoms of nausea, vomiting, or epigastric fullness. All were culture-negative for cytomegalovirus. All had endoscopic and histologic evidence of portal hypertensive gastropathy but none had antral erosions or ulcers. All demonstrated normal gastric emptying of a liquid meal. Following liver transplantation, 6 remained free of gastric cytomegalovirus while 5 developed a culture-confirmed gastric cytomegalovirus infection. Those that developed a gastric cytomegalovirus infection also had more gastric symptoms, and more gastric histologic abnormalities. Moreover, those with a gastric cytomegalovirus infection demonstrated enhanced gastric retention of a liquid meal (P less than 0.01).

Higher-level auditory/cognitive functions were evaluated in 16 children: eight with asymptomatic congenital cytomegalovirus (CMV) infections and eight children documented not to have asymptomatic congenital CMV infections. Hearing sensitivity was within normal limits in all subjects. Results in both groups were within the normal range on the screening measures of verbal abilities, visual perception, social behavior, and memory span. In contrast, results of the auditory measures revealed abnormal dichotic speech perception, delayed latencies on auditory brainstem evoked responses, and disproportionately slow reaction times in a difficult listening condition (Stroop task). With the exception of dichotic speech perception, however, the pattern of auditory results suggested subtle disorders that were difficult to discern unequivocally with the small subject sample. Further studies are encouraged to determine the status of higher-level auditory/cognitive functions in children with asymptomatic congenital CMV infections.

Thermally injured mice that were given intraperitoneal injections of murine cytomegalovirus (MCMV) appeared to be clinically septic and to have increased mortality rates. To evaluate the possible role of MCMV infection in promoting bacterial translocation in burned mice, mesenteric lymph nodes were cultured from two strains of mice (BALB/c and CBA) that were given thermal injuries alone, MCMV alone, or both. BALB/c mice injected with 5 X 10(5) plaque-forming units MCMV following a 15% to 16% total body surface area scald injury had increased incidence of positive mesenteric lymph node cultures compared with other groups. No intestinal mucosal histologies, mucosal dry weights, or wet-to-dry weight ratios in any animals were abnormal. Differences in cecal bacterial concentrations were not observed. Murine cytomegalovirus infection appears to enhance bacterial translocation in this model.

One hundred sixty-four patients were prospectively studied for evidence of cytomegalovirus (CMV) infection after renal transplantation to determine the effect of primary and recurrent CMV infection on early graft and patient survival. Primary infections occurred in 62% (21 of 34) of pretransplant seronegative recipients and recurrent infection infection in 93% (121 of 130) of seropositive recipients. Symptomatic infections occurred in 81% (17 of 21) of primarily infected and 31% (37 of 121) of recurrently infected recipients. CMV infections (determined by initial virus excretion) occurred in 86% of the primarily infected and 96% of the recurrently infected symptomatic recipients by the 9th post-transplant week. In contrast, only 53% of nonsymptomatic recipients excrete virus by the 9th week. Primarily infected recipients experienced a significantly lower graft survival at 6 months than uninfected seronegative or recurrently infected patients. However, there was no significant difference in patient or graft survival at 1 year. Recipients who developed recurrent symptomatic infections had a significantly lower graft and patient survival than those recipients who developed nonsymptomatic recurrent infections (P less than 0.0002 patient survival and P less than 0.001 graft survival at 12 months).

After 3 days of symptoms suggesting a viral illness, a 35-year-old man experienced three episodes of aphasia, right-sided sensory symptoms, and bifrontal headache. Each lasted several hours. CSF examination revealed a moderate lymphocytosis consisting of 80% OKT-8+ cells. Serum anti-cytomegalovirus (anti-CMV) antibody titer was elevated at 1:1,024 and subsequently fell to 1:64. Episodic symptoms recurred 5 months later, at which time the anti-CMV titer peaked at 1:8,192. A trial of inhaled oxygen aborted two episodes after several minutes each.

The incidence and severity of cytomegalovirus (CMV) infection were evaluated in 24 renal transplant patients treated with steroids and cyclosporine and compared with 40 patients treated with steroids and azathioprine: 58% of patients receiving azathioprine and 33% of patients receiving cyclosporine required additional therapy with antithymocyte globulin (ATG) to treat steroid-resistant rejections. CMV antibody titers and cultures of urine and saliva were determined monthly for 4-6 months following transplant in all patients. Both the frequency of CMV infection (occurring in 58% of patients on steroids and cyclosporine and in 48% of patients on steroids and azathioprine) and its severity (21% of cyclosporine-treated patients and 22% of azathioprine-treated patients with symptoms) were similar in both groups. Use of ATG was associated with an increased incidence of CMV disease, especially for patients in the azathioprine group. Both the incidence of CMV disease, and the number of patients with symptoms in the azathioprine group were significantly lower when patients who had received ATG were excluded from analysis. When results were analyzed in just the cadaveric recipients in each group, the incidence and severity of CMV infection tended to be higher in azathioprine-treated patients compared with those maintained on cyclosporine. This could have been explained by the more frequent use of ATG in 84% of azathioprine maintained patients compared with 35% of cyclosporine-treated patients (P less than 0.002) since other factors, such as risk for CMV infection and Solumedrol dose for rejection were similar in both groups. The data demonstrate that ATG has a deleterious influence on the incidence and severity of CMV infection in renal transplant patients, even when the dosage of other immunosuppressive drugs is decreased during ATG therapy. Since patients treated with steroids and azathioprine tend to require ATG to treat steroid-resistant rejection more frequently than do patients on cyclosporine, this effect of ATG must be taken into account when evaluating CMV infection in patients on these two drug regimens.

Cytomegalovirus (CMV) infection was diagnosed in 28% (n = 144) of 516 renal allograft recipients treated with cyclosporine-prednisone (CsA-Pred) immunosuppressive therapy. The majority of infections produced either asymptomatic (n = 37) or mild-to-moderate (n = 75) clinical disease, while 10% were lethal (n = 14). Transplantation from a seropositive donor to a seronegative recipient was associated with an increased incidence of (CMV) infection but did not predispose to more severe clinical disease. Similarly, donor source (cadaver [CAD] vs. living-related donor [LRD]), age greater than or equal to 45 years, and antecedent pulse steroid therapy for the treatment of acute rejection were not correlated with clinically more severe disease. An increase in serum creatinine to greater than or equal to 25% of preinfection nadir values occurred in association with CMV infection in 106 patients, returning to nadir values or below in 74.5% of these individuals. CMV infection did not impact on actual patient survival among recipients of LRD or CAD allografts or on actual 1-year HLA-haploidentical or HLA-identical LRD graft survival. In contrast, actual 1-year cadaveric graft survival was significantly lower among CMV-infected (n = 95) vs. uninfected (n = 198) patients (75.8% vs. 87.8%, P = .01). In association with the finding of reduced actual 1-year CAD graft survival, CMV-infected patients were found to be more predisposed to develop acute rejection episodes. Of the CMV-infected CAD graft recipients, 48.4% developed greater than or equal to 1 acute rejection episode during the first year following transplantation vs. 25.3% of their uninfected counterparts (P less than .001). The impact of CMV infection in CsA-Pred treated renal transplant recipients does not differ substantially from that reported historically in association with prednisone-azathioprine immunosuppressive therapy.

Two factors which have gained attention as possible contributors to success of renal allografts are freedom from infection with cytomegalovirus (CMV) after transplant and administration of multiple blood transfusions pretransplant. In order to determine the interrelationship of these two variables, we analyzed 55 recipients of well matched (at least two antigens) cadaveric kidneys. In this study, absence of CMV infection and receipt of multiple transfusions both provided favorable outcomes. When patients were grouped by both factors, those who were free of infection and received multiple transfusions did significantly better than any other combination. Infection with CMV decreased the frequency of allograft survival in multiply transfused patients to a point intermediate between the above group and those who had not been multiply transfused. Since CMV infection can be predicted by measurements made pretransplant, and since up to one-quarter of CMV infection which develops post-transplant is transmitted with the allograft, administration of multiple transfusion to all patients and the use of donors who are free of latent CMV infection for CMV antibody-negative potential recipients should increase allograft success. For those potential recipients who already have latent CMV infection, further study will be necessary to determine what stimuli can be given pretransplant to prevent the interference with the beneficial effect of multiple transfusion.