Systemic Cytomegalovirus Infection Research Articles

Cytomégalovirus et lupus érythémateux systémique : une infection grave de diagnostic difficile

There are a few reports only on cytomegalovirus (CMV) reactivation in lupus. Diagnosis of this infection is difficult and can be associated with of a poor outcome. We report three cases of infection with CMV that occurred in patients with lupus and review the literature. The three reported patients presented with fever, polyarthritis, myocarditis and enteritis. Lupus was longstanding and the patients were receiving corticosteroids or cyclophosphamide. There was no major CD4 lymphopenia. The diagnosis was obtained with the presence of antigenemia pp65. The outcome was favorable with antiviral therapy in two patients, while the remaining patient died. In the English literature, pulmonary and intestinal involvement seem frequent, and associated with poor prognosis. In systemic lupus CMV infection is often serious and difficult to diagnose. Risk factors, treatment and prophylaxis remain to be evaluated in this population. The incidence of this infection could increase among patients receiving a biotherapy.

Positive Cross-Match Living Donor Kidney Transplantation: Longer-Term Outcomes

The incidence and treatment of both systemic and pulmonary human cytomegalovirus (HCMV) infection as well as HCMV-specific T-cell immune responses were investigated in 57 consecutive lung transplant recipients (LTR) by using as cutoffs for preemptive therapy: 300 000 DNA copies/mL whole blood for systemic infections and 100 000 DNA copies/mL bronchoalveolar lavage fluid for lung infections. Results showed that out of 29/57 LTR (50.9%) needing preemptive antiviral therapy, 15 (51.7%) reached the blood cutoff, 8 (27.6%) the pulmonary cutoff and 6 (20.7%) both the blood and the lung cutoff (3 simultaneously and 3 subsequently). Recovery of HCMV-specific T-cell immune responses was achieved much earlier for CD8+ than CD4+ T cells. However, protection from HCMV reactivation was conferred by the presence of both arms of the T-cell response. In two LTR reaching the pulmonary cutoff and not preemptively treated, a full HCMV-specific CD4+ and CD8+ T-cell response was associated with resolution of lung infection. Antirejection steroid therapy suppressed T-cell immune responses, thus facilitating HCMV reactivation. In conclusion, in LTR, monitoring HCMV infection in both blood and lungs, may improve preemptive therapy efficacy. In addition, monitoring the HCMV-specific T-cell immune response appears useful for predicting control of HCMV infection in the posttransplant period.

Severe systemic cytomegalovirus infections in patients with steroid-refractory ulcerative colitis treated by an oral microemulsion form of cyclosporine: Report of two cases

CMV reactivation is frequently observed in acute flares of ulcerative colitis (UC), particularly those which do not respond to intravenous steroids. Several recent series have suggested that, in most cases, CMV reactivation does not lead to severe complications and resolves spontaneously with the UC flare and discontinuation of immunosuppression. In the present paper, we describe two patients with active UC who developed a severe systemic CMV infection during a treatment with an oral microemulsion form of cyclosporine. This is of concern, particularly in a context of increasing use of immunosuppressive drugs in UC. We propose a prophylactic and curative approach to decrease morbidity related to CMV infection in active UC.

Frequent Occult Infection with Cytomegalovirus in Cardiac Transplant Recipients despite Antiviral Prophylaxis

Despite antiviral prophylaxis, a high percentage (over 90%) of heart transplant patients experience active cytomegalovirus (CMV) infection, diagnosed by detection of viral DNA in peripheral blood polymorphonuclear leukocytes within the first few months posttransplantation. Viral DNA was detected in mononuclear cells prior to detection in granulocytes from CMV-seropositive recipients (R+) receiving a heart from a CMV-seropositive donor (D+). Based on assessment of systemic infection in leukocyte populations, both R+ subgroups (R+/D- and R+/D+) experienced a greater infection burden than the R-/D+ subgroup, which was aggressively treated because of a higher risk of acute CMV disease. Despite widespread systemic infection in all at-risk patient subgroups, CMV DNA was rarely (< 3% of patients) detected in transplanted heart biopsy specimens. The R+ patients more frequently exceeded the 75th percentile of the CMV DNA copy number distribution in leukocytes (110 copies/10(5) polymorphonuclear leukocytes) than the R-/D+ subgroup. Therefore, active systemic CMV infection involving leukocytes is common in heart transplant recipients receiving prophylaxis to reduce acute disease. Infection of the transplanted organ is rare, suggesting that chronic vascular disease attributed to CMV may be driven by the consequences of systemic infection.

A CASE OF STEROID-REFRACTORY ULCERATIVE COLITIS COMPLICATED WITH CYTOMEGALOVIRUS PNEUMONIA

We present a case of late-onset ulcerative colitis (UC) complicated with cytomegalovirus (CMV) pneumonia revealed by autopsy. A 77-year-old woman had a diagnosis of UC, and received high-dose steroids and leukocytapheresis. Then she received ganciclovir because CMV-pp65 antigenemia test revealed positive which suggested systemic or colonic CMV infection. But ganciclovir was discontinued because of thrombocytopenia and liver dysfunction. After that she had interstitial pneumonia and died of a respiratory failure. Autopsy revealed CMV colitis based on UC, and CMV pneumonia with diffuse alveolar damage. Evaluation of CMV infection in patients with steroid-refractory UC should be considered before proceeding with immunosuppressive therapy or surgery, especially in elderly patients.

Cytomegalovirus retinitis after intravitreous triamcinolone treatment of a vitrectomized eye in an immunocompetent patient.

To report a case of cytomegalovirus (CMV) retinitis after intravitreous injection of triamcinolone for a vitrectomized eye in an immunocompetent patient. Observational case report. Review of medical records. A 54-year-old woman with well-controlled type 2 diabetes developed anterior uveitis, papillitis, retinal vasculitis, and retinal exudates 3 months after intravitreous triamcinolone for the treatment of recurred macular edema. The intravitreal white mass of triamcinolone was ophthalmoscopically observed on the inferior peripheral retina. Polymerase chain reaction of the vitreous was positive for CMV DNA. There was no sign of systemic CMV infection. Laboratory examination revealed that the patient was a human T cell lymphotropic virus type 1 carrier and HIV negative. The retinitis responded well to systemic ganciclovir and intravitreous foscarnet, but the treatment of anterior uveitis and vitreous opacity needed repeated vitreous surgery. CMV retinitis can occur after intravitreous triamcinolone for a vitrectomized eye in an immunocompetent patient.

Cytomegalovirus Retinitis After Intravitreous Triamcinolone in an Immunocompetent Patient

To report the case of a 75-year-old man with diabetes who developed cytomegalovirus (CMV) retinitis after intravitreous injection of triamcinolone acetonide (IVTA). Observational case report. Review of medical records. A 75-year-old man with diabetic macular edema developed arcuate retinal whitening after IVTA. A presumptive diagnosis of viral retinitis was made, and a vitrectomy was performed. Polymerase chain reaction of the vitreous was positive for CMV DNA. An infectious disease consultant found no signs of systemic CMV infection, and laboratory examination revealed that the patient was HIV negative. The patient responded well to intravitreal ganciclovir and oral valganciclovir, but when therapy was discontinued, the retinitis recurred and CMV DNA was again detected in the vitreous. The retinitis once again responded to antiviral therapy. CMV retinitis can occur after local immunosuppression with IVTA. Clinicians should be aware of this rare complication of IVTA.

Disseminated Intravascular Coagulation Associated With Systemic Cytomegalovirus Infection During Cyclosporine Therapy for Ulcerative Colitis: Report of a Case

Disseminated Intravascular Coagulation Associated With Systemic Cytomegalovirus Infection During Cyclosporine Therapy for Ulcerative Colitis: Report of a Case

Greater Sensitivity of Pigtailed Macaques ( Macaca nemestrina) than Baboons to Total Body Irradiation

Two juvenile pigtailed macaques (animals 1 and 2) received total body irradiation (TBI) followed by autologous stem cell transplantation, by a procedure known to be well tolerated by baboons. In this procedure, the TBI consisted of treatment on two consecutive days with 255 cGy on one side, followed after 1–2 min by a similar dose on the other side. The two pigtailed macaques showed rapid haematopoietic engraftment, but succumbed either to systemic cytomegalovirus (CMV) infection and necrotising colitis or to haemorrhagic cystitis and tubulointerstitial nephritis. For four further pigtailed macaques (animals 3–6) the radiation procedure was changed to four equal doses of 255 cGy, given 6–12 h apart. Animals 4–6 all showed engraftment and survived for long periods (>218 days), with no, or only minor treatable, complications. Animal 3 failed to show engraftment and succumbed to radiation-induced vascular lesions and severe multiorgan haemorrhages. The results suggest that pigtailed macaques have a lower tolerance threshold than baboons, rhesus macaques or human beings to TBI, the adverse effects of TBI being indistinguishable from those seen in human patients. The results also suggest that a hyperfractionated radiation procedure can prevent radiation-induced morbidity and mortality in pigtailed macaques.

Association between Epstein-Barr virus infection and late acute transplant rejection in long-term transplant patients.

Recently we reported about a possible involvement of extrarenal systemic cytomegalovirus (CMV) infection in graft deteriorating immune processes. We now examined whether Epstein-Barr virus (EBV) may also be associated with late renal graft injury. We analyzed the expression of early antigen-, viral capsid antigen-, and a latency-associated EBV-RNA-transcript, which is not translated into protein in peripheral blood mononuclear cells of kidney transplant patients with histologically proven late acute rejection and no signs of CMV or any other infection (A), patients with stable graft function (B), and healthy probands (C). A total of 40% in group A vs. 5 and 0% in groups B and C, respectively, expressed early antigen-mRNA (P<0.05) suggesting an activation of lytic EBV infection. Response to steroid bolus therapy in group A was comparably poor with that observed in CMV-related graft injury. Our data suggest that extrarenal lytic EBV infection may also be involved in the pathogenesis of late graft injury. A controlled ganciclovir trial may prove the significance of our observation.

Further evidence against the implication of active cytomegalovirus infection in vascular atherosclerotic diseases

The possible contribution of cytomegalovirus (CMV) to pathogenetic events associated with atherosclerotic lesion establishment and progression is still controversial. We evaluated the possibility that active ongoing CMV infection could be correlated to evolution of unstable atheromatous lesion, by analyzing patients suffering from unstable angina ( n=61), acute myocardial infarction ( n=43), stable angina ( n=26) and peripheral arteriopathy ( n=22) as compared to healthy subjects ( n=30). Particularly, we assessed: past exposure to CMV by evaluating anti-CMV IgG antibodies; ongoing CMV infection by evaluating anti-CMV IgM antibodies and circulating interleukin (IL)-8 in serum; and CMV DNAemia in peripheral blood mononuclear cells (PBMC). Mean IgG values were significantly increased in patients from all groups, as compared to healthy subjects. CMV-specific IgM, as well as CMV DNAemia, were undetectable in both controls and patients. Circulating IL-8, significantly elevated in a group of individuals experiencing active CMV infection, was not significantly higher in cardiovascular disease patients, as compared to control subjects. These findings confirm previous evidence from the increased exposure to CMV infection in patients with atheromatous lesions. However, they provide further evidence against a direct implication of active systemic CMV infection in the pathogenesis of cardiovascular diseases, particularly those involving plaque instability.

Neuropathology and general autopsy findings in AIDS during the last 15 years

A retrospective study of 450 consecutive AIDS autopsy cases (397 males, 53 females; mean age at death 38.4 years) in Vienna, Austria, between 1984 and 1999 compares the central nervous system (CNS) findings in three cohorts: 1984-1992 (190 cases), 1993-1995 (162 cases) and 1996-1999 (98 cases, after introduction of triple antiretroviral therapy) and the relationship of CNS findings to systemic AIDS pathology in the latter two cohorts. In these two groups, following involvement of the lung (85% and 75%, respectively), the brain continued to be the second most frequently involved organ (decrease from 80% to 60%, respectively). Extracerebral protozoal (Pneumocystis carinii, toxoplasmosis), Mycobacterium avium complex, viral [e.g., cytomegalovirus (CMV)], multiple opportunistic organ and CNS infections, and Kaposi sarcoma significantly decreased over time. There was less decrease in fungal infections, while bacterial organ and CNS infections (except for mycobacteriosis), lymphomas, HIV-associated CNS lesions (around 30%), non HIV-associated changes (vascular, metabolic, etc.) and negative CNS findings (10-11%) remained unchanged. Nonspecific CNS changes (e.g., meningeal fibrosis) increased. Extracerebral pathology in subjects with advanced HIV-related CNS lesions showed more frequent but decreasing systemic bacterial and CMV infections than those with negative or nonspecific neuropathology, while other opportunistic and multiple organ infections and lymphomas showed no differences between both groups. In a cohort of drug abusers, HIV encephalitis, progressive multifocal leukoencephalopathy, bacterial infections, hepatic encephalopathy, and negative CNS findings were more frequent than in non-users who showed increased incidence of CMV, toxoplasmosis, or other opportunistic CNS infections, and nonspecific CNS findings; the frequency of lymphomas was similar in both drug abusers and non-users. Similar to a recent autopsy study from San Diego, these data suggest that despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding, while the increased incidence of HIV encephalitis in our small cohort of drug users was less than observed in other recent autopsy studies.

CYTOMEGALOVIRUS BALANITIS IN A RENAL TRANSPLANT RECIPIENT

Cytomegalovirus is a deoxyribonucleic acid herpesvirus that infects 90% of healthy individuals. 1 It can remain asymptomatic, resting latent in white blood cells, or can cause a mononucleosis-like infection. In patients with immunosuppression it can cause devastating systemic infections, such as esophagitis, hepatitis, pneumonitis and meningoencephalitis. 1 Additionally, cytomegalovirus is associated with significant morbidity in recipients of solid organ transplants. It has caused certain cutaneous infections and, even less commonly, penile ulcers. 2 We report on a renal transplant recipient with cytomegalovirus balanitis. CASE REPORT A 69-year-old male recipient of a renal transplant from a live nonrelated donor presented with a 3-week history of a nonhealing painless foreskin ulcer. He had been started on acyclovir 2 weeks earlier for a presumed herpetic lesion. There was no history of urethral discharge or prior sexually transmitted diseases and the patient was in a monogamous relationship. A verrucous, mildly erythematous lesion was present on the right lateral surface of the foreskin. A second well circumscribed ulcer with rolled edges was on the inner preputial area. The patient tested serologically negative for syphilis but was seropositive for cytomegalovirus, and the kidney he had received 6 years earlier was also seropositive. At circumcision adequate margins of grossly normal appearing foreskin were excised. Pathological examination of the excised foreskin revealed the classic intranuclear inclusions of cytomegalovirus infection (fig. 1). Immunoperoxidase staining for cytomegalovirus was positive and confirmed the diagnosis. Postoperatively, the patient was treated for 1 month with intravenous ganciclovir for systemic cytomegalovirus infection. He was evaluated 8 months later for 2 ulcerative lesions on the dorsal aspect of the penis at the circumcision incision line (fig. 2). Punch biopsy again confirmed cytomegalovirus balanitis and the patient was treated with another course of ganciclovir with complete resolution of the lesions. DISCUSSION

Microglial nodular encephalitis and ventriculoencephalitis due to cytomegalovirus infection in patients with AIDS: two distinct clinical patterns.

In patients with AIDS, cerebral infection due to cytomegalovirus (CMV) results in two distinct neuropathological patterns: microglial nodular encephalitis (MGNE) and ventriculoencephalitis (VE). In order to identify clinical features to facilitate the differential diagnosis of these two forms of CMV encephalopathy in living patients, we retrospectively reviewed the clinical records of 18 patients with MGNE or VE diagnosed at autopsy. We identified the following clinical features as distinguishing the two encephalopathies: (1) MGNE manifests earlier than VE; (2) the onset of MGNE is acute, whereas the onset of VE is insidious; (3) the onset of MGNE is marked by confusion and delirium, which do not occur in VE; (4) VE is frequently associated with radiculopathy, which is absent in MGNE; and (5) VE is associated with more marked alterations in cerebrospinal fluid (high protein levels and pleocytosis). The early neurological manifestations of MGNE should prompt a search for systemic CMV infection, which may lead to earlier treatment.

Systemic Murine Cytomegalovirus Infection of Mice with Retrovirus- Induced Immunodeficiency Results in Ocular Infection but Not Retinitis

Experiments were performed to explore the ability of murine cytomegalovirus (MCMV) to disseminate to the eye following intravenous inoculation and to cause infection of ocular tissues and necrotizing retinitis in C57BL/6 mice with retrovirus-induced immunodeficiency syndrome (MAIDS). Although infectious virus could be detected in whole eye homogenates of mice with MAIDS at 10 days after intravenous MCMV inoculation, a recombinant MCMV (RM461) that carries an MCMV IE1 promoter-LacZ insert was used as a tracer virus to confirm direct infection of ocular tissues. Evidence for MCMV replication (determined by RM461-induced expression of β-galactosidase) was consistently observed in the nonpigmented epithelium of the ciliary body of the eyes of MAIDS animals at 14 days after infection. In sharp contrast, however, the neurosensory retina was spared and necrotizing retinitis failed to develop. These findings demonstrate that systemic MCMV infection of mice with MAIDS results in ocular MCMV infection without development of ocular MCMV disease. Conversion of occult subclinical MCMV infection of ocular tissues to overt clinical MCMV retinitis may require as yet unidentified cofactor(s). Identification of these cofactors could lead to more innovative therapeutic approaches for prevention and/or treatment of CMV retinitis in patients with AIDS.

Septic Shock due to Cytomegalovirus Infection in Acute Respiratory Distress Syndrome after Falciparum Malaria.

Incidence of falciparum malaria in developed countries has increased in recent years due to tourism to tropical countries and immigration from Asia and Africa. In Switzerland, about 250 cases of malaria were reported in 1994 to the Federal Office of Health, including three cases with fatal outcome.1 The most commonly described complications of plasmodia infection are cerebral malaria, acute renal failure, and severe anemia with disseminated intravascular coagulation. However, pulmonary involvement occurs in 3 to 10% of cases and represents the most serious complication of this infection, with a lethality of 70%.2,3 Furthermore, a pronounced general immunosuppression has been reported in malaria patients, which may predispose them to opportunistic infections.4 We report a case of Plasmodium falciparum infection complicated by severe acute respiratory distress syndrome (ARDS) with development of systemic cytomegalovirus (CMV) infection leading to death. This evolution implies a severe immune deficiency associated with malaria, as previously suggested in the literature.

Congenital cytomegalovirus infection after recurrent infection in a mother with a renal transplant

A woman with a renal transplant developed a systemic cytomegalovirus infection. She recovered and 3 years later she became pregnant. She had 3 days of fever in the first trimester. She delivered an infant severely affected with congenital cytomegalovirus infection. The incidence of symptomatic congenital cytomegalovirus infection in infants born to immunosuppressed mothers who develop reactivated cytomegalovirus during their pregnancy seems high.

Thrombotic microangiopathy and cytomegalovirus disease in patients infected with human immunodeficiency virus.

Thrombotic microangiopathy (TMA) can occur during the course of human immunodeficiency virus (HIV) infection. Clinical and pathological data for 29 patients with TMA and HIV infection were recorded. In a retrospective case-control study, we analyzed the link between opportunistic infections or drug therapies and TMA. Twenty-five patients (mean CD4+ cell count +/- SD, 71.9 +/- 18.3/mm3) had renal impairment, and four had neurological dysfunction. In one-half the cases, the disease was progressive with isolated fragmentation anemia appearing several months before the clinical symptoms. The diagnosis of TMA was confirmed by histological examination of kidney biopsy specimens (18 cases). Endothelial cytomegalovirus (CMV) inclusions were associated with TMA in nine of 18 cases, whereas histological examination did not detect CMV in any control specimens (P < .001). The case-control study demonstrated a link between TMA and clinical CMV infection (odds ratio, 3.9; 95% confidence interval, 1.1-14). We conclude that TMA is a late complication of HIV infection and can be associated with systemic CMV infection in this setting.

Ganciclovir therapy for cytomegalovirus-associated liver disease in immunocompetent or immunocompromised children.

Ganciclovir therapy was given intravenously to 20 children with cytomegalovirus (CMV)-associated liver disease, of whom 6 were immunocompetent and 14 were immunocompromised (9 had AIDS and 5 had solid tumors). Immunocompetent children had isolated liver disease diagnosed at birth (4 children), or systemic congenital CMV infection including liver disease (2 children). Ganciclovir was used following two regimens: A) 5 mg/kg twice daily for 8 to 86 days (mean 21); B) 7.5 mg/kg twice daily for 14 days followed by 10 mg/kg three times weekly for three months. CMV infection was diagnosed by viral isolation, detection of viral antigens, and/or CMV DNA from blood and urine. All immunocompetent children had negative CMV culture and CMV DNA detection from blood and/or urine after 14 weeks of treatment. However, the three children who were treated with regimen B showed normal ALT levels at the end of the maintenance course, whereas the children who received ganciclovir with regimen A had normal ALT levels only after about 1 year. All children with tumors initiated regimen B, but only three, who had negative CMV detection and markedly decreased ALT levels, received full treatment; of the remaining two children, one recovered after only an initial course, and the other had therapy interrupted because of hepatic failure and died 9 days later. In contrast, the children with AIDS received several ganciclovir courses for different periods at the lower dosage: they generally improved during treatment but did not recover completely, and five children died with active CMV infections. Based on our study, CMV-associated liver disease can be efficiently treated with ganciclovir both in immunocompetent and immunodeficient children. However, a single ganciclovir course including a higher dosage and prolonged therapy appeared to be more effective than several courses with lower dosages.

Visual Loss in Cytomegalovirus Retinitis Caused by Cystoid Macular Edema in Patients without the Acquired Immune Deficiency Syndrome

Although serous macular exudation has been described in patients with the acquired immune deficiency syndrome (AIDS) with active cytomegalovirus (CMV) retinitis, cystoid macular edema (CME) is not encountered in this clinical setting. In contrast to these findings, we describe vision loss due to CME occurring in immunosuppressed patients without AIDS treated for CMV retinitis. Three patients (four eyes) with systemic immunodeficiency presenting with vision loss underwent ophthalmologic examination, including fundus photography and fluorescein angiography. Systemic evaluation was performed to establish the etiology of immunodeficiency and to rule out human immunodeficiency virus infection. Patients were treated with topical corticosteroid and nonsteroidal anti-inflammatory medications for CME. All patients had severe generalized immune deficiency, related either to drug-induced immunosuppression or primary immunodeficiency. Laboratory studies confirmed the presence of systemic CMV infection. Affected eyes had mild reduction of central vision (range, 20/40 to 20/60). Three of four affected eyes had resolving CMV retinitis outside the posterior pole with mild panuveitis. These eyes showed CME on clinical examination and fluorescein angiography. The CMV lesions regressed after reduction of immunosuppressive agents or after systemic antiviral treatment. Response of CME to topical anti-inflammatory medication was variable. Cystoid macular edema can occur in the setting of resolving CMV retinitis in patients with immunodeficiency other than AIDS. This entity is distinct from serous macular exudation, which can occur in patients with AIDS with active CMV retinitis involving the posterior pole. The disparity between patients with and without AIDS in the development of CME may be important in understanding the pathogenesis of CME.