Ef de Maar

Pulmonary involvement during cytomegalovirus infection in immunosuppressed patients

Abstract: Although cytomegalovirus (CMV) pulmonary involvement after solid organ transplantation is infrequently seen nowadays, CMV pneumonitis is still a potential lethal complication. Introduction of the pp65 antigenemia assay enabled early and rapid diagnosis of CMV viremia in transplant patients prior to symptoms. Also, in asymptomatic patients with CMV viremia, a decreased pulmonary diffusion capacity could be demonstrated. In this review, we discuss clinical and subclinical pulmonary involvement of CMV infection in the immunocompromised host with an emphasis on transplant recipients. The clinical course, diagnosis, therapy, prophylaxis, and pathophysiology of CMV pneumonitis are discussed.

Effects of changing immunosuppressive regimen on the incidence, duration, and viral load of cytomegalovirus infection in renal transplantation : a single center report

Abstract: Background. In this retrospective single center study we have evaluated the relation between the immunosuppressive regimen and the incidence and characteristics of cytomegalovirus (CMV) infection in the setting without CMV prophylaxis from 1989 through 1998. Methods. All (470) first cadaveric renal transplantations in nonsensitized (PRA < 60%) patients were analyzed. Immunosuppression consisted of cyclosporine A (Sandimmune) and prednisolone from 1989 through 2‐1993 (S; 189 patients), of cyclosporine microemulsion (Neoral) and prednisolone from 3‐1993 through 5‐1997 (N; 200 patients) and of mycophenolate mofetil, Neoral and prednisolone from 5‐1997 until 1998 (M; 81 patients). The CMV pp65‐antigenemia was measured routinely at least once weekly from day 10 till 12 weeks after transplantation or until pp65‐antigenemia became negative. No CMV‐prophylaxis was given. Results. By changing from Sandimmune to Neoral and by adding mycophenolate mofetil, respectively, we observed a higher frequency of especially secondary CMV infections (S vs. N vs. M, respectively, 28 vs. 50 vs. 63%, P = 0.026; S vs. N, P = 0.027; S vs. M, P = 0.015; and N vs. M, n.s). The CMV infections lasted longer (median duration antigenemia S vs. N vs. M, respectively, 3 vs. 5 vs. 7 weeks, P = 0.0003; S vs. N, P < 0.002; S vs. M, P < 0.001; and N vs. M, P < 0.05). Viral load was higher in M (median maximal pp65‐antigenemia S vs. N vs. M, respectively, 19 vs. 14.5 vs. 73, P < 0.01; S vs. N, n.s.; S vs. M, P < 0.001 and N vs. M, P < 0.01). Conclusions. The use of Neoral and the addition of mycophenolate mofetil caused significant changes in the incidence, duration and viral load of CMV infections.

Uptake of pp65 in in vitro generated pp65-positive polymorphonuclear cells mediated by phagocytosis and cell fusion?

Objective: The cytomegalovirus (CMV) antigenemia consists of the detection of CMV pp65 in the nucleus of polymorphonuclear granulocytes (PMN), but it is unclear where and how PMN pick up virus particles or proteins. In an in vitro model for CMV antigenemia we investigated the mechanism of pp65 uptake by PMN that results in its expression in the nucleus. Methods: A series of inhibitors of different mechanisms was used to study the uptake of pp65 by PMN during coculture with CMV-infected endothelial cells and we performed a morphological analysis by light and transmission electron microscopy. Results: Nocodazole and cytochalasin B inhibited uptake of pp65 by PMN with 59.4 ± 14.1 and 73.3 ± 12.7%, respectively. The presence of anti-CMV hyperimmune globulin or lactoferrin during coculture reduced the number of pp65-positive PMN with 45.8 ± 7.0 or 40.6 ± 3.2%. Furthermore, a small number of the pp65-positive PMN obtained after coculture had fused to large cells with multilobed nuclei. PMN were observed that enclosed viral particles as well as free viral particles containing PMN in the cytoplasm. Conclusion: Fusion of viral particles with PMN and phagocytosis are both involved in the uptake of pp65.

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open‐label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor‐specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

Overcoming the problem of cytomegalovirus infection after organ transplantation: Calling for Heracles?

Although diagnosis of CMV infections and treatment of CMV disease with effetive antiviral drugs have become much easier, the persistent problem of CMV infection after solid-organ transplantation still requires solid knowledge of the pathophysiology of its clinical manifestations in order to minimize the impact of CMV infections in the future. The complex symptomatology of CMV infection after solid-organ transplantation is reviewed as well as some of the new theories attempting to explain the myriad of symptoms seen after transplantation.

Subclinical pneumonitis during cytomegalovirus infection after kidney transplantation

ABSTRACT In addition to life-threatening pneumonia, cytomegalovirus (CMV) may also causesubclinical pulmonary dysfunction after kidney transplantation. To investigate therole of plugging of cytomegalic endothelial cells (CEC) in the pulmonary capillarybed we prospectively determined specific carbon monoxide diffusion capacity(KCOc), and its components: the pulmonary diffusing membrane factor (Dm) andpulmonary capillary blood volume (Vcap) before and during CMV infection in 13kidney transplant recipients and 13 controls.During CMV infection median KCOc decreased significantly due to a decrease inboth Vcap and Dm. We illustrate the course of pulmonary diffusion in a male kidneytransplant recipient with CMV infection.We conclude that kidney transplant recipients with CMV infection have signi-ficant pulmonary diffusion disturbances due to a combination of lower Vcap andlower Dm. The most likely explanation for this phenomenon is a local inflammatoryprocess due to CMV and not plugging of cytomegalic endothelial cells.