Chronic norovirus infection in primary immune deficiency disorders: an international case series.

OBJECTIVE: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking. METHOD: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group. RESULTS: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/µL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy. CONCLUSION: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI.

Travellers returning with measles from Thailand to Finland, April 2012: infection control measures.

Countries with no autochthonous measles run the risk of the virus being imported by travellers and transmitted to unprotected citizens. In April 2012, two travellers from Finland and one from Estonia were diagnosed with measles after returning from Phuket, Thailand. They were contagious on their return flights and subsequently exposed several individuals, prompting extensive infection control measures. Two secondary cases were detected: one child who had received one vaccine dose and another who was fully vaccinated.

Control of early Aspergillus mortality after lung transplantation: outcome and risk factors.

Historic treatment strategies in our institute had resulted in 10% Aspergillus mortality within the first posttransplant year. Despite nebulized amphotericin B (nAmB) prophylaxis, a significant incidence of Aspergillus infection, usually with poor outcome, is still reported. The aim of this single-center retrospective study was to evaluate the outcomes of patients receiving either standard nAmB or additional systemic caspofungin prophylaxis for selected high-risk patients. We also tried to define independent risk factors for either fungal infection or death. We followed 76 consecutive lung transplant patients performed at our center between 2002 and 2010 from the day of transplantation. The median follow-up duration was 953 days (2.6 years; range, 16-2,751 days). The endpoints were postoperative Aspergillus colonization or disease or death due to any cause. All patients received either nAmB deoxycholate (nAmBd, 15 patients) or nAmB lipid complex (nAmBLC, 61 patients). In addition, 33 patients also received short-term caspofungin prophylaxis. The overall cumulative mortality during the entire follow up was 14.5%. No clinically confirmed invasive Aspergillus infections (IPA) occurred during the first 2 postoperative years; however, there was 1 possible and 1 probable IPA. One patient died of bronchiolitis obliterans and IPA at 2 years 3 months. Twelve patients showed transient Aspergillus colonization. The antifungal prophylactic regimens were well tolerated. The risk factors for death were age >55 years and postoperative Aspergillus detection (P = .011 and P = .015, respectively). Preoperative Aspergillus colonization/disease was not a risk factor for death (P = 1.000). The strongest predictor of death was age >55 years, due to the elder probably being more susceptible to the adverse effects of immunosuppressants. Postoperative detection of Aspergillus still seems to be an indicator of a poorer outcome. Preoperative Aspergillus colonization is not necessarily a threat with prompt institution of antifungal prophylaxis.

Cases of Salmonella Urbana in Finland, the Czech Republic and Latvia, January-February 2010.

A cluster of 14 cases of Salmonella Urbana cases in Finland, the Czech Republic and Latvia were identified in January-February, 2010. The majority of cases (11) were male and children under 16 years of age. The investigation is currently ongoing and comparison of pulsed-field gel electrophoresis (PFGE) profiles of the isolates suggests that the cases may have a common source of infection.

Clinical characteristics, outcome and the role of viral load in nontransplant patients with Epstein-Barr viraemia.

Epstein-Barr virus (EBV) is important in the development of post-transplant lymphoproliferative disease in allogeneic stem cell and solid organ transplant recipients. We have studied the clinical significance of EBV DNAaemia among nontransplant patients in a tertiary referral hospital. We retrospectively reviewed the medical records for main diagnosis, outcome, immunosuppressive/cytotoxic chemotherapy and other opportunistic infections of the patients who were found positive in quantitative real-time PCR assay for EBV (EBV-qPCR) between the years 2000 and 2007. Allogeneic stem cell and solid organ transplant recipients were excluded, and all patients in nonsurgical adult wards were included. Altogether, 62 patients had at least one plasma sample positive with an EBV-qPCR. Fifteen were immunocompetent, most had primary EBV infection, and the outcome was good. On the other hand, 36 had malignant disease, seven had HIV infection and seven had immunosuppressive conditions of an other aetiology. All but one of the malignancies were of lymphoid origin, and most of these patients had a history of multiple cytotoxic treatments. Immunosuppressed patients had higher viral loads. EBV viraemia is associated with severe immunosuppression and lymphoid malignancies.

Inhibition of semicarbazide-sensitive amine oxidases decreases lymphocyte infiltration in the early phases of rat liver allograft rejection.

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation in vitro and in vivo. VAP-1 is also an ectoenzyme with semicarbazide-sensitive amine oxidase (SSAO) activity. In this study we investigated whether inhibition of SSAO influences the inflammatory infiltration in acute rat liver allograft rejection. BN recipients of DA liver allografts were treated with 50 mg/kg/d semicarbazide, an inhibitor of SSAO, or similar volumes of saline. 10 rats/group were followed for graft survival, and 10 rats/group were sacrificed on day 7 post-transplantation for histology and T-lymphocyte isolation. The area percentage of portal inflammatory infiltrates in the grafts was assessed from digital photomicrographs. The proportion of CD4-, CD8- and IL2-receptor positive lymphocytes in the graft was quantified with flow cytometry. On day 7, semicarbazide treatment significantly decreased the inflammatory infiltrate area in the grafts. CD4-, CD8- and IL2-receptor positive cells were equally affected. However, animal survival was not affected. Blockade of the enzymatic activity of VAP-1 has a significant effect on lymphocyte infiltration early in acute liver rejection. Later, activation of other adhesion pathways can by-pass the blockade caused by VAP-inhibition.

Cytomegalovirus infection, viral DNA, and immediate early-1 gene expression in rejecting rat liver allografts.

BACKGROUND: Cytomegalovirus (CMV) infection has been linked to acute and chronic rejection. We have previously shown that concomitant rat cytomegalovirus (RCMV) infection increases portal inflammation and bile duct destruction in rejecting rat liver allografts. Many of the pro-inflammatory effects of CMV have been attributed to the immediate early (IE) proteins of CMV. We wanted to investigate whether RCMV and IE-1 gene expression persist in the liver graft in our model. METHODS: Liver transplantations were performed from PVG (RT1c) into BN (RT1n) rats. One day after transplantation, the rats were infected with RCMV. No immunosuppression was given. The graft infection was studied by viral culture, immunofluorescence, DNA in situ hybridization and RT-PCR for the detection of IE-1 mRNA at various time points. RESULTS: RCMV caused an active infection from 5 days to 2 weeks after transplantation, during which infectious virus was found in the graft. Thereafter the cultures were negative. RCMV antigens and DNA were found in hepatocytes, endothelial, inflammatory, and bile duct cells during the active infection. At 4 weeks, RCMV DNA positive hepatocytes, endothelial, inflamma tory, and bile duct cells could still be found, but in much smaller quantities. IE-1 mRNA expression was, however, only detected during the active infection, not at 4 weeks postinfection. CONCLUSIONS: RCMV IE-1 expression does not persist in the graft after the active infection, although some viral DNA can be detected in the graft up to 4 weeks. In our model, the CMV-induced increase in graft damage does not seem to require the continued expression of IE-1.

Induction of vascular adhesion protein-1 during liver allograft rejection and concomitant cytomegalovirus infection in rats.

Vascular adhesion protein-1 (VAP-1) is an adhesion molecule controlling lymphocyte recirculation through high endothelial venules of the lymph nodes. It has also been shown to be induced and to mediate lymphocyte adhesion at sites of inflammation. We studied the expression of VAP-1 and two other inducible adhesion molecules ICAM-1 and VCAM-1 in our experimental model of rat liver allograft rejection and, in addition, the effect of concomitant rat cytomegalovirus (RCMV) infection on this expression. Expression of VAP-1, ICAM-1, and VCAM-1 was studied in rat liver allografts with or without RCMV infection, isografts, and normal rat liver. Immunoperoxidase technique and monoclonal antibodies including a novel anti-VAP-1 reagent were used. VAP-1 expression was induced by acute rejection in sinusoids, hepatocytes, and also in bile ducts, when compared to the isografts or normal liver, where only blood vessels were consistently positive. Sinusoidal and hepatocyte expression of VAP-1 was prolonged by the presence of RCMV. ICAM-1 and VCAM-1 expression was also induced by acute rejection. However, RCMV increased sinusoidal VCAM-1 expression compared to uninfected grafts. The present experimental study shows that VAP-1 is up-regulated in acute rejection of liver allografts, and that this up-regulation is prolonged by RCMV infection.

Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHOD: One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.

Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts.

It has been suggested that cytomegalovirus (CMV) infection is involved in allograft rejection. In liver transplantation, it has been suggested that CMV is associated with the development of vanishing bile duct syndrome (VBDS), and persistent CMV has been found in liver grafts that develop chronic rejection. In this experimental study, the effect of rat CMV (RCMV) infection on intragraft changes was investigated in a rat model of acute liver allograft rejection. Liver transplantations were performed in a rat strain combination of PVG (RT1c) --> BN (RT1n). No immunosuppression was given. One group of animals was infected with RCMV Maastricht Strain (10(5) plaque-forming units, intraperitoneally), and another group was left uninfected. The grafts were examined histologically after the rats were killed on postoperative days 7 through 9 at the early phase and days 20 through 30 at the late phase of rejection. Immunohistochemical studies were performed to demonstrate the immunological activation markers major histocompatibility complex class II and interleukin 2 receptors, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their ligands. RCMV infection was demonstrated from the grafts by culture and direct antigen detection. In liver allografts undergoing acute rejection, CMV significantly increased portal inflammation and caused more severe bile duct damage than in the uninfected grafts. CMV was also linked to the induction of VCAM-1 in the endothelial cells. The ongoing infection was found to vary over time in the different structures of the liver grafts, including the vascular endothelium and bile ducts. Our results support an association between CMV infection and the immunological mechanisms of rejection, as well as the role of CMV in the development of bile duct damage in liver allografts.

Manipulation of alcohol drinking by liver transplantation.

The procedure of liver transplantation in alcoholic liver disease raises the question whether it would be possible to regulate the recipient's future drinking by the choice of donor liver. To address this question, we conducted transplantations with rat lines selected for high (AA) and low (ANA) alcohol preference. AA recipients having alcohol experience before the operation remained heavy drinkers regardless of whether the graft came from an AA or ANA donor. However, in these AA recipients who started drinking only after the operation, differences emerged, with AA grafts creating heavy drinking and ANA donor livers resulting in very low drinking. An overall increase in the acetaldehyde levels was introduced by the ANA livers, thus reflecting the original line differences. Similarly, in subsequent experiments, it was observed that when the aldehyde dehydrogenase inhibitor calcium carbimide was introduced in different amounts to the diet, alcohol drinking was reduced more in animals not used to drinking. The magnitude of this effect, especially in situations with established heavy drinking, is of relevance in future contemplations about liver transplantations between humans with different aldehyde dehydrogenase genotypes.

A rat model of monitoring liver allograft rejection.

Rat models are often used to study liver allograft rejection. We have established a model for rat liver allograft rejection, monitored by fine needle aspiration biopsy (FNAB), in the strain combination PVG-to-BN with a mean survival time of 37 +/- 20 days. In this model, we observed acute rejection with an intense peak of lymphoid blasts and lymphocyte-dominated inflammation in the FNAB [9.1 +/- 3.0 corrected increment units (CIU)], and an eventual increase in macrophages (up to 4.2 +/- 4.4 CIU), together with fibrosis and parenchymal necrosis in the graft. Markers of immune activation, such as an increase in IL-2-receptor (from 1% +/- 2% to 21% +/- 13%) and class II (from 20% +/- 9% to 43% +/- 13%) expressing lymphoid cells and induction of ICAM-1 in the graft, were consistent with the overall cellular response. The FNAB correlated well with parallel graft histology. In this rat model, the atraumatic monitoring makes a close follow-up possible without having to sacrifice the experimental animals. This saves work, animals, and costs in the study of liver rejection.