Risk groups for clinical complications of norovirus infections: an outbreak investigation

Norovirus infections have been described as self-limiting diseases of short duration. An investigation of a norovirus outbreak in a university hospital provided evidence for severe clinical features in patients with several underlying diseases. Clinical outcomes of norovirus infection were defined. Risk-factor analysis targeting underlying diseases and medication was performed using multivariate analyses. In five outbreak wards, 84 patients and 60 nurses were infected (an overall attack rate of 32% in patients, and 76% in nurses). The causative agent was the new variant Grimsby virus. Severe clinical features, including acute renal failure, arrhythmia and signs of acute graft organ rejection in renal transplant patients, were observed in seven (8.3%) patients. In multivariate analyses, cardiovascular disease (OR 17.1, 95% CI 2.17-403) and renal transplant (OR 13.0, 95% CI 1.63-281) were risk-factors for a potassium decrease of >20%. Age >65 years (OR 11.6, 95% CI 1.89-224) was a risk-factor for diarrhoea lasting >2 days. Immunosuppression (OR 5.7, 95% CI 1.78-20.1) was a risk-factor for a creatinine increase of >10%. Norovirus infections in patients with underlying conditions such as cardiovascular disease, renal transplant and immunosuppressive therapy may lead to severe consequences typified by decreased potassium levels, increased levels of C-reactive protein and creatine phosphokinase. In the elderly, norovirus infection may lead to an increased duration of diarrhoea. Therefore patients at risk should be hospitalised early and monitored frequently. Strict preventional measures should be implemented as early as possible to minimise the risk of nosocomial outbreaks.     

Mycobacterium Tuberculosis Infection Incidence in Hospitalized Renal Transplant Patients in the United States, 1998–2000

The incidence, risk factors, and prognosis for Mycobacterium tuberculosis (MTB) infection have not been reported in a national population of renal transplant recipients. We performed a retrospective cohort study of 15,870 Medicare patients who received renal transplants from January 1, 1998 to July 31, 2000. Cox regression analysis derived adjusted hazard ratios (AHR) for factors associated with a diagnosis of MTB infection (by Medicare Institutional Claims) and the association of MTB infection with survival. There were 66 renal transplant recipients diagnosed with tuberculosis infection after transplant (2.5 cases per 1000 person years at risk, with some falling off of cases over time). The most common diagnosis was pulmonary TB (41 cases). In Cox regression analysis, only systemic lupus erythematosus (SLE) was independently associated with TB. Mortality after TB was diagnosed was 23% at 1 year, which was significantly higher than in renal transplant recipients without TB (AHR, 4.13, 95% CI, 2.21, 7.71, p < 0.001). Although uncommon, MTB infection is associated with a substantially increased risk of mortality after renal transplantation. High-risk groups, particularly those with SLE prior to transplant, might benefit from intensified screening.     

The Evolution of Nonimmune Histological Injury and Its Clinical Relevance in Adult-Sized Kidney Grafts in Pediatric Recipients

To describe the evolution, risk factors and impact of nonimmune histological injury after pediatric kidney transplantation, we analyzed 245 renal allograft protocol biopsies taken regularly from the time of transplantation to 2 years thereafter in 81 consecutive rejection-free pediatric recipients of an adult-sized kidney. Isometric tubular vacuolization was present early after transplantation was not progressive, and was associated with higher tacrolimus pre-dose trough levels. Chronic tubulo-interstitial damage and tubular microcalcifications were already noted at 3 months, were progressive and had a greater association with small recipient size, male donor gender, higher donor age and female recipient gender, but not with tacrolimus exposure. Renal function assessment showed that older recipients had a significant increase in absolute glomerular filtration rate with time after transplantation, which differed from small recipients who showed no increase. It is concluded that progressive, functionally relevant, nonimmune injury is detected early after adult-sized kidney transplantation in pediatric recipients. Renal graft ischemia associated with the donor-recipient size discrepancy appears to be a greater risk factor for this chronic histological injury, suggesting that the exploration of additional therapeutic approaches to increase allograft perfusion could further extend the graft survival benefit of adult-sized kidneys transplanted into small children.     

NK Cells Rapidly Reject Allogeneic Bone Marrow in the Spleen Through a Perforin- and Ly49D-Dependent, but NKG2D-Independent Mechanism

We have used a sensitive and specific in vivo killing assay to monitor the kinetics, anatomic location and mechanisms controlling NK-mediated rejection of Balb/c bone marrow by C57BL/6 natural killer (NK) cells. We find that NK killing of fully allogeneic bone marrow is a rapid, highly efficient process, leading to substantial rejection of transplanted marrow within 6 h of transplant and elimination of 85% of the transplanted cells within 2 days. NK-mediated rejection occurred predominantly in the spleen, with sparing of rejection in the bone marrow and lymph nodes. Rejection was dependent on Perforin gene function, but was independent of interferon-gamma. Finally, rejection of Balb/c bone marrow by B6 NK cells required signaling through the Ly49D receptor, but occurred despite blockade of NKG2D, which distinguishes these results from previous studies using semiallogeneic transplant pairs. These results identify NK cells as highly active mediators of bone marrow rejection, and suggest that inhibiting NK function early during transplantation may increase the efficiency of engraftment and allow successful engraftment of limiting doses of donor bone marrow.     

Transplant data: sources, collection and research considerations, 2004

The process of collecting and analyzing transplant data is complex. Familiarity with how these data are collected is crucial to a thorough understanding of the information. This article focuses on available OPTN-SRTR data and the continuing evolution of data collection mechanisms; how that data collection system is improving the data quality and reducing the data collection burden; how additional ascertainment of outcomes both completes and validates existing data; and caveats that remain for researchers. This year's article focuses further on research considerations related to cohort choice, timing of data submission, and potential biases in follow-up data. Ongoing improvements in data collection timeliness and scope are covered. The impact of extra ascertainment of outcomes, particularly for post-transplant kidney graft failure from Medicare data, are also examined. A section on graft failure reporting among different sources traces the steps by which the SRTR reconciles different data sources in its analyses. It is important that those reading and conducting transplant research understand the origin, structure, and scope of the available data. All of these issues should be carefully considered when choosing cohorts and data sources for analysis.     

Recrudescent Tobacco Exposure Following Heart Transplantation: Clinical Profiles and Relationship with Athero-Thrombosis Risk Markers

To identify tobacco recidivism among 86 heart transplant recipients who were smokers but demonstrated compliance with a smoking cessation program pre-transplant, we used a questionnaire and randomly tested urine for nicotine and its by-products. In 36 patients, we also evaluated circulating levels of HS-CRP, homocysteine and MPV. Twenty-eight (32.5%) of 86 patients met our definition for tobacco exposure. In this cohort, 28 (32.5%) of 86 patients met our definition for tobacco exposure. Of these 28, 12 patients self-reported tobacco use and demonstrated biochemical verification; 14 patients demonstrated only biochemical evidence of significant tobacco exposure; 2 patients self-reported tobacco use but did not demonstrate biochemical positivity. Smoking cessation within 6 months of transplantation (r = 0.52) and time post-transplantation (r = 0.43) were independent predictors for recidivism of tobacco use, p < 0.01. No differences in HS-CRP, homocysteine and MPV levels were noted among the groups. Our investigation demonstrates a high rate of tobacco recidivism among heart transplant recipients, yet few admit to it. The adverse effects of tobacco do not appear to be directly modulated by an effect on athero-thrombotic risk markers.     

Antibody Response Against the Glomerular Basement Membrane Protein Agrin in Patients with Transplant Glomerulopathy

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.     

Clinical Impact of Community-Acquired Respiratory Viruses on Bronchiolitis Obliterans After Lung Transplant

Community-acquired viral respiratory tract infections (RTI) in lung transplant recipients may have a high rate of progression to pneumonia and can be a trigger for immunologically mediated detrimental effects on lung function. A cohort of 100 patients was enrolled from 2001 to 2003 in which 50 patients had clinically diagnosed viral RTI and 50 were asymptomatic. All patients had nasopharyngeal and throat swabs taken for respiratory virus antigen detection, culture and RT-PCR. All patients had pulmonary function tests at regular intervals for 12 months. Rates of rejection, decline in forced expiratory volume (L) in 1 s (FEV-1) and bacterial and fungal superinfection were compared at the 3-month primary endpoint. In the 50 patients with RTI, a microbial etiology was identified in 33 of 50 (66%) and included rhinovirus (9), coronavirus (8), RSV (6), influenza A (5), parainfluenza (4) and human metapneumovirus (1). During the 3-month primary endpoint, 8 of 50 (16%) RTI patients had acute rejection versus 0 of 50 non-RTI patients (p=0.006). The number of patients experiencing a 20% or more decline in FEV-1 by 3 months was 9 of 50 (18%) RTI versus 0 of 50 non-RTI (0%) (p=0.003). In six of these nine patients, the decline in FEV-1 was sustained over a 1-year period consistent with bronchiolitis obliterans syndrome (BOS). Community-acquired respiratory viruses may be associated with the development of acute rejection and BOS.     

Prevalence of autoimmune diseases in islet transplant candidates with severe hypoglycaemia and glycaemic lability: previously undiagnosed coeliac and autoimmune thyroid disease is identified by screening.

AIMS: Autoimmune diseases such as Addison's or coeliac disease can contribute to hypoglycaemia or malabsorption and are more common in Type 1 diabetes (T1DM). This brief report describes the prevalence of known and newly detected autoimmune disease in clinical islet transplant candidates with longstanding T1DM and severe hypoglycaemia and/or glycaemic lability who are routinely screened for coexisting autoimmune disease. METHODS: One hundred and twenty-four C-peptide negative T1DM subjects [77 (62%) female, mean age 44 +/- 9 years, diabetes duration 28 +/- 11 years, body mass index 24.9 +/- 3.5 kg/m(2)] with indications for clinical islet transplantation at the University of Alberta were screened for autoimmune disease by history and measurement of anti-transglutaminase antibodies (positive > 10 U/ml), 09.00 h cortisol (followed by adrenocorticotrophic hormone-stimulation if < 495 nmol/l) and thyroid-stimulating hormone to determine the prevalence of coeliac disease, Addison's disease and autoimmune thyroid disease, respectively. RESULTS: Forty per cent of subjects had one or more coexisting autoimmune disease. The prevalence of autoimmune disease was 35%, coeliac disease 8% and Addison's disease 1.6%. In 11 individuals (9%), one or more autoimmune disease were newly detected (seven coeliac disease and five thyroid disease). Seven of 10 cases of coeliac disease were newly detected. A gluten-free diet in individuals with newly diagnosed coeliac disease reduced gastrointestinal symptoms, but indications for clinical islet cell transplantation persisted. CONCLUSIONS: Coexisting autoimmune disease is common in candidates for clinical islet cell transplantation. Screening in this group identified a substantial number of previously unrecognized cases. Clinicians should consider the presence of autoimmune disease even in the absence of classical symptoms.     

Rat Cytomegalovirus-Accelerated Transplant Vascular Sclerosis Is Reduced with Mutation of the Chemokine-Receptor R33

Cytomegalovirus (CMV) infection accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in both human and animal solid organ transplantation models. The host/viral mechanisms involved in this process are unclear. We examine the role of the rat CMV (RCMV)-encoded chemokine-receptor R33 in the development of TVS using a rat heart transplantation/CR model. F344 heart grafts were transplanted heterotopically into Lewis recipients. The ability of RCMV lacking the R33 gene (RCMV-Deltar33) to accelerate CR/TVS (neointimal index, NI) was compared to wild-type (WT) RCMV. Allograft recipients were infected with 1 x 10(5) pfu RCMV or RCMV-Deltar33 on postoperative day (POD) 1. Grafts from RCMV-Deltar33-infected recipients demonstrated an accelerated time to allograft CR compared to grafts from uninfected recipients (POD = 56 vs. 90), this was slower than that seen in grafts from WT-RCMV-infected recipients (POD = 45). Similarly, the degree of graft TVS formation at terminal rejection in RMCV-Deltar33 infected recipients was more severe than uninfected recipients (NI = 63 vs. 45), yet not as severe as in WT-RCMV infected recipients (NI = 83). In parallel, RCMV-Deltar33 failed to induce vascular smooth muscle cell (SMC) migration in vitro, whereas WT-RCMV induced substantial migration. The RCMV-encoded chemokine-receptor r33 is critical for RCMV-accelerated TVS/CR and vascular SMC migration.