Background Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory ...tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. Objective This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. Methods Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Results Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. Conclusion Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.
...the (genetic) diagnostic delay was long for many patients (see below). ...we looked at whether the patients' region of residence within France (which potentially influences access to a genetic ...diagnosis) was associated with the likelihood of receiving a genetic diagnosis. The progressive shift in genetic testing strategy from candidate-gene sequencing to gene panels or whole-exome or whole-genome sequencing4-6,9 is likely to have a major effect on the overall identification of PID-causing gene mutations. ...the present study might serve as a baseline for analyzing the contribution of next-generation sequencing–based testing to the genetic diagnosis of PIDs in the next 10 years.Methods The French National Reference Center for PIDs (CEREDIH) encompasses a network of pediatricians, adult clinicians, and immunologists working in immunology laboratories throughout mainland France and the overseas French territories. ...these factors were unlikely to significantly affect our overall results.
The presence of preformed donor‐specific antibodies in transplant recipients increases the risk of acute antibody‐mediated rejection (AMR). Results of an open‐label single‐arm trial to evaluate the ...safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased‐donor kidney transplants with preformed donor‐specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy‐proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow‐up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24‐70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010‐019631‐35).
In this study of terminal complement inhibition to prevent antibody‐mediated rejection in deceased‐donor kidney transplant recipients with donor‐specific antibodies, the treatment failure rate for eculizumab is low compared with the expected rate for standard of care, suggesting that terminal complement inhibition has the potential to prevent acute AMR in patients sensitized to their donors. See the companion article by Marks et al on page 2876.
Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, ...connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described.
We prospectively screened 21 adult STAT3-deficient patients corrected (median age, 26 years; range, 17-44 years) corrected for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the corrected carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models.
Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.
Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a ...French nationwide population of adult kidney recipients over 10 years.
A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses.
Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 μmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients.
This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.
Therapeutic drug monitoring of mycophenolic acid (MPA) may minimise the risk of acute rejection after transplantation. Area under the curve (AUC) rather than trough concentration-based monitoring is ...recommended and models for AUC estimation are needed.
To develop a population pharmacokinetic model suitable for Bayesian estimation of individual AUC in stable renal transplant patients.
The population pharmacokinetics of MPA were studied using nonlinear mixed effects modelling (NONMEM) in 60 patients (index group) receiving MPA on a twice-daily basis. Ten blood samples were collected at fixed timepoints from ten patients and four blood samples were collected at sparse timepoints from 50 patients. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements and covariates. The predictive performances of the Bayesian procedure were evaluated in an independent group of patients (test group) comprising ten subjects in whom ten blood samples were collected at fixed timepoints.
A two-compartment model with zero-order absorption best fitted the data. Covariate analysis showed that bodyweight was positively correlated with oral clearance. However, the weak magnitude of the reduction in variability (from 34.8 to 28.2%) indicates that administration on a per kilogram basis would be of limited value in decreasing interindividual variability in MPA exposure. Bayesian estimation of pharmacokinetic parameters using samples drawn at 20 minutes and 1 and 3 hours enabled estimation of individual AUC with satisfactory accuracy (bias 7.7%, range of prediction errors 0.43-15.1%) and precision (root mean squared error 12.4%) as compared with the reference value obtained using the trapezoidal method.
This paper reports for the first time population pharmacokinetic data for MPA in stable renal transplant patients, and shows that Bayesian estimation can allow accurate prediction of AUC with only three samples. This method provides a tool for therapeutic drug monitoring of MPA or for concentration-effect studies. Its application to MPA monitoring in the early period post-transplantation needs to be evaluated.
Summary
We present the results at 8 years of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in kidney transplant recipients at low immunologic risk. We assessed ...estimated glomerular filtration (eGFR), graft, patient, and death‐censored graft survival (log‐rank compared), de novo DSA appearance, risk of malignancy, post‐transplant diabetes mellitus (PTDM), and anemia. Intent‐to‐treat and on‐treatment analyses were performed. Graft survival was similar in both groups (sirolimus: 73.3%, cyclosporine: 77.7, P = 0.574). No difference was observed between treatment groups concerning patient survival (P = 0.508) and death‐censored graft survival (P = 0.858). In conditional intent‐to‐treat analysis, mean eGFR was greater in sirolimus than in cyclosporine group (62.5 ± 27.3 ml/min vs. 47.8 ± 17.1 ml/min, P = 0.004), in particular because graft function was excellent in patients maintained under sirolimus (eGFR = 74.0 ml/min). Importantly, no detrimental impact was observed in patients in whom sirolimus has been withdrawn (eGFR = 49.5 ml/min). Overall, 17 patients showed de novo DSAs, with no difference between the two groups (P = 0.520). Malignancy did not differ by treatment. An initial maintenance regimen based on sirolimus provides a long‐term improvement in renal function for kidney transplant patients, especially for those maintained on sirolimus.
Abstract The French National Reference Center of Primary Immunodeficiencies (CEREDIH) was established in 2005 and now constitutes a nationwide network of pediatric and adult medicine departments in ...university medical centers. The registry comprises a total of 3,083 patients (mainly children), with an overall prevalence of 4.4 cases per 100,000 inhabitants. Predominantly B-cell immunodeficiencies are the most common diseases observed (43%). The proportion of common variable immunodeficiencies (CVIDs, 14%) is lower than reported by national registries in other developed countries. The data suggest that although referral to expert centers is fairly adequate for children, this is not yet the case in France for adults. The distribution of primary immunodeficiencies (PIDs) varied significantly across distinct geographical areas and this suggested regional differences in patient care. As the world's largest national registry of PIDs, CEREDIH provides a basis for both further studies and activities aimed at raising the physicians' awareness of PIDs (notably in adults).
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