Muriel Stubbe

Antigen-Specific Central Memory CD4 + T Lymphocytes Produce Multiple Cytokines and Proliferate In Vivo in Humans

The function of Ag-specific central (TCM) and effector (TEM) memory CD4+ T lymphocytes remains poorly characterized in vivo in humans. Using CD154 as a marker of Ag-specific CD4+ T cells, we studied the differentiation of memory subsets following anti-hepatitis B immunization. Hepatitis B surface Ag (HBs)-specific memory CD4+ T cells were heterogeneous and included TCM (CCR7+CD27+) and TEM (CCR7−CD27+/−). HBs-specific TCM and TEM shared the capacity to produce multiple cytokines, including IL-2 and IFN-γ. Several years postimmunization, ∼10% of HBs-specific memory CD4+ T cells were in cycle (Ki67+) and the proliferating cells were CCR7+. These results suggest that the model of functional specialization of TCM and TEM cannot be applied to protein vaccine Ags and support the concept that TCM are capable of self-renewal and contribute to maintain the pool of memory cells.

Improving tetanus prophylaxis in the emergency department: a prospective, double-blind cost-effectiveness study.

Background: The choice of tetanus prophylaxis for patients with wounds depends on obtaining their vaccination history, which has been demonstrated to be unreliable. Use of a rapid immunoassay (Tétanos Quick Stick, the TQS), combined with knowledge of certain demographic characteristics, may improve the evaluation of tetanus immunity and thus help to avoid inadequate prophylactic measures and reduce costs. Objectives: To evaluate the contribution of the TQS in the choice of tetanus prophylaxis and to perform a cost-effectiveness analysis. The final aim was to define the place of the TQS in a modified algorithm for assessment of tetanus immunity in the emergency department. Method: In this Belgian prospective, double-blind, multicentre study, 611 adult patients with a wound were included; 498 (81.5%) records were valid. The TQS test was performed by a nurse before the vaccination history was taken and the choice of prophylaxis was made, using the official algorithm (Belgian Superior Health Council), by a doctor who was unaware of the TQS result. Results: The prevalence of protective anti-tetanus immunity was 74.1%. Immunity was lower in older patients and in female patients. The TQS was a cost-effective tool for patients presenting with a tetanus-prone wound and considered from the vaccination history to be unprotected. Use of the TQS would have improved management in 56.9% (95% CI 47.7% to 65.7%) of patients by avoiding unnecessary treatments, leading to a reduction in the mean cost per patient (€10.58/patient with the TQS versus €11.34/patient without). The benefits of the TQS use were significantly greater in patients <61 years old: unnecessary treatment would have been avoided in 76.9% (95% CI 65.8% to 85.4%) of cases and the mean cost per patient reduced to €8.31. Conclusion: In selected patients, the TQS is a cost-effective tool to evaluate tetanus immunity. An algorithm is proposed for ED assessment of tetanus immunity integrating age and the TQS result.

Characterization of a subset of antigen-specific human central memory CD4+ T lymphocytes producing effector cytokines.

CCR7+ central memory (TCM) CD4+ T cells play a central role in long‐term immunological memory. Recent reports indicate that a proportion of CD4+ TCM is able to produce effector cytokines. The phenotype and the role of this subset remain unknown. We characterized cytokine‐producing human CD4+ TCM specific for cleared protein and persistent viral Ag. Our results demonstrate that the type of Ag stimulation is a major determinant of CD4+ TCM differentiation. CMV‐specific TCM were significantly more differentiated than protein Ag‐specific TCM and included higher proportions of IFN‐γ‐producing cells. The expression of killer cell lectin‐like receptor G1 (KLRG1) by protein Ag‐ and CMV‐specific TCM was associated with increased production of effector cytokines. KLRG1+ TCM expressed high levels of CD127, suggesting that they can survive long term under the influence of IL‐7. The induction of KLRG1+ TCM may therefore represent an important target of vaccination against pathogens controlled by cellular immune responses.

Wegener’s Granulomatosis Strictly and Persistently Localized to One Organ Is Rare: Assessment of 16 Patients from the French Vasculitis Study Group Database

Objective. To study the frequency and characteristics of patients with Wegener’s granulomatosis (WG) strictly and persistently localized to one organ. Methods. Retrospective analysis of the French Vasculitis Study Group (FVSG) WG cohort. Results. Sixteen patients (3.2% of the cohort) were identified who had isolated lung nodules, ear-nose-throat, or ocular involvement that did not progress to systemic disease (median followup, 58 mo) over the period of observation. Ten received first-line therapy with cyclophosphamide, which was effective in 4. Cotrimoxazole alone achieved remission in one, combined with corticosteroids in 3. Eight required subsequent treatments because of first-line failure or relapse. Conclusion. Strictly and persistently localized WG is uncommon. Optimal treatment remains to be determined.

Abstract 50 Seroprotection against tetanus in patients presenting to an emergency department in Belgium and evaluation of a bedside immunotest (Tetanos Quick Stick): a prospective observational study

50 Seroprotection against tetanus in patients presenting to an emergency department in Belgium and evaluation of a bedside immunotest (Tetanos Quick Stick): a prospective observational study M. Stubbe, R. Swinnen, A. Crusiaux, F. Mascart and P. Lheureux Background Despite the existence of a highly efficient vaccine, immunity against tetanus is insufficient and the disease has not disappeared. In most Western countries, the annual prevalence is estimated at less than one case per million. The exact prevalence in Belgium is not known but is probably higher. The mortality rate remains more than 30%. When a wound is considered at risk, the prophylactic treatment scheme currently depends on the vaccine status of the patient that is entirely determined by the anamnesis, although the low performance of this anamnesis is not sufficient to fit the treatment with the actual immunity of the patient. The consequences are under or over administration of specific immunoglobulins and vaccine. This approach exposes the patient to the risk of avoidable adverse effects. ‘Tetanos Quick Stick’ (TQS) is a rapid, semiquantitative immunoassay for bedside use. In 10min, it gives reliable information about tetanus immunity of the patient and thus might improve tetanus prophylaxis in patients presenting with wounds to the emergency department (ED). Objectives (1) To determine the actual seroprevalence of tetanus immunity in the population attending our ED; (2) to identify predictive factors of protective immunity; (3) to evaluate the performance of the anamnesis and (4) to identify predictive factors of an incorrect anamnesis. The final purpose is to determine the potential value of TQS in a modified algorithm for ED assessment of tetanus immunity. Method This prospective observational study was performed in the ED of the Erasmus University Hospital (Brussels, Belgium) from 12 October 2004 to 29 March 2005. The protocol was approved by the local Ethical Committee. A total of 1002 adult patients were included. To avoid interference in the current prevention policy defined by the Belgian Superior Health Council, patients presenting with a wound as well as those in whom the anamnesis was impossible were excluded. Patients who agreed to participate responded to a questionnaire (age, birthplace, vaccine history, educational level, occupation, hobbies, military service, medical follow-up by family or occupational physician, general medical history). A TQS was performed and interpreted (positive, negative or doubtful) by the triage nurse. Doubtful tests were submitted to the main investigator (M.S.) who determined the final interpretation. In patients requiring blood sampling for reasons unrelated to the study (n1⁄4312), a 5ml blood sample was obtained and used for tetanus antitoxin level determination by the indirect enzyme-linked immunosorbent assay (ELISA) method. A cutoff of 0.15UI/ml was considered to be protective. Results were compared with those of TQS. Results Among the 1002 patients eligible, 204 (20.4%) refused to participate. No significant difference was observed in the median age (37 years, IQS 28 versus 40 years, IQS 26) and in the sex ratio (ratio M:F1⁄40.99:0.87) in comparison with the study population. The TQS demonstrated good concordance with the ELISA results (k1⁄40.72); the sensitivity was 85.3% and the specificity was 87.2%. After a second interpretation of the 50 doubtful tests, 784 tests were available, 4 were invalid and 10 were missing. The prevalence of protective immunity is estimated at 64.2% [95% confidence interval (CI) 60.8–67.5%]. A decline of seroprotection rate is observed with increasing age: 76.5% (18–24 years), 75.2% (25–44 years), 57.2% (45–64 years) and 35.4% (465 years). On the basis of the data collected, results of a logistic regression analysis identified four independent predictors of seroprotection: young age [odds ratio (OR) 7.66; 95% CI 3.00–19.58 for age group between 18 and 25 years)], born in Belgium (OR 5.72; 95% CI 2.81–11.66), male sex (OR 2.65; 95% CI 1.72–4.09) and follow-up by occupational medicine (OR 2.30; 95% CI 1.45–3.64). The seroprotection rate exceeds 95% in the group of patients who meet these four characteristics. Among the 762 participants who responded to the anamnesis, 54.6% did not know their status, 23.2% declared to be protected and 22.2% believed not to be protected. The concordance between anamnesis and ELISA is bad (k1⁄40.27). Among the participants who claimed to be protected, 81.8% had a protective antitoxin level (predictive positive value, PPV1⁄481.8%). Only 45.8% of the patients who thought they were not protected were actually not protected (predictive negative value, PNV1⁄445.8%). In comparison with anamnesis, TQS offers a significantly better PPV (92.1%, P1⁄40.012) and PNV (77.2%, Po0.0001), demonstrating the higher performance of TQS over anamnesis. No predictive factors of an incorrect anamnesis can be identified. Conclusion The lack of protective immunity against tetanus is frequent but difficult to evaluate with anamnesis. Several sociocultural and demographic characteristics are good predictors of adequate seroprotection. TQS could be a valuable diagnostic tool in selected patients and improves the use of prophylactic measures in those who present with wounds in the ED. Its appropriate use in a modified algorithm for ED assessment of tetanus immunity remains to be determined.