Age in addition to RETTS triage priority substantially improves 3-day mortality prediction in emergency department patients: a multi-center cohort study.

BACKGROUND: Previous studies have shown varying results on the validity of the rapid emergency triage and treatment system (RETTS), but have concluded that patient age is not adequately considered as a risk factor for short term mortality. Little is known about the RETTS system's performance between different chief complaints and on short term mortality. We therefore aimed to evaluate how well a model including both RETTS triage priority and patient age (TP and age model) predicts 3-day mortality compared to a univariate RETTS triage priority model (TP model). Secondarily, we aimed to evaluate the TP model compared to a univariate age model (age model) and whether these three models' predictive performance regarding 3-day mortality varies between patients with different chief complaints in an unsorted emergency department patient population. METHODS: This study was a prospective historic observational cohort study, using logistic regression on a cohort of patients seeking emergency department care in Stockholm during 2012-2016. Patient visits were stratified into the 10 chief complaint categories (CCC) with the highest number of deceased patients within 3 days of arrival, and to "other chief complaints". Patients with priority 1 were excluded. RESULTS: The studied cohort contained 1,690,981 visits by 788,046 different individuals. The TP and age model predicted 3-day mortality significantly and substantially better than both univariate models in the total population and in each studied CCC. The age model predicted 3-day mortality significantly and substantially better than the TP model in the total population and for all but three CCCs and was not inferior in any CCC. There were substantial differences between the studied CCCs in the predictive ability of each of the three models. CONCLUSIONS: Adding patient age to the RETTS triage priority system significantly and substantially improves 3-day mortality prediction compared to RETTS priority alone. Age alone is a non-inferior predictor of 3-day mortality compared to RETTS priority. The impact on 3-day mortality prediction of adding patient age to RETTS priority varies between CCCs but is substantial for all CCCs and for the total population. Including age as a variable in future revisions of RETTS could substantially improve patient safety.

The autoimmune T and B cell repertoires in monozygotic twins discordant for myasthenia gravis.

Two pairs of monozygotic twins, discordant for myasthenia gravis (MG) for more than 30 years, were studied regarding T cell and antibody reactivity against disease related autoantigens, the acetylcholine receptor, one idiotypic and one anti-idiotypic human monoclonal antibody. The healthy and myasthenic twins had very similar autoantibody repertoires. IgG fractions from both healthy and myasthenic twins had the same capacity to decrease the free acetylcholine receptor content in mice after passive transfer. In comparison with their myasthenic sisters, the healthy twins had lower T cell responses against the acetylcholine receptor.

The effect of thymectomy on autoreactive T- and B-lymphocytes in myasthenia gravis.

Eleven patients with myasthenia gravis were followed for three years after thymectomy. Acetylcholine receptor-specific T-cell stimulation was found in 8/11 patients before operation as compared to 2/11 three years after thymectomy. Changes of T-cell antireceptor-reactivity were commonly paralleled by changes in disease severity. The numbers of cells secreting IL-2 upon stimulation with human acetylcholine receptor correlated with those secreting IFN-gamma. T-cell reactivity against a monoclonal acetylcholine receptor antibody did not decrease after thymectomy. Such reactivity could reflect a beneficial immune response counteracting anti-receptor reactivity. The frequency of autoantibody-secreting cells remained unchanged, while the serum concentration of acetylcholine receptor antibodies started to decrease one year after thymectomy. All examined thymus-cell suspensions contained autoreactive T- and B-lymphocytes. There was a preferential enrichment of autoreactive lymphocytes in the thymus in a few patients with recent onset of disease.

Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity.

We treated a patient with severe myasthenia gravis with a chimeric (murine/human) anti-CD4 monoclonal antibody (cM-T412) for 7 days and followed the therapeutic effect by standardized muscle function tests, single-fiber electromyography, and immunologic examinations of disease-specific B- and T-cell functions. Clinical and electrophysiologic improvement began within 4 days, lasted for 3 months, and was maximal between days 16 and 58. The CD4+ lymphocytes decreased to a minimum of 80 cells per microliters of peripheral blood, recovered slowly during the first year of follow-up, and did not correlate with changes in disease severity. T-cell stimulation by human acetylcholine receptor was abolished by the treatment but became detectable at the time of worsening of symptoms. The concentration of acetylcholine receptor antibodies in serum was not decreased by the treatment. The results suggest that anti-CD4 antibody administration could be effective in the treatment of severe myasthenia gravis and indicate that acetylcholine receptor-specific T lymphocytes might contribute to the disturbed neuromuscular transmission in the disease.

Acetylcholine receptor-reactive T cells in myasthenia gravis: evidence for the involvement of different subpopulations of T helper cells.

Patients with myasthenia gravis have a high prevalence of acetylcholine receptor-specific T lymphocytes in the peripheral blood. Our earlier study shows that these T lymphocytes are stimulated to secrete interferon (IFN)-gamma and interleukin (IL)-2 in response to the autoantigen. Such stimulated T cells may be subdivided into different subsets according to the pattern of cytokine production. In the present study we have investigated the subpopulations of cells by analyzing their IL-4, IFN-gamma and IL-2 secretion pattern. Autoantigen-stimulated IL-4 secretion was found in 55% of the patients, IFN-gamma secretion in 86% and IL-2 secretion in 72%. T lymphocytes from all patients who responded with increased IL-2 secretion also showed increased IFN-gamma secretion. Stimulated IL-4 secretion was detected both in the presence and absence of stimulated IFN-gamma secretion. Depletion of monocytes/macrophages from peripheral blood mononuclear cell preparation and treatment of the cells with a mouse anti-human HLA-DR antibody abolished the secretion of IFN-gamma and IL-4. There were positive correlations between the numbers of IFN-gamma- and IL-2-secreting T cells and the numbers of B cells secreting antibodies against the acetylcholine receptor. Our results show that acetylcholine receptor-stimulated T lymphocytes secrete IL-4, IFN-gamma and/or IL-2. This T cell response is major histocompatibility complex (MHC) class II-restricted and monocyte/macrophage-dependent. Our study indicates that both Th1/Th2 or Th0 subpopulations of the T lymphocytes are involved in the autoimmune response in myasthenia gravis.

T-cell epitopes on the human acetylcholine receptor alpha-subunit residues 10-84 in myasthenia gravis.

In myasthenia gravis the production of anti-acetylcholine receptor antibodies is modulated by acetylcholine receptor-specific T cells. Most B- and T-cell epitopes are located on the alpha-subunit of the receptor. In order to map the fine specificity of the antigen-specific T cells in myasthenia gravis, T-cell stimulation in response to 70 hexapeptides was studied in 24 patients and 24 healthy individuals. The hexapeptides overlapped with one amino acid and represented residues 10-84 of the NH2-terminal part of the alpha-subunit of the receptor. The IFN-gamma secretion from single T cells was used to detect T-cell stimulation. A significant difference in the T-cell response to several of the peptides was found between patients and healthy controls. The majority of the hexapeptides induced T-cell stimulation in at least one of the patients. Peptide-induced T-cell stimulation was evident in all but one of the patients. The results indicate that different epitopes and multiple T-cell clones are involved in the T-cell recognition of the acetylcholine receptor.

Levels of CD5+ B lymphocytes do not differ between patients with myasthenia gravis and healthy individuals.

CD5+ B cells might be involved in autoimmunity mainly as autoantibody-producing cells. To investigate the possible role of these cells in myasthenia gravis, we studied the numbers of CD5+ B cells, CD5- B cells, and CD19+ B cells as well as CD5+ T cells in the peripheral blood from 31 patients with myasthenia gravis and 31 healthy individuals. Both absolute percentages (percent of peripheral blood mononuclear cells) and relative percentages (percent of total CD19+ B cells) of CD5+ B cells were the same in patients as in controls. The numbers of CD5- B cells and CD19+ B cells were the same in both groups, whereas CD5+ T cells were lower in the patients. There was no correlation between clinical stage, sex, thymectomy, or pathology of thymus and the levels of CD5+ B cells, CD5- B cells, or CD19+ B cells. Patients treated with azathioprine had lower levels of CD5+ B cells than untreated patients and controls. Our results show that patients with myasthenia gravis have the same levels of CD5+ B cells as healthy individuals.

T cells with specificity for idiotypic determinants on human monoclonal autoantibodies in myasthenia gravis.

The activation of T cells from 46 patients with myasthenia gravis and 28 healthy individuals by two human monoclonal autoantibodies was studied. B-cell clones were produced by transformation of peripheral lymphocytes from a patient using Epstein-Barr virus and subsequent cloning. Two myasthenia-specific autoantibodies, one anti-receptor-antibody and one antiidiotypic antibody, both carrying separate recurrent idiotopes, were used in this study. Single activated T cells were identified by their secretion of IL2 and IFN gamma using a cell enzyme-linked-immunosorbent technique. The idiotypic antibody activated T cells in patients but not in most of the controls at concentrations of 1 pg/ml and 10 pg/ml. High concentrations of antibody resulted in T-cell activation in both groups. A similar dose-response pattern was recorded using the antiidiotypic antibody. Incubation with the idiotypic antibody resulted in T-cell stimulation, measured as numbers of IFN gamma-secreting cells that exceeded the mean +2 SD of controls, in 78% of patients and in 7% of the healthy individuals (p less than 0.001). The antiidiotypic antibody activated T cells in 50% of patients and in 4% of the healthy individuals (p less than 0.001). T-cell activation measured as numbers of IL2-secreting cells showed a difference between patients and controls which was as significant as for IFN gamma secretion. The results demonstrate the presence of T cells with specificity for disease-specific determinants on idiotypic and antiidiotypic antibodies in myasthenia gravis.

Abnormal T-cell expansion and V-gene usage in myasthenia gravis patients.

To determine the extent of V-gene heterogeneity of blood T lymphocytes in patients suffering from Myasthenia Gravis (MG), we used eight recently available monoclonal antibodies (MoAb), directed against different V alpha and V beta gene products of the variable part of the T-cell receptor (TCR), covering approximately 25% of the alpha/beta T cells in normal peripheral blood (PBL) of healthy individuals. Using a two-colour immunofluorescence method, we could calculate the expression of alpha/beta V segments within the two major T-cell subsets, CD4-/CD8+ and CD4+/CD8- lymphocytes. Twenty-seven per cent (4/15) of the MG patients had T cells showing signs of abnormal expansion. Furthermore, among these expanded T cells, a restricted V beta 12 gene expansion could be seen, in three out of four patients. No correlation between TCR V-gene usage and HLA haplotypes (HLA-A, -B, -DR and -DQ) could be seen. Our data suggest that the majority of MG patients have abnormally expanded T-cell clones. The relevance of these findings is discussed.

Defective T lymphocyte function in nonthymectomized patients with myasthenia gravis.

In vitro functional properties of peripheral blood mononuclear cells were evaluated in 29 patients with myasthenia gravis and in 11 healthy controls. Spontaneous cell proliferation was higher in patients than in controls. The production of interleukin-2 and interferon-gamma and the proliferative response to different mitogens were reduced in the patients. A positive correlation was found between the production of interleukin-2 and interferon-gamma. These defects in T cell function were the most pronounced in nonthymectomized patients. Patients with severe disease had a higher percentage of cells bearing the interleukin-2 receptor and a higher spontaneous production of tumor necrosis factor alpha in cell culture than in patients with mild disease. There was no difference between patients and controls in the level of soluble interleukin-2 receptor in cell culture supernatants or in sera. The results indicate a partially suppressed T cell function in myasthenia gravis. This defect was less pronounced in patients studied after thymectomy.

Monoclonal gammopathy and antibody activity against the acetylcholine receptor.

A 50-year-old woman with muscular fatigue and monoclonal gammopathy of unknown significance was shown to have high levels of antibodies against the acetylcholine receptor of the skeletal muscle endplate. The specific antibody activity was exclusively associated with the monoclonal component. There were no objective signs of myasthenia gravis. This is the first reported case with antibody activity against the acetylcholine receptor found in a monoclonal immunoglobulin fraction.