Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsi

Unsatisfactory outcomes in myasthenia gravis: influence by care providers

Myasthenia gravis (MG) can be difficult to treat despite an available therapeutic armamentarium. Our aim was to analyze the factors leading to unsatisfactory outcome (UO). To this end we used the Myasthenia Gravis Foundation of America classification system. Forty one patients with autoimmune MG were followed prospectively from January 2003 to December 2007. Outcomes were assessed throughout follow-up and at a final visit. ‘Unchanged', ‘worse', ‘exacerbation' and ‘died of MG' post-intervention status were considered UOs. During follow-up, UO rates reached 54% and were related to undertreatment (41%), poor treatment compliance (23%), infections (23%), and adverse drug effects (13%). The UO rate at final study assessment was 20%. UO during follow-up was significantly (P=0.004) predictive of UOs at final assessment. When care was provided by neuromuscular (NM) specialists, patients had significantly better follow-up scores (P=0.01). At final assessment UO rates were 7% and significantly better in patients treated by NM specialists, compared to other physicians where UO rates reached 27%. UO was a frequent finding occurring in more than half our patients during follow-up. Nearly two-thirds of the UOs could have been prevented by appropriate therapeutic adjustments and improved compliance. The differential UO rates at follow-up, their dependency on the degree to which the management was specialized and their correlation with final outcomes suggest that specialized MG care improves outcome

Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response

Objective: We investigated the metabolic, hemodynamic, and inflammatory responses of pharmacological and physical therapies aimed at reducing body temperature in febrile critically ill patients. Design and setting: Open-label, randomized trial in a surgical ICU in a tertiary university hospital. Patients: Thirty analgosedated, mechanically ventilated patients with a temperature of 38.5°C or higher were randomized to receive either intravenous metamizol, intravenous propacetamol, or external cooling. Measurements and results: Body temperature and metabolic and hemodynamic variables were recorded at baseline and during the following 4h. Cytokine concentrations were assessed before and 4 and 12h after the initiation of antipyresis. Body temperature decreased significantly in all treatment groups. For a 1°C temperature decrease, the energy expenditure index increased by 5% with external cooling and decreased by 7% and 8% in the metamizol and propacetamol groups, respectively. Metamizol induced a significant decrease in mean arterial pressure and urine output compared to baseline and to the other two groups. C-reactive protein increased over time, but compared to the other groups it was significantly lower in patients receiving metamizol after 4h. Cytokine concentrations were not different among the three groups or over time, although interleukin 6 tended to decrease over time in the metamizol group. Conclusions: Metamizol, propacetamol, and external cooling equally reduced temperature. Considering the undesirable hemodynamic effects, metamizol should not be considered the first antipyretic choice in unstable patients. Propacetamol or external cooling should be preferred, although the latter should be avoided in patients unlikely to tolerate the increased metabolic demand induced by external coolin

Interferon-gamma release assays versus tuberculin skin testing for detection of latent tuberculosis in chronic haemodialysis patients

Background. End stage renal disease increases the risk of reactivating latent tuberculosis (LTBI). Interferon-γ release assays (IGRA) are an alternative to the tuberculin skin test (TST) for detecting LTBI. Methods. Sixty-two hemodialysis patients (46 male, 16 female, aged 65 ± 15 years) from 3 hemodialysis facilities in the Geneva area were submitted to a TST, 2 IGRA (T-SPOT.TB and QuantiFERON Gold in tube: QFT), a chest radiography, and a questionnaire to record social status, country of birth, history of prior TST, tuberculosis (TB), BCG (Bacillus of Calmette-Guérin vaccine), and any cause of immuno-suppression. LTBI was defined as prior "at risk” contact with a case of contagious TB and/or a chest X-ray suggestive of prior TB infection. Results. Positivity rate was 19% for TST, 21% for QFT and 29% for T-SPOT-TB; 8% of QFT and 11% of T-SPOT-TB were indeterminate. Agreement between IGRA was fair (κ= 0.60). After adjusting for age and BCG, OR (Odds Ratio) of having a positive QFT was 4.6-fold (p = 0.029) higher in patients with LTBI vs. those without LTBI. In contrast, no association was found between LTBI and having a positive T-SPOT.TB or a positive TST. As expected, there was a strong association between prior BCG vaccination and having a positive TST (OR 5.3, p = 0.017). QFT was the only test with a significant OR of having LTBI (adjusted OR: 4.4; 95%CI: 1.1 − 17.6; p = 0.034). Among 5 patients with definite prior TB, TST and T-SPOT.TB were positive in 1 and QFT, in 2. Conclusions. In this population, QFT was superior to TST for detecting LTBI, but both IGRAs and TST have important limitations, and are unreliable for screening for LTB

Anti-apolipoprotein A-1 IgG as an independent cardiovascular prognostic marker affecting basal heart rate in myocardial infarction

Aims To assess the prognostic value of anti-apolipoprotein A-1 (anti-apoA-1) IgG after myocardial infarction (MI) and its association with major cardiovascular events (MACEs) at 12 months and to determine their association with resting heart rate (RHR), a well-established prognostic feature after MI. Anti-apoA-1 IgG have been reported in MI without autoimmune disease, but their clinical significance remains undetermined. Methods and results A total of 221 consecutive patients with MI were prospectively included, and all completed a 12-month follow-up. Major cardiovascular events consisted in death, MI, stroke, or hospitalization either for an acute coronary syndrome or heart failure. Resting heart rate was obtained on Holter the day before discharge under the same medical treatment. Neonate rat ventricular cardiomyocytes (NRVC) were used in vitro to assess the direct anti-apoA-1 IgG effect on RHR. During follow-up, 13% of patients presented a MACE. Anti-apoA-1 IgG positivity was 9% and was associated with a higher RHR (P = 0.0005) and higher MACE rate (adjusted OR, 4.3; 95% CI, 1.46-12.6; P = 0.007). Survival models confirmed the significant nature of this association. Patients with MACE had higher median anti-apoA-1 IgG values at admission than patients without (P = 0.007). On NRVC, plasma from MI patients and monoclonal anti-apoA-1 IgG induced an aldosterone and dose-dependent positive chronotropic effect, abrogated by apoA-1 and therapeutic immunoglobulin (IVIG) pre-incubation. Conclusions In MI patients, anti-apoA-1 IgG is independently associated with MACE at 1-year, interfering with a currently unknown aldosterone-dependent RHR determinant. Knowing whether anti-apoA-1 IgG assessment could be of interest to identify an MI patient subset susceptible to benefit from apoA-1/IVIG therapy remains to be demonstrate

Anti-Apolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability

Aims Anti-Apolipoprotein A-1 auto-antibodies (anti-ApoA-1 IgG) represent an emerging prognostic cardiovascular marker in patients with myocardial infarction or autoimmune diseases associated with high cardiovascular risk. The potential relationship between anti-ApoA-1 IgG and plaque vulnerability remains elusive. Thus, we aimed to investigate the role of anti-ApoA-1 IgG in plaque vulnerability. Methods and results Potential relationship between anti-ApoA-1 IgG and features of cardiovascular vulnerability was explored both in vivo and in vitro. In vivo, we investigated anti-ApoA-1 IgG in patients with severe carotid stenosis (n = 102) and in ApoE−/− mice infused with polyclonal anti-ApoA-1 IgG. In vitro, anti-ApoA-1 IgG effects were assessed on human primary macrophages, monocytes, and neutrophils. Intraplaque collagen was decreased, while neutrophil and matrix metalloprotease (MMP)-9 content were increased in anti-ApoA-1 IgG-positive patients and anti-ApoA-1 IgG-treated mice when compared with corresponding controls. In mouse aortic roots (but not in abdominal aortas), treatment with anti-ApoA-1 IgG was associated with increased lesion size when compared with controls. In humans, serum anti-ApoA-1 IgG levels positively correlated with intraplaque macrophage, neutrophil, and MMP-9 content, and inversely with collagen. In vitro, anti-ApoA-1 IgG increased macrophage release of CCL2, CXCL8, and MMP-9, as well as neutrophil migration towards TNF-α or CXCL8. Conclusion These results suggest that anti-ApoA-1 IgG might be associated with increased atherosclerotic plaque vulnerability in humans and mic

Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor-α blockade in the knee joint

Introduction: Evaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-\u3b1 blockers in psoriatic arthritis (PsA). Methods: Systemic and local disease activity indexes (disease activity score [DAS]; the Ritchie articular index [mRAI], erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular [THOMP] and joint articular [KJAI]-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml - 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a ten week period. Total SF white blood cell (WBC) counts (WBC/ \u3bcl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8/14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105. Results: At baseline, CRP and/or ESR were significantly correlated with SF-CK (IL-1\u3b2, IL-1Ra, IL-6, IL-8) and CCK (CCL2, CCL3 and CCL4). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/\u3bcl and in SF-CK (TNF-\u3b1, IL- 1\u3b2, IL-1Ra, IL-6 and IL-22). Pre- and post- IAE injections, there were significant correlations between ST markers and SF-CK (IL-1\u3b2 with CD45; IL-1\u3b2 and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3)

Altered Humoral Immune Responses and IgG Subtypes in NOX2-Deficient Mice and Patients: A Key Role for NOX2 in Antigen-Presenting Cells

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting from loss of function mutations in the reactive oxygen species generating phagocyte NADPH oxidase (NOX2). CGD patients are prone to infection, but also have an increased susceptibility to autoimmune diseases. The aim of this study was to investigate the role of NOX2 in the regulation of specific immunity. In both CGD patients and NOX2-deficient mice, we observed an alteration in the basal proportions of IgG subtypes. Upon immunization with curdlan—a dectin 1 agonist—NOX2-deficient mice showed increased production of IgG2c compared to controls, and restimulation of lymph node-derived cells led to increased production of IFNγ, but not IL-5, indicative hallmark of an enhanced Th1 response. T cell activation was increased in NOX2-deficient mice and a similar trend was observed in vitro when T cells were co-cultured with NOX2-deficient bone marrow-derived cells. In contrast, no difference in T cell activation was observed when NOX2-deficient T cells were co-cultured with wild-type BMDC. Following stimulation of NOX2-deficient dendritic cells (DCs), no difference in costimulatory molecules was observed, while there was an increase in the release of Th1-driving cytokines. In summary, both CGD patients and CGD mice have an altered IgG subtype distribution, which is associated with an increased IFNγ production. Thus, NOX2 within DCs appears to be an important regulator at the interface of innate and specific immunity, especially after activation of the dectin 1 pathway, limiting immune activation and the development of autoimmunity