Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection.
To determine whether fever control by external cooling diminishes vasopressor ...requirements in septic shock.
In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours.
Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval 95% CI, -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013).
In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.
To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura.
Open-label prospective study. Outcomes in ...the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine.
Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France.
Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange.
Add-on rituximab therapy, four infusions over 15 days.
One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred.
Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.
Severe ADAMTS13 deficiency occurs in 13% to 75% of thrombotic microangiopathies (TMA). In this context, the early identification of a severe, antibody-mediated, ADAMTS13 deficiency may allow to start ...targeted therapies such as B-lymphocytes-depleting monoclonal antibodies. To date, assays exploring ADAMTS13 activity require skill and are limited to only some specialized reference laboratories, given the very low incidence of the disease. To identify clinical features which may allow to predict rapidly an acquired ADAMTS13 deficiency, we performed a cross-sectional analysis of our national registry from 2000 to 2007. The clinical presentation of 160 patients with TMA and acquired ADAMTS13 deficiency was compared with that of 54 patients with detectable ADAMTS13 activity. ADAMTS13 deficiency was associated with more relapses during treatment and with a good renal prognosis. Patients with acquired ADAMTS13 deficiency had platelet count < 30 x 10(9)/L (adjusted odds ratio OR 9.1, 95% confidence interval CI 3.4-24.2, P<.001), serum creatinine level < or =200 micromol/L (OR 23.4, 95% CI 8.8-62.5, P<.001), and detectable antinuclear antibodies (OR 2.8, 95% CI 1.0-8.0, P<.05). When at least 1 criteria was met, patients with a severe acquired ADAMTS13 deficiency were identified with positive predictive value of 85%, negative predictive value of 93.3%, sensitivity of 98.8%, and specificity of 48.1%. Our criteria should be useful to identify rapidly newly diagnosed patients with an acquired ADAMTS13 deficiency to better tailor treatment for different pathophysiological groups.
Primary hyperoxalurias (PH) are extremely rare genetic disorders characterized by clinical heterogeneity. Delay in diagnosing these conditions can have detrimental effects on patient outcomes. The ...primary objective of this study is to assess the current diagnostic delay for PH.
This nationwide, observational and retrospective study included patients who received a genetic diagnosis of PH types 1, 2 and 3 between 1 January 2015 and 31 December 2019. Diagnostic delay was defined as the duration between the onset of symptoms and the time of genetic diagnosis.
A total of 52 patients (34 children and 18 adults) were included in the study, with 40 PH1 (77%), 3 PH2 (6%) and 9 PH3 (17%). At the time of diagnosis, 12 patients (23%) required dialysis. Among the PH1 patients, the predominant symptom at onset in adults was renal colic (79% of cases), whereas symptoms in children were more diverse (renal colic in 17% of cases). The diagnostic delay was significantly shorter in children compared with adults median (interquartile range): 1.2 (0.1-3.0) versus 30 (17-36) years, respectively (
< .0001). RNA interference was utilized in 23 patients (58%). Five individuals (13%) underwent double liver-kidney transplantation, and five (13%) received isolated kidney transplantation, with lumasiran therapy in four patients. For PH2 and PH3 patients, the diagnostic delay ranges from 0 to 3 years, with renal colic as first symptom in 33% of cases.
This extensive and recent cohort of PH underscores the considerable delay in diagnosing PH, particularly in adults, even in a country with a dedicated organization for enhancing the overall management of rare diseases. These findings reinforce the imperative for increased awareness among relevant specialties regarding the evaluation of urolithiasis.
Fibrinogen A α-chain amyloidosis (AFib amyloidosis) is a form of amyloidosis resulting from mutations in the fibrinogen A α-chain gene (FGA), causing progressive kidney disease leading to kidney ...failure. Treatment may include kidney transplantation (KT) or liver-kidney transplantation (LKT), but it is not clear what factors should guide this decision. The aim of this study was to characterize the natural history and long-term outcomes of this disease, with and without organ transplantation, among patients with AFib amyloidosis and various FGA variants.
Case series.
32 patients with AFib amyloidosis diagnosed by genetic testing in France between 1983 and 2014, with a median follow-up of 93 (range, 4-192) months, were included.
Median age at diagnosis was 51.5 (range, 12-77) years. Clinical presentation consisted of proteinuria (93%), hypertension (83%), and kidney failure (68%). Manifestations of kidney disease appeared on average at age 57 (range, 36-77) years in patients with the E526V variant, at age 45 (range, 12-59) years in those with the R554L variant (P<0.001), and at age 24.5 (range, 12-31) years in those with frameshift variants (P<0.001). KT was performed in 15 patients and LKT was performed in 4. In KT patients with the E526V variant, recurrence of AFib amyloidosis in the kidney graft was less common than with a non-E526V (R554L or frameshift) variant (22% vs 83%; P=0.03) and led to graft loss less frequently (33% vs 100%). Amyloid recurrence was not observed in patients after LKT.
Analyses were based on clinically available historical data. Small number of patients with non-E526V and frameshift variants.
Our study suggests phenotypic variability in the natural history of AFib amyloidosis, depending on the FGA mutation type. KT appears to be a viable option for patients with the most common E526V variant, whereas LKT may be a preferred option for patients with frameshift variants.
Aims and objectives. To determine caregiver opinion on their intensive care unit’s policies with regard to visiting hours, how families are informed and participate in patient care.
Background. ...Benefits of improving family access to the intensive care unit, information delivery and participation of families in care have been suggested.
Design. Survey of caregivers working in French‐speaking intensive care units.
Methods. An e‐mail invitation to complete an online, closed‐ended questionnaire was issued to caregivers registered in the mailing list of the French society of intensive care.
Results. Caregivers (n = 731) working in 222 adult and 41 paediatric intensive care units completed the questionnaire. Unlike in paediatric intensive care units, 58% of adult intensive care unit had restricted visiting hours (<4 hour). However, 63% of respondents would recommend extended visiting periods. A 24‐hour policy existed in 7% of adult intensive care units; 10% of respondents from these intensive care units thought reducing visiting periods would be very useful or essential; 81% thought that a 24‐hour policy contributed to improved relations with families; and only 9% thought that it was a hindrance to care. Over 90% of caregivers thought that families should be informed of patient progress in a designated room in the presence of the patient’s nurse and that patient records should report family meetings. This policy was only implemented in half of the cases. Family participation in care procedures was strongly encouraged in only 0·5% of adult intensive care units.
Conclusions. Intensive care unit caregivers are in favour of longer visiting hours, increased use of designated rooms for, and nurse participation in, meetings with families. Although caregivers do not associate families with care procedures, they considered that their presence during most interventions should be authorised.
Relevance to clinical practice. Our results could help in implementing intensive care unit policies concerning visiting hours, how families are informed and participate in patient care.
A low tidal volume can induce alveolar derecruitment in patients with acute lung injury. This study was undertaken to evaluate whether this resulted mainly from the decrease in tidal volume or from ...the reduction in end-inspiratory plateau pressure and whether there is any benefit in raising the level of positive end-expiratory pressure (PEEP) while plateau pressure is kept constant.
Prospective crossover study.
Medical intensive care unit of a university teaching hospital.
Fifteen adult patients ventilated for acute lung injury (PaO2/FiO2, 158 +/- 34 mm Hg; lung injury score, 2.7 +/- 0.6).
Three combinations were tested: PEEP at the lower inflection point with 6 mL/kg tidal volume, PEEP at the lower inflection point with 10 mL/kg tidal volume, and high PEEP with tidal volume at 6 mL/kg, keeping the plateau pressure similar to the preceding condition.
Pressure-volume curves at zero PEEP and at set PEEP were recorded, and recruitment was calculated as the volume difference between both curves for pressures ranging from 15 to 30 cm H2O. Arterial blood gases were measured for all patients. For a similar PEEP at the lower inflection point (10 +/- 3 cm H2O), tidal volume reduction (10 to 6 mL/kg) led to a significant derecruitment. A low tidal volume (6 mL/kg) with high PEEP (14 +/- 3 cm H2O), however, induced a significantly greater recruitment and a higher Pao than the two other strategies.
At a given plateau pressure (i.e., similar end-inspiratory distension), lowering tidal volume and increasing PEEP increase recruitment and PaO2.
Abstract 2412
Poster Board II-387
Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) resulting from excessive von Willebrand factor ...(VWF)-mediated platelet clumping and capillary occlusion in relation with an autoantibody-mediated defect in the VWF-cleaving protease ADAMTS13. So far, the mechanisms leading to the loss of tolerance of the immune system against ADAMTS13 remain unknown. The usually switched isotype of the secreted anti-ADAMTS13 antibodies implies a cooperation between T lymphocytes and B lymphocytes and thus a recognition by T cell receptors of ADAMTS13 epitopes bound to human leukocyte antigen (HLA) molecules. We therefore hypothesized that particular HLA alleles may be involved in the process leading to a loss of tolerance of the immune system against ADAMTS13. Particularly, alleles within class I A and B loci and class II DRB1 and DQB1 loci are those most frequently associated with susceptibility to autoimmune diseases.
We have compared medium resolution typing of HLA class I (HLA-A, B) and II (HLA-DRB1, DQB1) loci in 61 Caucasian patients with idiopathic TTP and a documented severe (<5%) acquired, autoantibody-mediated, ADAMTS13 deficiency to 132 healthy Caucasian volunteer donors Caucasian individuals and to 42 Caucasian patients with atypical hemolytic uremic syndrome (HUS) who displayed a detectable ADAMTS13 activity.
The frequency of HLA-A, -B and -DQB1 alleles was comparable between patients with acquired idiopathic TTP, healthy individuals and patients with other forms of TMA. By contrast, the HLA DRB1*11 allele was observed in 62% of patients with acquired idiopathic TTP, whereas the usually reported incidence of this allele ranges from 13.5% to 24.5%, with the lower incidence in Asian/Pacific Islanders and Caucasians and the greater incidence in Afro-Caribbeans (http://www.allelefrequencies.net). Comparison to our group of healthy individuals confirmed this striking difference, which was statistically significant (20%, P = 10-7, odd ratio OR = 6.43, CI95% =2.3-12.7). The increased incidence of DRB1*11 in acquired idiopathic TTP was also significant when compared to patients with a diagnosis of atypical HUS (17%, P= 6×10-5). By contrast, DRB1*11 frequency in this latter group was comparable to this observed in healthy individuals (P = n.s). All patients were heterozygous for this allele. We also observed a decreased incidence of the DRB1*04 allele in acquired idiopathic TTP when compared to healthy individuals (10% versus 30%, respectively, Pcorr = 0.025). DRB1*04, resulting in the DR53 antigen when associated with DRB4, could thus be involved as a protective allele in acquired idiopathic TTP, as suggested in a previous work. We found no association between DRB1*11 and clinical features of autoimmunity, central nervous system involvement, antinuclear antibodies, anti-ADAMTS13 inhibitors, flare-up and relapse episodes and survival. Of note, the association between DRB1*11 with acquired idiopathic TTP was not observed in Afro-Caribbeans (3/12, 25%, p=0.04). High resolution typing of DRB1*11 allele revealed that both DRB1*1101 and DRB1*1104 alleles were significantly over-represented, suggesting that the generic DRB1*11 (and not the DRB1*11 alleles) is the predisposing factor.
The DRB1*11 was reported to be a risk factor for systemic sclerosis, early-onset juvenile chronic arthritis and sarcoidosis, and protective against multiple sclerosis and pemphigus vulgaris. Accordingly, we found no patient with one of those 2 latter diseases in our French National TTP registry, whereas a past history of systemic sclerosis, sarcoidosis and juvenile chronic arthritis was observed in 1 case each.
Our findings propose DRB1*11 as a strong risk factor for acquired idiopathic TTP in Caucasians. Indeed, the autoimmune response in acquired idiopathic TTP may involve the recognition by T cells of a class II region of DRB1*11, bound to a peptide fragment of ADAMTS13. We also suggest that acquired idiopathic TTP represents a subset of TMA with specific genetic risk factors, distinguishing it from the other forms of idiopathic TMA. The incomplete rate of concordance may be explained by other yet unexplored mechanisms, including additional predisposing genes and environmental triggers. Forthcoming genomewide association studies should lead to the identification of additional alleles associated with the risk of acquired idiopathic TTP.
No relevant conflicts of interest to declare.
Abstract 890
Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) resulting from an autoantibody-mediated defect in the von Willebrand ...factor-cleaving protease ADAMTS13. Therapeutical monoclonal antibodies directed against B-lymphocytes (rituximab) provided interesting results on preliminary studies.
We assessed rituximab efficacy and safety in adult patients with acquired idiopathic TTP who experienced a non optimal response to daily TPE, as defined by a refractory disease at day 5 or a flare-up of the disease within the first 15 days of standard intensive TPE treatment.
We conducted a prospective multicenter open-label single arm phase 2 trial. Patients with a non optimal response received 4 rituximab infusions at days 1, 4, 8 and 15, along with daily TPE continuation (R+ group). Peripheral blood B-lymphocyte count was evaluated before each rituximab administration, and then at 3, 6, 9 and 12 months. Outcome from the first TPE session was compared to this of 57 historical patients (R- group) treated by TPE alone (36 cases) or associated with vincristine (21 cases) for the same indication. ADAMTS13 activity was assessed at 3, 6, 9 and 12 months in both groups.
Both groups had comparable features on admission. Twenty-two patients were included to receive rituximab. All received 4 rituximab infusions. One patient died in a context of refractory disease, whereas the 21 others achieved durable remission. The median time to durable platelet count recovery was 20 days (extremes: 14-33), which required a median plasma volume of 950 mL/kg (extremes: 310-1940). The median time from the first rituximab infusion to durable platelet count recovery was 10 days (extremes: 5-27). All patients recovered platelet count before day-35. No relapse was observed during the first year. However, 3 (14.3%) patients relapsed after a mean follow-up of 21.2±13.8 months. In R- group, 4 patients died beyond day-5. The mean time to platelet count recovery and the mean plasma volume required to achieve remission did not significantly differ between survivors in R+ and R- groups (p=0.28 and 0.67, respectively). However, 13 (21.6%) patients of R- group were still thrombocytopenic at day-35 (p=0.01). Rituximab allowed a profound and sustained peripheral blood B-cell depletion as early as day day-4 despite associated daily plasmapheresis. Peripheral blood B-cells were undetectable from day-8 to the 6th or 9th month, and recovered at 1 year. Consistently, ADAMTS13 activity was significantly higher at 3, 6 and 9 months in R+ patients (85% 0-150, 90% 42-150, and 89% 92-125, respectively) when compared to R- patients (49% 0-150, 54% 0-130 and 40% 0-90, respectively, p<0.01, <0.05 and <0.001, respectively), which correlated with significantly lower levels of serum anti-ADAMTS13 antibodies (16 0-77, 8 0-18 and 10 0-25 U/L, respectively, in R+ group and 44 7-100, 33 12-100 and 34 10-130 U/L, respectively, in R- group; p=0.003, 0.007 and 0.04, respectively). However, these differences vanished at 12 months. Neither patient experienced side effects related to rituximab during infusions. No patient developed hypogammaglobulinemia. No significant infectious complications occurred during follow-up.
In patients with acquired idiopathic TTP, rituximab allows to shorten treatment duration in slow responders and prevents 1-year relapses by allowing a higher increase in ADAMTS13 activity. However, rituximab does not prevent long term relapses. Whether rituximab should be introduced systematically on diagnosis or only in patients identified as being slow responders with standard treatment remains a matter of debate which should be accurately assessed through larger, randomized trials.
No relevant conflicts of interest to declare.
Severe ADAMTS13 deficiency in thrombotic microangiopathies (TMA) was reported with a variable frequency, which ranges from 13% to 50%. Whether clinical presentation allows to predict accurately ...severe ADAMTS13 deficiency remains a matter of controversy. To assess this question, we considered all adult (≥ 18 year-old) patients with idiopathic TMA and ADAMTS13 deficiency (< 15% of normal activity) of our Registry, whose clinical characteristics were compared with those of patients with idiopathic TMA and a detectable (≥ 15% normal activity) ADAMTS13 activity. Inclusion criteria were the association of a microangiopathic hemolytic anemia (< 12 g/dL) with a thrombocytopenia (< 150 × 109/L), and no other identifiable cause for cytopenias (transplantation, cancer and chemotherapy, or HIV infection). Patients were included prospectively from October, 2000, to January, 2007, from 17 National centers. One hundred and thirty-five patients were consecutively included. One hundred and two had a severe ADAMTS13 deficiency (58/96 had a plasma inhibitor), and 33 had a detectable ADAMTS13 activity (mean ADAMTS13 activity: 52.7± 29%). Patients with a severe ADAMTS13 deficiency were younger, displayed a lower platelet count and creatinin level, and presented more frequently antinuclear antibodies (ANA) at diagnosis (39.9± 15 versus 49.6± 17.9 year-old, 20± 19.2 versus 56.6± 42.9 × 109/L, 127± 106 versus 425± 335 μmol/L, and 61.8% versus 24.4%, respectively, p<0.001 in all cases). Chronic renal failure occurred more frequently among patients with a detectable ADAMTS13 activity (19.2% versus 1.1%, p<0.001). In a multivariate logistic analysis, patients with severe ADAMTS13 deficiency were more likely to have ANA (Estimated Odds ratio OR 4.81, 95% confidence interval CI 1.5–15.4), a lower platelet count (OR 0.98, 95% CI 0.96–1), and a lower creatinin level (OR 0.99, 95% CI 0.98–0.99) than patients with detectable ADAMTS13 activity (p< 0.01, 0.14, and < 0.01, respectively). Positive ANA with a platelet count <31 × 109/L and a creatinin level <194 μmol/L represented a set of criteria that allowed to identify patients with a severe ADAMTS13 deficiency with 52% sensitivity, but with a high specificity, at 97%. These criteria had a high positive predictive value for a severe ADAMTS13 deficiency, at 98.2%, and a negative predictive value of 39.5%. ANA, platelet count and creatinin level can predict accurately a severe acquired ADAMTS13 deficiency in idiopathic TMA. This set of criteria may be helpful in the management of patients that require targeted therapies, in association with plasma exchanges.
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