Immunosuppression in patients with grade 3 acute-on-chronic liver failure at transplantation: A practice analysis study.

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV < 40% (P = .019), absence of early tacrolimus overdose (P = .033), use of anti-IL2-receptor antibodies (P = .034), and early mycophenolic acid introduction (P = .038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P = .001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation.

The 13-Valent Pneumococcal Conjugate Vaccine Elicits Serological Response and Lasting Protection in Selected Patients With Primary Humoral Immunodeficiency.

Background: Patients with primary humoral immunodeficiency are more prone to invasive as well as recurrent pneumococcal infections. Therefore, anti-pneumococcal vaccination including the 13-valent conjugate vaccine is recommended. Nevertheless, to date, no data is available on immunogenicity of this vaccine in this population. Objective: To assess the immunogenicity and the persistence of protection up to one year after a 13-valent pneumococcal conjugate vaccine in patients with primary humoral immunodeficiency. Methods: Twenty-nine patients with common variable immunodeficiency or IgG subclass deficiency were vaccinated. Immune response and immune protection at baseline as well as at one, six and twelve months after vaccination were evaluated by measuring specific IgG serum concentrations (ELISA), and opsonophagocytic activities directed against selected pneumococcal (MOPA). Results: By ELISA, half of the patients had protective IgG concentrations before vaccination, 35.7% showed an immune response one month after vaccination, 71.4%, 66.7% and 56.0% of the patients were protected at one, six and twelve months respectively. Conversely, by MOPA, 3.4% of the patients were protected at baseline, 10.7% showed an immune response and 28.6%, 48.2% and 33.3% were protected at one, six and twelve months respectively. IgG subclass deficiency, Ig replacement therapy and higher IgG2 concentrations at diagnosis were associated with long-term protection. Conclusion: Pneumococcal conjugate vaccine improves immune protection and antibodies' functionality in a subset of patients with primary immunodeficiency. Prime-boost vaccine strategy needs to be better and individually adapted.

Assessment of Magnetic Resonance Imaging Changes and Functional Outcomes Among Adults With Severe Herpes Simplex Encephalitis.

Importance: Current guidelines recommend brain magnetic resonance imaging (MRI) for clinical management of patients with severe herpes simplex encephalitis (HSE). However, the prognostic value of brain imaging has not been demonstrated in this setting. Objective: To investigate the association between early brain MRI data and functional outcomes of patients with HSE at 90 days after intensive care unit (ICU) admission. Design, Setting, and Participants: This multicenter cohort study was conducted in 34 ICUs in France from 2007 to 2019 and recruited all patients who received a clinical diagnosis of encephalitis and exhibited cerebrospinal fluid positivity for herpes simplex virus DNA in the polymerase chain reaction analysis. Data analysis was performed from January to April 2020. Exposures: All patients underwent a standard brain MRI during the first 30 days after ICU admission. Main Outcomes and Measures: MRI acquisitions were analyzed by radiologists blinded to patients' outcomes, using a predefined score. Multivariable logistic regression and supervised hierarchical classifiers methods were used to identify factors associated with poor outcome at 90 days, defined by a score of 3 to 6 (indicating moderate-to-severe disability or death) on the Modified Rankin Scale. Results: Overall, 138 patients (median [interquartile range {IQR}] age, 62.6 [54.0-72.0] years; 75 men [54.3%]) with an admission median (IQR) Glasgow Coma Scale score of 9 (6-12) were studied. The median (IQR) delay between ICU admission and MRI was 1 (1-7) days. At 90 days, 95 patients (68.8%) had a poor outcome, including 16 deaths (11.6%). The presence of fluid-attenuated inversion recovery MRI signal abnormalities in more than 3 brain lobes (odds ratio [OR], 25.71; 95% CI, 1.21-554.42), age older than 60 years (OR, 7.62; 95% CI, 2.02-28.91), and the presence of diffusion-weighted MRI signal abnormalities in the left thalamus (OR, 6.90; 95% CI, 1.12-43.00) were independently associated with poor outcome. Machine learning models identified bilateral diffusion abnormalities as an additional factor associated with poor outcome (34 of 39 patients [87.2%] with bilateral abnormalities had poor outcomes) and confirmed the functional burden of left thalamic lesions, particularly in older patients (all 11 patients aged >60 years had left thalamic lesions). Conclusions and Relevance: These findings suggest that in adult patients with HSE requiring ICU admission, extensive MRI changes in the brain are independently associated with poor functional outcome at 90 days. Thalamic diffusion signal changes were frequently observed and were associated with poor prognosis, mainly in older patients.

Predictive factors of success at the French National Ranking Examination (NRE): a retrospective study of the student performance from a French medical school.

BACKGROUND: The national ranking examination (NRE) marks the end of the second cycle (6th university year) of French medical studies and ranks students allowing them to choose their specialty and city of residency. We studied the potential predictive factors of success at the 2015 NRE by students attending a French School of Medicine. METHODS: From March 2016 to March 2017, a retrospective study of factors associated with the 2015 NRE success was conducted and enrolled 242 students who attended their sixth year at the school of medicine of Reims. Demographic and academic data collected by a home-made survey was studied using univariate and then multivariate analysis by generalized linear regression with a threshold of p <  0.05 deemed significant. RESULTS: The factors independently associated with a better ranking at the NRE were the motivation for the preparation of the NRE (gain of 3327 ± 527 places, p <  0.0001); to have participated in the NRE white test organized by la Revue du Praticien in November 2014 (gain of 869 ± 426 places, p <  0.04), to have participated in the NRE white test organized by la conférence Hippocrate in March 2015 (+ 613 places ±297, p <  0.04). The factors independently associated with poor NRE ranking were repeating the first year (loss of 1410 places ±286, p <  0.0001), repeating a year during university course (loss of 1092 places ±385, p <  0.005), attendance of hospital internships in 6th year (loss of 706 places ±298, p <  0.02). CONCLUSIONS: The student motivation and their white tests completion were significantly associated with success at the NRE. Conversely, repeating a university year during their course and attendance of 6th year hospital internships were associated with a lower ranking.

Intensive care for patients with gastric cancers: outcome and survival prognostic factors.

BACKGROUND: Admission and management of patients with solid malignancies in intensive care unit (ICU) is a controversial topic. To this day, there is no data published concerning patients with gastric cancers hospitalized in ICU. This single center retrospective study reports the characteristics, outcome and prognostic factors of patients hospitalized in ICU for medical reasons over a period of 10 years. METHODS: We performed a single center retrospective study which reports the characteristics, outcome and prognostic factors of patients hospitalized in ICU for medical reasons over a period of 10 years. RESULTS: Thirty-seven patients were included, among whom 24 (64.9%) had metastatic cancer. The most frequent diagnosis on admission was septic shock (48.6%) and 24 patients (64.9%) required intubation. Ten patients (27.0%) were alive 3 months after their admission in ICU. Metastatic cancer and intubation were independently associated with a higher risk of dying within 3 months of admission in multivariate analysis: odds ratio (OR) =13.7; 95% confidence interval (CI), 1.7-108 (P<0.01). Seventeen patients (45.9%) died during their ICU stay. Metastatic cancer: OR =89; 95% CI, 2.7-6,588, therapeutic intensification: OR =1,471; 95% CI, 9.8-811,973 and the logistic organ dysfunction score (LODS) on admission: OR =1.4; 95% CI, 1.1-2.3 were independently associated with mortality within the ICU in multivariate analysis (P<0.01). CONCLUSIONS: This is the first study that examines the outcome and prognostic factors of patients with gastric cancers who require life-sustaining therapy in ICU. The identification of 3 months and ICU mortality prognostic factors could contribute to guiding clinicians in the management of these patients and assist health professionals in their discussions with these patients and their families.

Critically ill elderly patients (≥ 90 years): Clinical characteristics, outcome and financial implications.

BACKGROUND: Patients aged over 90 are being admitted to intensive care units (ICUs) with increasing frequency. The appropriateness of such decisions still remains controversial due to questionable outcome, limited resources and costs. Our objective was to determine the clinical characteristics and outcome in elderly patients (≥ 90 years) admitted in a medical ICU, with an additional focus on medico-economic implications. METHODS: We reviewed the charts of all patients (≥ 90 years) admitted to our ICU. We compared them with all other ICU patients (< 90 years), sought to identify ICU mortality predictors and also performed a long-term survival follow-up. RESULTS: In the study group of 317 stays: median age was 92 years (IQR: 91-94 years); most patients were female (71.3%.). Acute respiratory failure (52.4%) was the main admission diagnosis; mean SAPS II was 55.6±21.3; half the stays (49.2%) required mechanical ventilation (duration: 7.2±8.8 days); withholding and withdrawing decisions were made for 33.4% of all stays. ICU and hospital mortality rates were 35.7% and 42.6% respectively. Mechanical ventilation (OR = 4.83, CI95%: 1.59-15.82) was an independent predictor of ICU mortality whereas age was not (OR = 0.88, CI95%: 0.72-1.08). Social security reimbursement was significantly lower in the study group compared with all other ICU stays, both per stay (13,160 vs 22,092 Euros, p< 0.01) and per day of stay (p = 0.03). CONCLUSION: Among critically ill elderly patients (≥ 90 years), chronological age was not an independent factor of ICU mortality. ICU care-related costs in this population should not be considered as a limiting factor for ICU admission.

In Trauma Patients, the Occurrence of Early-Onset Nosocomial Infections is Associated With Increased Plasma Concentrations of Chromogranin A.

In previously healthy persons suffering from acute illnesses, nosocomial infections (NIs) are frequent. Their prevalence suggests the existence of as yet unknown conditions that may promote care-related infection. This study assessed whether the measurement of plasma chromogranin A, a stress-related protein involved in innate defense, is related to NI risk, and whether any chromogranin A-derived fragment included in vasostatin-I displays immunosuppressive activities related to AP-1 or NF-kappa B downregulation. At the clinical level, trauma patients and healthy controls were recruited to be eligible. Clinical histories were recorded, and standard biological tests (including plasma chromogranin A) were performed. For 9 randomly chosen patients and 16 controls, the time-dependent concentrations of chromogranin A (CGA) were assessed twice a day over 66 h. The data show that trauma patients present a higher value of CGA concentration during 66 h in comparison with healthy controls. In addition, patients maintaining this significant increase in CGA readily develop NIs. We therefore studied the effects of chromogranin A-derived peptides on monocytes, focusing on transcription factors that play a central role in inflammation. In vitro assay demonstrated that a chromogranin A-derived fragment (CGA47-70) displays a significant inhibition of NF-kappa B and AP-1 transcriptional activities in these cells. In conclusion, the occurrence of NI in trauma patients is associated with significantly increased plasma CGA concentrations. Downregulation of the two transcription factors by CGA47-70 might induce early acquired immune defect after a serious medical stress.

Liver transplantation in critically ill patients: Preoperative predictive factors of post-transplant mortality to avoid futility.

BACKGROUND: The allocation of liver transplants to patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) with multi-organ failure who are admitted in ICU remains controversial due to their high post-transplant mortality rate and the absence of identified mortality risk factors. METHODS: We performed a single-center retrospective cohort study to determine the post-transplant mortality rate of patients with ALF and ACLF requiring ICU care prior to liver transplant (LT) and identified pretransplant factors of post-transplant mortality. RESULTS: Eighty-four patients (29 with ALF and 55 with ACLF) received a liver transplant while they were hospitalized at the ICU. Their mean model for end-stage liver disease (MELD) score was 41, and their mean sequential organ failure assessment (SOFA) was 15 the day before transplant. The overall 1-year survival rate was 66%. In multivariate analysis, pretransplant lactate level and acute respiratory distress syndrome (ARDS) were the only two independent factors associated with post-transplant mortality. The absence of ARDS and a pretransplant lactate level< 5 mmol/L led to the identification of a subgroup of ICU patients with a good 1-year post-transplant survival (>80%). CONCLUSIONS: Low lactatemia lactate level and the absence of ARDS could be useful criteria in selecting those patients in ICU who could be eligible for liver transplant.

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Atypical presentation of paroxysmal nocturnal hemoglobinuria treated by eculizumab: A case report.

RATIONALE: Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant acquired hematopoietic stem cell disease, which can be revealed by hemolytic anemia, thromboembolism, or bonemarrow failure. Thrombosis can occur at any site, but coronary thrombosis is extremely rare. Controlled trials have demonstrated that eculizimab, an inhibitor of the terminal complement cascade, was able to reduce both hemolysis and thrombosis, but its efficacy in cases of PNH with coronary thrombosis is unknown. PATIENT CONCERNS AND DIAGNOSES: We report herein the unusual case of a 73-year-old patient presenting with recurrent coronary syndromes without associated stenosis, fever, marked inflammatory syndrome, and anemia, leading to a delayed diagnosis of PNH. INTERVENTION AND OUTCOMES: Eculizumab allowed the resolution of fever and inflammation, and prevented further thromboembolism. LESSONS: This case emphasizes the importance of performing aflow cytometry test for PNH in front of unusual or unexplained recurrent thromboses. Thromboses, as observed in our case, may be associated with fever and marked inflammation. This case also provides useful information on eculizumab ability to prevent further thromboembolism in PNH patients with a medical history of arterial thrombosis.

Bevacizumab to Treat Cholangiopathy in Hereditary Hemorrhagic Telangiectasia: Be Cautious: A Case Report.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular dysplasia characterized by mucocutaneous telangiectasia and visceral arteriovenous malformations. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high-output cardiac failure. There is no curative treatment for the disease. Liver transplantation is indicated for life-threatening complications, but it carries significant risk due to surgery and immunosuppressive treatment. Some case reports or small open studies suggest that bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, should be efficient in limiting bleeding and in reducing liver disease in HHT.We report a case of a 63-year-old woman with HHT presenting with ischemic cholangiopathy. Liver transplant was indicated, but given a previous encouraging report showing a regression of biliary disease with bevacizumab in 3 patients with HHT this drug was proposed. No significant efficacy but a severe adverse effect was observed after 3 months: bilateral pulmonary embolisms, thrombosis in the right atrial cavity, and thrombosis of the right hepatic vein were evidenced. Bevacizumab was stopped; anticoagulant started. Four months later, the patient received a transplanted liver. She feels well 1 year later.This case report intends to provide the information for clinicians to consider the use of bevacizumab in HHT. Whereas several uncontrolled series and case reports have suggested the efficacy of this drug in reducing bleeding and liver disease, no severe side effects were mentioned to date. For the first time in HHT we report a life-threatening side effect of this drug and no efficacy. Moreover, systemic thrombosis, the observed complication, may preclude transplantation. To date, caution seems still indispensable when considering the use of bevacizumab in HHT.

Liver hilar abscesses secondary to gastrointestinal perforation by ingested fish bones: surgical management of two cases.

Several hepatobiliary complications secondary to gastrointestinal perforation after ingestion of a fish bone have been described in the literature, the most common being liver abscess, which can be potentially fatal. Treatment involves removal of the foreign body if possible (endoscopically or surgically), drainage of the abscess (radiologically or surgically), and appropriate antibiotic therapy. To our knowledge, no cases of hepatic hilar abscesses secondary to gastrointestinal perforation by a fish bone have been described in the literature. We report surgical management of two cases of abscess localized in the hepatic hilum secondary to the ingestion of fish bones.