Association of Sepsis With Neurologic Outcomes of Adult Patients Treated With Venoarterial Extracorporeal Membrane Oxygnenation.

OBJECTIVES: Neurologic outcomes of patients under venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be worsened by secondary insults of systemic origin. We aimed to assess whether sepsis, commonly observed during ECMO support, is associated with brain injury and outcomes. DESIGN: Single-center cohort study of the "exposed-non-exposed" type on consecutive adult patients treated by VA-ECMO. SETTING: Medical ICU of a university hospital, France, 2013-2020. PATIENTS: Patients with sepsis at the time of VA-ECMO cannulation ("sepsis" group) were compared with patients without sepsis ("no sepsis" group). The primary outcome measure was poor functional outcome at 90 days, defined by a score greater than or equal to 4 on the modified Rankin scale (mRS), indicating severe disability or death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 196 patients were included ("sepsis," n = 128; "no sepsis," n = 68), of whom 87 (44.4%) had presented cardiac arrest before VA-ECMO cannulation. A poor functional outcome (mRS ≥ 4) was observed in 99 of 128 patients (77.3%) of the "sepsis" group and 46 of 68 patients (67.6%) of the "no sepsis" group (adjusted logistic regression odds ratio (OR) 1.21, 95% CI, 0.58-2.47; inverse probability of treatment weighting (IPTW) OR 1.24; 95% CI, 0.79-1.95). Subsequent analyses performed according to pre-ECMO cardiac arrest status suggested that sepsis was independently associated with poorer functional outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest (adjusted logistic regression OR 3.44; 95% CI, 1.06-11.40; IPTW OR 3.52; 95% CI, 1.68-7.73), whereas no such association was observed in patients without pre-ECMO cardiac arrest (adjusted logistic regression OR 0.69; 95% CI, 0.27-1.69; IPTW OR 0.76; 95% CI, 0.42-1.35). Compared with the "no sepsis" group, "sepsis" patients presented a significant increase in S100 calcium-binding protein beta concentrations at day 1 (0.94 µg/L vs. 0.52 µg/L, p = 0.03), and more frequent EEG alterations (i.e., severe slowing, discontinuous background, and a lower prevalence of sleep patterns), suggesting brain injury. CONCLUSION: We observed a detrimental role of sepsis on neurologic outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest, but not in other patients.

Lupus activity and outcomes in lupus patients undergoing maintenance dialysis.

OBJECTIVES: Lupus activity has long been considered to decline after initiation of maintenance dialysis (MD). This assumption is based on limited historical data. We aimed to describe the natural history of lupus in patients undergoing MD. METHODS: We assembled a national retrospective cohort of lupus patients who started dialysis between 2008 and 2011, included in the REIN registry with a 5-year follow-up. We analysed healthcare consumption from the National Health Data System. We evaluated the proportion of patients 'off-treatment' (i.e. receiving 0-5 mg/d of corticosteroids, without any immunosuppressive therapy) after the start of MD. We describe the cumulative incidences of non-severe and severe lupus flares, cardiovascular events, severe infections, kidney transplantation and survival. RESULTS: We included 137 patients (121 females and 16 males), with a median age of 42 years. The proportion of patients 'off-treatment' at dialysis initiation was 67.7% (95% CI: 61.8, 73.8%), and increased to 76.0% (95% CI: 73.3, 78.8) at 1 year and 83.4% (95% CI: 81.0, 85.9%) at 3 years, with a lower proportion in younger patients. Lupus flares mainly occurred in the first year after MD initiation, and at 12 months 51.6% of patients had presented a non-severe lupus flare and 11.6% a severe lupus flare. In addition, 42.2% (95% CI: 32.9, 50.3%) and 23.7% (95% CI: 16.0, 30.7%) of patients at 12 months had been hospitalized for cardiovascular events or infections, respectively. CONCLUSION: The proportion of lupus patients off-treatment increases after MD initiation, but non-severe and severe lupus flares continue to occur, mainly during the first year. This calls for the continued follow-up of lupus patients by lupus specialists after dialysis initiation.

Impact of corticosteroids use on midterm sequelae in survivors of COVID-19 admitted to hospital: A prospective cohort study.

An understanding of the midterm sequelae in COVID-19 and their association with corticosteroids use are needed. Between March and July 2020, we evaluated 1227 survivors of COVID-19, 3 months posthospitalization, of whom 213 had received corticosteroids within 7 days of admission. Main outcome was any midterm sequelae (oxygen therapy, shortness of breath, one major clinical sign, two minor clinical signs or three minor symptoms). Association between corticosteroids use and midterm sequelae was assessed using inverse propensity-score weighting models. Our sample included 753 (61%) male patients, and 512 (42%) were older than 65 years. We found a higher rate of sequelae among users than nonusers of corticosteroids (42% vs. 35%, odds ratio [OR] 1.40 [1.16-1.69]). Midterm sequelae were more frequent in users of low-dose corticosteroids than nonusers (64% vs. 51%, OR 1.60 [1.10-2.32]), whereas no association between higher doses (≥20 mg/day equivalent of dexamethasone) and sequelae was evidenced (OR 0.95 [0.56-1.61]). Higher risk of sequelae with corticosteroids use was observed among subjects with propensity score below the 90th percentile. Our study suggest that corticosteroids use during hospitalization for COVID-19 is associated with higher risk of midterm sequelae.

Risk factors of second ventilator-associated pneumonia in trauma patients: a retrospective cohort study.

BACKGROUND: Ventilator acquired pneumonia (VAP) is a frequent and serious complication in ICU. Second episodes of VAP are common in trauma patients and may be related to severity of underlying conditions, treatment or bacterial factors of the first VAP. The aim of this study was to identify risk factors of second VAP episodes in trauma injured patients (defined as the development of a new pulmonary infection during or remotely following the first episode). DESIGN: This is a single-center, retrospective cohort study of trauma injured patients who underwent a first episode of VAP between January 1, 2013 and December 31, 2020 at Beaujon Hospital. RESULTS: A total of 533 patients with a first episode of VAP were analyzed, mostly with head and/or thoracic traumatic injury. A second episode of VAP occurred in one hundred sixty-seven patients (31.3%). The main risk factors found was the degree of hypoxemia at the time of the first episode [PaO2/FiO2 ratio 100-200, OR 3.12 (1.77-5.69); < 100, OR 5.80 (2.70-12.8)] and severe traumatic brain injury characterized by an initial GCS ≤ 8 [OR 1.65 (1.01-2.74)]. CONCLUSION: Depth of hypoxemia during the first VAP episode and severity of the initial brain injury are the main risk factors for VAP second episode in trauma injured patients.

Antimicrobial Stewardship for Ventilator Associated Pneumonia in Intensive Care (the ASPIC trial): study protocol for a randomised controlled trial.

INTRODUCTION: Ventilator-associated pneumonia (VAP) remains the leading cause of infections treated in the intensive care units (ICU). In a personalised care approach, we hypothesise that the duration of treatment of VAP can be reduced in function of the response to treatment. METHODS AND ANALYSIS: The Antimicrobial Stewardship for Ventilator-Associated Pneumonia in Intensive Care (ASPIC) trial is a pragmatic national multicentre, phase III, non-inferiority, comparative randomised (1:1) single-blinded clinical trial. Five hundred and ninety adult patients hospitalised in 24 French ICU with a microbiologically confirmed first episode of VAP that received appropriate empirical antibiotic therapy will be included. They will be randomly allocated to standard management with duration of appropriate antibiotic fixed for 7 days according to international guidelines or antimicrobial stewardship based on daily clinical assessment of clinical cure. The assessment of clinical cure will be repeated daily until at least three criteria of clinical cure are met, allowing the discontinuation of antibiotic therapy in experimental group. The primary endpoint is a composite endpoint combining of all-cause mortality measured at day 28, treatment failure or new episode of microbiologically confirmed VAP until day 28.The aim of the study is to demonstrate that a strategy to reduce the duration of antibiotic therapy for VAP based on clinical assessment is safe could lead to changes in practice as part of a personalised therapeutic approach, by reducing exposure to antibiotics and their side effects. ETHICS AND DISSEMINATION: The ASPIC trial has been approved by the French regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM; EUDRACT number 2021-002197-78, 19 August 2021) and an independent ethics committee the Comité de Protection des Personnes Ile-de-France III (CNRIPH : 21.03.25.60729, 10 October 2021) for the study protocol (version ASPIC-1.3; 03 September 2021) for all study centres. Participant recruitment is scheduled to begin in 2022. Results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT05124977.

Erratum: CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death.

[This corrects the article DOI: 10.1016/j.isci.2021.102711.].

Prevalence of post-acute coronavirus disease 2019 symptoms twelve months after hospitalization in participants retained in follow-up: analyses stratified by gender from a large prospective cohort.

OBJECTIVES: Persistent post-acute coronavirus disease 2019 (COVID-19) symptoms (PACSs) have been reported up to 6 months after hospital discharge. Herein we assessed the symptoms that persisted 12 months (M12) after admission for COVID-19 in the longitudinal prospective national French coronavirus disease cohort. METHODS: Hospitalized patients with a confirmed virological diagnosis of COVID-19 were enrolled. Follow-up was planned until M12 after admission. Associations between persistence of ≥3 PACSs at M12 and clinical characteristics at admission were assessed through logistic regression according to gender. RESULTS: We focused on participants enrolled between 24 January 2020 and 15 July 2020, to allow M12 follow-up. The M12 data were available for 737 participants. Median age was 61 years, 475 (64%) were men and 242/647 (37%) were admitted to intensive care units during the acute phase. At M12, 27% (194/710) of the participants had ≥3 persistent PACS, mostly fatigue, dyspnoea and joint pain. Among those who had a professional occupation before the acute phase, 91 out of 339 (27%) were still on sick leave at M12. Presence of ≥3 persistent PACS was associated with female gender, both anxiety and depression, impaired health-related quality of life and Medical Muscle Research Council Scale <57. Compared with men, women more often reported presence of ≥3 persistent PACSs (98/253, 39% vs. 96/457, 21%), depression and anxiety (18/152, 12% vs. 17/268, 6% and 33/156, 21% vs. 26/264, 10%, respectively), impaired physical health-related quality of life (76/141, 54% vs. 120/261, 46%). Women had less often returned to work than men (77/116, 66% vs. 171/223, 77%). CONCLUSIONS: One fourth of the individuals admitted to hospital for COVID-19 still had ≥3 persistent PACSs at M12 post-discharge. Women reported more often ≥3 persistent PACSs, suffered more from anxiety and depression and had less often returned to work than men.

Staple Line Intrathoracic Migration After Sleeve Gastrectomy: Correlation between Symptoms, CT Three-Dimensional Stomach Analysis, and 24-h pH Monitoring.

PURPOSE: Migration of the staple line is the definition of sliding hiatus hernia in sleeve gastrectomy patients. The main aim was to determine the frequency and measurement of intrathoracic staple line migration and its correlation with GERD symptoms and pH monitoring. MATERIALS AND METHODS: This was a prospective clinical trial including all patients who underwent sleeve gastrectomy more than 1 year previously. All the patients underwent computed tomography (CT) imaging, and migration of the proximal end of the suture above the level of the hiatus was measured in mm. All the patients with symptoms suggestive of GERD were assessed using the GERD impact scale (GIS), and wireless 24-h esophageal pH and symptom association monitoring (SAP) were carried out. Analysis of risk factors for postoperative staple line migration was performed. RESULTS: Between March 2018 and December 2018, 194 patients were evaluated (mean age 45.1 ± 11.2 years; 161 females); 88/194 (45.4%) presented an average intrathoracic migration of 16.2 ± 6.9 mm. Thirty-eight of 194 (19.5%) patients presented symptoms suggestive of gastroesophageal reflux. There was a significant relationship between staple line intrathoracic migration and postsleeve GERD symptomatology (p = 0.0004, OR = 4.25 [1.92-9.39]). However, there was no significant correlation between positive 24-h pH monitoring and intrathoracic migration of the staple line (p = 0.1). CONCLUSION: A migration greater than 17 mm was strongly correlated with postsleeve GERD symptoms but not with positive 24-h pH monitoring.

Empiric antimicrobial therapy for early-onset pneumonia in severe trauma patients.

PURPOSE: The bacterial ecology involved in early pneumonia of severe trauma patients is mostly commensal and would allow wide use of narrow-spectrum antibiotics. We describe risk factors for treatment failure of severe trauma patients' pneumonia with the use of narrow-spectrum antimicrobial therapy in order to develop a score that could help clinicians to determine which patients might be treated with narrow-spectrum antibiotics. METHODS: A retrospective, observational, monocentric cohort study was conducted of severe trauma patients requiring mechanical ventilation for > 48 h and developing a first episode of microbiologically confirmed pneumonia occurring within the first 10 days after admission. RESULTS: Overall, 370 patients were included. The resistance rate against narrow-spectrum antibiotics (amoxicillin/clavulanic acid) was 22.7% (84 pneumonia). In a multivariate analysis, two independent risk factors were associated with this resistance: prior antimicrobial therapy ≥ 48 h (OR 4.00; 95 CI [2.39; 6.75]) and age ≥ 30y (OR 2.10; 95 CI [1.21; 3.78]). We created a prediction score that defined patient with one or two risk factors at high risk of resistance. This score presented a sensitivity of 0.92 [0.88; 0.94], a specificity of 0.33 [0.28; 0.38], a positive predictive value of 0.29 [0.24; 0.33] and a negative predictive value of 0.93 [0.90; 0.95]. CONCLUSION: Simple risk factors may help clinicians to identify severe trauma patients at high risk of pneumonia treatment failure with the use of narrow-spectrum antimicrobial therapy and, thus, use better tailored empiric therapy and limit the use of unnecessary broad-spectrum antimicrobial therapy.

Persistent COVID-19 symptoms are highly prevalent 6 months after hospitalization: results from a large prospective cohort.

OBJECTIVES: Persistent COVID-19 symptoms have been reported up to 3 months after hospital discharge. Little is known on the frequency and the nature of persistent symptoms beyond 3 months. Here we have assessed, in the longitudinal prospective French COVID-19 cohort, symptoms that persisted 6 months after admission for COVID-19. METHODS: Hospitalized patients with virologically confirmed COVID-19 were enrolled. Follow-up was planned with a physician's visit at month (M)3 and M6 after admission. Associations between persistence of symptoms at M6 and clinical characteristics at admission were assessed through bivariate and multivariate logistic regression. RESULTS: M6 data were available for 1137 participants. Median age was 61 years (IQR 51-71) and 288 (29%, 95% CI 26-32%) were admitted to intensive care unit (ICU) during the acute phase. Six hundred and fifty-five (68%, 95% CI 65-71%) and 639 (60%, 95% CI 57-63%) participants had at least one symptom at M3 and M6 visit, respectively, mostly fatigue, dyspnoea, joint pain and myalgia. At M6, 255 (24%, 95% CI 21-27%) of participants had three or more persistent symptoms. The presence of three or more symptoms at M6 was independently associated with female gender (adjusted odds ratio (aOR) 2.40, 95% CI 1.75-3.30), having three or more symptoms at admission (aOR 2.04, 95% CI 1.45-2.89) and ICU admission/transfer during acute phase (aOR 1.55, 95% CI 1.09-2.18), but not significantly with age or having two or more comorbidities. One hundred and twenty-five (29%, 95% CI 25-34%) of those who initially had a professional occupation were not back to work at M6. DISCUSSION: A fourth of individuals admitted to hospital for COVID-19 still had three or more persistent symptoms at M6. Longitudinal follow-up of individuals with severe COVID-19 is warranted to better understand the pathophysiology underlying this long-term persistence.

CD177, a specific marker of neutrophil activation, is associated with coronavirus disease 2019 severity and death.

The identification of patients with coronavirus disease 2019 and high risk of severe disease is a challenge in routine care. We performed cell phenotypic, serum, and RNA sequencing gene expression analyses in severe hospitalized patients (n = 61). Relative to healthy donors, results showed abnormalities of 27 cell populations and an elevation of 42 cytokines, neutrophil chemo-attractants, and inflammatory components in patients. Supervised and unsupervised analyses revealed a high abundance of CD177, a specific neutrophil activation marker, contributing to the clustering of severe patients. Gene abundance correlated with high serum levels of CD177 in severe patients. Higher levels were confirmed in a second cohort and in intensive care unit (ICU) than non-ICU patients (P < 0.001). Longitudinal measurements discriminated between patients with the worst prognosis, leading to death, and those who recovered (P = 0.01). These results highlight neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.

Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort.

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients (P < 10-4). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, P < 10-3). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.

CD62L on blood basophils: a first pre-treatment predictor of remission in severe lupus nephritis.

BACKGROUND: Basophils were recently shown to contribute to lupus nephritis (LN). This study assessed blood basophil activation markers (BAMs) for the diagnosis of LN severity and as pre-treatment prognostic markers of the response to treatment in patients with severe LN. METHOD: The diagnostic study included all the patients of a monocentric prospective observational cohort built with consecutive patients diagnosed with LN on the basis of a renal biopsy. The prognostic study selected patients of this cohort according to the following inclusion criteria: ≥18 years old, Class III or IV A ± C ± Class V or pure Class V LN at the time of inclusion and treated with an induction treatment for LN. Clinical data and BAMs were obtained at the time of the kidney biopsy. LN remission status was recorded 12 months after induction therapy initiation. Associations between baseline data and histological severity of LN or LN remission were assessed using logistic regression. RESULTS: No significant association was found between BAMs and the histological severity of LN in 101 patients. Among the 83 patients included in the prognostic study, 64 reached renal remission. CD62L expression on blood basophils at baseline was independently negatively associated with remission at 12 months [odds ratio = 0.26, 95% confidence interval 0.08-0.82, P = 0.02 for quantitative CD62L expression >105 (geometric fluorescent intensity) gMFI]. CD62L <105 gMFI was associated with a probability of 0.87 of LN remission in the next 12 months after the start of induction therapy. CONCLUSION: Pre-treatment CD62L expression on blood basophils could be a first predictive biomarker of renal response to induction therapy at 12 months in patients with severe LN.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

A Machine Learning Approach for High-Dimensional Time-to-Event Prediction With Application to Immunogenicity of Biotherapies in the ABIRISK Cohort.

Predicting immunogenicity for biotherapies using patient and drug-related factors represents nowadays a challenging issue. With the growing ability to collect massive amount of data, machine learning algorithms can provide efficient predictive tools. From the bio-clinical data collected in the multi-cohort of autoimmune diseases treated with biotherapies from the ABIRISK consortium, we evaluated the predictive power of a custom-built random survival forest for predicting the occurrence of anti-drug antibodies. This procedure takes into account the existence of a population composed of immune-reactive and immune-tolerant subjects as well as the existence of a tiny expected proportion of relevant predictive variables. The practical application to the ABIRISK cohort shows that this approach provides a good predictive accuracy that outperforms the classical survival random forest procedure. Moreover, the individual predicted probabilities allow to separate high and low risk group of patients. To our best knowledge, this is the first study to evaluate the use of machine learning procedures to predict biotherapy immunogenicity based on bioclinical information. It seems that such approach may have potential to provide useful information for the clinical practice of stratifying patients before receiving a biotherapy.

Assessing the effect of genetic markers on drug immunogenicity from a mechanistic model-based approach.

BACKGROUND: With the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue. This immune response against a drug can be due either to pre-existing antibodies or to the novel production of antibodies from B-cell clones by a fraction of the exposed subjects. Identifying genetic markers associated with the immunogenicity of biotherapeutic drugs may provide new opportunities for risk stratification before the introduction of the drug. However, real-world investigations should take into account that the population under study is a mixture of pre-immune, immune-reactive and immune-tolerant subjects. METHOD: In this work, we propose a novel test for assessing the effect of genetic markers on drug immunogenicity taking into account that the population under study is a mixed one. This test statistic is derived from a novel two-part semiparametric improper survival model which relies on immunological mechanistic considerations. RESULTS: Simulation results show the good behavior of the proposed statistic as compared to a two-part logrank test. In a study on drug immunogenicity, our results highlighted findings that would have been discarded when considering classical tests. CONCLUSION: We propose a novel test that can be used for analyzing drug immunogenicity and is easy to implement with standard softwares. This test is also applicable for situations where one wants to test the equality of improper survival distributions of semi-continuous outcomes between two or more independent groups.

Impact of cardiac function, refractory ascites and beta blockers on the outcome of patients with cirrhosis listed for liver transplantation.

BACKGROUND & AIMS: Whether non-selective beta blockers (NSBBs) are deleterious in patients with end-stage cirrhosis and refractory ascites has been widely debated. We hypothesized that only the subset of patients on the liver transplant waiting list who had impaired cardiac performance would be at increased risk of mortality if receiving NSBBs. METHODS: This study included 584 consecutive patients with cirrhosis evaluated for transplantation between 1999 and 2014. All patients had right heart catheterization with hemodynamic measurements at evaluation. Fifty percent received NSBBs. Refractory ascites was present in 33%. Cardiac performance was assessed by left ventricular stroke work index (LVSWI). Waiting list mortality without liver transplantation was explored using competing risk analysis. RESULTS: LVSWI was significantly lower in patients with refractory ascites. In multivariate analysis using competing risk, refractory ascites, NSBBs and LVSWI were associated with waiting list mortality in the whole population, with a statistically significant interaction between NSBBs and LVSWI. The most discriminant value of LVSWI was 64.1 g-m/m2. In the final model, refractory ascites (subdistribution hazard ratio 1.52; 95% CI1.01-2.28; p = 0.0083) and treatment by NSBBs with LVSWI <64.1 g-m/m2 (subdistribution hazard ratio 1.96; 95% CI 1.32-2.90; p = 0.0009) were significantly associated with waiting list mortality, taking into account serum sodium and the model for end-stage liver disease score. CONCLUSIONS: This study suggests that compromised cardiac performance is more common in patients with refractory ascites and that NSBBs are deleterious in cirrhotic patients with compromised cardiac performance. These results highlight the prognostic value of cardiac function in patients with end-stage cirrhosis. LAY SUMMARY: There are still controversies concerning the impact of non-selective beta blockers on outcomes in patients with decompensated cirrhosis, especially in those with refractory ascites. In this study of 584 cirrhotic patients evaluated for liver transplantation, who underwent right heart catheterization, we have shown that global cardiac performance measured by left ventricular stroke work index is lower in patients with refractory ascites. Administration of non-selective beta blockers in patients with compromised cardiac performance may increase waiting list mortality. These results highlight the prognostic value of global cardiac performance in patients with end-stage cirrhosis.

Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A.

Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

Breast Cancer and Exposure to Organochlorines in the CECILE Study: Associations with Plasma Levels Measured at the Time of Diagnosis and Estimated during Adolescence.

Exposure to environmental chemicals with hormonal effects, such as organochlorine compounds (OCs), during developmental periods of breast cells may have an impact on the incidence of breast cancer later in life. However, the assessment of exposure to these chemicals that occurred in early life at the time of breast cancer development in adult women is a difficult challenge in epidemiological studies. Plasma levels of the OCs p,p'-dichlorodiphenyl dichloroethene (DDE) and polychlorinated biphenyl congener 153 (PCB153) were measured in 695 cases and 1055 controls of a population-based case-control study conducted in France (CECILE study). Based on these values, we used a physiologically-based pharmacokinetic (PBPK) model to estimate PCB153 levels at age 11⁻20 years when the women were adolescents. Overall, there was no clear association between breast cancer risk and measured levels of DDE and PCB153 at the time of diagnosis, but there was a trend of decreasing odds ratios of breast cancer with increasing DDE and PCB153 levels in women aged 50 years and over. The PBPK model revealed that PCB153 concentrations estimated during adolescence were highest in the youngest women born after 1960 who reached adolescence at a time when environmental contamination was maximum, and very low in the oldest women who attained adolescence before the contamination peak. Negative associations between breast cancer and PCB153 estimates during adolescence were also found. The negative associations between DDE and PCB153 levels measured at the time of diagnosis or estimated during adolescence in our study were unexplained. Further investigations are needed to clarify whether this finding is real or related to study artifacts. However, this study suggests that using PBPK models in epidemiological studies to back-estimate OC exposures during early life stages may be useful to address critical questions on cancer development.

Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis.

OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.