Safety profile of immune checkpoint inhibitors according to cancer type.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment in recent years, but have led to the emergence of new so-called immune-related adverse events (irAE). The objective of this study was to determine whether cancer type is a potential predictive factor of irAEs. METHODS: This retrospective study included patients who had started an ICI treatment between 2019 and 2020 at the Grenoble Alpes University Hospital. A logistic regression model and a Fine and Gray survival model with death as a competing risk were used to identify variables associated with grade≥2 irAEs and grade≥2 irAEs-free survival. RESULTS: Of the 512 patients included, 160 (31.2%) had a grade≥2 irAE. Grade≥2 irAEs were less frequent in head and neck cancer compared to other cancers. Ipilimumab (odds ratio [OR]: 6.05; 95% confidence interval [CI]: 2.81-13.7), treatment duration (OR: 1.01; 95% CI: 1.01-1.02), and history of autoimmune disease (OR: 6.04; 95% CI: 2.45-16.5) were independently associated with grade≥2 irAEs. With death as a competing risk, grade≥2 irAEs-free survival was independently improved with treatment duration (subdistribution hazard ratio [sdHR]: 0.93; 95% CI: 0.92-0.94), ipilimumab (sdHR: 0.24; 95% CI: 0.1-0.59) and history of autoimmune disease (sdHR: 0.23; 95% CI: 0.08-0.69) whereas it was poorer for patients with performance status≥2 (sdHR: 2.04; 95% CI: 1.5-2.76) and an older age (sdHR: 1.02; 95% CI: 1.00-1.03). CONCLUSION: Ipilimumab and history of autoimmune disease were both associated with the presence of grade≥2 irAEs and grade≥2 irAEs-free survival. The different cancer groups were not.

Rise and fall of thyroid radiologic density during the time course of amiodarone-induced thyrotoxicosis.

Background and Objective: It has been reported recently in a cross sectional study that patients with amiodarone induced thyrotoxicosis (AIT) showed a 'white' thyroid on unenhanced computed tomography, due to intrathyroid iodine accumulation. However, the link between increase in thyroid radiologic density and amiodarone induced thyrotoxicosis remains unknown. We sought to analyze this link. Methods: We present the case of a 34-year-old patient with severe sarcoidosis-related hypertrophic cardiomyopathy who was followed with successive unenhanced CT scans integrated with FDG PET scans. After the first CT scans the patient, who initially had a normal thyroid function, was exposed to amiodarone during 23 months and developed AIT, very likely by thyroiditis (AIT type 2). There were no thyroid antibodies, no evidence of thyroid sarcoidosis on FDG PET scan, while thyroid sonogram showed a homogenous 22 ml moderate goiter with normal echogenicity and no nodules. Results: Analysis of the successive enhanced CT scans revealed that after initiation of amiodarone treatment, thyroid radiologic density steadily increased before detection of AIT, peaked after cessation of amiodarone and initiation of thyrotoxicosis treatment, before returning to normal as thyrotoxicosis receded. Thyroid volume also showed a moderate increase, peaking at the detection of thyrotoxicosis, before returning to normal. Conclusion: This case suggests that AIT is preceded by a very high intrathyroid iodine accumulation before the 'burst' of thyroiditis occurs and that measurements of thyroid gland radiological density might predict the development and remission of AIT.

Screening of hepatitis E in patients presenting for acute neurological disorders.

INTRODUCTION: Hepatitis E virus (HEV) infection has been reported to be associated with neurological disorders. However, the real prevalence of acute hepatitis E in those diseases is still unknown. We determined the prevalence of anti-HEV IgM antibody in a population with acute non-traumatic, non-metabolic, non-vascular neurological injury. METHOD: A registry was created in Grenoble Hospital University from 2014 to 2018 to collect data on patients with acute (<3 months) non-traumatic, non-metabolic, non-vascular neurological injuries. Acute hepatitis E was defined as anti-HEV IgM-positive serum in immunocompetent patient, and as anti-HEV IgM-positive serum or HEV RNA-positive serum in immunocompromised patients. RESULTS: One hundred fifty-nine patients were included. Anti-HEV IgM seroprevalence in our cohort of non-traumatic, non-metabolic, non-vascular neurological injuries was 6.9% (eleven patients, including 4 Parsonage-Turner syndrome (PTS) and 2 Guillain-Barré syndrome (GBS)). Elevated transaminases were observed in only 64% of hepatitis E patients and cholestasis in 64%. CONCLUSION: In this study, 6·9% of patients with acute non-traumatic, non-metabolic, non-vascular neurological injuries had a probable recent HEV infection. HEV serology should be systematically performed in this population, even in patients with normal transaminase level.

Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission.

BACKGROUND: Severely ill patients might develop an alteration of their immune system called post-aggressive immunosuppression. We sought to assess the risk of ICU-acquired infection and of mortality according to the absolute lymphocyte count at ICU admission and its changes over 3 days. METHODS: Adults in ICU for at least 3 days with a shock or persistent low blood pressure were extracted from a French ICU database and included. We evaluated the impact of the absolute lymphocyte count at baseline and its change at day 3 on the incidence of ICU-acquired infection and on the 28-day mortality rate. We categorized lymphocytes in 4 groups: above 1.5 × 103 cells/µL; between 1 and 1.5 × 103 cells/µL; between 0.5 and 1 × 103 cells/µL; and below 0.5 × 103 cells/µL. RESULTS: A total of 753 patients were included. The median lymphocyte count was 0.8 × 103 cells/µL [0.51-1.29]. A total of 174 (23%) patients developed infections; the 28-day mortality rate was 21% (161/753). Lymphopenia at admission was associated with ICU-acquired infection (p < 0.001) but not with 28-day mortality. Independently of baseline lymphocyte count, the absence of lymphocyte count increase at day 3 was associated with ICU-acquired infection (sub-distribution hazard ratio sHR: 1.37 [1.12-1.67], p = 0.002) and with 28-day mortality (sHR: 1.67 [1.37-2.03], p < 0.0001). CONCLUSION: Lymphopenia at ICU admission and its persistence at day 3 were associated with an increased risk of ICU-acquired infection, while only persisting lymphopenia predicted increased 28-day mortality. The lymphocyte count at ICU admission and at day 3 could be used as a simple and reproductive marker of post-aggressive immunosuppression.

Complications of intravascular catheters in ICU: definitions, incidence and severity. A randomized controlled trial comparing usual transparent dressings versus new-generation dressings (the ADVANCED study).

PURPOSE: To describe all post-insertion complications involving most used intravascular access, and to determine whether the use of a new-generation transparent dressing (3M™ IV Advanced) might reduce their number and impact on ICU patient outcomes. METHODS: Patients older than 18, with an expected length of stay ≥48 h and requiring at least one central venous catheter (CVC), arterial catheter (AC), haemodialysis catheter (HDC), pulmonary arterial catheters (PAC) or peripheral venous catheter (PVC) were randomized into two groups: a new-generation transparent dressing, or the hospital's classical transparent dressing, and were followed daily for any infectious and non-infectious complications. Complications were graduated for severity by an independent international multicentre multidisciplinary panel of practitioners using a Delphi process. RESULTS: We included 628 patients, 2214 catheters (873 PVCs, 630 CVCs, 512 ACs and 199 HDCs and PACs) and 4836 dressings. Overall incidence rate was of 60.9/1000 catheter-days. The most common complication was dysfunction (34.6/1000 catheter-days), mainly for PVCs (16/1000 catheter-days) and ACs (12.9/1000 catheter-days). Infectious complications incidence rate in CVCs and ACs was of 14.5/1000, mostly due to colonization (14.2/1000 catheter-days). Thrombosis incidence was of 3.8/1000 catheter-days with severe and very severe complications in 16 cases (1.8/1000 catheter-days) and one thrombosis-related death. 3M™ IV Advanced dressing did not decrease the rate of catheters with at least a minor complication [57.37/1000 vs. 57.52/1000 catheter-days, HR 1.03, CI (0.84-1.27), p = 0.81]. Incidence rates for each single complication remained equivalent: infectious [HR 0.93 (0.62-1.40), p = 0.72], deep thrombosis [HR 0.90 (0.39-2.06), p = 0.80], extravasation and phlebitis [HR 1.40 (0.69-2.82), p = 0.35], accidental removal [1.07 (0.56-2.04), p = 0.84] and dysfunction [HR 1.04 (0.80-1.35), p = 0.79]. CONCLUSION: The ADVANCED study showed the overall risk of complications to intravascular catheters in ICU patients being dysfunction, infection and thrombosis. The 3M™ IV Advanced dressing did not decrease complication rates as compared to standard dressings.

Venous thromboembolism in the ICU: main characteristics, diagnosis and thromboprophylaxis.

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep venous thrombosis (DVT), is a common and severe complication of critical illness. Although well documented in the general population, the prevalence of PE is less known in the ICU, where it is more difficult to diagnose and to treat. Critically ill patients are at high risk of VTE because they combine both general risk factors together with specific ICU risk factors of VTE, like sedation, immobilization, vasopressors or central venous catheter. Compression ultrasonography and computed tomography (CT) scan are the primary tools to diagnose DVT and PE, respectively, in the ICU. CT scan, as well as transesophageal echography, are good for evaluating the severity of PE. Thromboprophylaxis is needed in all ICU patients, mainly with low molecular weight heparin, such as fragmine, which can be used even in cases of non-severe renal failure. Mechanical thromboprophylaxis has to be used if anticoagulation is not possible. Nevertheless, VTE can occur despite well-conducted thromboprophylaxis.

Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile.

OBJECTIVES: This study evaluated the influence of the immune profile on the outcome at day 28 (D28) of patients admitted to the ICU for septic shock or severe sepsis. METHODS: We conducted an observational study using a prospective multicenter database and included all patients admitted to 11 ICUs for severe sepsis or septic shock from January 1997 to August 2011. Seven profiles of immunodeficiency were defined. The prognostic analysis used a competitive risk model (Fine and Gray), in which being alive at ICU or hospital discharge before D28 competed with death. RESULTS: Among the 1,981 included patients, 607 (31%) were immunocompromised (including nonneutropenic solid tumor [19.6%], nonneutropenic hematologic malignancies [26.3%], and all-cause neutropenia [28%]). Compared with immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often with septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8% in immunocompetent patients (P = .26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (subdistribution hazard ratio [sHR], 1.37; 95% CI, 1.12-1.67). The immunodeficiency profiles independently associated with death were AIDS (sHR = 1.9), non-neutropenic solid tumor (sHR = 1.8), nonneutropenic hematologic malignancies (sHR = 1.4), and all-cause neutropenia (sHR = 1.7). CONCLUSIONS: Immunodeficiency is common in patients with severe sepsis or septic shock. Despite a similar crude mortality, immunodeficiency was associated with an increased risk of short-term mortality after multivariate analysis. Neutropenia and specific, but not all, profiles of immunodeficiency were independently associated with an increased risk of death.

Aspergillus in the lower respiratory tract of immunocompetent critically ill patients.

OBJECTIVES: To shed light on the meaning of Aspergillus-positive lower-respiratory-tract samples in non immunocompromized critically ill patients. METHODS: Multicentre matched case-control (1:5) study. We used prospectively collected data to identify risk factors for Aspergillus-positive specimens, as well as outcomes in Aspergillus-positive patients. RESULTS: 66 cases (5 with definite invasive pulmonary aspergillosis (IPA), 18 with probable IPA, and 43 colonisations) were matched to 330 controls. In the multivariate conditional logistic model, independent risk factors for at least one Aspergillus-positive respiratory-tract specimen were worse SAPSII at admission [OR, 1.10; 95%CI, 1.00-1.21], ARDS [OR, 2.64; 95%CI, 1.29-5.40]; long-term steroid therapy [OR, 4.77; 95%CI, 1.49-15.23]; steroid therapy started in the ICU [OR, 11.03; 95%CI, 4.40-27.67]; and bacterial infection [OR, 2.73; 95%CI, 1.37-5.42]. The risk of death, compared to the controls, was not higher in the cases overall [HR, 0.66; 95%CI, 0.41-1.08; p = 0.1] or in the subgroups with definite IPA [HR, 1.60; 95%CI, 0.43-5.94; p = 0.48], probable IPA [HR, 0.84; 95%CI, 0.28-2.50; p = 0.76], or colonisation [HR, 0.58; 95%CI, 0.33-1.02; p = 0.06]. In cases who received antifungal therapy, mortality was not lower than in untreated cases [HR, 0.67; 95%CI, 0.36-1.24; p = 0.20]. CONCLUSIONS: In critically ill immunocompetent patients, risk factors for presence of Aspergillus in lower respiratory tract specimens are steroid therapy (either chronic or initiated in the ICU), ARDS, and high severity of the acute illness. Prospective studies are warranted to further examine these risk factors and to investigate immune functions as well as the impact of antifungal therapy on patient outcomes.

Pulmonary embolism in mechanically ventilated patients requiring computed tomography: Prevalence, risk factors, and outcome.

OBJECTIVE: To estimate the rate of pulmonary embolism among mechanically ventilated patients and its association with deep venous thrombosis. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit of a university-affiliated teaching hospital. INCLUSION CRITERIA: mechanically ventilated patients requiring a thoracic contrast-enhanced computed tomography scan for any medical reason. EXCLUSION CRITERIA: a diagnosis of pulmonary embolism before intensive care unit admission, an allergy to contrast agents, and age younger than 18 yrs. INTERVENTIONS: All the mechanically ventilated patients requiring a thoracic computed tomography underwent the standard imaging protocol for pulmonary embolism detection. Therapeutic anticoagulation was given immediately after pulmonary embolism diagnosis. All the included patients underwent a compression ultrasound of the four limbs within 48 hrs after the computed tomography scan to detect deep venous thrombosis. RESULTS: Of 176 included patients, 33 (18.7%) had pulmonary embolism diagnosed by computed tomography, including 20 (61%) with no clinical suspicion of pulmonary embolism. By multiple logistic regression, independent risk factors for pulmonary embolism were male gender, high body mass index, history of cancer, past medical history of deep venous thrombosis, coma, and high platelet count. Previous prophylactic anticoagulant use was not a risk factor for pulmonary embolism. Of the 176 patients, 35 (19.9%) had deep venous thrombosis by compression ultrasonography, including 20 (57.1%) in the lower limbs and 24 (68.6%) related to central venous catheters. Of the 33 pulmonary embolisms, 11 (33.3%) were associated with deep venous thrombosis. The pulmonary embolism risk was increased by lower-limb deep venous thrombosis (odds ratio 4.0; 95% confidence interval 1.6-10) but not upper-limb deep venous thrombosis (odds ratio 0.6; 95% confidence interval 0.1-2.9). Crude comparison of patients with and without pulmonary embolism shows no difference in length of stay or mortality. CONCLUSIONS: In mechanically ventilated patients who needed a computed tomography, pulmonary embolism was more common than expected. Patients diagnosed with pulmonary embolism were all treated with therapeutic anticoagulation, and their intensive care unit or hospital mortality was not impacted by the pulmonary embolism occurrence. These results invite further research into early screening and therapeutic anticoagulation of pulmonary embolism in critically ill patients.

New materials and devices for preventing catheter-related infections.

Catheters are the leading source of bloodstream infections for patients in the intensive care unit (ICU). Comprehensive unit-based programs have proven to be effective in decreasing catheter-related bloodstream infections (CR-BSIs). ICU rates of CR-BSI higher than 2 per 1,000 catheter-days are no longer acceptable. The locally adapted list of preventive measures should include skin antisepsis with an alcoholic preparation, maximal barrier precautions, a strict catheter maintenance policy, and removal of unnecessary catheters. The development of new technologies capable of further decreasing the now low CR-BSI rate is a major challenge. Recently, new materials that decrease the risk of skin-to-vein bacterial migration, such as new antiseptic dressings, were extensively tested. Antimicrobial-coated catheters can prevent CR-BSI but have a theoretical risk of selecting resistant bacteria. An antimicrobial or antiseptic lock may prevent bacterial migration from the hub to the bloodstream. This review discusses the available knowledge about these new technologies.

New challenges in the diagnosis, management, and prevention of central venous catheter-related infections.

Catheters are the leading source of bloodstream infections in critically ill patients. Because the clinical signs of infection are nonspecific, such infections are overly suspected, which results in unnecessary removal of catheters. A conservative approach might be attempted in mild infections, whereas catheters should always be removed in cases of severe sepsis or septic shock. Nowadays, comprehensive unit-based improvement programs are effective to reduce catheter-related bloodstream infections (CR-BSIs). Rates of CR-BSI higher than 2 per 1000 catheter-days are no longer acceptable. A locally adapted checklist of preventive measures should include cutaneous antisepsis with alcoholic preparation, maximal barrier precaution, strict policy of catheter maintenance, and ablation of useless catheters. Antiseptic dressings and, to a lesser extent, antimicrobial-coated catheters, might be added to the prevention strategies if the level of infections remains high despite implementation of a prevention program. In the case of CR-BSI in intensive care units (ICUs), the catheter should be removed. In the case of persistence of fever or positive blood cultures after 3 days, inadequate antibiotic therapy, endocarditis, or thrombophlebitis should be ruled out.