Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells.

Chimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell-associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.

B-Mode Ultrasound Findings in a Patient With Suspected Pulmonary Gangrene.

OBJECTIVES: Lung ultrasound has shown increasing diagnostic value in many lung diseases and has become an efficient tool in the management of dyspnea. In the present case report, we describe a new ultrasound feature of potential interest. DATA SOURCES: Clinical observation of a patient. STUDY SELECTION: Case report. DATA EXTRACTION: Data were extracted from medical records, after obtaining consent from the patient's family. Illustrations were extracted from the imaging software and a video device. DATA SYNTHESIS: A 56-year-old man was admitted with pneumonia of adverse outcome. Lung ultrasound, a method increasingly considered as a bedside gold standard in critically ill patients due to its overwhelming advantages, was the only tool able to specify the lung injuries. We describe herein a distinctive sign unequivocally evoking a destructive process suggestive of pulmonary gangrene, a variant of the fractal sign combining a lung consolidation with an underlying heterogeneous free fluid. CONCLUSIONS: Lung ultrasound may help highlight pulmonary gangrene, a poorly-known disease, with this new ultrasonographic description. The next step will be to ascertain the relation between this new ultrasound feature and pulmonary gangrene and to assess how this bedside diagnosis could impact the prognosis of the disease.

A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder.

Characterization of extramedullary disease in B-ALL and response to CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cells effectively eradicate medullary B-cell acute lymphoblastic leukemia (B-ALL) and can traffic to and clear central nervous system (CNS) involvement. CAR T-cell activity in non-CNS extramedullary disease (EMD) has not been well characterized. We systematically evaluated CAR T-cell kinetics, associated toxicities, and efficacy in B-ALL non-CNS EMD. We conducted a retrospective review of B-ALL patients with non-CNS EMD who were screened for/enrolled on one of three CAR trials (CD19, CD22, and CD19/22) at our institution. Non-CNS EMD was identified according to histology or radiographic imaging at extramedullary sites excluding the cerebrospinal fluid and CNS parenchyma. Of ∼180 patients with relapsed/refractory B-ALL screened across multiple early-phase trials over an 8-year period, 38 (21.1%) presented with isolated non-CNS EMD (n = 5) or combined medullary/non-CNS EMD (n = 33) on 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging. A subset receiving CAR T cells (18 infusions) obtained FDG PET/CT scans preinfusion and postinfusion to monitor response. At best response, 72.2% (13 of 18) of patients showed a medullary minimal residual disease-negative complete remission and complete (n = 7) or partial (n = 6) non-CNS EMD response. Non-CNS EMD responses to CAR T cells were delayed (n = 3), and residual non-CNS EMD was substantial; rarely, discrepant outcomes (marrow response without EMD response) were observed (n = 2). Unique CAR-associated toxicities at non-CNS EMD sites were seen in select patients. CAR T cells are active in B-ALL non-CNS EMD. Still, non-CNS EMD response to CAR T cells may be delayed and suboptimal, particularly with multifocal disease. Serial FDG PET/CT scans are necessary for identifying and monitoring non-CNS EMD.

Severity Index for Suspected Arbovirus (SISA): Machine learning for accurate prediction of hospitalization in subjects suspected of arboviral infection.

BACKGROUND: Dengue, chikungunya, and Zika are arboviruses of major global health concern. Decisions regarding the clinical management of suspected arboviral infection are challenging in resource-limited settings, particularly when deciding on patient hospitalization. The objective of this study was to determine if hospitalization of individuals with suspected arboviral infections could be predicted using subject intake data. METHODOLOGY/PRINCIPAL FINDINGS: Two prediction models were developed using data from a surveillance study in Machala, a city in southern coastal Ecuador with a high burden of arboviral infections. Data were obtained from subjects who presented at sentinel medical centers with suspected arboviral infection (November 2013 to September 2017). The first prediction model-called the Severity Index for Suspected Arbovirus (SISA)-used only demographic and symptom data. The second prediction model-called the Severity Index for Suspected Arbovirus with Laboratory (SISAL)-incorporated laboratory data. These models were selected by comparing the prediction ability of seven machine learning algorithms; the area under the receiver operating characteristic curve from the prediction of a test dataset was used to select the final algorithm for each model. After eliminating those with missing data, the SISA dataset had 534 subjects, and the SISAL dataset had 98 subjects. For SISA, the best prediction algorithm was the generalized boosting model, with an AUC of 0.91. For SISAL, the best prediction algorithm was the elastic net with an AUC of 0.94. A sensitivity analysis revealed that SISA and SISAL are not directly comparable to one another. CONCLUSIONS/SIGNIFICANCE: Both SISA and SISAL were able to predict arbovirus hospitalization with a high degree of accuracy in our dataset. These algorithms will need to be tested and validated on new data from future patients. Machine learning is a powerful prediction tool and provides an excellent option for new management tools and clinical assessment of arboviral infection.

Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients.

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1ß and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.

Ultrasound examination of the lungs in the intensive care unit.

OBJECTIVE: Lung ultrasound is increasingly used in the critically ill adult. It allows prompt management based upon reproducible data and generates fewer computed tomography (CT) examinations, therefore decreasing irradiation, delays, cost, and discomfort to the patient. The aim of this article is to describe the value of ultrasound for lung imaging in the critically ill and state our experience in neonates. METHODS: Review of studies published in the peer-reviewed international literature analyzing consecutive critically ill adults admitted to intensive care units, assessing pleural effusion, alveolar consolidation, interstitial syndrome, and pneumothorax, using a standardized ultrasound approach to the lung, with CT as the reference. DATA SYNTHESIS: The sensitivity and specificity of ultrasound are 92% and 93% for pleural effusion, 90% and 98% for alveolar consolidation, 93% and 93% for interstitial syndrome, 100% and 96% for complete pneumothorax, 79% and 100% for radio-occult pneumothorax. DISCUSSION: This article reviews data that validate the scientific value of lung ultrasound in adult medical intensive care units. We then present observations in the critically ill neonate. The discussion points to the methodologic issues raised in lung ultrasound in the neonate, i.e. mainly the limited access to a pertinent gold standard (CT). Some CT correlations are presented, confirming the value of lung ultrasound in the neonate. CONCLUSIONS: The standardized signs assessed in the adult are also found in the critically ill neonate, meaning a potential use in this field. Awaiting confirmatory CT studies, lung ultrasound can be taken into consideration as a possible bedside tool for completing bedside radiography.

Nivolumab and Ipilimumab-induced Acute Inflammatory Demyelinating Polyradiculoneuropathy: A Case Report.

Immunotherapies such as the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab and the programmed cell death protein 1 inhibitor nivolumab have become ubiquitous in cancer treatment. Recently, the FDA approved nivolumab with or without ipilimumab for the treatment of refractory small cell lung cancer. Immunotherapies increase the immune response to cancer cells by interfering with inhibitory molecular pathways that prevent tumor cell killing, thus augmenting tumor cell death without many of the cytotoxic side effects associated with chemotherapy. However, this augmented immune response may result in unwanted immune-mediated inflammation of different organs and are therefore associated with immune-related adverse events, unlike traditional chemotherapies or targeted therapies. Here, we describe 1 patient with advanced small cell lung cancer who developed grade III-IV acute inflammatory demyelinating polyradiculoneuropathy after treatment with ipilimumab and nivolumab. The patient was treated with intravenous immunoglobulin alone and showed symptomatic improvement.

Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol.

BACKGROUND: This study assesses the potential of lung ultrasonography to diagnose acute respiratory failure. METHODS: This observational study was conducted in university-affiliated teaching-hospital ICUs. We performed ultrasonography on consecutive patients admitted to the ICU with acute respiratory failure, comparing lung ultrasonography results on initial presentation with the final diagnosis by the ICU team. Uncertain diagnoses and rare causes (frequency<2%) were excluded. We included 260 dyspneic patients with a definite diagnosis. Three items were assessed: artifacts (horizontal A lines or vertical B lines indicating interstitial syndrome), lung sliding, and alveolar consolidation and/or pleural effusion. Combined with venous analysis, these items were grouped to assess ultrasound profiles. RESULTS: Predominant A lines plus lung sliding indicated asthma (n=34) or COPD (n=49) with 89% sensitivity and 97% specificity. Multiple anterior diffuse B lines with lung sliding indicated pulmonary edema (n=64) with 97% sensitivity and 95% specificity. A normal anterior profile plus deep venous thrombosis indicated pulmonary embolism (n=21) with 81% sensitivity and 99% specificity. Anterior absent lung sliding plus A lines plus lung point indicated pneumothorax (n=9) with 81% sensitivity and 100% specificity. Anterior alveolar consolidations, anterior diffuse B lines with abolished lung sliding, anterior asymmetric interstitial patterns, posterior consolidations or effusions without anterior diffuse B lines indicated pneumonia (n=83) with 89% sensitivity and 94% specificity. The use of these profiles would have provided correct diagnoses in 90.5% of cases. CONCLUSIONS: Lung ultrasound can help the clinician make a rapid diagnosis in patients with acute respiratory failure, thus meeting the priority objective of saving time.

[Whole-body ultrasound in the ICU. A visual approach to the critically ill]. / L'échographie "corps entier" en réanimation, une approche visuelle du patient en état critique.

Sonography is a non invasive method allowing prompt diagnosis at the bedside, especially when sophisticated diagnostic tools are unavailable, as in the critical care setting. In particular, the lung, a vital organ, is fully accessible, and the signs are simple and standardized. Accurate diagnosis is possible in extreme emergencies, as in patients with pleural effusion, alveolar consolidation, interstitial syndrome or pneumothorax. The clinical relevance of these diagnoses, and especially the interstitial syndrome, is discussed. Sonography also allows cost savings and avoids unnecessary irradiation.

Lung Ultrasound (in the Critically Ill) Superior to CT: the Example of Lung Sliding.

This review article shows the potential of lung ultrasound in the critically ill (LUCI) to study lung sliding and describes the optimal equipment for its assessment. Then, it analyses the integration of lung sliding within lung ultrasound then whole body critical ultrasound. It describes the place of lung sliding in the BLUE-protocol (bedside lung ultrasound in emergency) (lung and venous ultrasound for diagnosing acute respiratory failure), the FALLS-protocol (fluid administration limited by lung sonography) (the role of lung sliding in circulatory failure), and the SESAME-protocol (sequential assessment of sonography assessing mechanism or origin of severe shock of indistinct cause) (whole body ultrasound in cardiac arrest). In the LUCIFLR project (LUCI favoring limitation of radiations), the consideration of lung sliding allows drastic reduction in irradiation and costs. In conclusion, lung sliding is proposed as a gold standard for indicating the presence of the lung at the chest wall and its correct expansion.

Lung ultrasound in the critically ill (LUCI): A translational discipline.

In the early days of ultrasound, it was not a translational discipline. The heart was claimed by cardiologists, with others, such as gynaecologists, urologists and vascular surgeons claiming their part while the rest was given to radiologists. Only recently, ultrasound transgressed and crossed the usual borders between the different disciplines, such as emergency and critical care medicine. The advent of portable machines in the early 1980s, allowed the critical care physician to perform bedside ultrasound, and the development of whole body critical care ultrasound (CCUS) was born. It may sound cynical that radiologists were the first to state that diagnostic sonography was truly the next stethoscope: poorly utilized by many but understood by few. Exactly the same radiologists then abandoned the use of ultrasound outside the radiology department, leaving a vast domain to other disciplines eager to welcome the modern stethoscope. In this review, we list the possibilities of lung ultrasound as a translational holistic discipline.

BLUE-protocol and FALLS-protocol: two applications of lung ultrasound in the critically ill.

This review article describes two protocols adapted from lung ultrasound: the bedside lung ultrasound in emergency (BLUE)-protocol for the immediate diagnosis of acute respiratory failure and the fluid administration limited by lung sonography (FALLS)-protocol for the management of acute circulatory failure. These applications require the mastery of 10 signs indicating normal lung surface (bat sign, lung sliding, A-lines), pleural effusions (quad and sinusoid sign), lung consolidations (fractal and tissue-like sign), interstitial syndrome (lung rockets), and pneumothorax (stratosphere sign and the lung point). These signs have been assessed in adults, with diagnostic accuracies ranging from 90% to 100%, allowing consideration of ultrasound as a reasonable bedside gold standard. In the BLUE-protocol, profiles have been designed for the main diseases (pneumonia, congestive heart failure, COPD, asthma, pulmonary embolism, pneumothorax), with an accuracy > 90%. In the FALLS-protocol, the change from A-lines to lung rockets appears at a threshold of 18 mm Hg of pulmonary artery occlusion pressure, providing a direct biomarker of clinical volemia. The FALLS-protocol sequentially rules out obstructive, then cardiogenic, then hypovolemic shock for expediting the diagnosis of distributive (usually septic) shock. These applications can be done using simple grayscale machines and one microconvex probe suitable for the whole body. Lung ultrasound is a multifaceted tool also useful for decreasing radiation doses (of interest in neonates where the lung signatures are similar to those in adults), from ARDS to trauma management, and from ICUs to points of care. If done in suitable centers, training is the least of the limitations for making use of this kind of visual medicine.

The "lung pulse": an early ultrasound sign of complete atelectasis.

OBJECTIVE: Complete atelectasis can be immediately generated by selective intubation. A dynamic lung ultrasound sign can be described as the association of absent lung sliding with the perception of heart activity at the pleural line, a sign which was called "lung pulse." We examined whether this sign be used promptly to confirm complete atelectasis due to selective intubation. DESIGN AND SETTING: Prospective study in the medical intensive care unit of a university-affiliated teaching hospital. PATIENTS: Consecutive patients with no history of respiratory disorders and needing intubation were enrolled. Fifteen patients with selective intubation of the right lung were compared with 30 patients with nonselective intubation and 15 healthy volunteers. INTERVENTIONS: The "lung pulse" was sought at the left anterolateral chest wall in intubated patients. Healthy subjects were studied during breathing and apnea. RESULTS: A left "lung pulse" was immediately present in 14 of 15 patients with right selective intubation, and absent, with normal lung sliding, in all 30 correctly intubated patients and in all 15 healthy subjects during breathing. All healthy subjects exhibited a "lung pulse" in apnea. The "lung pulse" had a sensitivity of 93% and a specificity of 100% for the diagnosis of complete atelectasis following selective intubation in patients without previous respiratory disorders. CONCLUSIONS: The "lung pulse" is a sign of complete atelectasis which is observable immediately before radiological changes. Its absence which is correlated with the absence of selective intubation and of conserved lung inflation can eliminate the need for confirmation radiography.

Ultrasound diagnosis of alveolar consolidation in the critically ill.

OBJECTIVE: Alveolar consolidation is a basic concern in critically ill patients. Radiography is not a precise tool, and referral to CT raises problems (transport, irradiation). The aim of this study was to assess the utility of ultrasound in the diagnosis of alveolar consolidation. DESIGN: Prospective clinical study. SETTING: The medical ICU of a university-affiliated teaching hospital. PATIENTS: A total of 65 cases of alveolar consolidation proven on CT were compared to 53 CT controls. MEASUREMENTS: Alveolar consolidation was defined as a tissue-like pattern visible at the chest wall, arising from the pleural line and devoid of centrifugal inspiratory dynamics. RESULTS: Feasibility was 99%. In 65 cases of alveolar consolidation, ultrasound was positive in 59 and negative in 6. In 52 analyzable controls, ultrasound was negative in 51 and positive in 1. Sensitivity of ultrasound was 90% and specificity 98%. A concordance test showed a Kappa coefficient of 0.89. Among 62 posterior locations on CT, ultrasound showed posterior consolidation patterns in 56 cases and was negative in 6. Ultrasound showed anterior involvement in all 3 cases of whole lung consolidation. CONCLUSIONS: Ultrasound provides a reliable non-invasive, bedside method for accurate detection and location of alveolar consolidation in critically ill patients.