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.

Recommendations for core critical care ultrasound competencies as a part of specialist training in multidisciplinary intensive care: a framework proposed by the European Society of Intensive Care Medicine (ESICM).

Critical care ultrasound (CCUS) is an essential component of intensive care practice. Although existing international guidelines have focused on training principles and determining competency in CCUS, few countries have managed to operationalize this guidance into an accessible, well-structured programme for clinicians training in multidisciplinary intensive care. We seek to update and reaffirm appropriate CCUS scope so that it may be integrated into the international Competency-based Training in Intensive Care Medicine. The resulting recommendations offer the most contemporary and evolved set of core CCUS competencies for an intensive care clinician yet described. Importantly, we discuss the rationale for inclusion but also exclusion of competencies listed. BACKGROUND/AIM: Critical care ultrasound (CCUS) is an essential component of intensive care practice. The purpose of this consensus document is to determine those CCUS competencies that should be a mandatory part of training in multidisciplinary intensive care. METHODS: A three-round Delphi method followed by face-to-face meeting among 32 CCUS experts nominated by the European Society of Intensive Care Medicine. Agreement of at least 90% of experts was needed in order to enlist a competency as mandatory. RESULTS: The final list of competencies includes 15 echocardiographic, 5 thoracic, 4 abdominal, deep vein thrombosis diagnosis and central venous access aid. CONCLUSION: The resulting recommendations offer the most contemporary and evolved set of core CCUS competencies for an intensive care clinician yet described.

Lung Ultrasound for Critically Ill Patients.

Point-of-care ultrasound is increasingly used at the bedside to integrate the clinical assessment of the critically ill; in particular, lung ultrasound has greatly developed in the last decade. This review describes basic lung ultrasound signs and focuses on their applications in critical care. Lung semiotics are composed of artifacts (derived by air/tissue interface) and real images (i.e., effusions and consolidations), both providing significant information to identify the main acute respiratory disorders. Lung ultrasound signs, either alone or combined with other point-of-care ultrasound techniques, are helpful in the diagnostic approach to patients with acute respiratory failure, circulatory shock, or cardiac arrest. Moreover, a semiquantification of lung aeration can be performed at the bedside and used in mechanically ventilated patients to guide positive end-expiratory pressure setting, assess the efficacy of treatments, monitor the evolution of the respiratory disorder, and help the weaning process. Finally, lung ultrasound can be used for early detection and management of respiratory complications under mechanical ventilation, such as pneumothorax, ventilator-associated pneumonia, atelectasis, and pleural effusions. Lung ultrasound is a useful diagnostic and monitoring tool that might in the near future become part of the basic knowledge of physicians caring for the critically ill patient.

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.

CARD9 deficiency and spontaneous central nervous system candidiasis: complete clinical remission with GM-CSF therapy.

We demonstrate autosomal-recessive Caspase Recruitment Domain-containing protein 9 (CARD9) deficiency in a patient with relapsing C. albicans meningoencephalitis. We identified a novel, hypomorphic mutation with intact Th17 responses, but impaired GM-CSF responses. We report complete clinical remission with adjunctive GM-CSF therapy, suggesting that a CARD9/GM-CSF axis contributes to susceptibility to candidiasis.

Lung ultrasound in the critically ill.

PURPOSE OF REVIEW: Lung ultrasound, which allows a bedside visualization of the lungs, is increasingly used in critical care. This review aims at highlighting a simple approach to this new discipline. RECENT FINDINGS: The 10 basic signs are the bat sign (indicating pleural line), lung sliding (yielding the seashore sign), the A line (horizontal artifact), the quad and sinusoid sign indicating pleural effusion regardless of its echogenicity, the tissue-like and shred sign indicating lung consolidation, the B line and lung rockets (artifacts indicating interstitial syndrome), abolished lung sliding with the stratosphere sign, suggesting pneumothorax, and the lung point, indicating pneumothorax. All these disorders were assessed using computed tomography (CT) as a gold standard with sensitivity and specificity ranging from 90 to 100%, allowing us to consider ultrasound as a reasonable bedside gold standard in the critically ill. We use a simple gray-scale unit (without Doppler) with a microconvex probe. SUMMARY: Lung ultrasound can be used for diagnosing acute respiratory failure (BLUE protocol), managing acute circulatory failure (Fluid Administration Limited by Lung Sonography protocol), and decreasing the use of radiograph or CT (the Lung Ultrasound in the Critically Ill Favoring Limitation of Radiation project). This can be extended from sophisticated ICUs to more austere settings, from neonates to bariatric adults without adaptation, trauma and several other disciplines (anesthesiology, emergency medicine, pulmonology, etc.). VIDEO ABSTRACT: http://links.lww.com/COCC/A8.

Empyema Secondary to Pneumonia: Whom Should We Operate?

Introduction: Empyema secondary to pneumonia is a common condition. A significant number of patients will require surgical intervention for drainage and decortication. The aim of this study was to identify predictive factors for surgical intervention. Materials and Methods: The medical records of patients who were diagnosed with empyema secondary to pneumonia between the years 2010 and 2019 in a university hospital were included in the study. Patients who underwent surgical intervention were defined as group A and nonoperative treatment as group B. Clinical and laboratory data were collected from medical records and patients' chest computerized tomography (CT) scans were reviewed. Results: A total of 194 patients were included in the study-86 patients were included in group A and 108 patients in group B. Several parameters on admission were found to have a statistically significant correlation with surgical intervention: younger age, higher systolic blood pressure, and elevated white blood count. Multivariant analysis showed that younger age was found to have a statistically significant correlation with operative intervention (adjusted odds ratio = 0.971, P = .023). A statistically significant correlation between surgical intervention and survival (adjusted hazard ratio [HR] = 1.762, P = .046) and an inverse correlation between age and survival (adjusted HR = 0.050, P < .001) were found. Surgical intervention was associated with increased survival irrespective of age. A total of 42 CT scans were available for review. The mean density of the empyema fluid in group A was higher by 4.3 hounsfield units compared to group B (P < .067). Conclusions: Younger age was found to be associated with surgical intervention among patients suffering from empyema secondary to pneumonia. Surgical intervention was associated with increased long-term survival, irrespective of patients' age. Several radiologic characteristics were associated with the need for surgery in this study: empyema fluid density, pleural thickening, and fluid loculations. Additional prospective studies are required to ascertain these results.

Lipoprotein(a) Levels in Severe Aortic Stenosis Referred for Transcatheter Aortic Valve Implantation Compared to Controls.

Background: Limited observational reports link elevated lipoprotein(a) (Lp[a]) levels to aortic stenosis (AS) or to disease progression. Data on large cohorts of verified severe AS patients are lacking. Objectives: The purpose of the study was to characterize Lp(a) levels of severe AS patients referred to transcatheter aortic valve implantation (TAVI) and compare them to a large cohort of Lp(a) samples derived from the general population. Methods: Lp(a) levels obtained from frozen serum samples of TAVI patients between 2012 and 2017 were compared to a control group for whom Lp(a) levels were obtained for any reason and stratified by gender. Multivariable binary logistic regression analyses were conducted to investigate associations between younger age at TAVI and an Lp(a) cutoff of 50 mg/dL. Results: Lp(a) levels of 503 TAVI were compared to 25,343 controls. Patients in the AS group had mildly higher median Lp(a) levels compared to controls (20.5 vs 18.7 mg/dL, P = 0.04). Lp(a) levels in males with severe AS were higher than controls (19.9 vs 16.6 mg/dL, P = 0.04). Females had a nonsignificant difference (22.1 vs 21.3 mg/dL, P = 0.87). In multivariable analysis, an Lp(a) cutoff of above 50 mg/dL was not associated with an earlier age at TAVI (beta: 1.04; 95% CI: 0.42-2.57; P = 0.94). Conclusions: Median Lp(a) levels were only mildly higher in severe AS patients undergoing TAVI in comparison to a large control group, mainly driven by higher Lp(a) levels in males. Higher Lp(a) levels were not associated with an earlier age at TAVI, rejecting its association with an accelerated disease progression.

Assessment of fluid unresponsiveness guided by lung ultrasound in abdominal surgery: a prospective cohort study.

A fluid challenge can generate an infraclinical interstitial syndrome that may be detected by the appearance of B-lines by lung ultrasound. Our objective was to evaluate the appearance of B-lines as a diagnostic marker of preload unresponsiveness and postoperative complications in the operating theater. We conducted a prospective, bicentric, observational study. Adult patients undergoing abdominal surgery were included. Stroke volume (SV) was determined before and after a fluid challenge with 250 mL crystalloids (Delta-SV) using esophageal Doppler monitoring. Responders were defined by an increase of Delta-SV > 10% after fluid challenge. B-lines were collected at four bilateral predefined zones (right and left anterior and lateral). Delta-B-line was defined as the number of newly appearing B-lines after a fluid challenge. Postoperative pulmonary complications were prospectively recorded according to European guidelines. In total, 197 patients were analyzed. After a first fluid challenge, 67% of patients were responders and 33% were non-responders. Delta-B-line was significantly higher in non-responders than responders [4 (2-7) vs 1 (0-3), p < 0.0001]. Delta-B-line was able to diagnose fluid non-responders with an area under the curve of 0.74 (95% CI 0.67-0.80, p < 0.0001). The best threshold was two B-lines with a sensitivity of 80% and a specificity of 57%. The final Delta-B-line could predict postoperative pulmonary complications with an area under the curve of 0.74 (95% CI 0.67-0.80, p = 0.0004). Delta-B-line of two or more detected in four lung ultrasound zones can be considered to be a marker of preload unresponsiveness after a fluid challenge in abdominal surgery.The objectives and procedures of the study were registered at Clinicaltrials.gov (NCT03502460; Principal investigator: Stéphane BAR, date of registration: April 18, 2018).

COVID-19 vaccination intention and behavior in a large, diverse, U.S. refugee population.

INTRODUCTION: Refugees often face increased risk of exposure to COVID-19 due to their disproportionate representation in the essential workforce and crowded household conditions. There is a paucity of data about risk factors for under-immunization for COVID-19 among refugees. METHODS: Refugees were surveyed in two phases that corresponded to before and after wide availability of COVID-19 vaccines. Participants were asked about their attitudes, and perceptions about COVID-19, previous acceptance of vaccines, sources utilized to obtain trusted health information, and intent to get vaccinated. The overall participant vulnerability was assessed using the social vulnerability index. In-depth semi-structured interviews were completed with key stakeholders through snowball sampling. RESULTS: Of 247 refugees, 244 agreed to participate in the initial survey. Among those, 140 (57.4%) intended to get vaccinated, 43 (17.6%) were unsure, and 61 (25%) did not intend to get vaccinated. In the follow up survey, all 215 who were reached, agreed to provide information about their vaccination status. Among those respondents, 141 (65.6%) were either vaccinated or expressed intent to do so, and 74 (34.4%) remained hesitant. We did not observe any significant correlation between socio-demographic variables, country of origin, and vaccination status/intent. Among those who initially intended to get vaccinated, nearly 1 in 5 changed their mind and decided to forego vaccination, and among those who initially did not plan getting vaccinated, 1 in 3 changed their mind and got vaccinated. Fears related to the vaccine, concerns that the vaccine is religiously prohibited, "wait and see" how others did with the vaccine, communication and transportation barriers were commonly cited as reason not to get vaccinated. CONCLUSIONS: Over a third of refugees in our study were hesitant to get vaccinated. Refugees desired additional education about the benefits and safety of vaccines along with easier access to vaccination clinics in their communities.

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.

Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia.

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.

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.