Progressive Multiorgan Dysfunction Research Articles

Renal protection after hemorrhagic shock in rats: Possible involvement of SUMOylation

Hemorrhagic shock (HS), a leading cause of preventable death, is characterized by severe blood loss and inadequate tissue perfusion. Reoxygenation of ischemic tissues exacerbates organ damage through ischemia–reperfusion injury. SUMOylation has been shown to protect neurons after stroke and is upregulated in response to cellular stress. However, the role of SUMOylation in organ protection after HS is unknown. This study aimed to investigate SUMOylation-mediated organ protection following HS. Male Wistar rats were subjected to HS (blood pressure of 40 ± 2 mmHg, for 90 min) followed by reperfusion. Blood, kidney, and liver samples were collected at various time points after reperfusion to assess organ damage and investigate the profile of SUMO1 and SUMO2/3 conjugation. In addition, human kidney cells (HK-2), treated with the SUMOylation inhibitor TAK-981 or overexpressing SUMO proteins, were subjected to oxygen and glucose deprivation to investigate the role of SUMOylation in hypoxia/reoxygenation injury. The animals presented progressive multiorgan dysfunction, except for the renal system, which showed improvement over time. Compared to the liver, the kidneys displayed distinct patterns in terms of oxidative stress, apoptosis activation, and tissue damage. The global level of SUMO2/3 in renal tissue was also distinct, suggesting a differential role. Pharmacological inhibition of SUMOylation reduced cell viability after hypoxia-reoxygenation damage, while overexpression of SUMO1 or SUMO2 protected the cells. These findings suggest that SUMOylation might play a critical role in cellular protection during ischemia–reperfusion injury in the kidneys, a role not observed in the liver. This difference potentially explains the renal resilience observed in HS animals when compared to other systems.

The effect of myocardial dysfunction on mortality in children with septic shock: a prospective observational study.

Pediatric septic shock is defined as progressive multi-organ dysfunction and cardiovascular dysfunction accompanying sepsis. Studies showing myocardial dysfunction associated with pediatric septic shock are very limited. The aim of this study was to evaluate the relationship between myocardial functions calculated by echocardiography, disease severity, and clinical outcomes in children with septic shock. This observational prospective study was conducted in a pediatric intensive care at a university-affiliated tertiary hospital. The patients diagnosed with septic shock between January 2021 and February 2022 were included in the study. The study was conducted with 56 patients. The rate of myocardial dysfunction (systolic and/or diastolic dysfunction) was 50%. Of these, 39.3% (n = 22) had systolic dysfunction, 17.9% (n = 10) had diastolic dysfunction, and 8.9% (n = 5) had both systolic and diastolic dysfunction. PRISM III score (p = 0.004), VIS (p < 0.001), lactate (p = 0.002), CK-MB (p = 0.023), troponin (p = 0.038), EF (p = 0.004) EF z-score (p = 0.003), MAPSE z-score (p = 0.049), TAPSE (p = 0.010), TAPSE z-score (p = 0.003), and mitral valve E/e ´z-score (p = 0.028) were statistically significant difference with mortality. No significant difference was found for mortality with MAPSE (p = 0.090), mitral valve E/A (p = 0.624), and mitral valve E/A z-score (p = 0.327). EF z-score was found to be associated with 30-day mortality (OR = 0,681, 95% CI 0,480 to 0.991, p = 0,045). We found the TAPSE z-score to be the most significant parameter with 30-day mortality (OR = 0,690, 95% CI 0,489 to 0.998, p = 0,032). Conclusion: We found left ventricular dysfunction associated factor with mortality. TAPSE showing right ventricular dysfunction was found to be the independent risk factor most associated with mortality. What is Known: • Studies showing myocardial dysfunction associated with pediatric septic shock are limited. • Little is known about the use of echocardiography in pediatric septic shock, and there are no specific guidelines for treatment and follow-up in pediatric patients. What is New: • Characteristics, echocardiographic measurements, and outcomes were comprehensively assessed in children with septic shock. • As a result of our analysis, we found that TAPSE, which is easily measured at the bedside, is the most critical parameter in relation to mortality. • We offer recommendations for its use in the follow-up of children with septic shock.

Prognostic factors for multi-organ dysfunction in pediatric oncology patients admitted to the pediatric intensive care unit.

Pediatric oncology patients who require admission to the pediatric intensive care unit (PICU) have worse outcomes compared to their non-cancer peers. Although multi-organ dysfunction (MOD) plays a pivotal role in PICU mortality and morbidity, risk factors for MOD have not yet been identified. We aimed to identify risk factors at PICU admission for new or progressive MOD (NPMOD) during the first week of PICU stay. This retrospective cohort study included all pediatric oncology patients aged 0 to 18 years admitted to the PICU between June 2018 and June 2021. We used the recently published PODIUM criteria for defining multi-organ dysfunction and estimated the association between covariates at PICU baseline and the outcome NPMOD using a multivariable logistic regression model, with PICU admission as unit of study. To study the predictive performance, the model was internally validated by using bootstrap. A total of 761 PICU admissions of 571 patients were included. NPMOD was present in 154 PICU admissions (20%). Patients with NPMOD had a high mortality compared to patients without NPMOD, 14% and 1.0% respectively. Hemato-oncological diagnosis, number of failing organs and unplanned admission were independent risk factors for NPMOD. The prognostic model had an overall good discrimination and calibration. The risk factors at PICU admission for NPMOD may help to identify patients who may benefit from closer monitoring and early interventions. When applying the PODIUM criteria, we found some opportunities for fine-tuning these criteria for pediatric oncology patients, that need to be validated in future studies.

Case report: Successful outcome of a young patient with rhabdomyolysis and shock caused by diquat poisoning.

The widespread use of diquat as a substitute for paraquat has led to an increase in poisoning deaths. A successful case of diquat poisoning complicated with rhabdomyolysis and shock was lacking. A 13-year-old previously healthy girl ingested 40 ml of diquat solution in a suicide attempt. The concentration of diquat in serum was 436.2 ug/L at 10 h after poisoning. The clinical course was characterized by progressive multi-organ dysfunction, particularly rhabdomyolysis and shock. The main treatments included intensive hemoperfusion combined with continuous renal replacement therapy (CRRT), drainage, and activated carbon adsorption. Meanwhile, accurate dilatation under the model of pulse indicator continuous cardiac output (PICCO) was essential for the successful treatment of shock. The serum concentration of diquat declined to 20 ug/L after 96 h of treatments. The patient was discharged from the hospital after 3 weeks of treatment without obvious symptoms. So far, this was the first successful case of diquat poisoning complicated with rhabdomyolysis and shock, which would enrich the experience of diquat poisoning treatment.

Clinical study of various forms of acute pancreatitis in a tertiary care centre

Background: Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of regional tissues and remote organ system. Severe acute pancreatitis (SAP) is characterized by a short course of progressive multi organ dysfunction syndrome (MODS), early hypoxemia and increased incidence of necrosis, infection, and abdominal compartment syndrome (ACS). The average mortality rate in severe acute pancreatitis approaches 2-10%. This study was conducted to observe etiological factors, the clinical presentations and outcome of various form of acute pancreatitis.Methods: A hospital record based retrospective study on one hundred (100) cases of various forms of acute pancreatitis in the department of surgery at tertiary care teaching hospital of South Gujarat from January 2019 to December 2019 to know the clinical presentation of acute pancreatitis patients.Results: The maximum patients were belonged to age group between 31-40 years. There was a high incidence of alcoholic pancreatitis as compared to the gallstone pancreatitis. In both males and females, alcohol was the main etiological factor. Few patients needed ICU admission and oxygenation. Surgery was the modality for some patients. Out of total, 89 cases were recovered.Conclusions: Early identification of sever and complicated acute pancreatitis prompts the highly dependent intensive care and early intervention. Gall stones are considered most common etiological factor for acute pancreatitis in India but alcoholism crosses this limit suggests changing life style of our people. Outcome is favourable in expectant conservative management of any form of acute pancreatitis.

Initial treatment of myxedema coma using oral levothyroxine: a case report from Tanzania.

SummaryMyxedema coma is a severe complication of hypothyroidism, commonly affecting women over 60 years of age, causing slow, progressive multi-organ dysfunction, and mental deterioration. Due to improved diagnostics and treatment of hypothyroidism, myxedema coma has become uncommon. However, it is hardly reported in resource-limited settings. We present an elderly female with a history of total thyroidectomy due to multi-nodular goiter. She presented with features of heart failure, excessive weight gain, and cold sensation. Although the patient was on levothyroxine replacement therapy, her laboratory tests were suggestive of overt primary hypothyroidism. During the course of her hospitalization, she developed subcutaneous bleeding with frank hematuria. This led to an altered mental state and hypotension that were suggestive of myxedema coma. Stroke and pulmonary embolism were ruled out as potential differential diagnoses of her current state. She was treated with a high dose of oral levothyroxine followed by 150 μg of oral levothyroxine daily, which resulted in a favorable outcome despite being a fatal emergency. She was also treated with intravenous hydrocortisone and furosemide. Oral thyroid hormone replacement may be an effective option in those resource-limited settings where intravenous thyroid hormone replacement is not available. However, early diagnosis and treatment with an adequate dose of thyroid hormones are crucial to achieve a favorable outcome.Learning pointsMyxedema coma is an uncommon complication of hypothyroidism with a fatal outcome.The diagnosis of myxedema coma is based on clinical suspicion, especially in patients with hypothyroidism and in the presence of precipitating factors. Although diagnostic and scoring criteria based on clinical, laboratory, and imaging features have been proposed, no consensus has been reached.This article shows an alternative treatment option for myxedema coma using oral levothyroxine, which led to a favorable outcome.

COVID-19-Induced acute pancreatitis – A case series

The present pandemic of the COVID-19 virus has caused enormous morbidity and mortality to humankind. Acute pancreatitis (AP) in otherwise healthy patients infected with the COVID-19 virus has been reported only as case reports and series. We report a series of three cases of AP including one adolescent with necrotizing pancreatitis due to COVID-19 infection, out of total 4117 COVID-19 admission (0.07%) in our hospital till February 8, 2022. Detailed investigations for etiological diagnosis of AP were within normal limits thus, the causation was attributed to COVID-19 viral infection as causative agent. One child succumbed to the illness as he also manifested with features of multisystem inflammatory syndrome and had progressive multi-organ dysfunction despite aggressive management. Further studies are required before a clear mechanism of causation due to the COVID-19 virus is proven in AP.

A bi‐centric experience of extracorporeal carbon dioxide removal (ECCO2R) for acute hypercapnic respiratory failure following allogeneic hematopoietic stem cell transplantation

Acute respiratory failure (ARF) is the main reason for ICU admission following allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal CO2 removal (ECCO2R) can be used as an adjunct to mechanical ventilation in patients with severe hypercapnia but has not been assessed in HSCT recipients. Retrospective analysis of all allogeneic HSCT recipients ≥18 years treated with ECCO2R at two HSCT centers. 11 patients (m:f = 4:7, median age: 45 [IQR: 32‐58] years) were analyzed. Acute leukemia was the underlying hematologic malignancy in all patients. The time from HSCT to ICU admission was 37 [8‐79] months, and 9/11 (82%) suffered from chronic graft‐versus‐host disease (GVHD) with lung involvement. Pneumonia was the most frequent reason for ventilatory decompensation (n = 9). ECCO2R was initiated for severe hypercapnia (PaCO2: 96 [84‐115] mm Hg; pH: 7.13 [7.09‐7.27]) despite aggressive mechanical ventilation (invasive, n = 9; non‐invasive, n = 2). ECCO2R effectively resolved blood gas disturbances in all patients, but only 2/11 (18%) could be weaned off ventilatory support, and one (9%) patient survived hospital discharge. Progressive respiratory and multiorgan dysfunction were the main reasons for treatment failure. ECCO2R was technically feasible but resulted in a low survival rate in our cohort. A better understanding of the prognosis of ARF in patients with chronic GVHD and lung involvement is necessary before its use can be reconsidered in this setting.

LIMB ISCHAEMIA AND MULTISYSTEM DYSFUNCTION AS A CONSEQUENCE OF CHOLESTEROL EMBOLIZATION SYNDROME

Following a Coronary artery bypass graft and insertion of an intra-aortic balloon pump, the 63 year-old male patient developed signs of progressive multi-organ dysfunction and ischaemic changes in both of his lower limbs. The diagnosis of cholesterol embolization syndrome was made. This condition has been noted to be a complication of invasive procedures and endovascular therapies, and is often overlooked and difficult to treat. While the patient’s renal function and pancreatitis showed improvement, the lower limb ischaemia was progressing. Eventually, the patient underwent a bilateral below knee amputation.

No footprint too small: case of intrauterine herpes simplex virus infection

Abstract Objectives To describe the case of a preterm infant with intrauterine HSV infection. To discuss the epidemiology, features and complications associated with intrauterine HSV infection by conducting a review of medical literature. Case presentation A preterm male infant was born with diffuse skin erosions in various stages of healing suggestive of denuded bullae. Prenatal ultrasound showed evolving fetal cerebral ventriculomegaly, suspected Dandy-Walker malformation, and oligohydramnios. Neonatal skin swabs were positive for herpes simplex virus type 2 by polymerase chain reaction and the patient was treated with intravenous acyclovir from birth. Cranial ultrasound and magnetic resonance imaging findings showed severe progressive ex-vacuo ventricular dilatation consistent with intrauterine herpes simplex infection. Due to those findings and progressive multi-organ dysfunction, care was redirected to a palliative path and the child expired at 21 days of age. In retrospect, the mother had a few atypical vesicles on the left hand 4–5 weeks prior to delivery with a presumptive diagnosis of pompholyx. Conclusions Although confirmed intrauterine herpes simplex virus (HSV) infections are very rare, the potentially devastating prognosis and complications as evidenced by our case show that awareness of intrauterine HSV is critical for pediatricians as well as physicians involved in antenatal care. In order to adequately assess, treat and counsel pregnant women, more work is required to detect HSV infection, evaluate possible congenital infection and improve outcomes with fetal and neonatal treatment.

Extracorporeal cardiopulmonary resuscitation for adults with shock-refractory cardiac arrest.

BackgroundVeno‐arterial extracorporeal membrane oxygenation has increasingly emerged as a feasible treatment to mitigate the progressive multiorgan dysfunction that occurs during cardiac arrest, in support of further resuscitation efforts.ObjectivesBecause the recent systematic review commissioned in 2018 by the International Liaison Committee on Resuscitation Advanced Life Support task did not include studies without a control group, our objective was to conduct a review incorporating these studies to increase available evidence supporting the use of extracorporeal cardiopulmonary resuscitation (ECPR) for cardiac arrest patients, while waiting for high‐quality evidence from randomized controlled trials (RCTs).MethodsMEDLINE, Embase, and Science Citation Index (Web of Science) were searched for eligible studies from database inception to July 20, 2020. The population of interest was adult patients who had suffered cardiac arrest in any setting. We included all cohort studies with 1 exposure/1 group and descriptive studies (ie, case series studies). We excluded RCTs, non‐RCTs, and observational analytic studies with a control group. Outcomes included short‐term survival and favorable neurological outcome. Short‐term outcomes (ie, hospital discharge, 30 days, and 1 month) were combined into a single category.ResultsOur searches of databases and other sources yielded a total of 4302 citations. Sixty‐two eligible studies were included (including a combined total of 3638 participants). Six studies were of in‐hospital cardiac arrest, 34 studies were of out‐of‐hospital cardiac arrest, and 22 studies included both in‐hospital and out‐of‐hospital cardiac arrest. Seven hundred and sixty‐eight patients of 3352 (23%) had short‐term survival; whereas, 602 of 3366 (18%) survived with favorable neurological outcome, defined as a cerebral performance category score of 1 or 2.ConclusionsCurrent clinical evidence is mostly drawn from observational studies, with their potential for confounding selection bias. Although studies without controls cannot supplant case‐control or cohort studies, several ECPR studies without a control group show successful resuscitation with impressive results that may provide valuable information to inform a comparison.

P1532 Segmental assessment of left ventricle in patients with Fabry"s disease

Abstract Anderson-Fabry disease (AFD) is a rare X-linked metabolic disorder due to deficiency in lysosomal enzyme activity of a-galactosidase A, resulting in pathological accumulation of glycosphingolipids in several tissues and a progressive multi-organ dysfunction. The Global Longitudinal Strain (GLS) of the left ventricle (LV) by Speckle-tracking echocardiography (STE) has been show to detect subclinical cardiac involvement in many cardiomyopathies. The Mechanical Dispersion (MD), derived from STE is considered able to reflect a heterogeneous myocardial contraction, evaluated in many cardiopathies. A reduction in GLS was associated with myocardial fibrosis in the subclinical stages of AFD cardiomyopathy, but there is no MD data in AFD. The aim of the study was to evaluate the distribution of GLS and MD of LV in patients with AFD. 47 consecutive AFD adult patients treated (37F, 12 M, age 45 + 17 years) were examined by a complete echocardiographic examination from a Vivid E95 ultrasound scanner (Horten, Norway). The STE post-processing was performed by Echopac 2.02, in apical long-axis, 4-chambers, and 2-chambers views to determine GLS and MD. Data were expressed as mean± standard deviation. The comparison between the AFD group and 20 normal subjects (N) was performed with unpaired T-test. Compared to N, the AFD group showed higher values of LVMi, LAVi, E/E’, and MD, but a lower value of GLS (Table). GLS was significantly lower in the basal (sept p&amp;lt;.002; post p&amp;lt;.0001) and mid segments (ant-sept p&amp;lt;.008; post p&amp;lt;.0001; ant p&amp;lt;.001). MD was significantly higher in the inferior (basal p&amp;lt;.003; mid p&amp;lt;.01; apical p&amp;lt;.005) and lateral segments (mid p&amp;lt;.004; apical p&amp;lt;.001). In patients with AFD, MD added to GLS seems to be a promising tool for the early diagnosis of segmental dysfunction . Table1: Results AFD N p&amp;lt; m SD m SD LVMi g/sqm 77.1 29.8 62.3 14.1 0.008 LVEF % 65.7 5 63.6 3.5 0.04 LAVi ml/sqm 25.5 11 18.2 4.5 0.000 E/E" 8.3 3 5.4 1.1 0.000 TV vmax m/s 2.2 0.4 2.1 0.3 - LV GLS % -17 4 -20 2 0.003 LV MD ms 52 38 29 8 0.000

Neurocognitive Testing in Pediatric Sickle Cell Disease: Full Scale IQ Assessment May Not be the Full Story

Introduction: Sickle Cell Disease (SCD) is a chronic, congenital hemoglobinopathy characterized by progressive multiorgan dysfunction (Vichinsky, ASH proceedings). The brain is one of the major organs affected by SCD. While it is known that neurocognitive defects can be seen even in the absence of overt stroke and silent cerebral infarcts, there are no specific guidelines for performing neurocognitive assessments on patients with SCD. We report our findings in 20 patients that received neurocognitive testing at our institution within the last 3 years Methods: Eligible participants were identified through the Chicago Sickle Cell Disease Research Group (CSCDRG) Registry in conjunction with the SCD medical team and pediatric psychologist. Enrolled subjects took part in child/caregiver interviews, caregiver questionnaires, and review of relevant medical and school records. Participants and caregivers completed a baseline neuropsychological evaluation, which included the Wechsler Intelligence Scale for Children (WISC). Questionnaires were also sent to participants' teachers. Medical chart review was used to collect information about genotype and relevant imaging. Results: Neurocognitive testing was performed on 20 pediatric patients ranging in age from 6 to 14 years of age. The majority of patients had sickle cell genotype Hgb SS (n=16, 80%). Five patients (25%) had an abnormal MRI prior to testing. Brain abnormalities included CVA (n=2), Moya Moya (n=2), and T2 signal intensity (n=4). Cohort average full scale IQ was 75. Average full-scale IQ scores did not differ between patients who had a known brain abnormality (75) and patients who did not have a known brain abnormality (76) prior to testing. Most of the patients (n=15, 75%) were in the grade appropriate for age but only about half of the patients had an Individualized Education Plan (IEP) at the school. Interestingly, we also found that prior to neurocognitive testing, only one patient had a known Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) diagnosis. Following testing, we identified ten additional patients who met criteria for at least one DSM-5 diagnosis. DSM-5 diagnoses in pediatric patients fell under primarily three categories including Neurodevelopmental Disorders (i.e., Attention-Deficit Hyperactivity Disorder, Specific Learning Disability in Mathematics), Trauma and Stressor Related Disorders (i.e., Adjustment Disorder with depressed mood), and Disruptive, Impulse Control and Conduct Disorders (i.e., Oppositional Defiant Disorder). Conclusion: We have described the differences in a pediatric sickle cell patient population who underwent neurocognitive testing. Our cohort of children with sickle cell disease exhibit significant neurocognitive deficits even in the absence of overt imaging findings or clinical stroke. Our findings also suggest that patients with SCD are at a higher risk of clinically significant mental health disorders which, if left undiagnosed, have the potential to hinder scholastic and occupational achievement. Individualized educational plans and specific interventions and addressing learning disabilities will help improve academic performance. Furthermore, neurocognitive testing should be a part of routine evaluation in patients with sickle cell disease. Disclosures No relevant conflicts of interest to declare.

Acute Respiratory Distress Syndrome as an Organ Phenotype of Vascular Microthrombotic Disease: Based on Hemostatic Theory and Endothelial Molecular Pathogenesis.

Acute respiratory distress syndrome (ARDS) is a life-threatening noncardiogenic circulatory disorder of the lungs associated with critical illnesses such as sepsis, trauma, and immune and collagen vascular disease. Its mortality rate is marginally improved with the best supportive care. The demise occurs due to progressive pulmonary hypoxia and multi-organ dysfunction syndrome (MODS) with severe inflammation. Complement activation is a part of immune response against pathogen or insult in which membrane attack complex (MAC) is formed and eliminates microbes. If complement regulatory protein such as endothelial CD59 is underexpressed, MAC may also cause pulmonary vascular injury to the innocent bystander endothelial cell of host and provokes endotheliopathy that causes inflammation and pulmonary vascular microthrombosis, leading to ARDS. Its pathogenesis is based on a novel “two-path unifying theory” of hemostasis and “two-activation theory of the endothelium” promoting molecular pathogenesis. Endotheliopathy activates two independent molecular pathways: inflammatory and microthrombotic. The former triggers the release inflammatory cytokines and the latter promotes exocytosis of unusually large von Willebrand factor multimers (ULVWF) and platelet activation. Inflammatory pathway initiates inflammation, but microthrombotic pathway more seriously produces “microthrombi strings” composed of platelet-ULVWF complexes, which become anchored on the injured endothelial cells, and causes disseminated intravascular microthrombosis (DIT). DIT is a hemostatic disease due to lone activation of ULVWF path without activated tissue factor path. It leads to endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and MODS. Thrombotic thrombocytopenic purpura (TTP)-like syndrome is the hematologic phenotype of EA-VMTD. ARDS is one of organ phenotypes among MODS associated with TTP-like syndrome. The most effective treatment of ARDS can be achieved by counteracting the activated microthrombotic pathway based on two novel hemostatic theories.

Primary systemic amyloidosis presenting as macroglossia

Primary amyloidosis is a group of monoclonal plasma cell disorders, characterized by extracellular deposition of immunoglobulin light chain fibrils in multiple organs leading to progressive multiorgan dysfunction. We report a 61-year-old female patient with an enlarged tongue, difficulty in speech, gradually changing quality of voice, and loss of weight. Diagnosis of amyloidosis and systemic nature confirmed by tongue biopsy and anterior abdominal fat biopsy using Hematoxylin and Eosin staining and Congo red staining. Urine examination positive for Bence–Jones proteins. Bone marrow aspiration cytology, bone marrow aspirate flow cytometry immunophenotyping, serum immunofixation electrophoresis, and urine immunoelectrophoresis revealed plasmacytosis, clonal plasma cell population, marked increased in lambda light chain in serum and urine, respectively. Based on these observations, a definitive diagnosis of primary systemic amyloidosis associated with plasma cell dyscrasia was made. He was treated with intravenous (IV) bortezomib and IV dexamethasone. A battery of tests is necessary to differentiate localized amyloidosis from its systemic forms for diagnosis, treatment and to assess treatment outcome.

Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with AL Amyloidosis

Background: Mortality in patients with AL Amyloidosis remains high due to progressive organ damage from amyloid deposition. Current therapies eliminate the plasma cell clone that produces amyloidogenic light chains. However, there are no approved therapies that directly target amyloid deposits, a major culprit of progressive multi-organ dysfunction. To address this, a murine (Mu) amyloid fibril-reactive monoclonal antibody (mAb) 11-1F4 was developed that binds to a conformational epitope present on human light-chain amyloid fibrils and initiates cell-mediated phagocytosis. In vivo testing of the Mu mAb and later its chimeric (Ch) form in mice with induced human AL amyloidomas resulted in rapid amyloidolysis without any evidence of toxicity [Hrncic 2000; Solomon 2003]. Subsequent evaluation of an I-124 labeled Mu mAb confirmed that it specifically bound to amyloid-laden organs as evidenced by PET/CT imaging [Wall 2010]. Because of these favorable results, GMP-grade amyloid fibril-reactive Ch IgG1 mAb 11-1F4 was produced by NCI's Biological Resource Branch for a phase 1a/b trial. An analysis of Phase 1a was presented at the American Society of Hematology's 2015 annual meeting. Here we report data from the phase 1a/b trial.Methods: Patients with relapsed or refractory AL Amyloidosis were enrolled in this open-label, dose-escalation phase 1a/b study of Ch IgG1 mAb 11-1F4 (NCT02245867). The primary objective was to determine safety and tolerability of the antibody when given as a single intravenous infusion (phase 1a) or as a series of weekly infusions for 4 weeks (phase 1b). Secondary objectives included pharmacokinetics and efficacy as evidenced by organ response. For both phase 1a and 1b, a dose-escalation "up and down" design was used where sequential doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m2 were administered to successive patients. Assessment of organ response was based on the International Society of Amyloidosis' revised consensus criteria [Pallidini 2012] and the clinically validated renal staging and response criteria [Pallidini 2014].Results: As of July 15th, 2016, 8 (2 κ and 6 λ) patients completed phase 1a and 11 (4 κ and 7 λ) patients commenced treatment in phase 1b. Median age was 67 years (range: 34 - 77) and median number of organs involved was 2 (range: 1 - 4) with heart and kidney being the most common. All patients received prior anti-plasma cell systemic treatment and achieved at least partial hematologic response. All patients tolerated the given dose of mAb 11-1F4. The maximum tolerated dose (MTD) was 500mg/m2 for phase 1a and 1b. There were no grade 4 or 5 adverse events (AEs) related to the drug. In phase 1a, one patient at dose level 4 developed a grade 2 rash 4 days after infusion. Skin biopsy revealed a so far undiagnosed cutaneous amyloidosis and immunohistochemical staining showed the mAb surrounding amyloid fibrils with an accompanying neutrophilic infiltrate. The same patient and another patient developed a similar rash during treatment in phase 1b suggesting mAb 11-1F4 binding. Although the primary objective of the trial was to evaluate safety, 63% of patients (5 of 8) with measurable disease burden demonstrated organ response after one infusion of mAb 11-1F4 in phase 1a. In phase 1b, 83% of patients (5 of 6 who completed follow up) showed organ response. At the time of presentation, we will report a complete analysis of the phase 1a and 1b clinical trial.Conclusions: Treatment with mAb 11-1F4 is well tolerated and safe without grade 4 or 5 AEs or dose limiting toxicity up to an MTD of 500mg/m2. Clinical efficacy data shows early and sustained organ response when the mAb is administered as a single infusion or as a weekly infusion for 4 weeks. Based on these very encouraging results, a phase 2 SWOG trial for patients with newly diagnosed AL Amyloidosis will be launched. Overall, we posit that amyloid fibril-specific 11-1F4 mAb represents a novel and promising adjunct to the treatment of AL Amyloidosis by safely promoting amyloid resolution and subsequent improvement in organ function. This may result in improved outcomes for patients with this devastating disease. DisclosuresWall:Prothena Inc: Patents & Royalties. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy.

Haploidentical transplantation as a promising therapy for relapsed hemophagocytic lymphohistiocytosis in an older adult patient

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe and often overwhelming systemic hyper-inflammatory syndrome generally presenting with unexplained fevers, hepatosplenomegaly, and progressive multi-organ dysfunction. Treatment of HLH has two major goals: Halting the triggering event and controlling the overactive immune system. However, patients with primary or recurrent secondary HLH should subsequently undergo allogeneic HCT for long lasting disease remission. Hereby we present the case of a 69 years old man with recurrent HLH who underwent a reduced intensity conditioning of fludarabine, cyclophosphamide and low dose total body irradiation followed by a haploidentical marrow graft and post-transplantation cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil as GVHD prophylaxis. He achieved a durable remission of HLH symptoms despite persistent myeloid mixed chimerism.The use of haploidentical donors and PTCy as tolerance inducing regimen is feasible in HLH. The achievement of mixed donor chimerism may be enough to control the clinical manifestations and to cure HLH.

Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin

Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is caused by the misfolding and deposition of the transthyretin (TTR) protein and results in progressive multi-organ dysfunction. TTR epitopes exposed by dissociation and misfolding are targets for immunotherapeutic antibodies. We developed and characterized antibodies that selectively bound to misfolded, non-native conformations of TTR.Methods: Antibody clones were generated by immunizing mice with an antigenic peptide comprising a cryptotope within the TTR sequence and screened for specific binding to non-native TTR conformations, suppression of in vitro TTR fibrillogenesis, promotion of antibody-dependent phagocytic uptake of mis-folded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue.Results: Four identified monoclonal antibodies were characterized. These antibodies selectively bound the target epitope on monomeric and non-native misfolded forms of TTR and strongly suppressed TTR fibril formation in vitro. These antibodies bound fluorescently tagged aggregated TTR, targeting it for phagocytic uptake by macrophage THP-1 cells, and amyloid-positive TTR deposits in heart tissue from patients with ATTR amyloidosis, but did not bind to other types of amyloid deposits or normal tissue.Conclusions: Conformation-specific anti-TTR antibodies selectively bind amyloidogenic but not native TTR. These novel antibodies may be therapeutically useful in preventing deposition and promoting clearance of TTR amyloid and in diagnosing TTR amyloidosis.

The Complex Relationship of Extracorporeal Membrane Oxygenation and Acute Kidney Injury: Causation or Association?

Extracorporeal membrane oxygenation (ECMO) is a modified cardiopulmonary bypass (CPB) circuit capable of providing prolonged cardiorespiratory support. Recent advancement in ECMO technology has resulted in increased utilisation and clinical application. It can be used as a bridge-to-recovery, bridge-to-bridge, bridge-to-transplant, or bridge-to-decision. ECMO can restitute physiology in critically ill patients, which may minimise the risk of progressive multiorgan dysfunction. Alternatively, iatrogenic complications of ECMO clearly contribute to worse outcomes. These factors affect the risk : benefit ratio of ECMO which ultimately influence commencement/timing of ECMO. The complex interplay of pre-ECMO, ECMO, and post-ECMO pathophysiological processes are responsible for the substantial increased incidence of ECMO-associated acute kidney injury (EAKI). The development of EAKI significantly contributes to morbidity and mortality; however, there is a lack of evidence defining a potential benefit or causative link between ECMO and AKI. This area warrants investigation as further research will delineate the mechanisms involved and subsequent strategies to minimise the risk of EAKI. This review summarizes the current literature of ECMO and AKI, considers the possible benefits and risks of ECMO on renal function, outlines the related pathophysiology, highlights relevant investigative tools, and ultimately suggests an approach for future research into this under investigated area of critical care.

Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.

Limited data exist about the international burden of severe sepsis in critically ill children. To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.