Fatal Septic Shock Research Articles

Antibacterial, Antibiofilm, and Anti-inflammatory Effects of a Novel Thrombin-Derived Peptide in Sepsis Models: Insights into Underlying Mechanisms.

We developed two short helical antimicrobial peptides, HVF18-a3 and its d-enantiomer, HVF18-a3-d, derived from the thrombin C-terminal peptide HVF18. These peptides exhibit potent antimicrobial activity against various bacteria by compromising both the outer and inner membranes, with low hemolytic activity. They are stable in the presence of physiological salts and human serum, exhibiting a low potential for developing drug resistance and excellent antibiofilm activity against Gram-negative bacteria. HVF18-a3-d also neutralized lipopolysaccharide (LPS) through direct binding interactions and suppressed the production of inflammatory cytokines through the inflammatory signaling pathway mediated by Toll-like receptor 4 in RAW264.7 cells stimulated with LPS. Both pre- and post-treatment with HVF18-a3-d significantly protected mice against fatal septic shock induced by carbapenem resistant Acinetobacter baumannii. These findings suggest HVF18-a3 and HVF18-a3-d are promising candidates for developing antibiotics against Gram-negative sepsis.

Dose-Dependent Effects of Lipopolysaccharide on the Endothelium-Sepsis versus Metabolic Endotoxemia-Induced Cellular Senescence.

The endothelium, the innermost cell layer of blood vessels, is not only a physical barrier between the bloodstream and the surrounding tissues but has also essential functions in vascular homeostasis. Therefore, it is not surprising that endothelial dysfunction is associated with most cardiovascular diseases. The functionality of the endothelium is compromised by endotoxemia, the presence of bacterial endotoxins in the bloodstream with the main endotoxin lipopolysaccharide (LPS). Therefore, this review will focus on the effects of LPS on the endothelium. Depending on the LPS concentration, the outcomes are either sepsis or, at lower concentrations, so-called low-dose or metabolic endotoxemia. Sepsis, a life-threatening condition evoked by hyperactivation of the immune response, includes breakdown of the endothelial barrier resulting in failure of multiple organs. A deeper understanding of the underlying mechanisms in the endothelium might help pave the way to new therapeutic options in sepsis treatment to prevent endothelial leakage and fatal septic shock. Low-dose endotoxemia or metabolic endotoxemia results in chronic inflammation leading to endothelial cell senescence, which entails endothelial dysfunction and thus plays a critical role in cardiovascular diseases. The identification of compounds counteracting senescence induction in endothelial cells might therefore help in delaying the onset or progression of age-related pathologies. Interestingly, two natural plant-derived substances, caffeine and curcumin, have shown potential in preventing endothelial cell senescence.

Tragedy Strikes: Infant's Eczema Complicated by Fatal Septic Shock

Tragedy Strikes: Infant's Eczema Complicated by Fatal Septic Shock

A First-in-Human Phase I Study of AT101, a Novel Anti-CD19 Chimeric Antigen Receptor T Cell Product Targeting a Membrane-Proximal Domain of CD19 in Adults with Relapsed or Refractory B Cell Non-Hodgkin Lymphoma

Introduction: Anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are highly efficacious against advanced B cell non-Hodgkin lymphoma (NHL) but the majority of patients (pts) ultimately fail. Several mechanisms contribute to CART19 failure, including CD19-neg escape and CART dysfunction. Notably, all four commercial CART19 products utilize the FMC63 single chain variable fragment (scFv) with high-avidity specificity to a CD19 membrane-distal epitope. Interestingly, loss of the FMC63-recognized epitope due to CD19 mutations ( Zhang Z, JITC, 2020) or epitope-masking (CAR19:CD19) ( Ruella M, Nat Med, 2018) has been described. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 with low avidity could: 1. mitigate CD19 epitope loss; but also 2. enhance CART functions ( Fig. 1A) . Methods and results: We developed an autologous, CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218) specific to a membrane-proximal epitope of CD19 (amino acids T51,S53, E55,K59 and K63). We previously reported initial preclinical data ( Patel R., ASH, 2021 #2798) that demonstrated h1218-CART19 recognize and kill B-cell leukemia that aberrantly expresses the FMC63-CAR19. More recently, we demonstrated that differently than FMC63-based CART, h1218-CART19 could respond to and kill tumor cells expressing point mutations of CD19 (L174V and R163L). Of note, h1218-CART19 had enhanced control of CD19+ B-cell neoplasms as compared to FMC63-CART19 both in vitro and in vivo. Mechanistically, thanks to the lower avidity and faster on/off rate, h1218-CART19 had decreased T cell exhaustion and activation-induced cell death. Given the promising preclinical results, we tested the clinical h1218-CART19 product (AT101) in a first-in-human, multi-center, phase I/II, dose-escalation clinical trial for pts with histologically confirmed relapsed or refractory B cell NHL (NCT05338931). For the phase I study, pts were treated with a single intravenous infusion of AT101 (day 0) in three dose levels (DL) based on a standard 3+3 design: DL1 (0.2 x 10 6 cells/kg), DL2 (1.0 x 10 6 cells/kg), or DL3 (5.0 x 10 6 cells/kg). All pts received lymphodepletion with intravenous fludarabine (250 mg/m 2) and cyclophosphamide (25 mg/m 2) on days -4, -3, and -2. The primary objective was to determine the maximum tolerated dose (MTD) of AT101. The secondary objectives were to evaluate AT101 pharmacokinetics and preliminary efficacy. At the July 3, 2023 data cut, 12 pts (median age 62.5 years (range 39-84); diffuse large B cell lymphoma (DLBCL, n=7, 58.3%), follicular lymphoma (FL, n=3, 25.0%), mantle cell lymphoma (MCL, n=1, 8.3%), and marginal zone lymphoma (MZL, n=1, 8.3%)) received AT101 ( Fig. 1B). The median follow-up after AT101 was 6.5 months (1.5-13.7 months), the median number of previous lines of treatment 3 (range 1-8); no prior cellular therapies. Five pts (41.7%) had previous autologous stem cell transplantation. Two pts (16.7%) had refractory disease and two pts (16.7%) received bridging therapy. Three pts (2 pts at DL2 and 1 pt at DL3) developed a grade (G) 1 cytokine-release syndrome (CRS) and one pt at DL3 developed a G3 CRS that resolved within 24 hours. Three pts (1 pt at each DL) developed immune-cell-related neurotoxicity syndrome (ICANS), of which one G4 dose-limiting toxicity (DLT) was reported at DL1 that corrected within 6 days. One DL3 pt experienced G3 sepsis that promptly resolved; the same pt ultimately developed fatal neutropenic septic shock outside the DLT period. Four additional patients experienced ≥G3 neutropenia without evidence of infection. Complete response (CR) occurred in 8/12 pts (66.6%) and overall response (CR+partial response) in 83.3% (95%CI, 51.6-97.9) at day 28 post-AT101 infusion ( Fig. 1B). Remarkably, in DL2 and DL3, the CR rate was 100.0%. Of the 8 pts in CR none has relapsed (median follow-up 6.0 months). AT101 cells expanded (peak in DL3 113.6 ± 6.50 x10 4 CAR gene copies/ug DNA) and persisted in patients' blood. Conclusion: In this first-in-human phase I trial, AT101 was tolerable with limited and manageable toxicities. Notable preliminary efficacy was observed at the RP2D with no evidence of disease relapse after achieving a CR. These results warrant the pursuit of the planned phase II expansion cohort.

Septic shock due to Clostridium botulinum: a case report

BackgroundClostridium botulinum is an anaerobic, Gram-positive, rod-shaped bacterium that forms spores and the neurotoxin botulinum. It is best known for its toxin-induced flaccid paralytic disease, which is deadly without correct treatment. In this report, we show a completely different clinical course with fatal outcome.Case presentationA 37-year-old African man born in Sierra Leone was admitted. After admission, his condition rapidly worsened due to severe septic shock and progressive multiorgan failure. No neurological signs were seen. Despite treatment with antibiotics, fluid resuscitation, and norepinephrine, the multiorgan failure deteriorated further and he died as a result. Blood and synovial fluid cultures showed Clostridium botulinum. No botulinum toxins were found.ConclusionThis is a rare case of fatal septic shock due to Clostridium botulinum-induced septic arthritis without any sign of the classic clinical syndrome of botulism.

Boerhaave’s syndrome in a case of acute exacerbation of chronic obstructive pulmonary disease managed with non-invasive ventilation: a case report

Barotraumatic esophageal rupture (Boerhaave’s syndrome) is a rare and life-threatening disease, described as a Non-Invasive Ventilation (NIV) complication in a very small series. We report the case of a 72-year-old man admitted to the Emergency Department (ED) for severe dyspnea in a Chronic Obstructive Pulmonary Disease (COPD) stage Gold III. After NIV treatment, the patient suffered esophageal perforation with mediastinal and pleural contamination: emergency surgical treatment was successful for the esophageal repair, but the patient developed a fatal septic shock 12 days after surgery. Among NIV complications, few cases concern esophagogastric perforation: our case report describes an uncommon clinical situation treated with a successful damage control surgery approach.

Fatal septic shock due to disseminated coccidioidomycosis: a case series and review of the literature

BackgroundCoccidioidomycosis is a fungal infection endemic to the southwestern United States and regions of Latin America. Disseminated disease occurs in < 1% of cases. Septic shock is even rarer, with high mortality despite therapy.Case summaryWe describe two cases of coccidioidal septic shock. Both patients were older men of Filipino ancestry presenting with respiratory failure and vasopressor-dependent shock. Antifungal drugs were initiated after failure to improve with empiric antibiotics; in both, Coccidioides was isolated from respiratory cultures. Despite aggressive care, both patients ultimately died of their infections. We provide a review of the published literature on this topic.ConclusionsMost of the 33 reported cases of coccidioidal septic shock occurred in men (88%) of non-white race and ethnicity (78%). The overall mortality rate was 76%. All survivors received amphotericin B as part of their treatment. Coccidioidomycosis-related septic shock is a rare disease with poor outcomes; delays in diagnosis and treatment are common. Improved diagnostic testing for coccidioidomycosis could enhance recognition of this disease in the future. Although data are limited, early treatment with amphotericin B in cases of coccidioidal septic shock may reduce mortality.

Septic arthritis and subsequent fatal septic shock caused by Pasteurella multocida in Vietnam

Pasteurella multocida is a facultative anaerobic and gram-negative bacteria. It lives in the upper airway of animals, especially dogs and cats. P. multocida infection commonly results in regional cellulitis, although septic shock complication is uncommon. Here, we report on a fatal case of septic shock developing from a natural knee joint infection.

Genetic characterization and passage instability of a novel hybrid virulence plasmid in a ST23 hypervirulent Klebsiella pneumoniae.

Hypervirulent variants of Klebsiella pnuemoniae (hvKP), which causes life-threatening infections, is a global priority pathogen and frequently harbours virulence plasmids. The virulence plasmids have emerged as the predominant vehicles carrying the major pathogenic determinants of hypermucoviscosity and hypervirulence phenotypes. In the present study, we characterized a novel virulence plasmid in AP8555, an ST23 hvKP strain, which induced a metastatic infection and fatal septic shock in a critically ill patient. The serum killing assay, the quantitative biofilm formation assay, the G.mellonella infection model, and the mouse lethality assay demonstrated that AP8555 was almost as virulent as the hvKP strain NUTH-K2044. The plasmid pAP855 could be conjugated to Klebsiella quasipneumoniae ATCC700603 and E. coli J53 at a frequency of 7.2× 10−5 and 8.7× 10−7, respectively. Whole-genome sequencing and bioinformatics analysis confirmed that the plasmid was novel, clustered to the incompatibility type of IncHI1B/IncFIB/IncFII and presented high similarity to the pK2044 plasmid. In contrast, a 130-kb large-fragment insertion was observed on the plasmid, which introduced a genetic hybrid zone with multiple conjugation-related genes of type IV secretion systems (T4SS) and CcdAB toxin-antitoxin systems (TAS) to the plasmid. In the transconjugants, the presence of pAP855 had a negative impact on bacterial fitness, but enhancing the virulence-associated phenotypes. In vitro evolution experiments showed that pAP855 in the transconjugants could not be stably inherited after 10 days of passage. Our study not only reports a novel hybrid plasmid but also highlights the putative pathway of conjugative virulence plasmid formation and evolution by means of genetic rearrangement through sequence insertion. These findings indicate that structural versatility could contribute to the dissemination of cointegrate virulence plasmid, although the plasmid incurred a fitness cost. Therefore, continuous monitoring the acquisition of conjugative virulence plasmids may have critical value for plasmid research and increase awareness of hvKP.

Emergence of a Carbapenem-Resistant Klebsiella pneumoniae Isolate Co-harbouring Dual bla NDM- 6 -Carrying Plasmids in China.

The widespread emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) with limited therapeutic options has become a global concern. In this study, a K. pneumoniae strain called KP2e was recovered from a human case of fatal septic shock in a Chinese hospital. Polymerase chain reaction and sequencing, antimicrobial susceptibility testing, conjugation experiments, S1 nuclease-pulsed field gel electrophoresis/southern blot, whole genome sequencing and comparative genomics were performed to investigate the phenotypic and molecular characteristics of this isolate. KP2e possessed the NDM-6-encoding gene and exhibited resistance to almost all β-lactams except for monobactam. This strain belonged to sequence type 4024, the complete genome of which was composed of one chromosome and three plasmids. Furthermore, blaNDM–6 coexisted on two self-transmissible plasmids, which were assigned to types IncFIB and IncN. A structure of IS26-composite transposon capturing an identical Tn125 remnant (ΔISAba125-blaNDM–6-bleMBL-trpF-dsbC-cutA-groES-ΔgroEL) was identified in the two plasmids, and this conserved blaNDM-surrounding genetic context was similar to that of few IncN plasmids found in other regions of China. Our research appears to be the first description of a clinical strain that emerged co-harbouring dual blaNDM-carrying plasmids, and the first report of NDM-6-positive CRKP in China. These findings demonstrated that IncN is a key medium in the evolution and expanding dissemination of blaNDM genes among various species, which indicates that close monitoring and rapid detection of blaNDM-harbouring plasmids is necessary.

Fatal septic shock due to Capnocytophaga canimorsus bacteremia masquerading as COVID-19 pneumonia - a case report

BackgroundCapnocytophaga canimorsus (C. canimorsus) infections are rare and usually present with unspecific symptoms, which can eventually end in fatal septic shock and multiorgan failure. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related coronavirus disease 2019 (COVID-19), on the other hand, is predominantly characterized by acute respiratory failure, although other organ complications can occur. Both infectious diseases have in common that hyperinflammation with a cytokine storm can occur. While microbial detection of C. canimorsus in blood cultures can take over 48 h, diagnosis of SARS-CoV-2 is facilitated by a widely available rapid antigen diagnostic test (Ag-RDT) the results of which are available within half an hour. These Ag-RDT results are commonly verified by a nucleic acid amplification test (NAAT), whose results are only available after a further 24 h.Case presentationA 68-year-old male patient with the diagnosis of COVID-19 pneumonia was referred to our Intensive Care Unit (ICU) from another hospital after testing positive on an Ag-RDT. While the initial therapy was focused on COVID-19, the patient developed a fulminant septic shock within a few hours after admission to the ICU, unresponsive to maximum treatment. SARS-CoV-2 NAATs were negative, but bacteremia of C. canimorsus was diagnosed post-mortem. Further anamnestic information suggest that a small skin injury caused by a dog leash or the subsequent contact of this injury with the patient’s dog could be the possible point of entry for these bacteria.ConclusionDuring the acute phase of hyperinflammation and cytokine storm, laboratory results can resemble both, sepsis of bacterial origin or SARS-CoV-2. This means that even in the light of a global SARS-CoV-2 pandemic, where this diagnosis provides the most salient train of thoughts, differential diagnoses must be considered. Ag-RDT can contribute to early detection of a SARS-CoV-2 infection, but false-positive results may cause fixation errors with severe consequences for patient outcome.

Polatuzumab Vedotin Combined with Obinutuzumab, Cyclophosphamide, Doxorubicin, and Prednisone (G-CHP) for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results of a Phase Ib/II Study

Polatuzumab Vedotin Combined with Obinutuzumab, Cyclophosphamide, Doxorubicin, and Prednisone (G-CHP) for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results of a Phase Ib/II Study

&amp;lt;i&amp;gt;Raoultella planticola&amp;lt;/i&amp;gt; Bacteremia-Induced Fatal Septic Shock and Sepsis-Induced Coagulopathy in a Patient with Pancreatic Cancer: A Case Report and Literature Review

Background: Raoultella planticola is a gram-negative rod-shaped bacterium commonly found in water and soil and considered to be a rare and possibly underestimated cause of severe human infection. Its presence should be suspected in older patients with a history of cancer, immune suppression and recent exposure to traumatic injuries or invasive medical procedures. Case presentation: A 78-year-old male with a history of hypertension was diagnosed with pancreatic adenocarcinoma. Whipple procedure (pancreaticoduodenectomy) was performed afterwards. On the 8th day of surgery, the patient was admitted to our tertiary ICU with septic shock. His initial Sequential Organ Failure Assessment (SOFA) score was 12 with predicted mortality 95.7%. Empirical antibiotic therapy with colymicin, meropenem and teikoplanin was administered immediately and two sets of blood cultures were obtained. Patient developed refractory septic shock despite the addition of vasopressin and the patient’s condition continued to deteriorate. Patient died on the third day of sepsis. His blood culture was positive for R. planticola, which was identified using the VITEK-2 biochemical identification system. Conclusions: Clinicians should be aware of fatal unusual infections in immunocompromised patients.

Safety and Efficacy of Decitabine Plus Ipilimumab in Relapsed or Refractory MDS/AML in the Post-BMT or Transplant Naïve Settings

Safety and Efficacy of Decitabine Plus Ipilimumab in Relapsed or Refractory MDS/AML in the Post-BMT or Transplant Naïve Settings

SCURVY: A FORGOTTEN DISEASE LEADING TO WOUND INFECTION AND SEPTIC SHOCK

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Scurvy is a nutritional deficiency of Vitamin C, which is classically related to the ‘Age of Sail’ (1571-1862) and is considered a disease of developing countries. Here we report a patient admitted to intensive care unit (ICU) for wound infection leading to septic shock who was later diagnosed with scurvy. CASE PRESENTATION: A 63-year-old female, resident of a nursing home, having a past medical history significant for ischemic stroke with right sided residual weakness, non-verbal since her stroke for the past ten years, deep vein thrombosis on anticoagulation, was brought to the hospital for worsening encephalopathy. Her blood pressure on arrival was 80/50 mmHg, with rest of the vitals being normal. On examination, she was somnolent, having poor dental hygiene, widespread scattered petechiae on the skin, stage 3 wound on the lower back with foul smelly discharge, cold extremities with good capillary refill while having normal cardiopulmonary and abdominal examination. Lab work showed stage 2 acute kidney injury (Creatinine 1.5 mg/dl from baseline 0.7 mg/dl), sodium 154 mmol/L, INR 8.3, macrocytic anemia with hemoglobin 7.6 g/dl (baseline >10 g/dl), platelet count 37,000 K/uL (baseline >150 K/uL). CT scan of head was negative for any new or acute intracranial pathology. She was managed as per sepsis guidelines requiring blood cultures, appropriate fluid resuscitation, broad spectrum antibiotics with suspected source of sepsis being the wound infection. She required hemodynamic support with vasopressors for hypotension and was admitted to ICU. Vitamin C level was checked considering her poor dental hygiene, scattered petechiae, which came back as undetectable. She was started on optimal replacement of Vitamin C which resulted in gradual improvement of her petechiae, wound and notably her thrombocytopenia completely resolved within a week of initiation of Vitamin C. DISCUSSION: Vitamin C is essential in collagen synthesis, helping in keeping our gums, skin, bone and hair healthy. Moreover, it plays role in prostaglandin metabolism thus potentially decreasing the inflammation or even sepsis. Although considered rare nowadays, scurvy or other nutritional deficiencies can be seen in elderly population, especially people from nursing home or poor socioeconomic status. Such population is at higher risk of getting worse wounds which could result in fatal sepsis or septic shock. CONCLUSIONS: Though rare, scurvy must be kept in the differentials as it carries a higher risk of septic shock which can be fatal if not timely diagnosed and treated. Reference #1: Svirbely, J.L. and A. Szent-Gyorgyi, The chemical nature of vitamin C. Biochem J, 1933. 27(1): p. 279-85. Reference #2: Ma, N.S., C. Thompson, and S. Weston, Brief Report: Scurvy as a Manifestation of Food Selectivity in Children with Autism. J Autism Dev Disord, 2016. 46(4): p. 1464-70. DISCLOSURES: No relevant relationships by Yahya Ahmad, source=Web Response No relevant relationships by Shujaa Faryad, source=Web Response No relevant relationships by Usama Talib, source=Web Response

Clinical Characteristics, Histopathology, and Tissue Immunolocalization of Chikungunya Virus Antigen in Fatal Cases.

Death in patients with chikungunya is rare and has been associated with encephalitis, hemorrhage, and septic shock. We describe clinical, histologic, and immunohistochemical findings in individuals who died following chikungunya virus (CHIKV) infection. We identified individuals who died in Puerto Rico during 2014 following an acute illness and had CHIKV RNA detected by reverse transcriptase-polymerase chain reaction in a pre- or postmortem blood or tissue specimen. We performed histopathology and immunohistochemistry (IHC) for CHIKV antigen on tissue specimens and collected medical data via record review and family interviews. Thirty CHIKV-infected fatal cases were identified (0.8/100 000 population). The median age was 61 years (range: 6 days-86 years), and 19 (63%) were male. Death occurred a median of 4 days (range: 1-29) after illness onset. Nearly all (93%) had at least 1 comorbidity, most frequently hypertension, diabetes, or obesity. Nine had severe comorbidities (eg, chronic heart or kidney disease, sickle cell anemia) or coinfection (eg, leptospirosis). Among 24 fatal cases with tissue specimens, 11 (46%) were positive by IHC. CHIKV antigen was most frequently detected in mesenchymal tissues and mononuclear cells including tissue macrophages, blood mononuclear cells, splenic follicular dendritic cells, and Kupffer cells. Common histopathologic findings were intra-alveolar hemorrhage and edema in the lung, chronic or acute tenosynovitis, and increased immunoblasts in the spleen. CHIKV infection likely caused fatal septic shock in 2 patients. Evaluation of tissue specimens provided insights into the pathogenesis of CHIKV, which may rarely result in septic shock and other severe manifestations.

Multiorgan failure following gastroenteritis: a\xa0case report

BackgroundThis report highlights the first published case of fatal septic shock associated with Clostridium perfringens and Enterococcus avium bacteremia due to infective gastroenteritis.Case presentationWe report a case of hepatic infarction, abscess, and death following gastroenteritis in a 63-year-old Aboriginal man who initially presented to a rural hospital with suspected food poisoning. The patient had persistent fever and was commenced on empirical antibiotics. His blood culture results were positive for Clostridium perfringens and Enterococcus avium. He was transferred to a tertiary center but developed organ failure and refractory shock. Initial computed tomography of the abdomen was unremarkable, but repeat imaging showed small bowel enteritis, hepatic abscess, and infarction as a result of portal vein septic thromboembolism. Despite maximal intensive care treatment, including percutaneous drainage of hepatic abscess and broad antibiotic cover, the patient died 6 days after initial presentation.ConclusionsThis case highlights the rare but commonly fatal course of sepsis associated with Clostridium perfringens bacteremia and demonstrates detrimental effects of coinfection with Enterococcus avium, including potential for rapidly seeding abscess formation. Lessons for rural practice are highlighted, including the need for urgent and early referral for intensive care support, particularly for patients with complex comorbidities.

Nursing Perspectives on the Impacts of COVID-19

Nursing Perspectives on the Impacts of COVID-19

Emergent Percutaneous Nephrostomy for Pyonephrosis: A Primer for the On-Call Interventional Radiologist.

Pyonephrosis is gross accumulation of pus within an obstructed renal collecting system that, if left untreated, can lead to potentially fatal septic shock. Treatment requires urgent decompression coupled with systemic antibiotics. Percutaneous nephrostomy (PCN) placement, first described in 1976 for the treatment of pyonephrosis, is now widely utilized for emergent decompression in these patients. When performed by an experienced interventional radiologist, PCN is a safe procedure with technical success rates of over 96 to 99%. This article will address the clinical presentation of pyonephrosis, and will discuss the indications, technique, complications, and outcomes of emergent PCN placement. Additionally, the expanded indications for PCN placement in nonemergent scenarios will also be described.

Safety and Efficacy of Tisagenlecleucel (CTL019) in B-Cell Acute Lymphoblastic Leukemia in Children, Adolescents and Young Adults: The French Experience

Objectives: Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell- therapy that reprograms autologous T cells to target CD19+ leukemia cells, approved in the US (2017) and in the EU (2018). This study reports the feasibility, safety and efficacy of CTL019 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated in Robert-Debré and Saint-Louis University Hospitals (Assistance Publique-Hôpitaux de Paris/Université de Paris). Methods: Patients (pts) with an apheresis performed between march 1, 2016 and june 15, 2019, included in sponsored-clinical trials or treated within the French compassionate program or with the commercial product, were analyzed. All infused pts received a fludarabine-cyclophosphamide based lymphodepletion before a single infusion of CAR-T cells (2 to 5 x 106 CTL019/kg if less than 50 kg; a fixed dose of 1 to 2.5 x 108 CTL019/kg if &gt; 50 kg) Results: 55 pts were referred from 25 French centers. Forty-one pts with a median number of relapses of 2 (range, 1-5) were infused with CTL019 at a median age of 18.2 y (range, 1-29.2). Eight pts were not infused due to progressive disease (n=4), screen failure (n=3) or fatal septic shock (n=1). Six pts were waiting to be infused at time of analysis. Out of the 41 infused pts, 26 had a prior history of allogeneic SCT (63%), 11 had received blinatumomab (27%). Among the 40 pts evaluable at one month post-infusion, 38 were in CR/CRi (95%) (one progression at day 5 after infusion and one toxic death at D6), 35/38 (92.1%) being clone-specific Ig-TCR MRD negative. After 3 months 21 out of 26 evaluable pts (81%) had a negative MRD. The 5 remaining MRD positive pts did relapse. No pt underwent allogeneic HSCT while in CR after CTL019 infusion. Median event free survival (EFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2-36.3). The 18-month OS probability was 80% (95%CI, 58%-92%). The 18-month EFS probability was 58 % (95%CI, 37%-74%). Ten pts relapsed after a median time of 3.4 months (range, 1.9-10): 3 relapses were CD19+ and 5 CD19- (4 out of these 5 pts had a preexposure to blinatumomab), 2 being of undetermined status. Loss of B-cell aplasia (BCA) occurred in 9 pts after a median time of 3 months (range, 2-12), followed by relapse for 2 pts (one concomitant with loss of BCA and one 7 months later). Three pts received a second infusion of CTL019 for loss of BCA with no further expansion of CAR-T cells. Prior treatment with blinatumomab was a significant predictive factor for relapse (HR=6.082, 95%CI, 1.2-30, p=0.0005) in a univariate analysis. There was a trend toward increased risk of relapse with increased disease burden (≥ 5%) before lymphodepletion regimen (HR=2.4, 95%CI, 0.7-8, p=0.14). Twenty-two pts experienced a CRS (≥ grade 3: n=13, all ≥ 10 y). ICU was required for 14 pts (34%). One 29 year-old pt died of an uncontrollable CRS at day 6. Ten pts received tocilizumab, 4 pts siltuximab and 9 pts corticosteroids. Age ≥ 10 y (p=0.04) and a high disease burden just before lymphodepletion (marrow blasts ≥ 5%) (p=0.01) were associated with a higher risk of CRS ≥ grade 3. Nine neurological events have been reported, being reversible except in 2 cases (one death in combination with grade 5 CRS-cf supra-, one HHV6-related encephalitis with neurological sequelae). Among the 9 pts who presented neurological events, 8 experienced CRS grade ≥ 3 (RR=17.2, 95%CI, 3.22-100.3, p=0.0001). By day 28, unresolved neutropenia grade ≥ 3 was reported for 13 pts. G-CSF treatment was required in 21 pts overall. Thrombocytopenia grade ≥3 was reported for 14 pts. Conclusion: CTL019 confirms its efficacy with a high response rate after infusion and very encouraging early outcomes in a cohort of pts heavily pretreated for refractory or multiply relapsed B-ALL. Persistent remissions with a potential for cure were observed without additional HSCT, relapses occurring within the first year after infusion of CTL019. Accurate assessment of a potentially deleterious effect of Blinatumomab preexposure notable on CD19 negative relapse will need more pts and a longer follow-up. Toxicity profile was tolerable and manageable thanks to collaboration between intensivists, neurologists and hematologists. The identification of severe CRS predictive risk factors (high disease burden just before lymphodepletion and age ≥ 10 y) points towards the reinforcement of toxicity monitoring and treatment anticipation in these cases. Disclosures Boissel: NOVARTIS: Consultancy. Baruchel:NOVARTIS: Consultancy.