Pseudomonas Pneumonia Research Articles

Postinjury Pneumonia Induces a Unique Blood Microbiome Signature.

Previous preclinical studies have demonstrated a pathobiome after traumatic injury; however, the impact of post-injury sepsis on gut epithelial permeability and bacterial translocation remains unknown. We hypothesized that polytrauma with post-injury pneumonia would result in impaired gut permeability leading to specific blood microbiome arrays. Male and proestrus female Sprague-Dawley rats were subjected to either polytrauma (PT), PT plus 2-hours daily chronic restraint stress (PT/CS), PT with postinjury day 1 inoculation with pseudomonas pneumonia (PT + PNA), PT/CS + PNA, or naive controls. Whole blood microbiome was measured serially using high-throughput 16S rRNA sequencing and QIIME2 bioinformatics analyses. Microbial diversity was assessed using Chao1/Shannon indices and principle coordinate analysis. Intestinal permeability was evaluated by plasma occludin and lipopolysaccharide-binding protein (LBP) assays. PT/CS + PNA had increased intestinal permeability compared to uninfected counterparts (PT/CS) with significantly elevated occludin (p < 0.01). Bacteria was not detected in the blood of naïve controls, PT or PT/CS, but was present in both PT + PNA and PT/CS + PNA on days two and seven. The PT/CS + PNA blood biome showed dominance of Streptococcus compared to PT + PNA at day two (p < 0.05). Females PT/CS + PNA had a significant abundance of Staphylococcus at day two and Streptococcus at day seven in the blood biome compared to male counterparts (p < 0.05). Multicompartmental trauma with post-injury pneumonia results in increased intestinal permeability and bacteremia with a unique blood biome, with sexual dimorphisms evident in the blood biome composition. These findings suggest that post-injury sepsis has clinical significance and could influence outcomes after severe trauma and critical illness.

Evaluation of Recurrence Rates of Pseudomonas Pneumonia in Mechanically Ventilated ICU Patients Receiving ≤7 Versus &gt;7 Days of Antibiotic Therapy

Background Pseudomonas aeruginosa (PA) is commonly implicated in ventilator-associated pneumonia (VAP). Consensus guidelines for VAP recommend a 7-day course of appropriate antibiotics. However, recent studies have shown higher recurrence rates of PA pneumonia with shorter courses of antibiotics. This study was designed to compare PA pneumonia recurrence rates in patients who received appropriate antibiotics for ≤7 days vs &gt;7 days. Methods A retrospective, single-center, observational cohort study of adults diagnosed with PA-VAP between January 2017 and May 2022 was conducted. Patients were divided into a &gt;7-day cohort or a ≤7-day cohort based on duration of appropriate antibiotics. The primary outcome was the recurrence rate of PA pneumonia. Results A total of 106 patients were included, 59 in the &gt;7-day cohort and 47 in the ≤7-day cohort. The median (interquartile range) duration of appropriate antipseudomonal therapy was 12 days (8–18 days) in the &gt;7-day cohort and 7 days (6–7 days) in the ≤7-day cohort. Pseudomonas aeruginosa recurrence was observed in 15 (25.4%) patients in the &gt;7-day cohort and 20 (42.6%) patients in the ≤7-day cohort (P = 0.059). Over 33% of patients in the &gt;7-day cohort had persistently positive PA cultures after at least 7 days of appropriate antibiotic therapy. Conclusion Extending duration of antipseudomonal antibiotics beyond 7 days did not significantly reduce the recurrence of PA pneumonia. However, the lower rate of recurrence in the &gt;7-day group and high rate of persistent positive cultures may be clinically significant, suggesting a role for extended treatment. Further prospective studies are needed to determine the optimal duration of therapy for PA-VAP.

Teclistamab in Relapsed/Refractory Multiple Myeloma: Real-World Outcomes at a Single Academic Center in the Midwest

CONCLUSIONS BCMA-directed CAR T-cell therapy is only available at certain academic centers in the Midwest and requires several weeks for manufacturing, leading to a bottleneck of patients who need therapy for relapsed/refractory multiple myeloma (R/R MM). Teclistamab is an off-the-shelf BCMA-directed bispecific T-cell engager (BiTE) that could help alleviate this bottleneck. The MajesTEC-1 trial was a phase I/II study of teclistamab in patients with R/R MM. Even in patients with triple class-exposed disease, teclistamab showed deep and durable responses. However, clinical trials generally enroll fitter patients, especially when compared to the typical MM patient at the late stages of their disease. We sought to describe the real-world treatment outcomes of patients with R/R MM who received teclistamab at Indiana University (IU). This study was conducted retrospectively at a single center. Patients who received teclistamab between October 25 th, 2022, and July 1 st, 2023, were included. Patients were hospitalized during step-up dosing. The teclistamab dosing and schedule were per standard of care. Response was assessed after each cycle based on the IMWG Uniform Response Criteria. CRS and ICANS were graded per Lee 2020, while other side effects were evaluated using CTCAE 5.0. Demographic information, response, and adverse events were reported descriptively, and survival outcomes were estimated using Kaplan-Meier analysis with Prism GraphPad 10.0. The baseline clinical characteristics are summarized in Table 1. Compared to MajesTEC-1, patients treated in this study were older and more heavily pretreated with a higher baseline burden of disease. Many exhibited organ dysfunction and poor performance status, and 20 of 33 patients were previously exposed to BCMA-directed therapy (BDT). The median follow-up duration was 17.6 weeks. The overall response rate (ORR) was 45.5%, including one-third of patients who achieved a very good partial response (VGPR) or better. When stratified by prior exposure to BDT, ORR was 35% in previously exposed patients and was 61.5% in naïve patients. Thirteen patients died during follow-up (9 from disease progression, 3 from infection, and 1 unexplained sudden cardiac death). Median overall survival in the entire cohort was 17.7 weeks. As shown in the Kaplan-Meier analysis in Figure 2, the median OS was not reached for patients who achieved a response, while patients who did not respond had a median OS of 16.7 weeks (p=.05). CRS was observed in 12 patients (36%), with one grade 3 event requiring tocilizumab, dexamethasone, and ICU transfer for hypoxemic respiratory failure - this patient ultimately died from a hospital-acquired infection. ICANS was observed in 5 patients (15.2%), with one grade 3 event - this patient became unresponsive, requiring intubation and mechanical ventilation. Sixteen of 33 patients had an infectious complication (48.5%), while 3 patients died of a treatment-related infection (Pseudomonas pneumonia, hospital-acquired pneumonia, and sepsis from a urinary source). Grade 3 or 4 neutropenia occurred in 12.1%. In a real-world cohort of heavily pretreated myeloma patients, including those with poor organ function, poor performance status, and prior exposure to BCMA-directed therapy, overall response to teclistamab was lower than previously observed in the MajesTEC-1 study. Achieving a PR or better led to a significantly improved OS, while survival among non-responders was poor. Receipt of prior BCMA-directed therapy led to a lower response rate. The incidence of CRS in the current study was lower than that seen in MajesTEC-1, while the rate of neurotoxicity was similar. High grade CRS and ICANS were infrequent but led to poor patient outcomes in our cohort. Despite a low rate of grade 3 or 4 neutropenia, there was a high rate of infection, even with use of prophylactic IVIG for hypogammaglobulinemia. There were 3 infection-related fatalities. This highlights the severely immunocompromised state of the patient population and the need for early recognition and improved strategies for infection prevention. The early use of BCMA BiTEs may improve access and tolerability. However, there is still a need for better understanding of resistance mechanisms.

Posttraumatic pneumonia exacerbates bone marrow erythropoietic dysfunction.

Pneumonia is a common complication after severe trauma that is associated with worse outcomes with increased mortality. Critically ill trauma patients also have persistent inflammation and bone marrow dysfunction that manifests as persistent anemia. Terminal erythropoiesis, which occurs in bone marrow structures called erythroblastic islands (EBIs), has been shown to be impacted by trauma. Using a preclinical model of polytrauma (PT) and pneumonia, we sought to determine the effect of infection on bone marrow dysfunction and terminal erythropoiesis. Male and female Sprague-Dawley rats aged 9 to 11 weeks were subjected to either PT (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofracture) or PT with postinjury day 1 Pseudomonas pneumonia (PT-PNA) and compared with a naive cohort. Erythroblastic islands were isolated from bone marrow samples and imaged via confocal microscopy. Hemoglobin, early bone marrow erythroid progenitors, erythroid cells/EBI, and % reticulocytes/EBI were measured on day 7. Significance was defined as p < 0.05. Day 7 hemoglobin was significantly lower in both PT and PT-PNA groups compared with naive (10.8 ± 0.6 and 10.9 ± 0.7 vs. 12.1 ± 0.7 g/dL [ p < 0.05]). Growth of bone marrow early erythroid progenitors (colony-forming units-granulocyte, erythrocyte, monocyte, megakaryocyte; erythroid burst-forming unit; and erythroid colony-forming unit) on day 7 was significantly reduced in PT-PNA compared with both PT and naive. Despite a peripheral reticulocytosis following PT and PT-PNA, the percentage of reticulocytes/EBI was not different between naive, PT, and PT-PNA. However, the number of erythroblasts/EBI was significantly lower in PT-PNA compared with naive (2.9 ± 1.5 [ p < 0.05] vs. 8.9 ± 1.1 cells/EBI macrophage). In addition to changes in EBI composition, EBIs were also found to have significant structural changes following PT and PT-PNA. Multicompartmental PT altered late-stage erythropoiesis, and these changes were augmented with the addition of pneumonia. To improve outcomes following trauma and pneumonia, we need to better understand how alterations in EBI structure and function impact persistent bone marrow dysfunction and anemia.

NARROWING THE GAP: PRECLINICAL TRAUMA WITH POSTINJURY SEPSIS MODEL WITH INCREASED CLINICAL RELEVANCE.

Background : Overall outcomes for trauma patients have improved over time. However, mortality for postinjury sepsis is unchanged. The use of relevant preclinical studies remains necessary to understand mechanistic changes after injury and sepsis at the cellular and molecular level. We hypothesized that a preclinical rodent model of multicompartmental injury with postinjury pneumonia and chronic stress would replicate inflammation and organ injury similar to trauma patients in the intensive care unit. Methods : Male and proestrus female Sprague-Dawley rats ( n = 16/group) were subjected to either polytrauma (PT) (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofracture), PT with daily chronic restraint stress (PT/CS), PT with postinjury day one Pseudomonas pneumonia (PT + PNA), PT/CS with pneumonia (PT/CS + PNA) or naive controls. Weight, white blood cell count, plasma toll-like receptor 4 (TLR4), urine norepinephrine (NE), hemoglobin, serum creatinine, and bilateral lung histology were evaluated. Results : PT + PNA and PT/CS + PNA groups lost more weight compared with those without sepsis (PT, PT/CS) and naive rats ( P < 0.03). Similarly, both PT + PNA and PT/CS + PNA had increased leukocytosis and plasma TLR4 compared with uninfected counterparts. Urine NE was elevated in PT + PNA and PT/CS + PNA compared with naive ( P < 0.03), with PT/CS + PNA exhibiting the highest levels. PT/CS + PNA exhibited worse acute kidney injury with elevated serum creatinine compared with PT/CS ( P = 0.008). PT/CS + PNA right and left lung injury scores were worse than PT + PNA ( P < 0.01). Conclusions : Sepsis, with postinjury pneumonia, induced significant systemic inflammation, organ dysfunction following polytrauma and chronic stress. Advanced animal models that replicate the critically ill human condition will help overcome the classic limitations of previous experimental models and enhance their translational value.

Duvelisib for Critically-Ill Patients with COVID-19 Disease: An Investigator-Initiated, Randomized, Placebo-Controlled Double-Blind Pilot Trial

Background: Severe and critical COVID-19, including acute respiratory distress syndrome (ARDS), cardiomyopathy, and shock, have been associated with a 28-day mortality exceeding 50%. While dexamethasone (dex) improves survival in such patients and highlights a role for anti-inflammatory therapy, mortality remains high especially in those who do not respond initially. Phase II/III studies of the PI3K-d/g inhibitor duvelisib in patients with chronic lymphocytic leukemia or follicular lymphoma have demonstrated that duvelisib significantly downregulates expression of inflammatory cytokines and chemokines (e.g. G-CSF, GM-CSF, macrophage inflammatory protein-1 α and β). These same inflammatory molecules are upregulated in ARDS and COVID-19. Several murine models of acute lung inflammation and sepsis have demonstrated improved markers of inflammation and survival of mice treated with PI3K inhibitors. The original SAR-CoV-1 coronavirus had demonstrated the ability to hijack the PI3K signaling machinery in order to persist within human airway cells. Additionally, in the context of neoplasia, duvelisib polarizes macrophages to the M1 phenotype which has antimicrobial effector functions in contrast to the pro-inflammatory M2 phenotype. In the context of chimeric antigen receptor T (CAR T) therapy, the DiPersio lab has identified duvelisib as a potent mediator of cytokine release syndrome (CRS) without T-cell inhibition, an overlapping concept with COVID-19. We hypothesized that duvelisib could attenuate COVID-19 ARDS and CRS through M1 macrophage polarization, reduction in cytokine signaling/production, and elimination of viral persistence. Methods: We conducted a multicenter, double-blind, placebo-controlled trial in which 28 patients were randomized 1:1 to duvelisib 25mg twice daily or placebo for 10 days. Eligible patients were 18 years or older hospitalized with a primary diagnosis of COVID-19 disease with either respiratory failure (≥ 50% lung involvement by imaging, invasive or non-invasive mechanical ventilation, or extracorporeal membrane oxygenation), new cardiomyopathy, and/or shock requiring vasopressor support. All patients were required to be receiving or have received dex 6mg daily or equivalent for at least 48 hours without improvement. All patients received prophylaxis for Pneumocystis jiroveci. We monitored viral load daily using quantitative RT-PCR to assess for changes in viral replication following initiation of therapy. Primary endpoint was 28-day survival. Secondary endpoints included: 60-day survival; duration on ventilator and vasopressors; hospital and ICU length of stay; viral kinetics; and adverse events. Correlatives included impact on cytokine expression measured by multiplex panel, viral kinetics by RT-PCR, and flow-cytometry to assess immune populations at various time points during therapy. Results: Baseline and disease characteristics were well-balanced with the exception of baseline renal replacement therapy (Table 1). At day 29, 67% of those in the duvelisib arm and 62% of those in the placebo arm were alive. Secondary efficacy endpoints were comparable between the two cohorts. There was a trend toward improved 60-day OS in the duvelisib arm (60% vs. 46%, p = 0.36, Figure 1) and some patients in the treatment arm were noted to have quick radiographic and clinical improvements. Of those on ECMO at initiation 3/5 (60%) in the duvelisib arm and 1/4 (25%) in the placebo arm were successfully weaned. Adverse events (AEs) occurred at similar rates between arms. Among AEs of special interest previously reported with the use of duvelisib, one patient developed colitis ultimately deemed to be stercoral colitis and unrelated to treatment. No CMV reactivation or Pneumocystis jiroveci pneumonia occurred. Eighty percent of overall deaths were due to respiratory failure from disease progression. In the placebo arm, one patient died of Pseudomonas pneumonia and one died of cholecystitis. Conclusion: In our pilot study, duvelisib did not show improvement in 28-day survival in a critically-ill, steroid-refractory population. However, there was a trend toward improved 60-day OS. No added toxicity was observed in those receiving duvelisib. Based on comparable safety, notable improvements in select patients, and a continued unmet need in this population, we believe larger studies are justified. Correlative data will also be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BETA BLOCKER AND CALCIUM CHANNEL BLOCKER OVERDOSE COMPLICATED BY COVID-19 PNEUMONIA AND RENAL FAILURE IN A PATIENT WITH SEVERE OBESITY

BETA BLOCKER AND CALCIUM CHANNEL BLOCKER OVERDOSE COMPLICATED BY COVID-19 PNEUMONIA AND RENAL FAILURE IN A PATIENT WITH SEVERE OBESITY

The RIPK3 Scaffold Regulates Lung Inflammation During Pseudomonas Aeruginosa Pneumonia.

RIPK3 (receptor-interacting protein kinase 3) activity triggers cell death via necroptosis, whereas scaffold function supports protein binding and cytokine production. To determine if RIPK3 kinase or scaffold domains mediate pathology during Pseudomonas aeruginosa infection, control mice and those with deletion or mutation of RIPK3 and associated signaling partners were subjected to Pseudomonas pneumonia and followed for survival or killed for biologic assays. Murine immune cells were studied invitro for Pseudomonas-induced cytokine production and cell death, and RIPK3 binding interactions were blocked with the viral inhibitor M45. Human tissue effects were assayed by infecting airway epithelial cells with Pseudomonas and measuring cytokine production after siRNA inhibition of RIPK3. Deletion of RIPK3 reduced inflammation and decreased animal mortality after Pseudomonas pneumonia. RIPK3 kinase inactivation did neither. In cell culture, RIPK3 was dispensable for cell killing by Pseudomonas and instead drove cytokine production that required the RIPK3 scaffold domain but not kinase activity. Blocking the RIP homotypic interaction motif (RHIM) with M45 reduced the inflammatory response to infection invitro. Similarly, siRNA knockdown of RIPK3 decreased infection-triggered inflammation in human airway epithelial cells. Thus, the RIPK3 scaffold drives deleterious pulmonary inflammation and mortality in a relevant clinical model of Pseudomonas pneumonia. This process is distinct from kinase-mediated necroptosis, requiring only the RIPK3 RHIM. Inhibition of RHIM signaling is a potential strategy to reduce lung inflammation during infection.

Actinomyces and Kartagener syndrome: Case report and literature review

Kartagener syndrome, which is part of the subgroup of the primary ciliary dyskinesias, predisposes to recurrent respiratory tract infections due to Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae. The case of a patient with a diagnosis of Kartagener syndrome in whom colonization by Pseudomonas fluorescens and pneumonia complicated with empyema by Actinomyces spp is a rare association in the literature, which is described below.

Efficacy and Safety of the Janus Kinase 1 Inhibitor Itacitinib (ITA) in Patients with Bronchiolitis Obliterans (BOS) Syndrome Following Double Lung Transplant

<h3>Purpose</h3> To evaluate efficacy and safety of the Janus kinase 1 inhibitor ITA in patients (pts) with BOS following double lung transplantation. Phase 1 of the study is presented. <h3>Methods</h3> INCB39110-214 (NCT03978637) is an open-label, phase 1/2 study evaluating 3 doses of ITA: 300 mg twice daily (BID), 400 mg once daily (QD) and 600 mg QD. Key inclusion criteria were age ≥18 years; double lung transplantation ≥1 year before screening; and a diagnosis of BOS stage 1-3 in the past year or in the past 2 years with either a ≥200-mL decrease in forced expiratory volume 1 (FEV1) in the past 12 months or a ≥50-mL decrease in FEV1 in the last 2 measurements. Co-primary endpoints were safety and frequency of ≥10% absolute increase in FEV1 vs baseline in 2 consecutive assessments. <h3>Results</h3> 23 pts were randomized to ITA 300 mg BID (n=7), 400 mg QD (n=7), 600 mg QD (n=8), or 200 mg QD (n=1; enrolled under previous protocol version). Baseline pt demographics/characteristics were similar across doses. Prior treatment for BOS included azithromycin (n=9), alemtuzumab (n=1), antithymocyte globulin (n=3), corticosteroids (n=7), extracorporeal photophoresis (n=1), and montelukast (n=4). Mean FEV1 was 1.61 L at study enrollment across all doses of ITA (n=23). No clear dose-related trends were seen; therefore, results are reported as pooled across all doses. Post enrollment mean FEV1 increased at subsequent time points (Week 4, 1.69 L [n=19]; Week 8, 1.76 L [n=12]; Week 12, 1.86 L [n=13]). Protocol-defined FEV1 response was observed in 5 pts (21.7%). Overall incidence of treatment-emergent adverse events (AEs) was similar across all doses (87.0% of all pts); grade ≥3 AEs occurred in 60.9% of pts. The most common AEs were cytomegalovirus (CMV) reactivation/viremia (30.4%), diarrhea (21.7%), and fatigue (21.7%). Infections of any cause occurred in 14 pts (60.9%), and grade ≥3 infections were observed in 7 pts (30.4%). One pt discontinued treatment owing to a treatment-related AE (pseudomonas pneumonia). <h3>Conclusion</h3> Lung function stabilized or improved in a subset of pts who were treated with ITA following a recent diagnosis with progressive BOS stage 1-3. Although AEs were frequent, they were generally not dose limiting; CMV reactivation/viremia and overall infection rates were high but manageable. Further study in pts after lung transplant is warranted.

DNA Methyltransferase 3b in Myeloid Cells Does Not Affect the Acute Immune Response in the Airways during Pseudomonas Pneumonia.

DNA methyltransferase 3b (Dnmt3b) has been suggested to play a role in the host immune response during bacterial infection. Neutrophils and other myeloid cells are crucial for lung defense against Pseudomonas (P.) aeruginosa infection. This study aimed to investigate the role of Dnmt3b in neutrophils and myeloid cells during acute pneumonia caused by P. aeruginosa. Neutrophil-specific (Dnmt3bfl/flMrp8Cre) or myeloid cell-specific (Dnmt3bfl/flLysMCre) Dnmt3b-deficient mice and littermate control mice were infected with P. aeruginosa PAK via the airways. Bacteria burdens, neutrophil recruitment, and activation (CD11b expression, myeloperoxidase, and elastase levels), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) were measured in bronchoalveolar lavage fluid (BALF) at 6 and 24 h after infection. Our data showed that the bacterial loads and neutrophil recruitment and activation did not differ in BALF obtained from neutrophil-specific Dnmt3b-deficient and control mice, whilst BALF IL-6 and TNF levels were lower in the former group at 24 but not at 6 h after infection. None of the host response parameters measured differed between myeloid cell-specific Dnmt3b-deficient and control mice. In conclusion, dnmt3b deficiency in neutrophils or myeloid cells does not affect acute immune responses in the airways during Pseudomonas pneumonia.

M169 STAT-3 DEFICIENT CHILD FOUND TO BE SYMPTOMATIC CARRIER OF CYSTIC FIBROSIS

Although unlikely, the presence of one immune deficiency does not exclude another. We present a child with STAT-3 deficiency and Hyper IgE Syndrome (HIES) who developed pseudomonas pneumonia and was also found to be a symptomatic carrier for cystic fibrosis (CF).

S2905 Prolonged Cholestasis After COVID-19

Introduction: The coronavirus SARS-CoV-2 (COVID-19) is known to cause both pulmonary and hepatic injury. Cholangiocytes have an abundance of angiotensin-converting enzyme 2 receptors, which are the main mode of entry for the virus. Whether the liver injury is caused directly by the virus or as a result of the cytokine storm remains unknown. We present a case of prolonged cholestatic liver injury secondary to COVID-19. Case Description/Methods: A 55-year-old woman presented to our institution with sudden onset of right leg pain and swelling. She had hypertension, diabetes, obesity, and hypothyroidism. She denied any history of liver disease, toxic habits and was not taking any hepatotoxic medications or supplements. Two months prior to presentation, she was admitted to another hospital with severe COVID-19 pneumonia requiring mechanical ventilation. She had received Remdesivir, Convalescent Plasma, Extra Corporeal Membrane Oxygenation (ECMO), and hemodialysis for acute renal failure, before being discharged. During this admission, she was found to have a right lower extremity thrombus and was started on Enoxaparin. Her liver function tests were significant for a markedly elevated alkaline phosphatase level. An ultrasound abdomen was significant only for a fatty liver. CT scan of the abdomen with contrast and an MRCP did not reveal any hepatobiliary abnormalities. Viral hepatitis serology and autoimmune workup were negative. She underwent a liver biopsy which demonstrated cholestasis, mild lobular necroinflammation, and macrovesicular steatosis. There was no PCR evidence of SARS-CoV-2. Her hospital course was complicated by MRSA and pseudomonas pneumonia. She suffered a cardiac arrest and ultimately succumbed to her infection 2 months later. Her Alkaline phosphatase remained elevated throughout her hospital stay. Discussion: Although our patient’s liver biopsy did not demonstrate PCR evidence of SARS-COV-2, it was consistent with histological features of COVID-19 related hepatic injury. Macrovesicular steatosis is the most common histological finding, followed by lobular necroinflammation, according to a case series of 40 patients who died of COVID-19. PCR for SARS-COV-2 in liver biopsy was positive in only 55% of patients. Recent reports have identified ECMO as a cause of secondary sclerosing cholangitis in critically ill patients, which remains a possibility in our case. However, a normal bilirubin level and MRCP did not support this diagnosis in our patient.Figure 1.: (A) 4 x magnification, (B) 10 x magnification, and (C) 40 x magnification of a liver biopsy specimen demonstrating hepatocellular cholestasis with feathery degeneration of hepatocytes, mild lobular neuroinflammation, and mild macrovesicular steatosis. There is sinusoidal dilatation and glycogenated nuclei. Portal tracts show mild to moderate mixed cellular infiltration, including eosinophils, endothelilitis, ductular reaction, and focal mild bile duct damage. There is no pericellular fibrosis to indicate non-alcoholic chronic steatohepatitis, although rare perivenular ballooned hepatocytes are noted on the H&E slide. CK7 immunostain shows moderate to marked ductular reaction, rare cholestatic hepatocytes, and damaged bile ducts. Findings are those of subacute cholestatic hepatitis.Table 1.: Laboratory values from the previous hospitalization, on admission day of this hospitalization, at 1-month of hospitalization, and prior to death.

COLD CASE: MYXEDEMA COMA TRIGGERED BY PNEUMONIA

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Myxedema coma is severe hypothyroidism with associated hypothermia, altered mental status and multi-organ dysfunction. Mortality is over 60% and cases usually occur after a precipitating incident in patients with untreated hypothyroidism. CASE PRESENTATION: The patient is a 78 year old male with a history of congestive heart failure, diabetes, CKD, bronchiectasis, prior adenocarcinoma s/p right middle lobectomy, and untreated hypothyroidism who presented to the hospital with altered mental status. Six months prior, the patient was admitted to the hospital for pseudomonas pneumonia and had an elevated TSH at that time. On presentation, the patient was reported to have had upper respiratory symptoms for three days with generalized weakness. When he arrived to the hospital, he was found to be lethargic (GCS 6), bradycardic (35-55 bpm), hypotensive (82/36), hypoxic (50% on 2L home nasal cannula), and hypothermic (33.5C). He was given multiple doses of atropine with slight improvement in his heart rate and was started on norepinephrine and epinephrine. The patient was started on cefepime and vancomycin for antibiotic coverage after a chest x-ray was concerning for bilateral pneumonia. He was subsequently intubated for respiratory failure and altered mental status. Upon admission to the intensive care unit, the patient's condition remained unchanged despite appropriate interventions. A TSH was ordered and returned at 94.6 mU/L with a T4 of 0.04 ng/dl. He was given 300mcg of levothyroxine and 100mg of hydrocortisone IV. The patient was weaned off of pressors that day and transferred to the floor two days later. Both medications were continued during his hospital stay. Unfortunately, the patient ended up developing end stage renal disease that hospitalization and subsequently passed away while on hospice. DISCUSSION: This case offers a classic presentation of myxedema coma. In this case, the patient had known hypothyroidism but had gone untreated for months. He presented lethargic, hypotensive, hypoxic, bradycardic, and edematous. He was refractory to treatment and rapidly improved once levothyroxine was administered. The mortality for myxedema though is quite high and this patient unfortunately did not survive long term. Typical dosing of T4 should be 4mcg/kg IV (100-400mcg) and continued at 100mcg daily, which was done in this case. T3 can also be administered at 5-20mcg IV followed by 2.5-10mcg q8h, but was not done in this case. Steroids were given for this patient and are used for associated adrenal insufficiency. Typical dosing of hydrocortisone is 100mg q8h IV, but dexamethasone can be given as well. CONCLUSIONS: Myxedema coma is a rare but severe complication from hypothyroidism. An intensivist should remain vigilant about patients with hypothyroidism that present critically ill with symptoms described in this case. Early recognition and treatment is key to saving these patient's lives. REFERENCE #1: Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751. doi:10.1089/thy.2014.0028 REFERENCE #2: Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi K, Tanaka Y. Clinical characteristics and outcomes of myxedema coma: Analysis of a national inpatient database in Japan. J Epidemiol. 2017;27(3):117-122. doi:10.1016/j.je.2016.04.002 REFERENCE #3: Kim JJ, Kim EY. Myxedema coma precipitated by diabetic ketoacidosis after total thyroidectomy: a case report. J Med Case Rep. 2019;13(1):50. Published 2019 Mar 4. doi:10.1186/s13256-019-1992-0 DISCLOSURES: No relevant relationships by Kyle Gronbeck, source=Web Response

PSEUDOANEURYSM OF THE ASCENDING THORACIC AORTA AS A COMPLICATION OF BILATERAL LUNG TRANSPLANT AND THE RISK OF UNDERGOING A NEW CARDIOTHORACIC SURGERY

TOPIC: Transplantation TYPE: Fellow Case Reports INTRODUCTION: Lung transplantation is an effective option for those with advanced lung disease. Acute or chronic graft failure may lead to significant morbidity and mortality. Lung retransplantation is an alternative for patients that develop allograft dysfunction. Preoperative investigation must consider complications from previous cardiothoracic procedures that may impose additional risk. We herein reported on a previously undiagnosed pseudoaneurysm of the thoracic ascending aorta (PTA) successfully treated during a bilateral lung retransplantation. CASE PRESENTATION: Patient is a 24-year-old female with history of bilateral lung transplant due to cystic fibrosis with pulmonary manifestation. She was admitted for bilateral retransplantation after progressive decline in lung function. Initial decompensation consisted of acute respiratory failure with hypoxemia secondary to Pseudomonas pneumonia, consistent with A4 pulmonary allograft rejection. She rapidly progressed to other episodes of respiratory failure, infection, dyspnea on minimal exertion, rest tachycardia, and significant decline in spirometry consistent with Bronchiolitis Obliterans Syndrome. After general anesthesia, upon intraoperative Transesophageal echocardiography, the anesthesiologist detected a previously undiagnosed PTA on the anterior surface. A redo bilateral sequential lung transplantation with PTA repair was performed under cardiopulmonary bypass (CPB) with transverse sternotomy and cannulation of right common femoral artery and vein. With the heart decompressed, the PTA, which was 2x1.5x2cm and located at the previous cannulation site, was dissected from the surrounding adhesions. The PTA was resected and repaired by partial clamping of the aorta, followed by an uneventful bilateral lung transplant. Pathology reports of the resected PTA showed fibroadipose and benign thymic tissues. Cultures were negative. The patient had an uncomplicated post-operative course and was discharged after 19 days. DISCUSSION: This is the first report of PTA as a complication of lung transplant. Postoperative PTA is rare and has been described only in cardiac procedures. It usually occurs in previous suture lines and in immunocompromised patients such as transplant recipients it is commonly related to infection in these endothelial damaged sites. It is crucial to be aware that they can be asymptomatic or misdiagnosed due to the primary clinical conditions such as lung rejection or multiple infections in the present case. In hindsight, the PTA was present in the patient's previous chest CTs and would have been easily identified if the arterial phase was performed. CONCLUSIONS: It is imperative that the multidisciplinary team involved in the care of patients undergoing lung retransplantation is vigilant about the possibility of PTA. Preoperative diagnosis can be lifesaving by avoiding rupture and exsanguination in a new cardiothoracic procedure REFERENCE #1: Glanville AR, Verleden GM, Todd JL, Benden C, Calabrese F, Gottlieb J, Hachem RR, Levine D, Meloni F, Palmer SM, Roman A, Sato M, Singer LG, Tokman S, Verleden SE, von der Thüsen J, Vos R, Snell G. Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019 May;38(5):483-492. REFERENCE #2: Behzadnia N, Ahmadi ZH, Mandegar MH, Salehi F, Sharif-Kashani B, Pourabdollah M, Ansari-Aval Z, Kianfar AA, Mirhosseini SM, Eiji M. Asymptomatic mycotic aneurysm of ascending aorta after heart transplantation: a case report. Transplant Proc. 2015 Jan-Feb;47(1):213-6. REFERENCE #3: Sullivan KL, Steiner RM, Smullens SN, Griska L, Meister SG. Pseudoaneurysm of the ascending aorta following cardiac surgery. Chest. 1988 Jan;93(1):138-43. DISCLOSURES: No relevant relationships by Thais Peclat, source=Web Response No relevant relationships by Si Pham, source=Web Response No relevant relationships by Eduardo Rodrigues, source=Web Response

Identification of unique microRNA expression patterns in bone marrow hematopoietic stem and progenitor cells after hemorrhagic shock and multiple injuries in young and old adult mice.

After severe trauma, the older host experiences more dysfunctional hematopoiesis of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs), and dysfunctional differentiation of circulating myeloid cells into effective innate immune cells. Our main objective was to compare BM HSPC microRNA (miR) responses of old and young mice in a clinically relevant model of severe trauma and shock. C57BL/6 adult male mice aged 8 to 12 weeks (young) and 18 to 24 months (old) underwent multiple injuries and hemorrhagic shock (polytrauma [PT]) that engenders the equivalent of major trauma (Injury Severity Score, >15). Pseudomonas pneumonia (PNA) was induced in some young and old adult mice 24 hours after PT. MicroRNA expression patterns were determined from lineage-negative enriched BM HSPCs isolated from PT and PT-PNA mice at 24 and 48 hours postinjury, respectively. Genome-wide expression and pathway analyses were also performed on bronchoalveolar lavage (BAL) leukocytes from both mouse cohorts. MicroRNA expression significantly differed among all experimental conditions (p < 0.05), except for old-naive versus old-injured (PT or PT-PNA) mice, suggesting an inability of old mice to mount a robust early miR response to severe shock and injury. In addition, young adult mice had significantly more leukocytes obtained from their BAL, and there were greater numbers of polymorphonuclear cells compared with old mice (59.8% vs. 2.2%, p = 0.0069). Despite increased gene expression changes, BAL leukocytes from old mice demonstrated a more dysfunctional transcriptomic response to PT-PNA than young adult murine BAL leukocytes, as reflected in predicted upstream functional pathway analysis. The miR expression pattern in BM HSPCs after PT (+/-PNA) is dissimilar in old versus young adult mice. In the acute postinjury phase, old adult mice are unable to mount a robust miR HSPC response. Hematopoietic stem and progenitor cell miR expression in old PT mice reflects a diminished functional status and a blunted capacity for terminal differentiation of myeloid cells.

Long-term follow-up results of a multicenter first-in-human study of the dual BCMA/CD19 Targeted FasT CAR-T GC012F for patients with relapsed/refractory multiple myeloma.

8014 Background: The dual CAR-T GC012F developed on the novel FasT CAR-T platform targeting B cell maturation antigen (BCMA), and CD19 was designed to improve depth of response and overall efficacy for CAR-T as therapy for Multiple Myeloma. Here, we present updated data for study (NCT04236011; NCT04182581) including additional pts treated. Methods: From October 2019 to July 2020, 19 heavily pretreated Relapsed/Refractory Multiple Myeloma (RRMM) pts (age 27-71) with a median of 5 prior lines (range 2-9) received a single infusion of GC012F. 94.7% (18/19) were high risk (HR- defined by mSMART), 5 pts had extramedullary disease, 1 pts presented with plasma cell leukemia, and 15/19 were refractory to last therapy. 4/19 pts had received prior anti- CD38, 18/19 pts prior IMiD. 18/19 pts were refractory to PI, 17 pts to IMiD, 3 pts being primary refractory. After lymphodepletion over 2-3 days (30 mg/m2/d, 300mg/ m2/d Flu/Cy) CAR-T cells were administered as single infusion at 3 dose levels: 1x105/kg (DL1) n=1, 2x105/kg (DL2) n=9 and 3x105/kg (DL3) n=9. Results: As of Jan 12, 2021 cut-off, 19 pts were evaluated for response. Overall response rate (ORR) was 94.7% - all responses VGPR or better (94.7% - 16/18 sCR, 2/18 VGPR) with all pts MRD- by flow cytometry (10-4-10-6) - earliest response d 28 post infusion. 100% of pts achieved a reduction of paraprotein, 18/19 a 100% reduction. Best response was MRD- sCR in 16/19 patients (84.2%). In DL3 (n=9) 4 additional pts were response evaluable for 6 mth follow-up: 100% (9/9) of pts achieved MRD-sCR as best response, 87.5% (7/8) of response evaluable pts maintained MRD-sCR at landmark analysis of 6 mths. At data cut off, the median time to follow up was 13.8 mths (6.1-16.4) – median duration of response not yet reached. Cytokine Release Syndrome (CRS) and ICANs were graded by ASBMT criteria: grade 1-2 n=16 (84.2%), grade 3 n=2 (10.5%). Median duration of CRS was 4 d (1-8 d). No grade 4/5 CRS or ICANS were observed. 2 deaths occurred on study and were assessed as not related to therapy – one reported previously; one patient was diagnosed with pseudomonas pneumonia on Day 52, refused life-saving treatment and passed. CAR-T median Tmax was 10 d (range 8-14d), median peak copy number (Cmax) was 127548 (16,011-374,346) copies /ug DNA with long duration of persistence of up to 60 weeks at time of data cut off. Patients continue to be monitored for safety and efficacy. Conclusions: BCMA-CD19 dual FasT CAR-T GC012F showed early, deep and durable responses with a high ORR (94.7% - VGPR and better) including a high MRD- sCR rate (DL3=100%, n=9) in high risk RRMM pts including those refractory to anti-CD38, PI and IMIDs with a favorable safety profile consistent with previous findings. BCMA-CD19 dual FasT CAR-T GC012F may present a new treatment approach for patients with RRMM including those with high-risk features refractory to standard of care. Clinical trial information: NCT04236011; NCT04182581.

Predisposing Factors of Pseudomonas Pneumonia: A Hospital Based Cross-sectional Study

Introduction: Pseudomonas aeruginosa (P. aeruginosa) is a usual causative organism of both hospital-acquired pneumonia and community-acquired pneumonia. Although, it is less commonly reported in otherwise healthy hosts, most patients have an identifiable risk factor for disease. These risk factors include those with structural lung abnormalities like bronchiectasis and those with a compromised immune system. With the emergence of multidrug resistant strains of P. aeruginosa, the severity of infection and mortality associated with pneumonia has increased drastically. The insight into the risk factors of Pseudomonas pneumomia helps to suspect and treat the condition at the earliest and thereby reduce the mortality as well as the duration of hospital stay. Aim: To determine various risk factors associated with P. aeruginosa pneumonia. Materials and Methods: An observational cross-sectional study was conducted from November 2018 to November 2020 at Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, Inida, after obtaining Institutional Ethics Committee (IEC) approval. A total of 89 patients with diagnosis of Pseudomonas pneumonia, defined as the presence of signs and symptoms of pneumonia along with sputum or tracheal culture positive for P. aeruginosa were enrolled in the study. These patients were thoroughly assessed by clinical history, physical examination and relevant investigations to detect any risk factors like age, diabetes, smoking, Chronic Obstructive Pulmonary Disease (COPD), chronic steroid use and prior hospital admission. Data analysis was done using Statistical Package for Social Sciences (SPSS version 22.0). Categorical variables were compared with the Chi-square test. Results: Out of 89 patients with Pseudomonas pneumonia, 77.5% were above 40 years of age, 37.08% were smokers, 25.84% had COPD, 22.47% had bronchiectasis, 31.46% were diabetic, 15.73% were on long term steroid use and 14.61% had history of prior hospital admission. Conclusion: Age, smoking, structural lung diseases like COPD, bronchiectasis, long term steroid use and prior hospital admission are important risk factors for Pseudomonas pneumonia.

Gut Microbiota Profiles of Treatment-Naïve Adult Acute Myeloid Leukemia Patientswith Neutropenic Fever during Intensive Chemotherapy

Background : The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse and may play a role in clinical decisions regarding antimicrobial de-escalation with predictive complications. However, there are few reports of microbiota alteration of adult acute myeloid leukemia (AML) patients. Methods : Stool samples of each treatment-naïve AML patient were collected the day before the initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. Results : Ten AML patients (4 men and 6 women) were included with a median age of 39 years (range: 19-49). Twenty-four stool samples were collected and assigned into three groups: (1) pretreatment (n = 10); (2) first date of febrile neutropenia (n=9); and (3) first date of bone marrow recovery (n=5). All of patients developed febrile neutropenia; three patients had detectable infectious organisms and all of these cases had invasive pulmonary aspergillosis with two being co-infected with Pseudomonas pneumonia and Escherichia coli septicemia. Median absolute neutrophil count was 2.85 x 109/L (range: 1.42-7.67 x 109/L), 0.04 x 109/L (range: 0.01-0.43 x 109/L) and 3.65 x 109/L (range: 2.09-5.78 x 109/L) at pretreatment, first date of febrile neutropenia and first date of bone marrow recovery, respectively. At the phylum level, Firmicutes dominated over the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. At the genus level, Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference of 20.2, [95%CI (5.9, 34.6)]; P &amp;lt;0.01) whileBacteroides and Escherichia notably declined during the same period (mean difference of -11.7, [95%CI (-21.9, -1.4)]; P= 0.027 and -11.6, [95%CI (-22.7, -0.4)]; P = 0.034, respectively). At the operational taxonomic units (OTUs) level, there was a significantly higher level of overall richness in the pretreatment period than in the febrile neutropenic episode (mean OTUs of 203.1 vs. 131.7; P = 0.012). Both of the diversity indexes of Shannon and Simpson showed a significant decrease in the febrile neutropenic period. Conclusions : Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow. Figure Disclosures No relevant conflicts of interest to declare.

A RARE CASE OF VANISHING BRONCHUS SYNDROME

SESSION TITLE: Medical Student/Resident Procedures Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Airway complications are seen in up to one-third of lung transplant patients, most commonly as airway stenosis.[1] An infrequent and extreme form of this is called Vanishing Bronchus Syndrome (VBS). Herein we highlight the challenge of maintaining airway patency in a patient with recurrent multi-segment VBS complicated by diffuse exophytic granulation tissue formation. CASE PRESENTATION: A 61 year-old woman with end-stage COPD due to A1AT-Deficiency presented to an academic quaternary referral center for a bilateral sequential lung transplantation by clamshell thoracotomy. Early post-infectious complications included methicillin-resistant staphylococcus aureus and pseudomonas pneumonia, and candida empyema. Two months post-transplant she returned with progressive respiratory failure requiring mechanical ventilation. Bronchoscopy revealed severe bilateral anastomotic stenosis and malacia, as well as severe non-anastomotic stenosis in all lobes. The right middle lobe could not be visualized. Airway patency was restored using cryo-recanalization, balloon bronchoplasty, contrast bronchography, and placement of several self-expandable metallic stents. This facilitated successful extubation and discharge. One month later she was readmitted with critical re-stenosis of several non-anastomotic airways and obstruction of the lobar stents due to granulation tissue formation. Despite serial balloon dilations and multiple stent revisions the patient continued to experience rapid, recurrent, and extensive airway stenosis. She remains ventilator dependent in the intensive care unit. DISCUSSION: We present a unique case of VBS where our patient had diffuse, bilateral lobar and segmental stenosis with recurrent development of granulation tissue requiring repeated mechanical intervention. Few cases in the literature report such extensive non-anastomotic airway involvement as this case. The pathophysiology of VBS is poorly understood and little is reported about the significance of granulation tissue formation in these cases. We know infections predispose patients to numerous complications, including anastomotic stenosis,[2] but less is known about how the post-transplant microbiome predisposes to the development of VBS. CONCLUSIONS: Literature is lacking about how to best manage Vanishing Bronchus Syndrome. Our future considerations include Mitomycin C, brachytherapy, or photodynamic therapy (PDT) but the efficacy of these modalities is uncertain. Reference #1: Moreno P, Alvarez A, Algar FJ, et al. Incidence, management and clinical outcomes of patients with airway complications following lung transplantation. Eur J Cardiothorac Surg. 2008;34(6):1198-1205. Reference #2: Santacruz JF, Mehta AC. Airway complications and management after lung transplantation: ischemia, dehiscence, and stenosis. Proc Am Thorac Soc. 2009;6(1):79-93. DISCLOSURES: No relevant relationships by Elliot Backer, source=Web Response No relevant relationships by Roy Cho, source=Web Response No relevant relationships by Thomas Meehan, source=Web Response No relevant relationships by Daniel VanDerhoef, source=Web Response