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2.
Cytotherapy ; 23(5):S55, 2021.
Article in English | EMBASE | ID: covidwho-1368862

ABSTRACT

Background & Aim: The Cellular Immuno-Therapy for COVID-19 related ARDS (CIRCA-19) was a phase 1, single site, dose escalation trial using a 3+3+3 design to determine the safety and maximum feasible tolerated dose of intravenously delivered, freshly cultured UC-MSCs. Nine patients, each receiving repeated unit doses of UC-MSCs over 3 consecutive days, were enrolled into 3 dose panels: Panel 1: 25×106 cells/dose (cumulative dose: 75×106 MSCs);Panel 2: 50×106 cells/dose (cumulative dose: 150×106 MSCs);Panel 3: up to 90×106 cells/dose (cumulative dose: 270×106 MSCs). Methods, Results & Conclusion: UC-MSCs were isolated from cords of healthy term pregnancies delivered by C-section. Cords were mechanically and enzymatically digested, and UC-MSCs were propagated in xeno-free conditions for 2 weeks prior to cryopreservation in a cord specific cell bank. One fully validated cell bank was used in CIRCA-19 that was free of adventitious agents (HBV, HCV, HSV1/2, Parvo B19 and Retroviruses), had high viability (>95%) and MSC identity with positive expression (>95%) of CD73, CD90 and CD105 and negative expression (<5%) of CD14, CD19, CD34, CD45 and HLA-DR. UC-MSCs also demonstrated high proliferative capacity (EdU+ >45%;DBT = 22h) and enhanced IDO expression (ΔΔCq?>18) when treated with IFN-γ. For the final product, UC-MSCs were thawed, plated and cultured for 24 to 120 h before harvesting to produce a batch of the final drug product formulated as 2.5×106 fresh UC-MSCs/mL suspended in PlasmaLyte A containing 5% Human Albumin, to be infused within 48h. Batches were tested for viability, endotoxin level, ACE-2 expression, tissue factor activity, sterility and mycoplasma. Sixteen batches of UC-MSCs were produced for a total of 41 cell doses (16 doses of 25M;13 doses of 50M;12 doses of 90M cells each). Twenty-seven of the 41 doses (9 doses of 25M, 50M and 90M cells each) were used to treat trial participants. The remaining doses were used for stability studies. All drug products had high viability (> 95%), endotoxin levels of <0.2 EU/mL and tested negative for mycoplasma and bacterial contaminants. All UC-MSC batches were negative for ACE-2 expression (Cq?>35;GAPHD Cq: 15±2;no detectable levels by western blotting) and had tissue factor activity levels between 250-310pM. UC-MSC drug product was stable for up to 96h (>80% viability) and had?>90% viability up to 48h in all 3 dose panels. This study demonstrates the feasibility of manufacture and delivery of a multi-dose fresh cell product in an emergent ICU setting.

5.
Journal of the American Society of Nephrology ; 31:289, 2020.
Article in English | EMBASE | ID: covidwho-984380

ABSTRACT

Introduction: Severe COVID-19 infection can cause 'cytokine storm' and endorgan dysfunction. OXIRIS, a blood-purification filter, was recently approved by the FDA under emergency use authorization for this indication due to its ability to remove cytokines and endotoxin through its AN-69ST membrane. We describe our experience with the first two cases treated at our institution. Case Description: Case 1: 58 year-old female patient with a baseline creatinine of 0.8 mg/dL & history of hemoglobin SC disease was admitted with respiratory failure due to COVID-19 infection. She deteriorated on hospital day (HD) 6 and was intubated. She received broad-spectrum antibiotics and convalescent plasma. On HD 15 she had increasing vasopressor requirement, anuric AKI and was started on continuous renal replacement therapy (CRRT). Due to worsening clinical status on HD18 she was started on the OXIRIS hemofilter through the CRRT circuit for 48 hours. Oxygenation improved and there was some improvement in inflammatory markers (IM) (table 1), however, the family withdrew care on HD 20. Case 2: 29-year-old male with no prior past medical history apart from morbid obesity presented with fever and dry cough in the setting of recent COVID-19 exposure. He was found to be COVID-19 positive and rapidly deteriorated with resultant intubation on HD4. He received hydroxychloroquine, doxycycline, remdesivir and convalescent plasma. OXIRIS hemoperfusion was initiated on HD8 due to worsening hypoxia despite high FiO2. Oxygenation improved by HD10 (table 1) and he was successfully extubated on HD16. Discussion: We present our first 2 cases using the OXIRIS hemofilter. We treated the patients for 48 hours with a scheduled filter exchange at 24 hours. We used a blood flow of 250 ml/min and dialysate flow of 25 ml/kg/hour with either systemic heparin or regional citrate anticoagulation along with 1L/hr of pre-filter saline. For hemoperfusion we used the same parameters without dialysate. We observed rapid improvements in oxygenation (Figure 1). The findings are hypothesis generating though more data is needed to determine optimal timing and efficacy of this filter.

6.
Journal of the American Society of Nephrology ; 31:306, 2020.
Article in English | EMBASE | ID: covidwho-984274

ABSTRACT

Background: During the initial phase of the SARS CoV-2 pandemic our institution had high rates of acute kidney injury (AKI) requiring renal replacement therapy (RRT). Nephrocheck (NC), a renal biomarker, indicating renal stress was the basis of a continuous quality improvement (CQI) program to identify patients at risk for AKI & RRT. Methods: Patients admitted from 4/17-5/15/2020 were all tested for SARS CoV-2. All positive patients ≥ 18 years old & with a creatinine <2.0 mg were tested with NC. Values ≥ 0.7 led to nephrology consults & utilization of a renal-protective strategy including monitoring volume status, scrutinizing nephrotoxic medications & urine studies. A 'Plan-Do-Study-Act' approach was used to increase utilization of NC and the resulting protocol for positive results. Intervention was biphasic with a follow up maintenance phase, each lasting 10 days. Phase 1 was adding NC to the SARS CoV2 admission order set & Phase 2 was educating hospitalist providers about using and interpreting NC to increase appropriate nephrology consults. Education was reinforced with protocol cards & reminders via encrypted text services. Additionally, intervention team members reviewed charts daily & reminded providers in real time. Results: In Phase 1, 58% of the SARS CoV-2 positive patients had a NC but only 48% of NC positive patients had a renal consult. In Phase 2, 79% of SARS CoV-2 positive patients had a NC with 80% of positive patients getting a renal consult. In the maintenance phase, 67% of SARS CoV-2 positive patients had NC with 59% of NC positive patients getting a renal consult. Conclusions: During our CQI project, efforts to mitigate severe AKI by using a biomarker-based alert for nephrology consultation saw the number of SARS CoV2 positive patients screened with NC & the number of positive NC patients seen by nephrologists rise significantly. Barriers to implementation included the weekly turn-over of house staff & a reliable alert system to ensure adequate screening. The multidisciplinary team reviewing charts and reminding hospitalists of the protocol also helped significantly but was difficult to sustain.

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