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PURPOSE: Approximately 3-15% of COVID-19 patients will require prolonged mechanical ventilation thereby requiring consideration for tracheotomy. Guidelines for tracheotomy in this cohort of patients are therefore required with assessed outcomes of tracheotomies. PATIENTS AND METHODS: A retrospective chart review was performed of COVID-19 patients undergoing tracheotomy. Inclusion criteria were the performance of a tracheotomy in COVID-19 positive patients between March 11 and December 31, 2020. Exclusion criteria were lack of consent, extubation prior to the performance of a tracheotomy, death prior to the performance of the tracheotomy, and COVID-19 patients undergoing tracheotomy who tested negative twice after medical treatment. The primary predictor variable was the performance of a tracheotomy in COVID-19 positive patients and the primary outcome variable was the time to cessation of mechanical ventilation with the institution of supplemental oxygen via trach mask. RESULTS: Seventeen tracheotomies were performed between 4-25 days following intubation (mean = 17 days). Seven patients died between 4 and 16 days (mean = 8.7 days) following tracheotomy and 10 living patients realized cessation of mechanical ventilation from 4 hours to 61 days following tracheotomy (mean = 19.3 days). These patients underwent tracheotomy between 4 and 22 days following intubation (mean = 14 days). The 7 patients who died following tracheotomy underwent the procedure between 7 and 25 days following intubation (mean = 18.2 days). Seven patients underwent tracheotomy on or after 20 days of intubation and 3 survived (43%). Ten patients underwent tracheotomy before 20 days of intubation and 7 patients survived (70%). Significant differences between the mortality groups were detected for age (P = .006), and for P/F ratio at time of consult (P = .047) and the time of tracheotomy (P = .03). CONCLUSIONS: Tracheotomies are safely performed in COVID-19 patients with a standardized protocol. The timing of tracheotomy in COVID-19 patients is based on ventilator parameters, P/F ratio, patient prognosis, patient advanced directives, and family wishes.

Background: Chimeric antigen receptor (CAR)-T cell therapy targeting the CD19 antigen has been effective in treating B-cell acute lymphoblastic leukemia. As CAR-T cells targeting new antigens are being explored for the treatment of other cancers in adults, parallel studies are warranted for pediatric cohorts. We have previously shown the safety and efficacy in adults of CAR-T cells targeting CD30, which is expressed in classical Hodgkin Lymphoma (HL) and in some Non-Hodgkin Lymphoma (NHL). We have therefore sought to study the feasibility and the safety of CD30.CAR-T cells in pediatric patients with relapsed/refractory CD30-expressing HL and Anaplastic Large Cell Lymphoma (ALCL). Design/Methods: Six pediatric patients (ages 9 to 17 years) with CD30+ HL (4) and NHL (2) were enrolled on two trials at the University of North Carolina. One NHL patient with ALK+ ALCL was enrolled on both trials. Two patients, one HL and one NHL, were enrolled on a phase I study and received 2x10 7 CD30.CAR-T cells/m 2 as consolidation for high-risk of relapse after autologous stem cell transplant (ASCT, NCT02663297). Five patients, 3 HL and 2 NHL, were enrolled on a phase Ib/II study and received 1x10 8 CD30.CAR-T cells/m 2, as treatment for relapsed disease, after lymphodepletion with bendamustine and fludarabine (NCT02690545). HL patients had failed multiple lines of therapies (5-6), including 2 with prior pembrolizumab, 2 with prior ASCT, and all 3 with prior brentuximab vedotin (BV) and radiation therapy. The two NHL patients both had ALCL, one was ALK positive and one was ALK negative. Both had been treated with prior BV. The ALK negative patient had been treated with 3 prior lines of therapy and the ALK positive patient had been treated with 6 lines of prior therapy including ASCT and two ALK inhibitors, crizotinib and brigatinib. The brigatinib was stopped 3 weeks prior to starting lymphodepletion. Results: CD30.CAR-T cells were successfully manufactured for all 7 patients and no differences were observed as compared to products manufactured for adults, based on cell number, transduction, potency or immunophenotype. For all patients, infusions were well-tolerated and no neurotoxicity experienced. On the post-ASCT study, 1 patient with HL and 1 with ALCL were treated. All adverse events (AE) were less than grade 4. The patient with HL remains in complete remission (CR) 41 months following therapy, while the patient with ALCL progressed. Five patients with relapsed/refractory disease (3 HL and 2 ALCL) were treated on the post-lymphodepletion study. Most grade 3 or higher AEs were anticipated hematologic toxicity secondary to lymphodepletion. The youngest HL patient on the study developed symptoms consistent with grade 2 cytokine release syndrome (CRS) and a concomitant pneumonia based on imaging, accompanied by a marked inflammatory response based on labs with maximum ferritin 9,920 ng/mL and CRP 150.7 mg/L. He responded to antibacterial agents and two doses of tocilizumab, as well as brief supplemental oxygen by nasal cannula. He did not require vasopressors. One patient with ALK+ ALCL had symptoms compatible with CRS and macrophage activation syndrome (maximum ferritin >100,000 ng/mL and CRP 39.7 mg/L), which were ultimately determined to be secondary to progressive disease, confirmed at autopsy 5 weeks post therapy. The other four patients (3 HL and 1 ALCL) achieved CR and remain in CR 4 to 27 months post CAR-T cell infusion. Of note, 2 of the HL patients chose to come off study while in CR to receive treatment with checkpoint inhibitor therapy. Conclusion: Our studies show that CD30.CAR-T cells are well tolerated in pediatric patients. CRs were observed in all heavily pre-treated and refractory HL patients, highlighting the potential of this strategy. All patients treated on both studies had previously received BV, which suggests CD30.CAR-T cells are effective even post BV progression. We continue to investigate how to better tailor CD30.CAR-T cells in NHL given the need for better therapies in ALCL, which is often aggressive at relapse. One patient with ALK negative ALCL remains in CR while the patient with ALK+ ALCL had rapid relapse. After study initiation, UNC entered into a research collaboration with Tessa Therapeutics. Disclosures Savoldo: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Dotti: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Grover: Tessa: Consultancy; Kite: Other: Advisory Board; Novartis: Consultancy; Genentech: Research Funding; ADC: Other: Advisory Board. Morrison: Vesselon: Consultancy. Riches: Jazz Pharmaceuticals: Other: Payment; ATARA Biotherapeutics: Other: Payment; BioIntelect: Membership on an entity's Board of Directors or advisory committees. Serody: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma.

Moyamoya syndrome occurs in sickle cell disease (SCD) as a secondary complication of large-artery stenosis. Moyamoya increases the risk of stroke, but its optimal management in SCD is not established. Encephaloduroarteriosynangiosis (EDAS) is a neurosurgical revascularization procedure for moyamoya whose use has been reported in SCD patients. We report the outcomes of 11 patients with SCD systematically evaluated for EDAS by a multidisciplinary team and compare the rate of stroke in patients who received EDAS to those who did not. Moyamoya syndrome was diagnosed by flow abnormalities on magnetic resonance angiography at median age of 8.2 years. Four patients deferred surgery. Seven patients underwent EDAS at median age of 19 years. There were no intraoperative complications, perioperative strokes, or deaths. Transient postoperative complications occurred in six cases (86%). On follow-up, three patients (43%) had no evidence of flow in their EDAS grafts, and one later developed a hemorrhagic stroke. Five EDAS patients (71%) had radiographically stable vasculopathy. Compared to the four patients who deferred surgery, the incidence of stroke in EDAS group was no different. The optimal use of EDAS in patients with SCD-associated moyamoya syndrome requires further investigation by a prospective, controlled clinical trial.

Mucormycosis is uncommon in patients with chronic granulomatous disease (CGD). We report a 7-year-old boy with X-linked CGD and absent oxidative burst who developed fatal Lichtheimia ramosa infection with fungal thrombosis of the kidneys, spleen and other organs after hematopoietic stem cell transplantation. Lichtheimia infection is rarely reported in patients with CGD and could be related to iatrogenic immunosuppression.

Intro/Objectives Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency defined by its symptoms and CXC chemokine receptor 4 (CXCR4) gene mutation. This leads to myelokathexis in which mature neutrophils cannot exit the bone marrow, causing severe neutropenia. Use of hematopoietic cell transplant (HCT) to correct a primary immunodeficiency is well accepted; yet, due to the rarity of WHIM, data on HCT in this setting are limited. We present a successful matched sibling donor (MSD) bone marrow (BM) transplant in a 6 year old male with WHIM who developed unexpected respiratory complications post HCT. Methods/Results The patient was initially followed for congenital neutropenia and therapy consisted of weekly filgrastim. At age 5 years, he was diagnosed with WHIM by CXCR4 sequencing. Treatment was changed to plerixafor, but he required frequent dose escalation. HLA typing revealed his brother was an 8/8 allele match. Patient's history was significant for asthma, but no recent flares. He was unable to perform pulmonary function tests due to age. At 6 years old he received an MSD BM graft after myeloablative conditioning with busulfan, cyclophosphamide, and ATG. GVHD prophylaxis consisted of cyclosporine and short course methotrexate. Myeloid engraftment ocurred on day +20 with >95% donor chimerism after day +55. On days +76, +87, and +104, he was admitted for respiratory distress. Infectious evaluations only revealed EBV PCR in a BAL specimen obtained during the second admission. For this he received four weeks of rituximab. On each admission, he improved quickly with albuterol and systemic steroids, but symptoms recurred soon after returning home. During his third admission it was found that he was exposed to an African Grey Parrot in his home. Due to the close association of his symptoms with returning home, and his exquisite response to steroids, Pulmonology consultation lead to a diagnosis of hypersensitivity pneumonitis. The bird was relocated, the home extensively cleaned, and while staying in temporary housing from day +110 to +275 the patient did not relapse. After returning home the patient had no further respiratory events. The bird was allowed to return on day +367. Patient has remained well on inhaled corticosteroids as of day +473. Conclusion Hypersensitivity pneumonitis is a type IV hypersensitivity reaction that can be linked to bird exposure. It is T cell mediated and IgE independent. Acquisition of IgE mediated allergies has been reported after HCT, but there are no reports of new type IV hypersensitivity development. Neither patient nor donor had previous hypersensitivity to the bird. Due to the transient nature of the pneumonitis in our patient, this likely represents an unusual case of abnormal T cell maturation post HCT. This case also emphasizes the importance of environmental exposures in post HCT respiratory symptoms.

Sickle cell disease (SCD) describes a family of molecular disorders in which patients inherit the hemoglobin S (HbS) mutation and a second beta-globin mutation that impairs normal hemoglobin production and causes clinical sickling. People with SCD have a dramatically increased risk of pain, lung disease, renal failure, bone necrosis, sepsis, stroke, and early death.

Return oriented programming (ROP) is a form of code-reuse attack employed in many modern exploitation attacks. Current defenses such as address-space randomization, structured exception handling, and memory space permissions have thus far proven only speed bumps for attackers. Utilizing new hardware capabilities in the upcoming Intel Haswell platform, we have leveraged a hardware-based approach to protect against a ROP attack. With our process, an application s and associated libraries code segments in memory are marked non-executable and the page faults created when switching execution between pages are utilized as events during which invoke the decision engine. The decision engine is designed to examine the program s actions which caused it to attempt to pass a page boundary and report to an enforcement component which ensures the program s execution terminators. Our proof of concept decision engine examines returns that cross page boundaries and ensures that the target of a return is preceded by a call operation. Should a page transition be approved by a decision engine, the requested memory is marked executable. Otherwise, the enforcement engine will set the program counter register to zero, causing the application to crash.