Incidence of barotrauma in patients with COVID-19 (alpha- and beta-predominant period) requiring mechanical ventilation: Single-center retrospective study

Objective: We sought to determine predictors, incidence, and interventions required for patients who developed barotrauma. Pneumothorax, subcutaneous emphysema, and pneumomediastinum have all been reported as complications related to COVID-19-positive patients requiring invasive mechanical ventilation. Methods: In this retrospective study, clinical and imaging data from COVID-19 patients were collected and reviewed by two independent intensivists between January 4, 2020 and January 10, 2020. Data were used to identify COVID-19-positive patients requiring invasive mechanical ventilation and the incidence of barotrauma. Two separate cohorts were created as non-injured (no barotrauma) and injured (barotrauma present). We then sought to identify the risk factors for barotrauma in the non-injured cohort on Days 0, 7, 10, and 14 after intubation and day of injury in the injured cohort. Results: Of the 264 patients with COVID-19, 55.8% were African American. The non-injured group was older (60 ± 15 versus 49 ± 16, p = 0.006), with male predominance in the injured group versus non-injured group (75% versus 55%). A total of 16 (6.5%) patients developed one or more complications of barotrauma, defined as subcutaneous emphysema, pneumothorax, or pneumomediastinum. Length of stay was longer for the injured group versus non-injured group (47 versus 25 days). Plateau pressure (p = 0.024), fraction of inspired oxygen (p < 0.001), and driving pressure (p = 0.001) were statistically significant in injured cohort. Mortality rate in non-injured versus injured was 49.4% versus 69%. Using random effect model, fraction of inspired oxygen (p = 0.003) and mean airway pressure (p = 0.010) were significant at the time of injury. When comparing alive versus deceased in the injured cohort, thoracostomy placement in alive versus deceased was 80% versus 54.5%. Conclusion: COVID acute respiratory distress syndrome patients requiring invasive mechanical ventilation had a higher rate of barotrauma and were younger than those who did not develop barotrauma. Possible interventions to be considered to decrease barotrauma are decreased driving pressure goal and universal use of esophageal balloon manometry.

Incidence of barotrauma in patients with COVID-19 (alpha- and beta-predominant period) requiring mechanical ventilation: Single-center retrospective study.

Objective: We sought to determine predictors, incidence, and interventions required for patients who developed barotrauma. Pneumothorax, subcutaneous emphysema, and pneumomediastinum have all been reported as complications related to COVID-19-positive patients requiring invasive mechanical ventilation. Methods: In this retrospective study, clinical and imaging data from COVID-19 patients were collected and reviewed by two independent intensivists between January 4, 2020 and January 10, 2020. Data were used to identify COVID-19-positive patients requiring invasive mechanical ventilation and the incidence of barotrauma. Two separate cohorts were created as non-injured (no barotrauma) and injured (barotrauma present). We then sought to identify the risk factors for barotrauma in the non-injured cohort on Days 0, 7, 10, and 14 after intubation and day of injury in the injured cohort. Results: Of the 264 patients with COVID-19, 55.8% were African American. The non-injured group was older (60 ± 15 versus 49 ± 16, p = 0.006), with male predominance in the injured group versus non-injured group (75% versus 55%). A total of 16 (6.5%) patients developed one or more complications of barotrauma, defined as subcutaneous emphysema, pneumothorax, or pneumomediastinum. Length of stay was longer for the injured group versus non-injured group (47 versus 25 days). Plateau pressure (p = 0.024), fraction of inspired oxygen (p < 0.001), and driving pressure (p = 0.001) were statistically significant in injured cohort. Mortality rate in non-injured versus injured was 49.4% versus 69%. Using random effect model, fraction of inspired oxygen (p = 0.003) and mean airway pressure (p = 0.010) were significant at the time of injury. When comparing alive versus deceased in the injured cohort, thoracostomy placement in alive versus deceased was 80% versus 54.5%. Conclusion: COVID acute respiratory distress syndrome patients requiring invasive mechanical ventilation had a higher rate of barotrauma and were younger than those who did not develop barotrauma. Possible interventions to be considered to decrease barotrauma are decreased driving pressure goal and universal use of esophageal balloon manometry.

RAMIHM generates fully human monoclonal antibodies by rapid mRNA immunization of humanized mice and BCR-seq.

As a clinical vaccine, lipid nanoparticle (LNP) mRNA has demonstrated potent and broad antibody responses, leading to speculation about its potential for antibody discovery. Here, we developed RAMIHM, a highly efficient strategy for developing fully human monoclonal antibodies that employs rapid mRNA immunization of humanized mice followed by single B cell sequencing (scBCR-seq). We immunized humanized transgenic mice with RAMIHM and generated 15 top-ranked clones from peripheral blood, plasma B, and memory B cell populations, demonstrating a high rate of antigen-specificity (93.3%). Two Omicron-specific neutralizing antibodies with high potency and one broad-spectrum neutralizing antibody were discovered. Furthermore, we extended the application of RAMIHM to cancer immunotherapy targets, including a single transmembrane protein CD22 and a multi-transmembrane G protein-coupled receptor target, GPRC5D, which is difficult for traditional protein immunization methods. RAMIHM-scBCR-seq is a broadly applicable platform for the rapid and efficient development of fully human monoclonal antibodies against an assortment of targets.

Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2.

The Omicron variant of SARS-CoV-2 recently swept the globe and showed high level of immune evasion. Here, we generate an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and test its activity in animals, both alone and as a heterologous booster to WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicits strong antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA show a > 40-fold reduction in neutralization potency against Omicron than WT two weeks post boost, which further reduce to background level after 3 months. The WT or Omicron LNP-mRNA booster increases the waning antibody response of WT LNP-mRNA vaccinated mice against Omicron by 40 fold at two weeks post injection. Interestingly, the heterologous Omicron booster elicits neutralizing titers 10-20 fold higher than the homologous WT booster against Omicron variant, with comparable titers against Delta variant. All three types of vaccination, including Omicron alone, WT booster and Omicron booster, elicit broad binding antibody responses against SARS-CoV-2 WA-1, Beta, Delta variants and SARS-CoV. These data provide direct assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to WT mRNA vaccine.

Variant-specific vaccination induces systems immune responses and potent in vivo protection against SARS-CoV-2.

Lipid nanoparticle (LNP)-mRNA vaccines offer protection against COVID-19; however, multiple variant lineages caused widespread breakthrough infections. Here, we generate LNP-mRNAs specifically encoding wild-type (WT), B.1.351, and B.1.617 SARS-CoV-2 spikes, and systematically study their immune responses. All three LNP-mRNAs induced potent antibody and T cell responses in animal models; however, differences in neutralization activity have been observed between variants. All three vaccines offer potent protection against in vivo challenges of authentic viruses of WA-1, Beta, and Delta variants. Single-cell transcriptomics of WT- and variant-specific LNP-mRNA-vaccinated animals reveal a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induces a systemic increase of reactive CD8 T cells and altered gene expression programs in B and T lymphocytes. BCR-seq and TCR-seq unveil repertoire diversity and clonal expansions in vaccinated animals. These data provide assessment of efficacy and direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solve several cryo-EM structures at ~3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and reveal distinct epitopes, binding patterns, and conformations. The lead clones also show potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generate and characterize a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.

Effective Use of Angiotensin II in Coronavirus Disease 19-Associated Mixed Shock State: A Case Report.

The rapid spread of Coronavirus Disease 2019 (COVID-19) has sparked a search for effective therapies. The discovery that the virus binds the angiotensin-converting enzyme 2 (ACE2) receptor has led to investigation of the renin-angiotensin system for possible therapeutic targets. We present a case of an elderly woman with multiple comorbidities who developed severe acute respiratory distress syndrome (ARDS), a cardiomyopathy, and vasodilatory shock secondary to COVID-19 and was treated with exogenous angiotensin II. She rapidly demonstrated significant hemodynamic improvement without noted adverse effects. Thus, we propose further investigation into possible benefits of angiotensin II in shock secondary to COVID-19.