Activation of CD8+ T Cells in Chronic Obstructive Pulmonary Disease Lung.

Rationale: Despite the importance of inflammation in chronic obstructive pulmonary disease (COPD), the immune cell landscape in the lung tissue of patients with mild-moderate disease has not been well characterized at the single-cell and molecular level. Objectives: To define the immune cell landscape in lung tissue from patients with mild-moderate COPD at single-cell resolution. Methods: We performed single-cell transcriptomic, proteomic, and T-cell receptor repertoire analyses on lung tissue from patients with mild-moderate COPD (n = 5, Global Initiative for Chronic Obstructive Lung Disease I or II), emphysema without airflow obstruction (n = 5), end-stage COPD (n = 2), control (n = 6), or donors (n = 4). We validated in an independent patient cohort (N = 929) and integrated with the Hhip+/- murine model of COPD. Measurements and Main Results: Mild-moderate COPD lungs have increased abundance of two CD8+ T cell subpopulations: cytotoxic KLRG1+TIGIT+CX3CR1+ TEMRA (T effector memory CD45RA+) cells, and DNAM-1+CCR5+ T resident memory (TRM) cells. These CD8+ T cells interact with myeloid and alveolar type II cells via IFNG and have hyperexpanded T-cell receptor clonotypes. In an independent cohort, the CD8+KLRG1+ TEMRA cells are increased in mild-moderate COPD lung compared with control or end-stage COPD lung. Human CD8+KLRG1+ TEMRA cells are similar to CD8+ T cells driving inflammation in an aging-related murine model of COPD. Conclusions: CD8+ TEMRA cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease. Further study of these CD8+ T cells may have therapeutic implications for preventing severe COPD.

Bebtelovimab-Induced Bradycardia Leading to Cardiac Arrest.

Bebtelovimab is a monoclonal antibody used to prevent progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Complications of SARS-CoV-2 infection can include cardiac effects including sinus bradycardia. CASE SUMMARY: We describe the case of an 86-year-old male infected with SARS-CoV-2 who experienced bradycardia with cardiac arrest immediately following infusion of Bebtelovimab with return of spontaneous circulation obtained following 1 minute of chest compressions and administration of atropine. His bradycardia resolved, and he was extubated on hospital day 1, found to be neurologically intact, and discharged on hospital day 9. CONCLUSIONS: Due to the time course of the patient's symptomatology, we attribute the bradycardic arrest to the Bebtelovimab infusion. This case illustrates the need for further research into the etiology of bradycardia due to SARS-CoV-2 infection and to examine potential links to monoclonal antibody infusion. It also serves as important caution to maintain close cardiac monitoring while administering monoclonal antibodies for SARS-CoV-2.

Empirical Assessment of U.S. Coronavirus Disease 2019 Crisis Standards of Care Guidelines.

To establish the feasibility of empirically testing crisis standards of care guidelines. DESIGN: Retrospective single-center study. SETTING: ICUs at a large academic medical center in the United States. SUBJECTS: Adult, critically ill patients admitted to ICU, with 27 patients admitted for acute respiratory failure due to coronavirus disease 2019 and 37 patients admitted for diagnoses other than coronavirus disease 2019. INTERVENTIONS: Review of electronic health record. MEASUREMENTS AND MAIN RESULTS: Many U.S. states released crisis standards of care guidelines with algorithms to allocate scarce healthcare resources during the coronavirus disease 2019 pandemic. We compared state guidelines that represent different approaches to incorporating disease severity and comorbidities: New York, Maryland, Pennsylvania, and Colorado. Following each algorithm, we calculated priority scores at the time of ICU admission for a cohort of patients with primary diagnoses of coronavirus disease 2019 and diseases other than coronavirus disease 2019 (n = 64). We assessed discrimination of 28-day mortality by area under the receiver operating characteristic curve. We simulated real-time decision-making by applying the triage algorithms to groups of two, five, or 10 patients. For prediction of 28-day mortality by priority scores, area under the receiver operating characteristic curve was 0.56, 0.49, 0.53, 0.66, and 0.69 for New York, Maryland, Pennsylvania, Colorado, and raw Sequential Organ Failure Assessment score algorithms, respectively. For groups of five patients, the percentage of decisions made without deferring to a lottery were 1%, 57%, 80%, 88%, and 95% for New York, Maryland, Pennsylvania, Colorado, and raw Sequential Organ Failure Assessment score algorithms, respectively. The percentage of decisions made without lottery was higher in the subcohort without coronavirus disease 2019, compared with the subcohort with coronavirus disease 2019. CONCLUSIONS: Inclusion of comorbidities does not consistently improve an algorithm's performance in predicting 28-day mortality. Crisis standards of care algorithms result in a substantial percentage of tied priority scores. Crisis standards of care algorithms operate differently in cohorts with and without coronavirus disease 2019. This proof-of-principle study demonstrates the feasibility and importance of empirical testing of crisis standards of care guidelines to understand whether they meet their goals.

Protocol for assessing and predicting acute respiratory decline in hospitalized patients.

This protocol aids both new and experienced researchers in designing retrospective clinical and translational studies of acute respiratory decline in hospitalized patients. This protocol addresses (1) the basics of respiratory failure and electronic health record research, (2) defining patient cohorts as "mild, progressive, or severe" instead of "ICU versus non-ICU", (3) adapting physiological indices, and (4) using biomarker trends. We apply these approaches to inflammatory biomarkers in COVID-19, but this protocol can be applied to any progressive respiratory failure study. For complete details on the use and execution of this protocol, please refer to Mueller et al. (2020).

Inflammatory Biomarker Trends Predict Respiratory Decline in COVID-19 Patients.

In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization.