This cohort study assesses the potential use of red blood cell distribution width for risk stratification of patients with coronavirus disease 2019.

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Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) 2 resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date. Objectives: To validate the use of forced oscillation R5 2 R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma. Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 2 R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137). Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 2 R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 2 R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%. Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 2 R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Multiple‐breath washout (MBW) is a pulmonary function test (PFT) that is used to infer lung function through measurement of ventilation heterogeneity (VH). However, the body position that a test is taken in may also influence VH, due to the “Slinky” effect of gravity on the lungs. In healthy subjects this has minimal effect, but in unhealthy groups, PFT outputs have been seen to change drastically with body position. In this study, we used a combined computational and clinical approach to better understand the response of outputs from the MBW to body position. A patient‐specific model of the MBW was developed, then validated against clinically measured washout data, as well as broader results in the literature. This model was then used to compare changes in MBW outputs with respect to body position, showing that output changes sensitively predict regional airway size differences between lobes. We then highlight cases in which body position effects may bias MBW outputs, leading to elevated or masked responses to bronchoconstriction. We close by placing this result in context with broader clinical practice, and showing how it can help improve interpretation of test outputs.

Many lung diseases lead to an increase in ventilation heterogeneity (VH). Two clinical practices for the measurement of patient VH are in vivo imaging, and the inert gas multiple breath washout (MBW). In this study computational modelling was used to compare the responses of MBW indices LCI and s and MRI measured global and local ventilation indices, σ and σ, to constriction of airways in the conducting zone of the lungs. The simulations show that s, LCI and σ behave quite similarly to each other, all being sensitive to increases in the severity of constriction, while exhibiting little sensitivity to the depth at which constriction occurs. In contrast, the local MRI index σ shows strong sensitivity to depth of constriction, but lowered sensitivity to constriction severity. We finish with an analysis of the sensitivity of MRI indices to grid sizes, showing that results should be interpreted with reference to the image resolution. Overall we conclude that the application of both local and global VH measures may help to classify different types of bronchoconstriction.

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate haematopoiesis is unclear. Here we show that B lymphocytes were an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system which reduced hematopoiesis. Single cell RNA sequencing identified 9 clusters of cells that expressed the acetylcholine receptor Chrna7 in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells. Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in LepR + stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and patients with cardiovascular disease.

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

BackgroundCoronavirus disease 2019 is an acute respiratory illness with a high rate of hospitalization and mortality. Prognostic biomarkers are urgently needed. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. MethodsWe retrospectively studied the relationship between RDW and COVID-19 mortality risk for 1198 adult patients diagnosed with SARS-CoV-2 at 4 Partners ResultsElevated RDW (> 14.5%) was associated with increased mortality in patients of all ages with a risk ratio of 2.5 (95% CI, 2.3 -2.8). Stratified by age, the risk ratio was 6.2 (4.4 -7.9, N = 312) < 50 years, 3.2 (2.5 -4.1, N = 230) 50-60, 2.3 (1.6 -3.1, N = 236) 60-70, 1.2 (0.7 -1.8, N = 203) 70-80, and 1.9 (1.5 -2.3, N = 216) > 80 years. RDW was significantly associated with mortality in Cox proportional hazards models adjusted for age, D-Dimer, absolute lymphocyte count, and common comorbidities (p < 1e-4 for RDW in all cases). Patients whose RDW increased during admission had a ~3-fold elevation in mortality risk compared to those whose RDW did not change. ConclusionsElevated RDW at diagnosis and an increase in RDW during admission are both associated with increased mortality risk for adult COVID-19 patients at a large academic medical center network.