Eosinophil Recovery in Hospitalized COVID-19 Patients is Associated with Lower Rates of ICU Admission and In-Hospital Mortality: An Observational Cohort Analysis

Background Admission eosinopenia (<100 cells/μL) is associated with poor clinical outcomes in hospitalized COVID-19 patients. However, the effects of eosinophil recovery (defined as reaching ≥50 eosinophils/μL) during hospitalization on COVID-19 outcomes have been inconsistent. Methods The study included 1,831 patients admitted to UCLA hospitals between February 2020 and February 2021 with PCR-confirmed COVID-19. Using competing risk regression and modeling eosinophil recovery as a time-dependent covariate, we evaluated the longitudinal relationship between eosinophil recovery and in-hospital outcomes including ICU admission, need for mechanical ventilation, and in-hospital mortality. All analyses were adjusted for covariates including age, BMI, tobacco smoke exposure, comorbidities known to be risk factors for COVID-19 mortality, and treatments including dexamethasone and remdesivir. Results Eosinophil recovery was evaluated in patients with <50 eosinophils/μL on admission (n=1282). These patients cumulatively amassed 11,633 hospital patient-days;3,985 of those days qualified as eosinophil recovery events, which were represented by 781 patients achieving at least one instance of eosinophil recovery during hospitalization. Despite no significant difference in the rate of mechanical ventilation, eosinophil recoverers had significantly lower rates of in-hospital mortality (aHR: 0.44 [0.29, 0.65], P=0.001) and ICU admission (aHR: 0.25 [0.11, 0.61], P=0.002). Conclusion Trending eosinophil counts during hospitalization is simple and can be performed in resource-limited healthcare settings to track the inflammatory status of a patient. Lack of eosinophil recovery events can identify those at risk for future progression to severe COVID.

Reducing the Risk of Mortality in Chronic Obstructive Pulmonary Disease With Pharmacotherapy: A Narrative Review.

In 2020, chronic obstructive pulmonary disease (COPD) was the fifth leading cause of death in the United States excluding COVID-19, and its mortality burden has been rising since the 1980s. Smoking cessation, long-term oxygen therapy, noninvasive ventilation, and lung volume reduction surgery have had a beneficial effect on mortality; however, until recently, the effects of pharmacologic therapies on all-cause mortality have been unclear. Inhaled pharmacologic treatments for patients with COPD include combinations of long-acting muscarinic receptor antagonists (LAMAs), long-acting-ß2-agonists (LABAs), and inhaled corticosteroids (ICS). The recent IMPACT and ETHOS clinical trials reported mortality benefits with ICS/LAMA/LABA triple therapy compared with LAMA/LABA dual therapy. In IMPACT, fluticasone furoate/umeclidinium/vilanterol therapy significantly reduced the risk of on-/off-treatment all-cause mortality vs umeclidinium/vilanterol (hazard ratio, 0.72; 95% CI, 0.53 to 0.99; P=.042). The ETHOS trial found a reduction in the risk of on-/off-treatment all-cause mortality in patients treated with budesonide/glycopyrrolate/formoterol vs glycopyrrolate/formoterol (hazard ratio, 0.51 [0.33 to 0.80]; nominal P=.0035). Both trials included populations of patients with symptomatic COPD at high risk of future exacerbations, and a post hoc analysis of the final retrieved vital status data suggested that the observed mortality benefits are conferred by the ICS component. In conclusion, triple therapy reduces the risk of mortality in patients with symptomatic COPD characterized by moderate or severe airflow obstruction and a recent history of moderate or severe exacerbations. This benefit is likely to be driven by reductions in exacerbations. Future research efforts should focus on improving the long-term prognosis of patients living with COPD.

Chronic Obstructive Pulmonary Disease is Not Associated with In-Hospital Mortality in COVID-19: An Observational Cohort Analysis.

Background: Chronic obstructive pulmonary disease (COPD) is associated with worsened outcomes in COVID-19 (coronavirus disease 2019). However, data remain fraught with heterogeneity and bias from comorbid conditions. Additionally, data on the impact of COPD-specific factors, such as pre-hospital medications and pulmonologist involvement, remain sparse. Objective: We report a single-center analysis of COPD patients hospitalized with COVID-19 compared to those without COPD. Primary outcomes include ICU admission, mechanical ventilation, and in-hospital mortality. Methods: We evaluated all patients ≥40 years admitted with PCR-confirmed COVID-19 between February 2020 and February 2021. COPD was defined by documented ICD-10 diagnosis of COPD, confirmed smoking history, and active bronchodilator use. We compared outcomes between COPD patients and the remainder of the COVID-19 cohort. Multivariable analyses were adjusted for age, sex, smoking status, and comorbid conditions. Results: Of 1537 hospitalized COVID-19 patients, 122 (7.9%) carried a diagnosis of COPD. The COPD cohort was older (74 ± 13 vs 66 ± 15 years, P < 0.001) and more often former smokers (P < 0.001). Comorbid conditions including diabetes, cardiovascular disease, and kidney disease were more prevalent in the COPD group (P < 0.001). After adjusting for comorbid conditions, the COPD cohort had higher severity scores and trended towards fewer hospital-free days. Among patients with COPD, pre-hospital use of aspirin was associated with decreased ICU admissions (aHR 0.56, P = 0.049) and mechanical ventilation (aHR 0.25, P = 0.008), while LAMAs (long-acting muscarinic antagonists) were associated with decreased in-hospital mortality (aHR 0.34, P = 0.047). Involvement of pulmonology in pre-hospital management of COPD was not found to significantly affect outcomes. Conclusion: When corrected for comorbid illnesses, COPD was associated with more severe disease but not with increased ICU admission, mechanical ventilation, or in-hospital mortality rates. Among COPD patients, prehospital treatment with aspirin and COPD-directed therapies were associated with improved outcomes.

Cannabis consumption is associated with lower COVID-19 severity among hospitalized patients: a retrospective cohort analysis.

BACKGROUND: While cannabis is known to have immunomodulatory properties, the clinical consequences of its use on outcomes in COVID-19 have not been extensively evaluated. We aimed to assess whether cannabis users hospitalized for COVID-19 had improved outcomes compared to non-users. METHODS: We conducted a retrospective analysis of 1831 patients admitted to two medical centers in Southern California with a diagnosis of COVID-19. We evaluated outcomes including NIH COVID-19 Severity Score, need for supplemental oxygen, ICU (intensive care unit) admission, mechanical ventilation, length of hospitalization, and in-hospital death for cannabis users and non-users. Cannabis use was reported in the patient's social history. Propensity matching was used to account for differences in age, body-mass index, sex, race, tobacco smoking history, and comorbidities known to be risk factors for COVID-19 mortality between cannabis users and non-users. RESULTS: Of 1831 patients admitted with COVID-19, 69 patients reported active cannabis use (4% of the cohort). Active users were younger (44 years vs. 62 years, p < 0.001), less often diabetic (23.2% vs 37.2%, p < 0.021), and more frequently active tobacco smokers (20.3% vs. 4.1%, p < 0.001) compared to non-users. Notably, active users had lower levels of inflammatory markers upon admission than non-users-CRP (C-reactive protein) (3.7 mg/L vs 7.6 mg/L, p < 0.001), ferritin (282 µg/L vs 622 µg/L, p < 0.001), D-dimer (468 ng/mL vs 1140 ng/mL, p = 0.017), and procalcitonin (0.10 ng/mL vs 0.15 ng/mL, p = 0.001). Based on univariate analysis, cannabis users had significantly better outcomes compared to non-users as reflected in lower NIH scores (5.1 vs 6.0, p < 0.001), shorter hospitalization (4 days vs 6 days, p < 0.001), lower ICU admission rates (12% vs 31%, p < 0.001), and less need for mechanical ventilation (6% vs 17%, p = 0.027). Using propensity matching, differences in overall survival were not statistically significant between cannabis users and non-users, nevertheless ICU admission was 12 percentage points lower (p = 0.018) and intubation rates were 6 percentage points lower (p = 0.017) in cannabis users. CONCLUSIONS: This retrospective cohort study suggests that active cannabis users hospitalized with COVID-19 had better clinical outcomes compared with non-users, including decreased need for ICU admission or mechanical ventilation. However, our results need to be interpreted with caution given the limitations of a retrospective analysis. Prospective and observational studies will better elucidate the effects cannabis use in COVID-19 patients.

Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

Restoring Pulmonary and Sleep Services as the COVID-19 Pandemic Lessens. From an Association of Pulmonary, Critical Care, and Sleep Division Directors and American Thoracic Society-coordinated Task Force.

Background: In March 2020, many elective medical services were canceled in response to the coronavirus disease 2019 (COVID-19) pandemic. The daily case rate is now declining in many states and there is a need for guidance about the resumption of elective clinical services for patients with lung disease or sleep conditions.Methods: Volunteers were solicited from the Association of Pulmonary, Critical Care, and Sleep Division Directors and American Thoracic Society. Working groups developed plans by discussion and consensus for resuming elective services in pulmonary and sleep-medicine clinics, pulmonary function testing laboratories, bronchoscopy and procedure suites, polysomnography laboratories, and pulmonary rehabilitation facilities.Results: The community new case rate should be consistently low or have a downward trajectory for at least 14 days before resuming elective clinical services. In addition, institutions should have an operational strategy that consists of patient prioritization, screening, diagnostic testing, physical distancing, infection control, and follow-up surveillance. The goals are to protect patients and staff from exposure to the virus, account for limitations in staff, equipment, and space that are essential for the care of patients with COVID-19, and provide access to care for patients with acute and chronic conditions.Conclusions: Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a dynamic process and, therefore, it is likely that the prevalence of COVID-19 in the community will wax and wane. This will impact an institution's mitigation needs. Operating procedures should be frequently reassessed and modified as needed. The suggestions provided are those of the authors and do not represent official positions of the Association of Pulmonary, Critical Care, and Sleep Division Directors or the American Thoracic Society.

The use of nebulized pharmacotherapies during the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19), caused by the highly contagious novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a worldwide pandemic and currently represents a major public health issue. COVID-19 has highlighted the need for clear and accurate guidance on the use of aerosol-generating procedures, such as nebulization, for the treatment of patients with respiratory diseases with or without COVID-19. Despite the lack of evidence, there is heightened concern about the potential risk of transmission of SARS-CoV-2 in the form of aerosolized respiratory droplets during the nebulized treatment of patients with COVID-19. Consequently, the use of metered-dose inhalers (MDIs) has risen considerably as an alternative to nebulized therapy, which has led to inadequate supplies of MDIs in some parts of the United States. In this article, we review and discuss the role of nebulization in patients with SARS-CoV-2 and the treatment of noninfected patients with chronic respiratory diseases. The following two important questions are addressed: (1) should nebulized therapy be used in hospital or home settings by patients infected with SARS-CoV-2; and (2) should nebulized therapy be continued in patients already using it for chronic respiratory disease management in hospital or home settings?The reviews of this paper are available via the supplemental material section.