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RATIONALE Extensive interdependencies exist between dietary intake, metabolic dysregulation, and asthma; however, the dietary pattern in adults with asthma remains unknown. OBJECTIVES To evaluate the association between dietary patterns and asthma ER visits and explore the effect of the interaction between race and diet on asthma. METHODS Using NHANES data, we compared dietary patterns between adults with asthma with and without asthma-related emergency room (ER) visits in the previous year, and between subjects of different races. The 2015 Healthy Eating Index (HEI-2015) was used to assess alignment between dietary patterns and the 2015-2020 Dietary Guideline for Americans. RESULTS Among 1681 individuals included in the study, 193 reported asthma-related ER visit. Patients with asthma had low fruit and vegetable intake, and a low mean (SE) HEI-2015 score [52.6 (0.53)]. Individuals with asthma-related ER visits had lower vegetable consumption compared to those without (median 0.61 vs. 0.85 cup equivalents). Furthermore, non-Hispanic Blacks (NHB) reported lower amount of vegetable (median cup equivalent 0.58 vs. 0.89) and fruit intake (0.17 vs. 0.39) and had a lower HEI-2015 score (49.9 vs. 52.9) comparing to non-Hispanic Whites. No association was discovered between dietary patterns and ER visits in multivariable analysis, or significant interactions between diet and race in predicting the need for ER visits. CONCLUSIONS Dietary patterns in adult with current asthma are frequently misaligned with current dietary guidelines. Patients with asthma-related ER visits and of NHB race had lower vegetable consumption; however, the associations disappeared in multivariable analysis. The impact of diet on asthma is not straightforward and deserves further investigation. Supplemental data for this article is available online at at www.tandfonline.com/ijas.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Significance Although resistance to glucocorticoids is a major clinical problem, the underlying mechanisms are unknown. It is known that glucocorticoid use can suppress adrenal androgen production. In population studies, animal models, and cell culture experiments, androgens are associated with several benefits in asthma, but neither androgen use in glucocorticoid-resistant asthma nor the genetic determinants of androgen responsiveness have been studied in humans. A missense-encoding variant in HSD3B1 is known to regulate conversion from adrenal precursors to potent androgens and clinical outcomes in prostate cancer. This is the first genetic evidence to our knowledge that implicates an androgen synthesis variant in resistance to glucocorticoids for asthma or any other inflammatory disease. Furthermore, this study demonstrates an adverse consequence of adrenal androgen suppression with glucocorticoid therapy., Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

BACKGROUND: During the COVID-19 pandemic, the need for judicious use of diagnostic tests and to limit personnel exposure has led to increased use and dependence on point-of-care ultrasound (POCUS) examinations. We reviewed POCUS findings in patients admitted to the intensive care unit (ICU) for acute respiratory failure with COVID-19 and correlated the findings to severity of illness and 30-day outcomes. METHODS: Patients admitted to the ICU in March and April 2020 were reviewed for inclusion (acute hypoxemic respiratory failure secondary to COVID-19 pneumonia; documentation of POCUS findings). RESULTS: Forty-three patients met inclusion criteria. B lines and pleural thickening were associated with a lower PaO(2)/FiO(2) by 71 (P = .005; adjusted R(2) = 0.24). Right ventricle (RV) dilation was more common in patients with 30-day mortality (P = .02) and was a predictor of mortality when adjusted for hypertension, diabetes mellitus, and age (odds ratio, 12.0; P = .048). All patients with RV dilation had bilateral B lines with pleural irregularities. CONCLUSIONS: Although lung ultrasound abnormalities are prevalent in patients with severe disease, RV involvement seems to be predictive of outcomes. Further studies are needed to discern the etiology and pathophysiology of RV dilation in COVID-19.

Endothelial hemoglobin (Hb)α regulates endothelial nitric oxide synthase (eNOS) biochemistry. We hypothesized that Hb could also be expressed and biochemically active in the ciliated human airway epithelium. Primary human airway epithelial cells, cultured at air–liquid interface (ALI), were obtained by clinical airway brushings or from explanted lungs. Human airway Hb mRNA data were from publically available databases; or from RT-PCR. Hb proteins were identified by immunoprecipitation, immunoblot, immunohistochemistry, immunofluorescence and liquid chromatography- mass spectrometry. Viral vectors were used to alter Hbβ expression. Heme and nitrogen oxides were measured colorimetrically. Hb mRNA was expressed in human ciliated epithelial cells. Heme proteins (Hbα, β, and δ) were detected in ALI cultures by several methods. Higher levels of airway epithelial Hbβ gene expression were associated with lower FEV1 in asthma. Both Hbβ knockdown and overexpression affected cell morphology. Hbβ and eNOS were apically colocalized. Binding heme with CO decreased extracellular accumulation of nitrogen oxides. Human airway epithelial cells express Hb. Higher levels of Hbβ gene expression were associated with airflow obstruction. Hbβ and eNOS were colocalized in ciliated cells, and heme affected oxidation of the NOS product. Epithelial Hb expression may be relevant to human airways diseases.

Introduction Among individuals with severe asthma, FEV1 is low in individuals with low dehydroepiandrosterone (DHEA) sulfate (DHEAS) levels. In the Severe Asthma Research Program (SARP), no women with DHEAS > 200 μg/dL had an FEV1 1 in asthmatic women with low DHEAS. Methods Premenopausal, nonsmoking, otherwise healthy women, 18-50 years old, with mild or moderate asthma and baseline FEV1 > 60% predicted received 100 mg DHEA orally every 12 h for 2 weeks. Spirometry and DHEAS were measured at the initial visit and 2 weeks later, after completion of DHEA treatment. Based on our previous work, the primary outcome variable for this pilot study was post-albuterol spirometry in the low-DHEAS group. Subjects also continued their other routine asthma management. Results Serum DHEAS increased with DHEA treatment in women with starting DHEAS n = 10; p = 0.0001). The increase in the high-DHEAS group was smaller. Post-albuterol FEV1 increased by 51 mL, from 3.026 ± 0.5 to 3.077 ± 0.49 L (n = 10; p = 0.034 by paired t test, significant after Bonferroni), in women with low DHEAS. In the high-DHEAS group (baseline DHEAS ≥ 200 µg/dl), post-albuterol FEV1 did not change significantly (n = 3, p = NS). Three subjects were excluded: one had comorbid COPD, one could not perform spirometry, and one did not take the DHEA. There were no adverse effects of DHEA treatment in this trial. Conclusions Endocrine treatments (corticosteroids) are a mainstay of anti-inflammatory management for moderate and severe asthma. Their use has improved asthma outcomes. Androgens also reduce airway inflammation and promote airway smooth muscle relaxation, but are rarely used clinically for asthma treatment. Our results suggest that the over-the-counter steroid DHEA may improve lung function in asthma outcomes among women with DHEAS

Asthma is a common disorder that affects genders differently across the life span. Earlier in life, it is more common in boys. At puberty, asthma becomes more common and often more severe in girls and women. The effect of sex hormones on asthma incidence and its severity is difficult to differentiate from other asthma severity risk factors, such as racial background, socioeconomic factors, obesity, atopy, environmental exposure, and, in particular, lung aging. Recognizing gender-associated and age-associated differences is important to understanding the pathobiology of asthma and to providing effective education and personalized care for patients with asthma across the life course.

This study investigates whether androgen receptor deficiency is associated with increased asthma risk.

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to

Patients with advanced COPD develop skeletal muscle loss (sarcopenia) that is associated with adverse clinical outcomes including mortality. We evaluated if thoracic muscle area is associated with clinical outcomes in patients with severe COPD. We analyzed consecutive patients with severe COPD undergoing evaluation for lung volume reduction from 2015 to 2019 (n=117) compared to current and former smoking controls undergoing lung cancer screening with normal lung function (n=41). Quantitative assessments of pectoralis muscle (PM) and erector spinae muscle (ESM) cross sectional area (CSA) were related to clinical outcomes including composite endpoints. Our results showed a reduction in PM CSA but not ESM CSA was associated with the severity of GOLD stage of COPD. Current smokers demonstrated reduced PM CSA which was similar to that in COPD patients who were GOLD stages 3 and 4. PM CSA was associated positively with FEV1, FEV1% predicted, FVC, DLCO, and FEV1/FVC ratio, and was associated negatively with the degree of radiologic emphysema. ESM correlated positively with DLCO, RV/TLC (a marker of hyperinflation), and correlated negatively with radiologic severity of emphysema. Kaplan-Meier analysis showed that reductions in PM but not ESM CSA was associated with the composite end point of mortality, need for lung volume reduction, or lung transplant. In conclusion, in well-characterized patients with severe COPD referred for lung volume reduction, PM CSA correlated with severity of lung disease, mortality and need for advanced therapies. In addition to predicting clinical outcomes, targeting sarcopenia is a potential therapeutic approach in patients with severe COPD.

Sex-related differences in lung growth exist and result in differences in lung function during the prenatal period and across the life span. This translates into disparity in the susceptibility and severity of several lung diseases. In general, lung diseases, such as acute respiratory distress and bronchopulmonary dysplasia, are worse in males during the neonatal period and during childhood. After puberty, women are affected more than men by lung diseases, such as asthma and cystic fibrosis. Lung function and disease severity also fluctuate with the menstrual cycle; abundant evidence suggests a benefit of androgens. Understanding sex-related differences in lung development and their impact on lung disease is important to predict outcomes and provide sex-based personalized management plans across the life span.

Rationale Patients with COPD who are afflicted with COVID-19 have an increased risk for adverse outcomes. Inhaled Corticosteroids (ICS) are commonly prescribed to patients with severe COPD and recurrent exacerbations. Given the concern for increased viral shedding related to oral corticosteroids seen with the related coronaviruses MERS-CoV and SARS-CoV-1, our study analyzed the impact of ICS on COPD patients with COVID-19. Methods This study examined 27,810 patients with COPD from the Cleveland Clinic COVID-19 registry between March 8th and September 16th, 2020. We used electronic health records (EHR) to gather patient data on the diagnosis of COPD, ICS use and clinical outcomes. Patients with a concurrent diagnosis of asthma and less than a 10 pack year smoking history, and those aged 35 and younger, were excluded to minimize bias and uncertainty about the diagnosis of COPD. Multivariate logistic regression was used to adjust for demographics, month of COVID-19 testing, and comorbidities known to be associated with increased COVID-19 risk for infection and severe disease. Results Amongst the COPD patients who were tested for COVID-19, 44.1% of those taking an ICS-containing inhaler tested positive versus 47.2% who tested negative (p=0.033). Of those who tested positive for COVID-19 (n=1288), 371 (28.8%) required hospitalization. Comparing the groups of individuals with COPD treated with, and without ICS, there was no significant difference in terms of age (66.9+14.0 vs 67.1+15.0, p=0.92) or gender (38.3% [77/201] vs 46.7% [79/170] males, p=0.13) respectively. In-hospital outcomes were not significantly different when comparing ICS versus no ICS in terms of sepsis (28.4% [57/201] vs 26.5% [45/170], p=0.77), shock (15.9% [32/201] vs 12.4% [21/170], p=0.41), ICU admission (36.8% [74/201] vs 31.2% [53/170], p=0.30), endotracheal intubation (21.9% [44/201] vs 16.5% [28/170], p=0.24), or mortality (18.4% [37/201] vs 20.0% [34/170], p=0.80). Multivariate logistic regression demonstrated that ICS therapy in patients with COPD was associated with less COVID-19 infection (adj OR 0.85, CI: 0.76-0.96);however, there were no significant differences in hospitalization (adj OR 1.12, CI: 0.90-1.38), ICU admission (adj OR: 1.31, CI: 0.82-2.10), need for mechanical ventilation (adj OR 1.65, CI: 0.69-4l02), or mortality (OR: 0.80, CI: 0.43-1.49). Conclusions The lack of adverse outcomes from ICS therapy among individuals with COPD infected with COVID-19 infection as demonstrated in this study, and the known advantages of ICS therapy in lowering the risk of COPD exacerbations, support continuing ICS in individuals with COPD who meet the recommended criteria.

Alcohol use disorder (AUD) is associated with significant direct morbidity and mortality. The impact of alcohol on chronic asthma and obstructive lung disease is unknown. AUD treatment may represent a potential target to improve healthcare utilization and healthcare costs in this patient population. Utilizing data from the 2012-2015 Nationwide Readmissions Database (NRD) and Nationwide Emergency Department Sample (NEDS), patients with a primary admission diagnosis of asthma or COPD were identified. Documented substance misuse, rates of hospitalization, frequency of hospital readmission, markers of admission severity, and cost were assessed. Within the NEDS cohort, 2,048,380 patients with a diagnosis of COPD or asthma were identified. Patients with documented AUD were more likely to present with respiratory failure [OR 1.32 (1.26, 1.39); p 0.001] and more likely to require mechanical ventilation in the emergency room [OR 1.30 (1.19, 1.42); p 0.001]. Within the NRD cohort, 1,096,663 hospital admissions were identified, of which 4.1% had documented AUD. AUD was associated with an increased length of stay [percentage increase estimate: 5% (4,6); p 0.001], increased hospitalization cost, and an increased likelihood of 30-day readmission in patients with a primary admission diagnosis of COPD or asthma [OR 1.24 (1.2, 1.28); p 0.001]. AUD is associated with increased disease morbidity and healthcare utilization in patients admitted with asthma or COPD. This impact persists after adjusting for substance misuse and associated comorbidities. Identifying and treating AUD in this patient population may improve disease, patient, and health-system outcomes.

BACKGROUND: Chronic obstructive lung disease, specifically chronic asthma and COPD, impacts more than 500 million adults worldwide, and is associated with high healthcare spending and significant disease related morbidity. While the direct impact of substance use disorder is well documented, little is known about the indirect impact of substance misuse within this patient population. The healthcare cost and indirect morbidity secondary to substance misuse in obstructive lung disease has yet to be quantified. OBJECTIVE: To determine the indirect impact of substance misuse on disease severity, healthcare utilization and healthcare costs in patients with chronic obstructive lung disease across the United States. METHODS: Utilizing data from the 2012–2015 National Readmissions Database (NRD) patients with a diagnosis of COPD or asthma were identified. Documented substance misuse, rates of hospitalization, frequency of hospital readmission, markers of admission severity and cost were assessed utilizing weighted regression analysis. RESULTS: 1,087,226 patients with an index admission for asthma or COPD were identified. Substance misuse was documented in 4.0% of patients. Substance misuse was associated with a 30% increase in odds of readmission and a higher cost per index admission. The additional index admission costs totaled $24 million for our cohort. CONCLUSION: Substance misuse is associated with an increase in healthcare utilization and healthcare cost in patients with chronic obstructive lung disease. Targeting substance misuse in this patient population has the potential for significant cost savings to the healthcare system.

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.

Background We sought to determine whether COPD conferred a higher risk for healthcare utilization in terms of hospitalization and clinical outcomes due to COVID-19. Methods A cohort study with covariate adjustment using multivariate logistic regression was conducted at the Cleveland Clinic Health System in Ohio and Florida. Symptomatic patients aged 35 years and older who were tested for SARS-CoV-2 between March 8 and May 13, 2020 were included. Findings 15,586 individuals tested for COVID-19 at the Cleveland Clinic between March 8, 2020 and May 13, 2020 met our inclusion criteria. 12.4% of COPD patients (164/1319) tested positive for COVID-19 compared to 16.6% (2363/14,267) of the non-COPD population. 48.2% (79/164) of COVID-19 positive COPD patients required hospitalization and 45.6% (36/79) required ICU admission. After adjustment for covariates, rates of COVID-19 infection were not significantly different than the non-COPD population (adj OR 0.97; CI: 0.89–1.05), but COPD patients had increased healthcare utilization as demonstrated by risk for hospitalization (adj OR 1.36; CI: 1.15–1.60), ICU admission (OR 1.20; CI: 1.02–1.40), and need for invasive mechanical ventilation (adj OR 1.49; CI: 1.28–1.73). Unadjusted risk for in-hospital mortality was higher in the COPD population (OR 1.51; CI: 1.14–1.96). After adjusting for covariates however, the risk for in-hospital mortality was not significantly different than the non-COPD population (adj OR 1.08: CI: 0.81–1.42). Interpretation Our analysis demonstrated that COPD patients with COVID-19 had a higher risk for healthcare utilization, although adjusted in-hospital mortality risk was not different than the non-COPD patients with COVID-19.

Background Asthma exacerbations result in significant health and economic burden, but are difficult to predict. Research Question Can machine learning (ML) models with large-scale outpatient data predict asthma exacerbations? Study Design and Methods We analyzed data extracted from electronic health records (EHRs) of asthma patients treated at the Cleveland Clinic from 2010 through 2018. Demographic information, comorbidities, laboratory values, and asthma medications were included as covariates. Three different models were built with logistic regression, random forests, and a gradient boosting decision tree to predict: (1) nonsevere asthma exacerbation requiring oral glucocorticoid burst, (2) ED visits, and (3) hospitalizations. Results Of 60,302 patients, 19,772 (32.8%) had at least one nonsevere exacerbation requiring oral glucocorticoid burst, 1,748 (2.9%) requiring and ED visit and 902 (1.5%) requiring hospitalization. Nonsevere exacerbation, ED visit, and hospitalization were predicted best by light gradient boosting machine, an algorithm used in ML to fit predictive analytic models, and had an area under the receiver operating characteristic curve of 0.71 (95% CI, 0.70-0.72), 0.88 (95% CI, 0.86-0.89), and 0.85 (95% CI, 0.82-0.88), respectively. Risk factors for all three outcomes included age, long-acting β agonist, high-dose inhaled glucocorticoid, or chronic oral glucocorticoid therapy. In subgroup analysis of 9,448 patients with spirometry data, low FEV1 and FEV1 to FVC ratio were identified as top risk factors for asthma exacerbation, ED visits, and hospitalization. However, adding pulmonary function tests did not improve models’ prediction performance. Interpretation Models built with an ML algorithm from real-world outpatient EHR data accurately predicted asthma exacerbation and can be incorporated into clinical decision tools to enhance outpatient care and to prevent adverse outcomes.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus–host protein–protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56–0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription–polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54–0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52–0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31–0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19., This study uses network medicine methodologies along with multiomic observations (including SARS-CoV-2 and human interactome, transcriptome, and proteome) to identify widespread disease manifestations and drug repurposing candidates (including melatonin) for COVID-19, validating these findings using a large-scale patient registry database.

BACKGROUND AND OBJECTIVE COPD is the third most common cause of death worldwide and fourth most common in the United States. In hospitalized patients with COPD, mortality, morbidity and healthcare resource utilization are high. Skeletal muscle loss is frequent in patients with COPD. However, the impact of muscle loss on adverse outcomes has not been systematically evaluated. We tested the hypothesis that patients hospitalized for COPD exacerbation with, compared to those without, a secondary diagnosis of muscle loss phenotype (all ICD-9 codes associated with muscle loss including cachexia) will have higher mortality and cost of care. METHODS The NIS database of hospitalized patients in 2011 (1 January-31 December) in the United States was used. The impact of a muscle loss phenotype on in-hospital mortality, LOS and cost of care for each of the 174 808 hospitalizations for COPD exacerbations was analysed. RESULTS Of the subjects admitted for a COPD exacerbation, 12 977 (7.4%) had a secondary diagnosis of muscle loss phenotype. A diagnosis of muscle loss phenotype was associated with significantly higher in-hospital mortality (14.6% vs 5.7%, P

BACKGROUND AND AIMS. There is very limited data on the healthcare burden of muscle loss, the most frequent complication in hospitalized cirrhotics. We determined the healthcare impact of a muscle loss phenotype in hospitalized cirrhotics. METHODS. The Nationwide Inpatient Sample (NIS) database (years 2010–2014) was analyzed. Search terms included cirrhosis and its complications, and an expanded definition of a muscle loss phenotype that included all conditions associated with muscle loss. In-hospital mortality, length of stay (LOS), post-discharge disposition, co-morbidities and cost during admission were analyzed. Univariate and multivariate analyses were performed to identify associations between a muscle loss phenotype and outcomes. Impact of muscle loss in cirrhotics was compared to that in a random sample (2%) of general medical inpatients. RESULTS. A total of 162,694 hospitalizations for cirrhosis were reported, of which 18,261(11.2%) included secondary diagnosis codes for a muscle loss phenotype. A diagnosis of muscle loss was associated with a significantly (p

Background Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. Methods To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6–18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. Results From pre−/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. Conclusions These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. Trial registration ClinicalTrials.gov registration number: NCT01748175. Electronic supplementary material The online version of this article (10.1186/s12890-018-0612-x) contains supplementary material, which is available to authorized users.

Background Sites of entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly expressed in nasal epithelial cells; however, little is known about the impact of intranasal corticosteroids (INCS) on coronavirus disease 2019 (COVID-19)-related outcomes. Objective To determine the association between baseline INCS use and COVID-19-related outcomes. Methods Using the Cleveland Clinic COVID-19 Research Registry, we performed a propensity score matching for treatment with INCS before SARS-CoV-2 infection (April 1, 2020, to March 31, 2021). Of the 82,096 individuals who tested positive, 72,147 met inclusion criteria. Our endpoints included the need for hospitalization, admission to the intensive care unit (ICU), or in-hospital mortality. Results Of the 12,608 (17.5%) who were hospitalized, 2935 (4.1%) required ICU admission and 1880 (2.6%) died during hospitalization. A significant proportion (n = 10,187; 14.1%) were using INCS before SARS-CoV-2 infection. Compared with nonusers, INCS users demonstrated lower risk for hospitalization (adjusted odds ratio [OR] [95% confidence interval (CI)]: 0.78 [0.72; 0.85]), ICU admission (adjusted OR [95% CI]: 0.77 [0.65; 0.92]), and in-hospital mortality (adjusted OR [95% CI]: 0.76 [0.61; 0.94]). These findings were replicated in sensitivity analyses where patients on inhaled corticosteroids and those with allergic rhinitis were excluded. The beneficial effect of INCS was significant after adjustment for baseline blood eosinophil count (measured before SARS-CoV-2 testing) in a subset of 30,289 individuals. Conclusion INCS therapy is associated with a lower risk for COVID-19-related hospitalization, ICU admission, or death. Future randomized control trials are needed to determine if INCS reduces the risk for severe outcomes related to COVID-19.

Asthma, a common respiratory disease that affects about 10% of the US population, represents a significant public health issue. In the last decade, cumulative evidence has demonstrated sex disparities in asthma, including significant differences in epidemiology, clinical presentation, response to therapies, and health outcomes. Understanding sex-related differences in asthma enables clinicians to provide personalized asthma care and improve asthma outcome. Recent studies on sex-related differences in asthma inform us on mechanism underlying asthma pathogenesis across all age groups. Sex hormones directly modulate immune pathways crucial in asthma pathogenesis and affect individual’s response to environmental triggers and medications, such as leukokotriene inhibitors. Not surprisingly, the use of external sex hormone supplementations appears to modulate asthma risk. Identification of sex-specific asthma risk loci through genome-wide association studies also provides supporting evidence on sex-related differences in asthma. There is an interaction between sex and obesity, an interaction that could place females at higher risk for systemic inflammation and, consequently, asthma. In this article, we review epidemiological and clinical studies on sex-related differences in asthma, with a special focus on the role of sex hormones, including hormonal therapies and the asthma-obesity interaction.

Background Tools for quantification of asthma severity are limited. Objective We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. Methods Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. Results ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. Conclusions The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

Background Asthma is a prevalent disease with a high economic cost. More than 50% of its direct cost relates to asthma hospitalizations. Diabetes mellitus (DM) is a significant comorbidity in asthmatic patients, yet its impact on asthma-related hospitalizations is unknown. Objective To compare the outcome of asthma-related hospitalizations in patients with and without DM. Methods Using Healthcare Cost and Utilization Project Nationwide Readmissions Database, we analyzed data of all adults with index admission for asthma and with no other chronic pulmonary conditions, and compared outcomes between patients with and without DM. Weighted regression analysis was used to determine the impact of DM on hospitalization outcomes. All multivariate regression models were adjusted for patient demographics, socioeconomic status, and chronic medical comorbidities. Results A total of 717,200 asthmatic patients were included, with 202,489 (28.3%) having DM. Diabetic patients were older and had more comorbidities. When hospitalized for asthma, diabetic patients had increased hospital length of stay, cost, and risk for 30-day all-cause and asthma-related readmission. They also had a higher risk for developing nonrespiratory complications during their hospital stay compared with nondiabetic patients. The risk of mortality was similar between the 2 groups. Conclusions Patients hospitalized for asthma with coexisting DM had increased hospital length of stay, cost, and risk for readmission. Interventions are urgently needed to reduce the risk for hospital admission and readmission in patients with coexisting DM and asthma. These interventions would have profound economic and societal impact.

Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma.We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence.Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually.At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/μL.In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.

Background The effect of age on asthma severity is poorly understood. Objectives The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. Methods SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. Results Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. Conclusions The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).