Vitamin D Status and Mortality from SARS CoV-2: A Prospective Study of Unvaccinated Caucasian Adults.

COVID-19 and a low vitamin D state share common risk factors, which might explain why vitamin D deficiency has been linked with higher COVID-19 mortality. Moreover, measures of serum vitamin D may become lower during systemic inflammatory responses, further confounding the association via reverse causality. In this prospective study (recruited over 12 months), we examined whether the association between a low vitamin D state and in-hospital mortality due to SARS-CoV-2 pneumonia in unvaccinated subjects is explained by (i) the presence of shared risk factors (e.g., obesity, advanced age) or (ii) a reduction in serum 25(OH)D due to COVID-19 (i.e., reverse causality). In this cohort of 232 (mean age = 56 years) patients (all had SARS-CoV-2 diagnosed via PCR AND required supplemental oxygen therapy), we failed to find an association between serum vitamin D and levels of CRP, or other inflammatory markers. However, the hazard ratio for mortality for subjects over 70 years of age (13.2) and for subjects with a serum 25(OH)D level less than 30 nmol·L−1 (4.6) remained significantly elevated even after adjustment for gender, obesity and the presence of diabetes mellitus. Subjects <70 years and >70 years had significantly higher mortality with a serum 25(OH)D less than 30 nmol·L−1 (11.8% and 55%), than with a serum 25(OH)D greater than 30 nmol·L−1 (2.2% and 25%). Unvaccinated Caucasian adults with a low vitamin D state have higher mortality due to SARS CoV-2 pneumonia, which is not explained by confounders and is not closely linked with elevated serum CRP.

COVID-19 in adults: test menu for hospital blood science laboratories.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), is a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Clinical Blood Sciences Laboratory (CBSL) plays a key role in supporting the monitoring and management of patients with COVID-19 disease. OBJECTIVE: To provide a comprehensive CBSL testing protocol to support the medical management of SARS-CoV-2 infection. METHODS: Description of the biochemical, haematological and immunological tests that have a role in the assessment and monitoring of patients with COVID-19 infection. RESULTS: We provide a test menu for clinical laboratories to ensure the effective monitoring, management and prognostication of COVID-19 patients in hospital. CONCLUSION: Given the rapidity with which patients with COVID-19 disease can deteriorate, we recommend regular testing with vigilance paid to the rate and trajectory of change in each of these parameters.

Aging and the microbiome: implications for asthma in the elderly?

In the elderly, asthma remains a clinical challenge. Recognition, diagnosis and treatment are all complex. Influenced by processes, such as aging, the identification of an 'asthma microbiome' presents a further challenge. This editorial discusses aging and the 'asthma microbiome' separately and then evaluates their potential relationship. Current evidence suggests that differences in the airway microbiome are associated with asthma, however, whether such associations are comparable or different for late-onset disease is yet to be established. Microbes are now linked to fundamental physiological processes, such as aging, based on data from invertebrate systems. This will likely confer implications for asthma in the elderly, and it is crucial that such emerging scientific data are considered in the context of aging, asthma and late-onset disease.

Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood.

BACKGROUND: Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. METHODOLOGY/PRINCIPAL FINDINGS: Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. CONCLUSIONS/SIGNIFICANCE: This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

Effect of the addition of montelukast to inhaled fluticasone propionate on airway inflammation.

The aim of the study was to investigate the effect of addition of montelukast to inhaled fluticasone propionate (FP) therapy, compared with FP therapy alone (100 microg twice a day) on airway immunopathology in individuals with mild asthma. Twenty-eight subjects received FP (100 microg twice a day) or FP (100 microg twice a day) plus montelukast (10 mg at night) for 8 weeks and were then crossed over to the alternate treatment for a further 8 weeks. Physiological measurements and bronchial biopsies were obtained at +/- 2 days before treatment and +/- 2 days at the end of each treatment period. A two-period crossover analysis was performed and the mean and SE were calculated. There was no significant difference in percent predicted FEV1 (p = 0.51) or PC20 mg/ml (p = 0.81) between the two treatment regimes after 8 weeks of therapy. There was no difference in the efficacy of either treatment in decreasing T cell (p = 0.97), CD45RO+ (p = 0.37), mast cell (p = 0.37), or activated eosinophils (p = 0.55) numbers in bronchial biopsies. There was no significant difference in the percentage area stained for IFN-gamma (p = 0.76) or interleukin-4 (p = 0.61) between treatments. Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP plus montelukast was not significantly different from the reduction observed with FP alone in individuals with mild asthma.

Effects of varying doses of fluticasone propionate on the physiology and bronchial wall immunopathology in mild-to-moderate asthma.

OBJECTIVES: Inhaled corticosteroids (ICS) are typically associated with a flat dose-response curve when traditional efficacy values are examined (eg, FEV(1)). The aim of the present study was to investigate if a dose-response relationship exists for lung function and inflammatory cell numbers in bronchial biopsy specimens. METHODS: Bronchial biopsy specimens were obtained from 36 patients randomized to receive 100 micro g, 500 microg, or 2,000 microg/d of fluticasone propionate (FP). Lung physiology and bronchial biopsies were performed at baseline and after 2 weeks of treatment. RESULTS: Improvement in lung function and suppression of airway inflammation were optimal at a dose of 500 microg/d of FP. Significant changes from baseline following treatment were documented in FEV(1) (p = 0.02), forced expiratory flow (p = 0.002), FEV(1)/FVC (p = 0.007), provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)) [p = 0.02], T-cell numbers (p = 0.0005), activated eosinophils (p = 0.01), and numbers of macrophages (p = 0.01) in the group treated with 500 microg/d of FP. Comparison between groups administered different doses of FP failed to demonstrate a dose-response relationship for change from baseline in PC(20) (p = 0.43), any of the lung function parameters, T-cell numbers (p = 0.64), activated T cells (p = 0.46), eosinophils (p = 0.53), activated eosinophils (p = 0.48), or macrophage numbers (p = 0.68). CONCLUSION: The apparent lack of a dose-response for ICS treatment in patients with asthma further validates the preferential use of add-on therapy over increasing the dose of ICS.

Airway dehydration: a therapeutic target in asthma?

BACKGROUND: Airway dehydration triggers exercise-induced bronchoconstriction in virtually all patients with active asthma. We are not aware of any investigations of airway dehydration in patients with naturally occurring asthma exacerbations. We wish to investigate whether airway dehydration occurs in acute asthmatic patients in the emergency department, and its functional significance. METHODS: In a pilot study on 10 asthmatic patients and 10 control subjects in the emergency department, respiratory rate was counted manually, and relative humidity of expired air was recorded using an air probe hygrometer. In parallel laboratory studies carried out over 2 consecutive days, 19 asthmatics and 10 control subjects were challenged initially with dry air, and on the second day with humidified air. FEV(1) and humidity measurements were made immediately before and after the tachypnea challenges. RESULTS: In the emergency department, the asthmatic group was more tachypneic (p < 0.0001) and their expired air was drier (p < 0.0001) than the control group. Following a dry-air tachypnea challenge in the laboratory, which caused dehydration of the expired air in all subjects, half of the asthmatics, but none of the control subjects, demonstrated a fall of > 10% in FEV(1) from baseline. This bronchoconstriction was prevented by humidifying the inspired air; tachypnea with no water loss did not affect lung function in asthmatic subjects. CONCLUSIONS: Dehydration of the expired air is present in asthmatic patients in the emergency department. The bronchoconstriction triggered by dry-air tachypnea challenge in the laboratory can be prevented by humidifying the inspired air. Airway rehydration merits further investigation as a potential adjunct to acute treatment of asthma exacerbations.

Alterations in airway inflammation and lung function during corticosteroid therapy for atopic asthma.

INTRODUCTION: Although corticosteroid therapy for asthma improves lung function and reduces airway inflammation, the relation between these two events is unclear. This article investigates associations between changes in bronchial inflammation and lung function during high-dose inhaled corticosteroid therapy for asthma. METHODS: Nine subjects with atopic asthma received high-dose inhaled fluticasone propionate (FP), 2,000 microg/d for 8 weeks. Fiberoptic bronchoscopy with endobronchial biopsies, spirometry, and histamine provocation challenge were performed on each subject at baseline, after 2 weeks, and again after 8 weeks of therapy. Spearman rank correlation coefficients between changes in parameters of bronchial inflammation and lung function were computed. RESULTS: As expected, significant down-regulation of airway inflammation and improvements in lung function were observed after both short-term and long-term therapy with high-dose inhaled FP. During corticosteroid therapy, changes in lymphocyte and macrophage numbers in bronchial biopsy specimens were closely correlated. Changes in EG1+ eosinophils were associated with changes in EG2+ eosinophils after 8 weeks of therapy. Although changes in airway inflammation and changes in lung function were not closely associated after 2 weeks of therapy, changes in eosinophils (EG1) in bronchial biopsy specimens correlated with changes in bronchodilator response (r = 0.77, p = 0.016) after 8 weeks of therapy. CONCLUSION: In patients with atopic asthma, changes in bronchial eosinophils and lung function during steroid therapy are closely related but do not occur simultaneously.