Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID.

Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of a variety of chronic, inflammatory diseases, including long COVID, as are small, insoluble, 'fibrinaloid' microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block the flow of blood through microcapillaries and thus cause tissue hypoxia, are not simply correlated with but in fact, by preceding it, may be a chief intermediary cause of POTS, in which tachycardia is simply the body's exaggerated 'physiological' response to hypoxia. Similar reasoning accounts for the symptoms bundled under the term 'fatigue'. Amyloids are known to be membrane disruptors, and when their targets are nerve membranes, this can explain neurotoxicity and hence the autonomic nervous system dysfunction that contributes to POTS. Taken together as a system view, we indicate that fibrinaloid microclots can serve to link POTS and fatigue in long COVID in a manner that is at once both mechanistic and explanatory. This has clear implications for the treatment of such diseases.

COVID-19 and children.

There has been substantial research on adult COVID-19 and how to treat it. But how do severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections afflict children? The COVID-19 pandemic has yielded many surprises, not least that children generally develop less severe disease than older adults, which is unusual for a respiratory disease. However, some children can develop serious complications from COVID-19, such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid, even after mild or asymptomatic COVID-19. Why this occurs in some and not others is an important question. Moreover, when children do contract COVID-19, understanding their role in transmission, especially in schools and at home, is crucial to ensuring effective mitigation measures. Therefore, in addition to nonpharmaceutical interventions, such as improved ventilation, there is a strong case to vaccinate children so as to reduce possible long-term effects from infection and to decrease transmission. But questions remain about whether vaccination might skew immune responses to variants in the long term. As the experts discuss below, more is being learned about these important issues, but much more research is needed to understand the long-term effects of COVID-19 in children.

Refractory asthma - beyond step 5, the role of new and emerging adjuvant therapies.

A small percentage of asthmatics have 'severe refractory asthma', where there is suboptimal response to currently available therapies. A number of novel therapies targeting key biological targets are becoming available. Asthma is a heterogeneous disease, and systematic evaluation of patients is important to target therapies to the underlying inflammatory subtype and clinical features. This review article outlines new and emerging treatments for severe asthma, including monoclonal antibodies targeting eosinophilic disease, anti-neutrophil strategies, novel bronchodilators and bronchial thermoplasty. We highlight the importance of individualized investigation, treatment and management of severe asthmatics.

Reduced glucocorticoid receptor expression and function in airway neutrophils.

Chronic Obstructive Pulmonary Disease (COPD) is a glucocorticoid resistant condition characterised by airway neutrophilia. Reduced glucocorticoid receptor (GR) expression in COPD airway neutrophils may be a mechanism that contributes to glucocorticoid resistance. Our objective was to investigate the expression and function of GR within COPD airway neutrophils. Dual-label immunofluorescence was used to analyse airway neutrophil expression of GR within peripheral lung tissue samples (11 COPD patients, 7 healthy non-smokers [NS]) and induced sputum (7 COPD patients, 7 NS). TNFα and CXCL8 release were measured in neutrophils isolated from induced sputum and peripheral blood (7 COPD patients) in the presence of dexamethasone. In lung tissue, GR was abundantly expressed in macrophages and lymphocytes, but very low expression was observed in neutrophils (means 6.8% and 4.3% in COPD patients and NS respectively). Similarly low expression was observed in sputum neutrophils (means 3.8% and 6.9% in COPD patients and NS respectively). In contrast, GR was expressed by 100% of blood neutrophils. Dexamethasone had less suppressive effect on TNFα and CXCL8 production in vitro by neutrophils from induced sputum compared to neutrophils from paired blood samples. Airway neutrophils have low expression of GR in both COPD patients and controls. The effects of glucocorticoids on cytokine production from airway neutrophils are reduced. Increased numbers of airway neutrophils lacking GR may contribute to glucocorticoid resistance in COPD patients.

A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354) in subjects with asthma.

BACKGROUND: IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody (CAT-354) in adults with asthma. METHODS: This was a multiple-dose, randomised, double-blind, placebo-controlled phase 1 study in asthmatics (forced expiratory volume in 1 second [FEV1] >or= 80% predicted). Subjects were randomised to receive three intravenous infusions of CAT-354 (1 mg/kg, 5 mg/kg or 10 mg/kg) or placebo at 28-day intervals. Blood samples were taken for pharmacokinetic measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory and pulmonary function parameters. RESULTS: Twenty-three subjects (aged 21-60 years, FEV1 88-95% predicted) received >or= 1 dose of study medication. The half-life of CAT-354 was 12-17 days and was dose-independent. The maximum serum concentration and area under the curve were dose-dependent. Clearance (2.2-2.6 mL/day/kg) and volume of distribution (44-57 mL/kg) were both low and dose-independent. The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels, consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve. Most adverse events were deemed mild to moderate and unrelated to study medication. One SAE was reported and deemed unrelated to study drug. There were no effects of clinical concern for vital signs, ECG, laboratory or pulmonary parameters. CONCLUSIONS: CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile. These findings suggest that at the doses tested, CAT-354 can be safely administered in multiple doses to patients with asthma. TRIAL REGISTRATION: NCT00974675.

Reduced exhaled breath condensate pH in asthmatic smokers using inhaled corticosteroids.

BACKGROUND AND OBJECTIVES: Exhaled breath condensate (EBC) pH has been proposed as a biomarker of airway inflammation and oxidative stress in asthma. Cigarette smoking reduces EBC pH in mild asthma. The effects of smoking on EBC pH in more symptomatic asthmatic patients using inhaled corticosteroids (ICS) are unknown. We aimed to compare EBC pH in asthmatic smokers (AS) and non-smokers (ANS) with moderate to severe disease, who were taking ICS. We also investigated the relationship between EBC pH and biomarkers of airway inflammation and oxidative stress. METHODS: AS (n = 18) and ANS (n = 17), who were using ICS, were recruited and EBC pH, sputum inflammatory cell counts and sputum supernatant 8-isoprostane concentrations were measured. Full lung function testing was performed. RESULTS: EBC pH was significantly lower in AS than in ANS (6.91 vs 7.41). In AS there was a significant inverse correlation between EBC pH and 8-isoprostane levels (r = -0.54, P = 0.03). There was no correlation between EBC pH and sputum neutrophil counts. CONCLUSIONS: EBC pH appears to be a biomarker of the level of oxidative stress in smokers with moderate to severe asthma. EBC pH may have applications for the longitudinal monitoring of the effects of smoking on the airways of asthmatic patients.

The effects of smoking on the lipopolysaccharide response and glucocorticoid sensitivity of alveolar macrophages of patients with asthma.

BACKGROUND: Cigarette smoking in asthma patients causes insensitivity to inhaled glucocorticoids (GCs). We tested the hypothesis that smoking causes GC insensitivity in alveolar macrophages (AMs) obtained from patients with asthma. METHODS: Nineteen asthmatic nonsmokers (ANSs) and 13 asthmatic smokers (ASMs) underwent BAL. AMs were cultured with or without dexamethasone, 0.1 to 1,000 nmol/L, for 2 h before lipopolysaccharide (LPS) [1 microg/mL] stimulation. After 6 h, supernatants were harvested for enzyme-linked immunosorbent assay, and messenger RNA was collected for real-time (RT)-polymerase chain reaction (PCR). RESULTS: ASMs had higher numbers of AMs per milliliter of BAL fluid than ANSs (1.98 vs 0.75 x 10(6) cells/mL, respectively; p = 0.007). Cigarette smoking significantly attenuated the LPS response for all three cytokines tested among ANSs vs ASMs (tumor necrosis factor [TNF]-alpha, 31.6 vs 10.6 ng/mL, respectively (p = 0.01); interleukin [IL]-6, 25.8 vs 10.8 ng/mL, respectively (p = 0.002); IL-8, 62.5 vs 36.1 ng/mL, respectively (p = 0.001)). There was no difference in dexamethasone dose-response curves between ANSs and ASMs (p > 0.05 for all comparisons). The inhibitory concentration of 50% (IC(50)) for IL-6 was 120.6 vs 83.3, respectively, and for TNF-alpha it was 4.9 vs 8.6, respectively; an IC(50) was not achieved for IL-8. RT-PCR also showed no difference in the suppression of cytokine messenger RNA levels between groups, with IL-8 being the most GC-insensitive cytokine. CONCLUSION: Cigarette smoking in patients with asthma increases the number of airway AMs and attenuates their response to LPS, which may have implications in host immune function. Cigarette smoking does not alter the GC sensitivity of AMs in patients with asthma. There was differential cytokine sensitivity, with IL-8 being the least GC-sensitive cytokine. GC-insensitive IL-8 production from AMs may be a mechanism by which neutrophils are attracted into the airways.