Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness. Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID stable patients), patients with COVID-19 requiring ICU admission (COVID ICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP ICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID ICU patients could be clearly differentiated from COVID stable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP ICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission ( P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution ( P < 0.0001). Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

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Alpha-1 antitrypsin (AAT) is the most abundant serine protease inhibitor circulating in the blood. AAT deficiency (AATD) is an autosomal codominant condition affecting an estimated 3.4 million individuals worldwide. The clinical disease associated with AATD can present in a number of ways including COPD, liver disease, panniculitis and antineutrophil cytoplasmic antibody vasculitis. AATD is the only proven genetic risk factor for the development of COPD, and deficient individuals who smoke are disposed to more aggressive disease. Principally, AAT is a serine protease inhibitor; however, over the past number of years, the assessment of AAT as simply an antiprotease has evolved, and it is now recognized that AAT has significant anti-inflammatory properties affecting a wide range of cells, including the circulating neutrophil.

Cystic fibrosis (CF) is a multisystem disorder with significantly shortened life expectancy. The major cause of mortality and morbidity is lung disease with increasing pulmonary exacerbations and decline in lung function predicting significantly poorer outcomes. The pathogenesis of lung disease in CF is characterised in part by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. This leads to accumulation of viscous mucus in the CF airway, providing an ideal environment for bacterial pathogens to grow and colonise, propagating airway inflammation in CF. The use of nebulised hypertonic saline (HTS) treatments has been shown to improve mucus clearance in CF and impact positively upon exacerbations, quality of life, and lung function. Several mechanisms of HTS likely improve outcome, resulting in clinically relevant enhancement in disease parameters related to increase in mucociliary clearance. There is increasing evidence to suggest that HTS is also beneficial through its anti-inflammatory properties and its ability to reduce bacterial activity and biofilm formation. This review will first describe the use of HTS in treatment of CF focusing on its efficacy and tolerability. The emphasis will then change to the potential benefits of aerosolized HTS for the attenuation of receptor mediated neutrophil functions, including down-regulation of oxidative burst activity, adhesion molecule expression, and the suppression of neutrophil degranulation of proteolytic enzymes.

Alpha-1 antitrypsin (AAT) is an acute phase protein that possesses immune regulatory and anti-inflammatory functions independent of anti-protease activity. AAT deficiency (AATD) is associated with early onset emphysema and chronic obstructive pulmonary disease. Of interest are the AATD nonsense mutations (termed Null or Q0) the majority of which arise from premature termination codons (PTC) in the messenger RNA coding-region. We have recently demonstrated that plasma from an AATD patient homozygous for the Null Bolton-allele (Q0bolton) contains AAT protein of truncated size. Although the potential to alleviate the phenotypic consequences of AATD by increasing levels of truncated protein holds therapeutic promise, protein functionality is key. The goal of this study was to evaluate the structural features and anti-inflammatory capacity of Q0bolton-AAT. A low abundance, truncated AAT protein was confirmed in plasma of a Q0bolton- AATD patient and was secreted by patient-derived iPSC-hepatic cells. Functional assays confirmed the ability of purified Q0bolton-AAT protein to bind neutrophil-elastase and to inhibit protease activity. Q0bolton-AAT bound interleukin-8 and leukotriene B4, comparable to control M-AAT, and significantly decreased leukotriene B4 induced neutrophil adhesion (P=0.04). Through a mechanism involving increased mRNA stability (P=0.007), ataluren treatment of HEK-293 significantly increased Q0bolton-AAT mRNA expression (P=0.03) and Q0bolton-AAT truncated protein secretion (P=0.04). Results support the rationale for treatment with pharmacological agents that augment levels of functional Q0bolton-AAT protein, thus offering a potential therapeutic option for AATD patients with rare mutations of similar theratype.

Figure 1). This injurious inflation pattern is known to cause overstretch and tidal recruitment in dependent, atelectatic lung, and thereby worsen dependent lung injury (7-9). Reverse triggering increased dependent lung stretch equivalent to that applied by VT of up to 15 ml/kg during muscle paralysis, despite a constant VT (Figure 2). Second, the magnitude of negative swing in Pes during reverse triggering is proportional to the local lung stretch in dependent lung, reflecting greater propensity to injury. Monitoring Pes or electrical activity of diaphragm could contribute in two ways. Each of these modalities increases the recognition of reverse triggering, and they quantify the magnitude of inspiratory muscle force during reverse triggering. Although reverse triggering associated with breath stacking is readily detected, in the absence of breath stacking it is likely to be unnoticed by clinicians relying on standard waveforms (e.g., airway pressure and flow). In addition, it will be underestimated when VT is controlled (4). Reverse triggering occurs in deeply sedated patients, a scenario in which clinicians consider the risk for asynchrony to be minimal (4), in contrast to easily detected vigorous effort, which is widely recognized to be harmful (2, 10). Thus, sedation may reduce harm from vigorous effort but increase the incidence of subtle and unsuspected reverse triggering. Finally, estimation of inspiratory muscle force during reverse triggering may be important to decrease dependent lung stretch and potentially lessen injury. It is uncertain whether the inflation pattern associated with reverse triggering is also observed with other ventilator modes. In conclusion, during reverse triggering, injurious inflation occurred in dependent lung despite the constant overall VT, and dependent lung stretch was proportional to the negative deflection in Pes. Early recognition of reverse triggering may be beneficial. n Author disclosures are available with the text of this letter at www.atsjournals.org.

AAT heterozygous status in RA is strongly associated with positive ACPAs and may define a distinct subset of patients with increased disease severity.

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