A scoping review of mHealth monitoring of pediatric bronchial asthma before and during COVID-19 pandemic.

Mobile (m) Health technology is well-suited for Remote Patient Monitoring (RPM) in a patient's habitual environment. In recent years there have been fast-paced developments in mHealth-enabled pediatric RPM, especially during the COVID-19 pandemic, necessitating evidence synthesis. To this end, we conducted a scoping review of clinical trials that had utilized mHealth-enabled RPM of pediatric asthma. MEDLINE, Embase and Web of Science were searched from September 1, 2016 through August 31, 2021. Our scoping review identified 25 publications that utilized synchronous and asynchronous mHealth-enabled RPM in pediatric asthma, either involving mobile applications or via individual devices. The last three years has seen the development of evidence-based, multidisciplinary, and participatory mHealth interventions. The quality of the studies has been improving, such that 40% of included study reports were randomized controlled trials. In conclusion, there exists high-quality evidence on mHealth-enabled RPM in pediatric asthma, warranting future systematic reviews and/or meta-analyses of the benefits of such RPM.

Implementation and use of mHealth home telemonitoring in adults with acute COVID-19 infection: a scoping review protocol.

INTRODUCTION: mHealth refers to digital technologies that, via smartphones, mobile apps and specialised digital sensors, yield real-time assessments of patient's health status. In the context of the COVID-19 pandemic, these technologies enable remote patient monitoring, with the benefit of timely recognition of disease progression to convalescence, deterioration or postacute sequelae. This should enable appropriate medical interventions and facilitate recovery. Various barriers, both at patient and technology levels, have been reported, hindering implementation and use of mHealth telemonitoring. As systematised and synthesised evidence in this area is lacking, we developed this protocol for a scoping review on mHealth home telemonitoring of acute COVID-19. METHODS AND ANALYSIS: We compiled a search strategy following the PICO (Population, Intervention, Comparator, Outcome) and PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendation for Scoping Reviews) guidelines. MEDLINE, Embase and Web of Science will be searched from 1 March 2020 to 31 August 2021. Following the title and abstract screening, we will identify, systematise and synthesise the available knowledge. Based on pilot searches, we preview three themes for descriptive evidence synthesis. The first theme relates to implementation and use of mHealth telemonitoring, including reported barriers. The second theme covers the interactions of the telemonitoring team within and between different levels of the healthcare system. The third theme addresses how this telemonitoring warrants the continuity of care, also during disease transition into deterioration or postacute sequelae. ETHICS AND DISSEMINATION: The studied evidence is in the public domain, therefore, no specific ethics approval is required. Evidence dissemination will be via peer-reviewed publications, conference presentations and reports to the policy makers.

The Phosphodiesterase Inhibitor Ensifentrine Reduces Production of Proinflammatory Mediators in Well Differentiated Bronchial Epithelial Cells by Inhibiting PDE4.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of proinflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function; thus, there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects; therefore, we examined whether ensifentrine alters the production of proinflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 and granulocyte monocyte colony-stimulating factor (GM-CSF) during challenge with interleukin-1ß Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors, respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the ß 2-adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate that ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with ß 2-adrenergic agonists or corticosteroids. SIGNIFICANCE STATEMENT: Airway inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the cystic fibrosis (CF) lung. We show here that ensifentrine beneficially modulates the release of proinflammatory factors in well differentiated CF bronchial epithelial cells that is further enhanced when combined with ß2-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of ensifentrine, alone and in combination with ß2-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.

Airway hyperreactivity is frequent in non-asthmatic children with sickle cell disease.

BACKGROUND: Asthma is associated with poorer outcomes in sickle cell disease (SCD). Whether AHR can exist in SCD as a distinct entity, separate and independent of asthma, is unknown. AIMS: Our goal was to elucidate the prevalence of AHR, as measured by a methacholine challenge test (MCT), in children with SCD who did not have concomitant asthma or any recent history of acute chest syndrome (ACS). To determine if AHR was associated with asthma-like symptoms, we compared the results of the MCT to a validated asthma questionnaire. We also examined if a correlation between AHR and inflammatory markers exists. METHODS: AHR was identified with a positive MCT defined as a provocation concentration (PC20 ) < 4 mg/ml. The children and/or their parents completed the ISAAC (International Study of Asthma and Allergies in Children) questionnaire. We obtained blood, urine, and exhaled breath condensate samples. We measured cysteinyl leukotriene levels in urine and exhaled breath condensate via enzyme immunoassay. RESULTS: Twenty-nine of forty children (72.5%) had a positive MCT. Nine (31.0%) also reported asthma-like symptoms on questionnaire. Inflammatory markers did not correlate with AHR. Among MCT positive subjects, those on hydroxyurea had significantly less severe AHR as quantified by PC20 (P = 0.014). CONCLUSIONS: In children with SCD, there is a high prevalence of AHR that is not associated with asthma-like symptoms. AHR may be a distinct entity in children with SCD, existing in the absence of concomitant asthma. Hydroxyurea therapy might lessen the severity of AHR in affected individuals. Pediatr Pulmonol. 2016; 51:950-957. © 2015 Wiley Periodicals, Inc.

Rhinovirus Load Is High despite Preserved Interferon-ß Response in Cystic Fibrosis Bronchial Epithelial Cells.

Lung disease in cystic fibrosis (CF) is often exacerbated following acute upper respiratory tract infections caused by the human rhinovirus (HRV). Pathophysiology of these exacerbations is presently unclear and may involve deficient innate antiviral or exaggerated inflammatory responses in CF airway epithelial cells. Furthermore, responses of CF cells to HRV may be adversely affected by pre-exposure to virulence factors of Pseudomonas (P.) aeruginosa, the microorganism that frequently colonizes CF airways. Here we examined production of antiviral cytokine interferon-ß and inflammatory chemokine interleukin-8, expression of the interferon-responsive antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1), and intracellular virus RNA load in primary CF (delF508 CFTR) and healthy airway epithelial cells following inoculation with HRV16. Parallel cells were exposed to virulence factors of P. aeruginosa prior to and during HRV16 inoculation. CF cells exhibited production of interferon-ß and interleukin-8, and expression of OAS1 at levels comparable to those in healthy cells, yet significantly higher HRV16 RNA load during early hours post-inoculation with HRV16. In line with this, HRV16 RNA load was higher in the CFBE41o- dF cell line overexpessing delF508 CFTR, compared with the isogenic control CFBE41o- WT (wild-type CFTR). Pre-exposure to virulence factors of P. aeruginosa did not affect OAS1 expression or HRV16 RNA load, but potentiated interleukin-8 production. In conclusion, CF cells demonstrate elevated HRV RNA load despite preserved interferon-ß and OAS1 responses. High HRV load in CF airway epithelial cells appears to be due to deficiencies manifesting early during HRV infection, and may not be related to interferon-ß.

Stimulation of the RIG-I/MAVS Pathway by Polyinosinic:Polycytidylic Acid Upregulates IFN-ß in Airway Epithelial Cells with Minimal Costimulation of IL-8.

Pharmacological stimulation of the antiviral cytokine IFN-ß in the airways may help to counter deleterious virus-induced exacerbations in chronic inflammatory lung diseases (asthma, chronic obstructive pulmonary disease, or cystic fibrosis). Polyinosinic-polycytidylic acid [poly(I:C)] is a known inducer of IFN-ß but also costimulates an inflammatory response. The latter response is undesirable given the pre-existing airway inflammation in these diseases. The objective of our study was to identify conditions for poly(I:C) to selectively upregulate IFN-ß in airway epithelial cells without a concomitant inflammatory response. The inflammatory response was gauged by production of the chemokine IL-8. Using cell lines and primary airway epithelial cells (both submerged and well-differentiated), we observed that pure poly(I:C) stimulated IFN-ß mainly through the TLR3/TRIF pathway and IL-8 through an unidentified pathway. The magnitude of the IL-8 response stimulated by pure poly(I:C) matched or even exceeded that of IFN-ß. Furthermore, this IL-8 response could not be pharmacologically downregulated without affecting IFN-ß. In contrast, we show that stimulation of the RIG-I/MAVS pathway, such as when poly(I:C) is delivered intracellularly in a complex with liposomes or via nucleofection, selectively stimulates IFN-ß with low IL-8 costimulation. The magnitude of IFN-ß stimulation by liposome-encapsulated poly(I:C) is markedly diminished in well-differentiated cells. In conclusion, it is feasible to augment IFN-ß production in airway epithelial cells without excessive costimulation of IL-8 if the RIG-I/MAVS pathway is stimulated, such as via liposomal delivery of poly(I:C). Better cytoplasmic delivery vehicles are needed to efficiently stimulate this pathway in well-differentiated cells.

Pressurized whey protein can limit bacterial burden and protein oxidation in Pseudomonas aeruginosa lung infection.

BACKGROUND: Lung infection caused by Pseudomonas aeruginosa is associated with an exuberant inflammatory response, oxidative stress, and lung damage. Whey protein is a rich source of cysteine, and anti-inflammatory and immune-enhancing peptides. Anti-inflammatory and antioxidant properties of whey are augmented by hyperbaric pressure treatment. In this study, we tested whether dietary supplementation with pressurized whey protein enhances the host ability to clear P. aeruginosa infection compared with native (i.e., unpressurized) whey. METHODS: Using a minimally invasive, non-lethal model of murine (female C57Bl/6) model of P. aeruginosa infection (mucoid strain embedded in agar beads), we studied kinetics of infection, inflammation, and oxidative stress at d 1, 3, and 7 postinfection. A parallel set of mice were fed for 4 wk a semipurified diet containing either native or pressurized whey and subsequently infected with P. aeruginosa. In these mice, the parameters mentioned previously were studied at d 1 and 3 postinfection. RESULTS: Infection with P. aeruginosa resulted in inflammation and protein oxidation sustained beyond bacterial clearance. Animals that were fed pressurized whey had fewer bacteria at day 3 than mice on native whey. Weight loss or broncho-alveolar lavage cell content were comparable. Airway protein oxidation was attenuated, whereas airway leukocyte bacterial killing ability and oxidative burst in response to opsonized bacteria were increased in the pressurized whey-fed animals. CONCLUSIONS: Use of nutritionally derived substances with anti-inflammatory and antioxidant properties, such as pressurized whey, aids in limiting airway bacterial infection, particularly, under conditions of ongoing oxidative stress.

Whey protein hydrolysates decrease IL-8 secretion in lipopolysaccharide (LPS)-stimulated respiratory epithelial cells by affecting LPS binding to Toll-like receptor 4.

UNLABELLED: Whey proteins (WP) exert anti-inflammatory and antioxidant effects. Hyperbaric pressurisation of whey increases its digestibility and changes the spectrum of peptides released during digestion. We have shown that dietary supplementation with pressurised whey improves nutritional status and systemic inflammation in patients with cystic fibrosis (CF). Both clinical indices are largely affected by airway processes, to which respiratory epithelial cells actively contribute. Here, we tested whether peptides released from the digestion of pressurised whey can attenuate the inflammatory responses of CF respiratory epithelial cells. Hydrolysates of pressurised WP (pWP) and native WP (nWP, control) were generated in vitro and tested for anti-inflammatory properties judged by the suppression of IL-8 production in CF and non-CF respiratory epithelial cell lines (CFTE29o- and 1HAEo-, respectively). We observed that, in both cell lines, pWP hydrolysate suppressed IL-8 production stimulated by lipopolysaccharide (LPS) to a greater magnitude compared with nWP hydrolysate. Neither hydrolysate suppressed IL-8 production induced by TNF-α or IL-1ß, suggesting an effect on the Toll-like receptor (TLR) 4 pathway, the cellular sensor for LPS. Further, neither hydrolysate affected TLR4 expression or neutralised LPS. Both pWP and nWP hydrolysates similarly reduced LPS binding to surface TLR4, while pWP tended to more potently increase extracellular antioxidant capacity. IN CONCLUSION: (1) anti-inflammatory properties of whey are enhanced by pressurisation; (2) suppression of IL-8 production may contribute to the clinical effects of pressurised whey supplementation on CF; (3) this effect may be partly explained by a combination of reduced LPS binding to TLR4 and enhanced extracellular antioxidant capacity.

Down-regulation of cytokine-induced interleukin-8 requires inhibition of p38 mitogen-activated protein kinase (MAPK) via MAPK phosphatase 1-dependent and -independent mechanisms.

Down-regulation of overabundant interleukin (IL)-8 present in cystic fibrosis (CF) airways could ease excessive neutrophil burden and its deleterious consequences for the lung. IL-8 production in airway epithelial cells, stimulated with e.g. inflammatory cytokines IL-1ß and tumor necrosis factor (TNF)-α, is regulated by several signaling pathways including nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK). We previously demonstrated that the anti-inflammatory drugs dexamethasone and ibuprofen suppress NF-κB; however, only dexamethasone down-regulates cytokine-induced IL-8, highlighting the importance of non-NF-κB mechanisms. Here, we tested the hypothesis that down-regulation of cytokine-induced IL-8 requires modulation of the MAPK phosphatase (MKP)-1/p38 MAPK/mRNA stability pathway. The effects of dexamethasone (5 nm) and ibuprofen (480 µm) on this pathway and IL-8 were studied in CF (CFTE29o-, CFBE41o-) and non-CF (1HAEo-) airway epithelial cells. We observed that dexamethasone, but not ibuprofen, destabilizes IL-8 mRNA and up-regulates MKP-1 mRNA. Further, siRNA silencing of MKP-1, via p38 MAPK, leads to IL-8 overproduction and diminishes the anti-IL-8 potential of dexamethasone. However, MKP-1 overexpression does not significantly alter IL-8 production. By contrast, direct inhibition of p38 MAPK (inhibitor SB203580) efficiently suppresses IL-8 with potency comparable with dexamethasone. Similar to dexamethasone, SB203580 decreases IL-8 mRNA stability. Dexamethasone does not affect p38 MAPK activation, which excludes its effects upstream of p38 MAPK. In conclusion, normal levels of MKP-1 are necessary for a full anti-IL-8 potential of pharmacological agents; however, efficient pharmacological down-regulation of cytokine-induced IL-8 also requires direct effects on p38 MAPK and mRNA stability independently of MKP-1.

Combined effect of dietary supplementation with pressurized whey and exercise training in chronic obstructive pulmonary disease: a randomized, controlled, double-blind pilot study.

Pressurized whey supplementation, by its antioxidant and nutritional properties, may improve exercise tolerance and potentiate the effects of exercise training in patients with chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, placebo-controlled study, 22 patients with COPD were allocated to receive active pressurized whey or placebo (casein) dietary supplementation for a 16-week period. Patients continued their usual physical activities for the first 8 weeks, whereas they were subjected to an exercise training program for the remaining 8 weeks of the study. Patients were evaluated at baseline, after 8 weeks of supplementation alone (time point, 8 weeks), and after 8 weeks of its combination with exercise training (time point, 16 weeks). The constant workrate cycle endurance test (CET), potentiated quadriceps twitch force, mid-thigh cross-sectional area, and Chronic Respiratory Questionnaire (CRQ) were used to evaluate the effects of treatments. The inflammatory (C-reactive protein and interleukin-6) and oxidant/antioxidant (protein oxidation and glutathione) blood profiles were also characterized. At week 8, there was no increase in CET time in either group. At week 16, there was a statistically significant increase in CET time in the whey-only group (P < .05). Further, at week 16, there was clinically significant improvement in the Dyspnea and the Mastery scales of the CRQ in both groups. Also, the Fatigue and Emotional Control scales of the CRQ showed clinically significant improvement in the whey-only group. Study interventions did not modify significantly the systemic inflammatory and oxidative stress markers that were assessed. Thus dietary supplementation with pressurized whey may potentiate the effects of exercise training on exercise tolerance and quality of life in patients with COPD.

Ibuprofen modulates NF-kB activity but not IL-8 production in cystic fibrosis respiratory epithelial cells.

BACKGROUND: High-dose ibuprofen is clinically effective in cystic fibrosis (CF); however, its molecular mechanisms are poorly understood. OBJECTIVE: To test the hypothesis that clinically relevant concentrations of ibuprofen suppress activation of nuclear factor (NF)-kappaB and thus down-regulate stimulated interleukin (IL)-8 production in CF respiratory epithelial cells. METHODS: The majority of experiments were conducted in CFTE29o- cells (F508del-mutated CF transmembrane regulator, CFTR). Key experiments were confirmed in CFBE41o- cells (F508del-mutated CFTR) and 1HAEo- cells (wild-type CFTR). NF-kappaB and IL-8 were stimulated with tumour necrosis factor (TNF)-alpha or IL-1beta. NF-kappaB and IL-8 suppression by ibuprofen (480 microM) was compared to dexamethasone (5 nM). RESULTS: Both TNF-alpha and IL-1beta activated NF-kappaB and stimulated IL-8 production. Both ibuprofen and dexamethasone demonstrated comparably modest suppression of NF-kappaB transcriptional activity. However, ibuprofen had no effect on stimulated IL-8 mRNA and protein. By contrast, dexamethasone significantly down-regulated stimulated IL-8 mRNA and protein. CONCLUSIONS: The present data do not support the hypothesis that ibuprofen down-regulates IL-8 production in response to TNF-alpha and IL-1beta in CF respiratory epithelium. Suppression of NF-kappaB transcriptional activity does not discriminate between anti-inflammatory drugs with or without effects on IL-8 production. We speculate that NF-kappaB-independent mechanisms may be responsible for anti-IL-8 effects of dexamethasone.

High-Dose Ibuprofen in Cystic Fibrosis.

Cystic Fibrosis (CF) is the most common lethal genetic disorder in North America and Europe. Most patients succumb to progressive lung disease characterized by an exaggerated neutrophilic inflammation. In animal models of chronic infection, high-dose ibuprofen was demonstrated to reduce inflammation without hindering bacterial clearance. This led to two clinical trials, which demonstrated a benefit in slowing the progression of lung disease in CF. However, concerns about potential adverse effects have limited the use of high-dose ibuprofen in CF patients. There are a variety of potential mechanisms to account for the observed clinical benefit. A better understanding of these mechanisms could potentially lead to more targeted and better-tolerated anti-inflammatory therapies.

Antioxidant properties of cystic fibrosis sputum.

Oxidative stress is a likely contributor to the pathogenesis of cystic fibrosis (CF) lung disease. However, hydrogen peroxide (H(2)O(2)), a physiological oxidant, is not elevated in CF exhalates. H(2)O(2) may be neutralized by antioxidants in CF airway secretions. The H(2)O(2)-detoxifying capacity of CF airway secretions, obtained via sputum induction, was studied in an in vitro H(2)O(2) cytotoxicity model. 16HBE14o- cells were exposed to H(2)O(2) in culture medium containing either 0 or 10% fetal bovine serum (FBS) or 10% CF sputum supernatant (extracted without use of dithiothreitol). The efficiency of H(2)O(2) neutralization was estimated by measuring intracellular oxidant levels (dihydrorhodamine 123) after 2 h and cell viability (propidium iodide) after 24 h of H(2)O(2) exposure. Furthermore, the presence of reduced thiols (DTNB assay) and reduced glutathione (recycling assay) in CF sputum samples was evaluated. CF sputum extracts completely prevented intracellular oxidant accumulation seen in cells incubated with H(2)O(2) in both control media (i.e., 0 or 10% FBS). Furthermore, CF sputum abolished cell death in 16HBE14o- cells exposed to up to 1 mM H(2)O(2). In contrast, there was 100% cytotoxicity in cells exposed to 600 microM H(2)O(2) in both control media. The H(2)O(2)-detoxifying potential of CF sputum was sustained after catalase and heme peroxidases were inactivated by sodium azide, which does not affect glutathione peroxidase. In addition, reduced protein thiols were found in abundance in CF sputum. In conclusion, CF sputum is capable to neutralize H(2)O(2) and abundant reduced thiols and/or glutathione peroxidase are fully sufficient to detoxify H(2)O(2).

Effects of S-acetylglutathione in cell and animal model of herpes simplex virus type 1 infection.

Intracellular glutathione (GSH) plays an important regulatory role in the host response to viral infections. Replenishment of intracellular GSH is a desirable yet challenging goal, since systemic GSH supplementation is rather inefficient due to a short half-life of GSH in blood plasma. Further, GSH is not taken up by cells directly, but needs to be broken down into amino acids and resynthesized to GSH intracellularly, this process often being impaired during viral infections. These obstacles may be overcome by a novel glutathione derivative S-acetylglutathione (S-GSH), which is more stable in plasma and taken up directly by cells with subsequent conversion to GSH. In the present study, in vitro effects of supplementation with S-GSH or GSH on intracellular GSH levels, cell survival and replication of human herpes simplex virus type 1 (HSV-1) were studied in human foreskin fibroblasts. In addition, in vivo effects of supplementation with S-GSH or GSH on HSV-1-induced mortality were studied in hr/hr mice. In cell culture, viral infection resulted in a significant decrease of intracellular GSH levels. S-GSH efficiently and dose-dependently (5 and 10 mM tested) restored intracellular GSH, and this replenishment was more efficient than with GSH supplementation. In mice, S-GSH, but not GSH, significantly decreased HSV-1-induced mortality ( P<0.05). The data suggest that S-GSH is a suitable antiviral agent against HSV-1 both in vitro and in vivo, indicating that this drug may be of benefit in the adjunctive therapy of HSV-1 infections.

Expression of human beta defensin (HBD-1 and HBD-2) mRNA in nasal epithelia of adult cystic fibrosis patients, healthy individuals, and individuals with acute cold.

BACKGROUND: Lack or inactivation of defensins may facilitate chronic bacterial colonization in the cystic fibrosis (CF) lung. CF nasal epithelium exhibits typical biochemical abnormalities and can be used to study defensin expression in CF. OBJECTIVES: To evaluate the expression of beta defensin (HBD-1 and HBD-2) mRNA and the presence of inflammatory markers (percentage of neutrophils and IL-8 mRNA expression) in CF and non-CF nasal mucosa. METHODS: Case-control study. Nasal brushing samples were obtained from 22 stable adult CF patients and 32 non-CF controls (25 healthy individuals and 7 individuals with acute cold). Samples were subjected to analysis involving mRNA expression (semiquantitative RT-PCR) and differential cell counting. RESULTS: Defensins and inflammatory markers were expressed at low levels in healthy individuals and at high levels in subjects with acute cold. In non-CF controls, defensin expression correlated significantly with inflammatory parameters (p < 0.001). In CF, defensin mRNA expression was comparable to healthy individuals (p = 0.2). In contrast to non-CF controls, in CF patients high levels of inflammatory markers did not correlate with defensin mRNA levels. CONCLUSIONS: Defensin expression is not upregulated in CF epithelium in response to inflammatory stimuli. Further studies are necessary to elucidate whether this is a consequence of the CF gene mutation.