Sputum inflammatory, neural, and remodeling mediators in eosinophilic and noneosinophilic asthma.

BACKGROUND: Neural and remodeling mechanisms may play a role in asthma, particularly noneosinophilic asthma (NEA). OBJECTIVE: To assess sputum mediators associated with neural, remodeling, and inflammatory mechanisms in eosinophilic asthma (EA), NEA, and participants without asthma. METHODS: A total of 111 participants with and 62 without asthma (14-21 years old) underwent sputum induction, exhaled nitric oxide, atopy, and spirometry tests. There were 24 mediators measured in sputum using enzyme-linked immunosorbent assay or bead array. Eosinophilic asthma (n = 52) and NEA (n = 59) were defined using a sputum eosinophil level cut-point of greater than or equal to 2.5%. RESULTS: Elevated levels of nociceptin (median: 39.1 vs 22.4 ng/mL, P = .03), periostin (33.8 vs 9.4 ng/mL, P = .01), and ECP; (220.1 vs 83.7 ng/mL, P = .03) were found in patients with asthma compared with those without asthma. Nociceptin was elevated in EA (54.8 vs 22.4 ng/mL, P = .02) compared with participants without asthma. Eosinophilic asthma had higher levels of inflammatory mediators (ECP: 495.5 vs 100.3 ng/mL, P ≤ .01; interleukin-1ß: 285.3 vs 209.3 pg/mL, P = .03; histamine: 5805.0 vs 3172.5 pg/mL, P < .01) and remodeling mediators (VEGF-A); 3.3 vs 2.5 ng/mL, P = .03; periostin: 47.7 vs 22.1 ng/mL, P = .04) than NEA. Whereas macrophages were associated with neural mediators, for example, neurokinin A (r = 0.27, P = .01) and nociceptin (r = 0.30, P = .02), granulocytes were associated with inflammatory and remodeling mediators (eg, ECP and VEGF-A correlated with neutrophils (r = 0.53 and r = 0.33, respectively, P < .01) and eosinophils (r = 0.53 and r = 0.29 respectively, P ≤ .01). CONCLUSION: Elevated levels of nociceptin and inflammatory and remodeling markers were found in EA, but no evidence for neural and remodeling pathways was found in NEA. Neural and remodeling mechanisms seem to coexist with inflammation.

Heart rate variability as a marker of autonomic nervous system activity in young people with eosinophilic and non-eosinophilic asthma.

OBJECTIVE: An imbalance in autonomic nervous system (ANS) activity may play a role in asthma, but it is unclear whether this is associated with specific pathophysiology. This study assessed ANS activity by measuring heart rate variability (HRV) in eosinophilic (EA) and non-eosinophilic asthma (NEA) and people without asthma. METHODS: HRV, combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), skin prick tests to measure atopy, and spirometry tests were conducted in teenagers and young adults (14-21 years) with (n = 96) and without (n = 72) generally well-controlled asthma. HRV parameters associated with sympathetic and parasympathetic ANS branches were analyzed. EA and NEA were defined using a 2.5% sputum eosinophil cut-point. Airway hyperreactivity (AHR) was defined as ≥15% reduction in FEV1 following saline challenge. RESULTS: HRV parameters did not differ between asthmatics and non-asthmatics or EA and NEA. They were also not associated with markers of inflammation, lung function or atopy. However, increased absolute low frequency (LFµs2; representing increased sympathetic nervous system (SNS) activity) was found in asthmatics who used ß-agonist medication compared to those who did not (median: 1611, IQR 892-3036 vs 754, 565-1592; p < 0.05) and increased normalized low frequency (LF nu) was found in those with AHR compared to without AHR (64, 48-71 vs 53, 43-66; p < 0.05). CONCLUSION: ANS activity (as measured using HRV analysis) is not associated with pathophysiology or inflammatory phenotype in young asthmatics with generally well-controlled asthma. However, enhanced SNS activity can be detected in asthmatics with AHR or who use ß-agonist medication.

Global health classroom: mixed methods evaluation of an interinstitutional model for reciprocal global health learning among Samoan and New Zealand medical students.

BACKGROUND: Global health education partnerships should be collaborative and reciprocal to ensure mutual benefit. Utilisation of digital technologies can overcome geographic boundaries and facilitate collaborative global health learning. Global Health Classroom (GHCR) is a collaborative global health learning model involving medical students from different countries learning about each other's health systems, cultures, and determinants of health via videoconference. Principles of reciprocity and interinstitutional partnership informed the development of the GHCR. This study explores learning outcomes and experiences in the GHCR between students from New Zealand and Samoa. METHODS: This study used a mixed methods approach employing post-GHCR questionnaires and semi-structured face-to-face interviews to explore self-reported learning and experiences among medical students in the GHCR. The GHCR collaboration studied was between the medical schools at the University of Otago, New Zealand and the National University of Samoa, Samoa. RESULTS: Questionnaire response rate was 85% (74/87). Nineteen interviews were conducted among New Zealand and Samoan students. Students reported acquiring the intended learning outcomes relating to patient care, health systems, culture, and determinants of health with regards to their partner country. Interview data was indicative of attitudinal changes in relation to cultural humility and curiosity. Some reported a vision for progress regarding their own health system. Students in the GHCR reported that learning with their international peers in the virtual classroom made learning about global health more real and tangible. The benefits to students from both countries indicated reciprocity. CONCLUSIONS: This study demonstrates GHCR to be a promising model for collaborative and reciprocal global health learning using a student-led format and employing digital technology to create a virtual classroom. The self-reported learning outcomes align favourably with those recommended in the literature. In view of our positive findings, we present GHCR as an adaptable model for equitable, collaborative global health learning between students in internationally partnered institutions.

Exposure of Pseudomonas aeruginosa to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis.

Myeloperoxidase is a major neutrophil antimicrobial protein, but its role in immunity is often overlooked because individuals deficient in this enzyme are usually in good health. Within neutrophil phagosomes, myeloperoxidase uses superoxide generated by the NADPH oxidase to oxidize chloride to the potent bactericidal oxidant hypochlorous acid (HOCl). In this study, using phagocytosis assays and LC-MS analyses, we monitored GSH oxidation in Pseudomonas aeruginosa to gauge their exposure to HOCl inside phagosomes. Doses of reagent HOCl that killed most of the bacteria oxidized half the cells' GSH, producing mainly glutathione disulfide (GSSG) and other low-molecular-weight disulfides. Glutathione sulfonamide (GSA), a HOCl-specific product, was also formed. When neutrophils phagocytosed P. aeruginosa, half of the bacterial GSH was lost. Bacterial GSA production indicated that HOCl had reacted with the bacterial cells, oxidized their GSH, and was sufficient to be solely responsible for bacterial killing. Inhibition of NADPH oxidase and myeloperoxidase lowered GSA formation in the bacterial cells, but the bacteria were still killed, presumably by compensatory nonoxidative mechanisms. Of note, bacterial GSA formation in neutrophils from patients with cystic fibrosis (CF) was normal during early phagocytosis, but it was diminished at later time points, which was mirrored by a small decrease in bacterial killing. In conclusion, myeloperoxidase generates sufficient HOCl within neutrophil phagosomes to kill ingested bacteria. The unusual kinetics of phagosomal HOCl production in CF neutrophils confirm a role for the cystic fibrosis transmembrane conductance regulator in maintaining HOCl production in neutrophil phagosomes.

Changes in asthma severity in the first year of school and difficulty learning to read.

Objective: Asthma is a risk factor for poor early reading in children, for reasons that are unclear. This analysis examines the relationship between changes in asthma severity during the first year of school and being in the lowest quartile of reading achievement after 1 year of school.Methods: We used previously unreported data from our cohort study. Parent interviews and teacher questionnaires enquired about asthma and covariates of achievement at school entry (T1) and 12 months later (T2). Asthma severity scores at T1 and T2 showed that in 27 of 51 children with asthma, symptoms improved over the year, whereas in 24, symptoms persisted or worsened. Word and story reading were assessed at T1 and T2. We compared reading achievement at both timepoints between children with asthma and children who had no reported respiratory symptoms between birth and T2 (controls, N = 74), and between those with persistent versus improved symptoms.Results: More children with asthma than controls were in the lowest quartiles for reading. Further, significantly more children in the persistent group compared to the improved group were in the lowest quartiles for word reading (58 versus 30%, respectively) and story reading (54 versus 26%, respectively). School absences, increased behavior problems, stressful life events or parental mental health were not associated with the differences in either comparison. Logistic regression modeling identified persistent asthma as the most important variable associated with being in the lowest quartile of reading after 1 year in school.Conclusions: Active asthma symptoms during early school may influence early reading achievement.

Electronic cigarettes: A position statement from the Thoracic Society of Australia and New Zealand.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.

Missed opportunities for antimicrobial stewardship in pre-school children admitted to hospital with lower respiratory tract infection.

AIM: To describe the usage of multiplex polymerase chain reaction on nasopharyngeal swab (NPS) samples in pre-school children presenting with lower respiratory tract infection (LRTI) at Christchurch Hospital, and its impact on the use of antibiotics empirically and at discharge. METHODS: This retrospective cohort study included 237 children, ages 3 months to 5 years, admitted to hospital during the winter months of 2012-2015 with a diagnosis of community-acquired LRTI. Children were identified by discharge coding and their notes reviewed. RESULTS: A significantly larger proportion of children who had a NPS sample taken (42/146, 36%) received no empiric antibiotics compared with children who did not have a sample taken (7/91, 7.7%, P < 0.001). Of those who did have a NPS sample taken 17 of 146 (11.6%) had their antibiotics discontinued prior to or at the time of discharge compared with only 3 of 91 (3.3%) of those who did not have a NPS sample (P < 0.025). Children with influenza detected were more likely to receive no antibiotics or have their antibiotics discontinued prior to or at discharge. Only a small proportion of children with other viruses identified had their antibiotics discontinued. CONCLUSIONS: It appears that clinicians were generally reluctant to stop antibiotics prior to discharge in young children with LRTI in whom influenza or other viruses were identified. In our view, it makes sense to stop antibiotics when the clinical presentation and NPS testing is consistent with a viral aetiology. Not stopping antibiotics at or before discharge in these children represents a missed opportunity for antimicrobial stewardship.

Infant wheeze: is asthma a possibility?

Most infant wheeze is not asthma. Nonetheless, infants are able to develop reversible airway obstruction with or without allergic sensitisation, and asthma does occur at this age. The many other causes of infant wheeze, however, make asthma more difficult to distinguish from the background 'noise'. Consideration of risk factors and clinical features can enable some infants to be given a provisional diagnosis and, if their symptoms are disabling, a cautious trial of asthma treatment.

Cough and cough hypersensitivity as treatable traits of asthma.

Cough is a common and troublesome symptom in people with asthma and is often associated with poorer asthma control and exacerbations. Apart from asthma, other causes or comorbidities might underlie cough in asthma, such as rhinosinusitis and bronchiectasis. Eosinophilic inflammation and bronchoconstriction can lead to an acute episode of cough or worsen chronic cough. Cough hypersensitivity with laryngeal paraesthesia, allotussia, and hypertussia might underlie the cough of asthma through augmented sensory nerve excitability of upper-airway vagal sensory nerves. Cough associated with bronchoconstriction and type 2 inflammation should respond to inhaled corticosteroids and long-acting ß-adrenoceptor agonist therapy. For cough hypersensitivity in adults, speech and language therapy and neuromodulators (eg, gabapentin) could be considered. In children, there is no consistent association of asthma with cough sensitivity or between cough and asthma severity. Further research is needed to realise the potential of cough as a measure of asthma control, to understand the mechanisms of cough in asthma, and to develop safe, effective treatments and a precision-medicine approach to the management of cough in asthma in children and adults.

Breastfeeding protects against current asthma up to 6 years of age.

OBJECTIVE: To investigate the effects of breastfeeding on wheezing and current asthma in children 2 to 6 years of age. STUDY DESIGN: Infants (n=1105) were enrolled in a prospective birth cohort in New Zealand. Detailed information about infant feeding was collected using questionnaires administered at birth and at 3, 6, and 15 months. From this, durations of exclusive and any breastfeeding were calculated. Information about wheezing and current asthma was collected at 2, 3, 4, 5, and 6 years. Logistic regression was used to model associations between breastfeeding and outcomes with and without adjustment for confounders. RESULTS: After adjustment for confounders, each month of exclusive breastfeeding was associated with significant reductions in current asthma from 2 to 6 years (all, P<.03). Current asthma at 2, 3, and 4 years was also reduced by each month of any breastfeeding (all, P<.005). In atopic children, exclusive breastfeeding for ≥ 3 months reduced current asthma at ages 4, 5, and 6 by 62%, 55%, and 59%, respectively. CONCLUSION: Breastfeeding, particularly exclusive breastfeeding, protects against current asthma up to 6 years. Although exclusive breastfeeding reduced risk of current asthma in all children to age 6, the degree of protection beyond 3 years was more pronounced in atopic children.

Asthma, atopy and exhaled nitric oxide in a cohort of 6-yr-old New Zealand children.

BACKGROUND: Exhaled nitric oxide has been promoted as a non-invasive measure of airway inflammation, with clinical utility for the diagnosis and management of asthma. AIM: We studied associations between exhaled nitric oxide, asthma and atopy in a variety of clinically relevant phenotypes in a cohort of 6-yr-old children. METHOD: Asthma was defined using standard questionnaire criteria, atopy was measured using skin prick tests (SPT) and specific IgE to common allergens, and exhaled nitric oxide was measured using a chemiluminescence analyser according to American and European Thoracic Society criteria. RESULTS: Exhaled nitric oxide was strongly related to atopy and in particular to sensitization to house dust mites. Children with non-allergic asthma had no increase in exhaled nitric oxide compared with non-asthmatic children. Compared with children who never wheezed both late onset and persistent, wheezing was associated with increased FE(NO), while early transient wheezing was not. Elevated levels of exhaled nitric oxide amongst children with allergic asthma were almost entirely explained by their levels of specific IgE to aeroallergens, predominantly D pteronyssinus. CONCLUSION: Airway inflammation as measured by exhaled nitric oxide in young New Zealand children is related to their level of specific IgE to aeroallergens. This has implications for the utility of nitric oxide as a diagnostic and management tool in childhood asthma and for the importance of specific IgE as a marker of asthma severity.

Time trends and risk factors for rhinoconjunctivitis in New Zealand children: an International Study of Asthma and Allergies in Childhood (ISAAC) survey.

AIM: To investigate prevalence, time trends and factors associated with rhinitis and rhinoconjunctivitis not related to acute infections in New Zealand. METHODS: The International Study of Asthma and Allergies in Childhood (ISAAC) surveyed children aged 6-7 and 13-14 years for symptoms of these conditions. Five New Zealand centres were surveyed on two occasions (Phase One and Phase Three) 8-10 years apart. In Phase Three, questions were included on environmental factors, which might be associated with rhinoconjunctivitis. We report findings related to symptoms of rhinoconjunctivitis among 24 190 New Zealand children. RESULTS: Symptoms of rhinoconjunctivitis in the past year were reported in 11.4% of 6- to 7-year-old children and 18% of 13- to 14-year-old adolescents in Phase Three compared with 9.5 and 19.1%, respectively, in Phase One. Severe symptoms of rhinoconjunctivitis were reported in 0.5% of children and 0.8% of adolescents. Current symptoms were more common in males at 6-7 years and in females of 13-14 years, and Maori and Pacific Island ethnic groups had higher prevalence compared with those of European descent, especially in the older age group. For immigrant children, there was a very strong positive relationship between symptoms and length of time resident in New Zealand, supporting the probable importance of environmental factors. A positive association was found between symptoms and use of paracetamol in infancy or in the last year, and weaker associations were noted for antibiotic use, exercise, and regular pasta ingestion. CONCLUSIONS: Further study of environmental factors is recommended.

E-cigarette use patterns, brand preference and knowledge about vaping among teenagers (13-16 years) and parents of children attending Christchurch Hospital.

AIM: Parents attending hospital with children in New Zealand are routinely asked about tobacco use, but information about vaping is lacking. We assessed e-cigarette use, brand preferences, and knowledge during paediatric outpatient attendance at Christchurch Hospital. METHOD: We undertook an anonymous online survey of teenagers and parents attending paediatric outpatient clinic in December 2021 to February 2022. The sample (n=95) were 16% Maori and 8.4% currently smoked (4.8% teenagers, 11.3% parents). We used descriptive and contingency table analysis. RESULTS: Ever vaping was reported in 33.3% of teenagers and 30.8% of parents, and current use in 7.1% vs 15.1%, respectively. Most teenagers selected "curiosity/just wanted to try them" as their reason for vaping, whereas parents selected vaping to quit or reduce/avoid smoking. More teenagers than parents used nicotine-containing e-cigarettes (100% vs 86.7%) and more parents vaped indoors (in home or car) when other people were present. The most important reasons for choosing particular e-cigarette brands among teenagers were price and flavours, with fruit flavours preferred. No teenagers obtained their e-cigarettes from vape shops versus 40% of parents. The primary source of information about vaping for teenagers and parents was friends/peers. CONCLUSION: Vaping was common among teenagers and parents; teenagers vaped for curiosity and flavours and obtained vape products from sources other than vape shops.

Enhanced airway sensory nerve reactivity in non-eosinophilic asthma.

BACKGROUND: Neural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics. METHODS: Thirty-eight asthmatics and 19 non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, fractional exhaled nitric oxide, atopy and spirometry tests, followed by capsaicin challenge. EA and NEA were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. RESULTS: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared with non-asthmatics (n=19) (geometric mean C5: 58.3 µM, 95% CI 24.1 to 141.5 vs 193.6 µM, 82.2 to 456.0; p<0.05). NEA tended to also have greater capsaicin sensitivity than EA, with the difference in capsaicin sensitivity between NEA and EA being of similar magnitude (58.3 µM, 24.1 to 141.5 vs 191.0 µM, 70.9 to 514.0) to that observed between NEA and non-asthmatics; however, this did not reach statistical significance (p=0.07). FEV1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control or treatment were observed. CONCLUSION: NEA, but not EA, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of NEA.

2-Aminoacetophenone as a potential breath biomarker for Pseudomonas aeruginosa in the cystic fibrosis lung.

BACKGROUND: Pseudomonas aeruginosa infections are associated with progressive life threatening decline of lung function in cystic fibrosis sufferers. Growth of Ps. aeruginosa releases a "grape-like" odour that has been identified as the microbial volatile organic compound 2-aminoacetophenone (2-AA). METHODS: We investigated 2-AA for its specificity to Ps. aeruginosa and its suitability as a potential breath biomarker of colonisation or infection by Solid Phase Micro Extraction and Gas Chromatography-Mass Spectrometry (GC/MS). RESULTS: Cultures of 20 clinical strains of Ps. aeruginosa but not other respiratory pathogens had high concentrations of 2-AA in the head space of in vitro cultures when analysed by GC/MS. 2-AA was stable for 6 hours in deactivated glass sampling bulbs but was not stable in Tedlar® bags. Optimisation of GC/MS allowed detection levels of 2-AA to low pico mol/mol range in breath. The 2-AA was detected in a significantly higher proportion of subjects colonised with Ps. aeruginosa 15/16 (93.7%) than both the healthy controls 5/17 (29%) (p < 0.0002) and CF patients not colonised with Ps. aeruginosa 4/13(30.7%) (p < 0.001). The sensitivity and specificity of the 2-AA breath test compared to isolation of Ps. aeruginosa in sputum and/or BALF was 93.8% (95% CI, 67-99) and 69.2% (95% CI, 38-89) respectively. The peak integration values for 2-AA analysis in the breath samples were significantly higher in Ps. aeruginosa colonised subjects (median 242, range 0-1243) than the healthy controls (median 0, range 0-161; p < 0.001) and CF subjects not colonised with Ps. aeruginosa (median 0, range 0-287; p < 0.003). CONCLUSIONS: Our results report 2-AA as a promising breath biomarker for the detection of Ps. aeruginosa infections in the cystic fibrosis lung.

Breastfeeding protects against adverse respiratory outcomes at 15 months of age.

The relationship between breastfeeding, respiratory and other allergic disorders has been controversial. Our aim was to investigate the relationships between breastfeeding, respiratory outcomes, eczema and atopy at 15 months of age in a prospective birth cohort in New Zealand. A total of 1105 children were enrolled at birth, and 1011 (91.2%) were followed up at 15 months. Logistic regression was used to model associations between breastfeeding duration and respiratory outcomes, eczema and atopy after adjusting for relevant confounding variables: ethnicity, socio-economic status, parity, body mass index, smoking in pregnancy, gender and respiratory infections in the first 3 months of life. Breastfeeding was associated with a significant reduction in the risk of adverse respiratory outcomes at 15 months. After adjustment for confounders, each month of exclusive breastfeeding reduced the risk of doctor-diagnosed asthma by 20% (odds ratio 0.80, 95% confidence interval 0.71 to 0.90), wheezing by 12% (0.88, 0.82 to 0.94) and inhaler use by 14% (0.86, 0.78 to 0.93). Associations for both exclusive and additional breastfeeding durations, and respiratory outcomes remained independently significant when modelled simultaneously. Although independently associated with all respiratory outcomes, adjusting for parental history of allergic disease or maternal history of asthma did not alter our findings. Breastfeeding was not associated with eczema or atopy at 15 months. In conclusion, there was a significant protective effect of breastfeeding on infant wheezing and other adverse respiratory outcomes that may be early indicators of asthma in New Zealand children.