Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study.

BACKGROUND: Although asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient and the condition is referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC). METHODS: EBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of 120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9. RESULTS: The tissue macrophages in ACO were substantially higher in the epithelium and RBM than in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher in number than COPD-CS (P < 0.05). The mast cell numbers in ACO were lower than in NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than  HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in number in epithelium and LP across groups. CD4+ T-cells remained lower in number across all regions and groups. CONCLUSION: These results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.

Differential airway remodeling changes were observed in patients with asthma COPD overlap compared to patients with asthma and COPD alone.

Management of patients with asthma COPD overlap (ACO) is clinically challenging due to insufficient evidence of pathological changes in these patients. In this cross-sectional study, we evaluated airway remodeling in endobronchial biopsies from a total of 90 subjects, which included 12 ACO, 14 patients with asthma, 12 COPD exsmokers (ES), 11 current smokers (CS), 28 healthy controls (HC), and 13 normal lung function smokers (NLFS). Tissue was stained with Masson's trichrome. Epithelium, goblet cells, reticular basement membrane (RBM), cellularity, lamina propria (LP), and smooth muscle (SM) changes were measured using Image-Pro Plus v7 software. Differential airway remodeling pattern was seen in patients with ACO. A limited change was noted in the ACO epithelium compared with other pathological groups. RBM was substantially thicker in patients with ACO than in HC (P < 0.0002) and tended to be thicker than in patients with asthma and NLFS. The total RBM cells were higher in ACO than in the HC (P < 0.0001), COPD-CS (P = 0.0559), -ES (P = 0.0345), and NLFS (P < 0.0002), but did not differ from patients with asthma. Goblet cells were higher in the ACO than in the HC (P = 0.0028) and COPD-ES (P = 0.0081). The total LP cells in ACO appeared to be higher than in HC, COPD-CS, and NLFS but appeared to be lower than in patients with asthma. Finally, SM area was significantly lower in the ACO than in patients with asthma (P = 0.001), COPD-CS (=0.0290), and NLFS (P = 0.0011). This first comprehensive study suggests that patients with ACO had distinguishable tissue remodeling that appeared to be more severe than patients with asthma and COPD. This study will help in informed decision-making for better patient management in clinical practice.

Emergency department childhood anaphylaxis presentations in regional/remote Australia.

AIM: Explore the prevalence of childhood anaphylaxis and clinical presentation of anaphylaxis in children across two regional emergency departments over a 7-year period. METHODS: Retrospective audit of all children (0-18 years) presenting to emergency from 1 January 2010 to 31 December 2016 with anaphylaxis, defined by Australasian Society of Clinical Immunology and Allergy definitions and doctor diagnosis. RESULTS: Seven hundred and twenty-four patients were identified with allergic diagnosis, 60% were diagnosed with non-anaphylaxis allergic reactions or unspecified urticaria and 40% with anaphylaxis (n = 286). Annual prevalence of anaphylaxis remained stable over the study period (M = 30.9/10 000 cases, range: 20.8-48.3/10 000). Gender distribution was equal, median age was 9.48 years (interquartile range = 4-15). Most (71%) arrived by private transport. 23% had a prior history of anaphylaxis. Food triggers (44%) were the most common cause of anaphylaxis. Insect bites/stings triggers occurred in 21%. Patients were promptly assessed (average wait time = 13 min), 16% received prior adrenaline injections. Adrenaline was administered in 26% and 20% were admitted to hospital. On discharge, 29% had a follow-up plan, 9% received an allergy clinic referral, 6% anaphylaxis action plan, 26% adrenaline autoinjector prescriptions and allergy testing performed in 6%. CONCLUSIONS: We found a relatively low prevalence of overall childhood anaphylaxis in a regional area. The two most common causes of anaphylaxis in this population (food and bites/stings) recorded increased prevalence providing an opportunity for further study. Significant gaps in evidence-based care of anaphylaxis were noted, demonstrating the need for improved recognition and treatment guideline implementation in regional areas.

Dysregulation of endocytic machinery and ACE2 in small airways of smokers and COPD patients can augment their susceptibility to SARS-CoV-2 (COVID-19) infections.

Lungs of smokers and chronic obstructive pulmonary disease (COPD) are severely compromised and are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attack. The dangerous combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L, and lysosomal associated membrane protein-1 (LAMP-1) as lysosome markers in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I or GOLD stage II COPD, of which 9 were current smokers with COPD (COPD-CS) and 10 were ex-smokers with COPD (COPD-ES), 10 were normal lung function smokers, and 10 were never-smoking normal controls. Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Furthermore, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1-stained areas per total area of epithelium or subepithelium, using Image ProPlus v7.0 software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.

New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways.

Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, chronic obstructive pulmonary disease (COPD) accounting for approximately 3 million deaths annually. Frequent acute exacerbations (AEs) of COPD (AECOPD) drive clinical and functional decline in COPD and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs. Infections with a small subgroup of pathogens precipitate the majority of AEs and consequently constitute a significant comorbidity in COPD. However, current pharmacological interventions are ineffective in preventing infectious exacerbations and their treatment is compromised by the rapid development of antibiotic resistance. Thus, alternative preventative therapies need to be considered. Pathogen adherence to the pulmonary epithelium through host receptors is the prerequisite step for invasion and subsequent infection of surrounding structures. Thus, disruption of bacterial-host cell interactions with receptor antagonists or modulation of the ensuing inflammatory profile present attractive avenues for therapeutic development. This review explores key mediators of pathogen-host interactions that may offer new therapeutic targets with the potential to prevent viral/bacterial-mediated AECOPD. There are several conceptual and methodological hurdles hampering the development of new therapies that require further research and resolution.

Prevalence of asthma and allergic disorders in regional, rural, and indigenous children aged 6-8 years in Tasmania.

Objective: Asthma and allergic diseases are poorly described in rural areas. The objective of this study was, therefore, to determine the prevalence of wheezing, asthma, and other allergic disorders among children living in regional and rural Tasmania. Methodology: Data from a cross-sectional survey using standardized questionnaires of asthma, allergic conditions and food allergies were collected from 39 primary schools across North West Tasmania. We enrolled 1075 children between 6 and 8 years. The main outcomes were prevalences of wheezing, asthma, and other allergic disorders further stratified by sex and indigenous status. Results: Baseline characteristics were as follows: median age 8.1 years (IQR: 7.6, 8.7) with equal sex distribution, most (80.1%) attended public schools and 11.0% identified as indigenous. We report prevalences of current wheezing (22.7%), allergic rhinoconjunctivitis (16.3%) and atopic eczema (16.6%), with higher prevalences among boys (except eczema). Food allergies were reported in 8.6% and food-related anaphylaxis in 1.6% of the sample. Indigenous children had significantly higher prevalence of current wheezing (indigenous 31.1% versus non-indigenous 21.6%; p = 0.02). Further, children with current wheezing and no asthma diagnosis, had similar prevalence of other atopic diseases (hayfever 31.4%, eczema 44.0%, and food reaction 23.2%) compared with diagnosed asthmatics, although likely shared the illness. Conclusions: Childhood asthma is more prevalent in regional Tasmania compared with national estimates, especially among indigenous children. This appears not to be driven by an allergic response. Also, a significant proportion of children are likely to have undiagnosed asthma which has implications for rural health service delivery.

Do children with cystic fibrosis receiving outreach care have poorer clinical outcomes than those treated at a specialist cystic fibrosis centre?

INTRODUCTION: Although cystic fibrosis (CF) centre care is generally considered ideal, children living in regional Australia receive outreach care supported by the academic CF centres. METHODS: This is a retrospective database review of children with CF treated at the Royal Children's Hospital in Melbourne and its outreach clinics in Albury (Victoria), and Tasmania. The aim was to compare the outcomes of children with CF managed at an academic centre with that of outreach care, using lung function, nutritional status and Pseudomonas aeruginosa colonisation. Three models of care, namely CF centre care, Shared care and predominantly Local care, were compared, based on the level of involvement of CF centre multidisciplinary team. In our analyses, we controlled for potential confounders, such as socio-economic status and the degree of remoteness, to determine its effect on the outcome measures. RESULTS: There was no difference in lung function, i.e. forced expiratory volume in 1 s (FEV1 ), the prevalence of Pseudomonas aeruginosa colonisation or nutritional status (body mass index (BMI)) between those receiving CF centre care and various modes of outreach care. Neither socio-economic status, measured by the Socio-Economic Index for Area (SEIFA) for disadvantage, nor distance from an urban centre (Australian Standard for Geographical Classification (ASGC)) were associated with lung function and nutritional outcome measures. There was however an association between increased Pseudomonas aeruginosa colonisation and poorer socio-economic status. CONCLUSION: Outcomes in children with CF in regional and remote areas receiving outreach care supported by an academic CF centre were no different from children receiving CF centre care.

5-grass-pollen SLIT effectiveness in seasonal allergic rhinitis: Impact of sensitization to subtropical grass pollen.

Background: Temperate grass (eg, ryegrass) pollen is a major driver of seasonal allergic rhinitis (SAR) and asthma risks, including thunderstorm asthma. Data for the effectiveness of temperate grass pollen allergen immunotherapy (AIT) in SAR patients from the southern hemisphere, who are frequently polysensitized to subtropical grass pollens, are limited. The 300 IR 5-grass pollen sublingual immunotherapy tablet (300 IR 5-grass SLIT) is known to be effective in polysensitized SAR patients with primary allergy to temperate grasses, however, the influence of polysensitization to subtropical grass pollen on treatment responses has yet to be specifically addressed. Key aims of this study were to measure patient treatment satisfaction during 300 IR 5-grass SLIT treatment and evaluate how polysensitization to subtropical grass pollens affects treatment responses. Methods: A prospective observational study was conducted in 63 patients (aged ≥5 years) in several temperate regions of Australia prescribed 300 IR 5-grass SLIT for SAR over 3 consecutive grass pollen seasons. Ambient levels of pollen were measured at representative sites. Patient treatment satisfaction was assessed using a QUARTIS questionnaire. Rhinoconjunctivitis Total Symptom Score (RTSS) and a Hodges-Lehmann Estimator analysis was performed to evaluate if polysensitization to subtropical grass pollen affected SAR symptom intensity changes during SLIT. Results: A diagnosis of ryegrass pollen allergy was nearly universal. There were 74.6% (47/63) polysensitized to subtropical and temperate grass pollens. There were 23.8% (15/63) monosensitized to temperate grass pollens. From the first pollen season, statistically significant improvements occurred in SAR symptoms compared with baseline in both monosensitized and polysensitized patients, particularly in those polysensitized (P = 0.0297). Improvements in SAR symptoms were sustained and similar in both groups in the second and third pollen seasons, reaching 70-85% improvement (P < 0.01). Polysensitized patients from both northerly and southerly temperate regions in Australia showed similar improvements. Grass pollen counts in both regions were consistently highest during springtime. Conclusions: 300 IR 5-grass SLIT is effective in a real-life setting in SAR patients in the southern hemisphere with primary allergy to temperate grass pollen and predominantly springtime grass pollen exposures. Importantly, SLIT treatment effectiveness was irrespective of the patient's polysensitization status to subtropical grass pollens.

Diagnostic approaches in COVID-19: clinical updates.

INTRODUCTION: COVID-19 is a recent emerging pandemic whose prognosis is still unclear. Diagnostic tools are the main players that not only indicate a possible infection but can further restrict the transmission and can determine the extent to which disease progression would occur. AREAS COVERED: In this paper, we have performed a narrative and critical review on different technology-based diagnostic strategies such as molecular approaches including real-time reverse transcriptase PCR, serological testing through enzyme-linked immunosorbent assay, laboratory and point of care devices, radiology-based detection through computed tomography and chest X-ray, and viral cell cultures on Vero E6 cell lines are discussed in detail to address COVID-19. This review further provides an overview of emergency use authorized immunodiagnostic and molecular diagnostic kits and POC devices by FDA for timely and efficient conduction of diagnostic tests. The majority of the literature cited in this paper is collected from guidelines on protocols and other considerations on diagnostic strategies of COVID-19 issued by WHO, CDC, and FDA under emergency authorization. EXPERT OPINION: Such information holds importance to the health professionals in conducting error-free diagnostic tests and researches in producing better clinical strategies by addressing the limitations associated with the available methods.

An Audit of Pre-Pregnancy Maternal Obesity and Diabetes Screening in Rural Regional Tasmania and Its Impact on Pregnancy and Neonatal Outcomes.

Maternal obesity in pregnancy, a growing health problem in Australia, adversely affects both mothers and their offspring. Gestational diabetes mellitus (GDM) is similarly associated with adverse pregnancy and neonatal complications. A low-risk digital medical record audit of antenatal and postnatal data of 2132 pregnant mothers who gave birth between 2016-2018 residing in rural-regional Tasmania was undertaken. An expert advisory group guided the research and informed data collection. Fifty five percent of pregnant mothers were overweight or obese, 43.6% gained above the recommended standards for gestational weight gain and 35.8% did not have an oral glucose tolerance test. The audit identified a high prevalence of obesity among pregnant women and low screening rates for gestational diabetes mellitus associated with adverse maternal and neonatal pregnancy outcomes. We conclude that there is a high prevalence of overweight and obesity among pregnant women in rural regional Tasmania. Further GDM screening rates are low, which require addressing.

Electronic Cigarette Aerosol Is Cytotoxic and Increases ACE2 Expression on Human Airway Epithelial Cells: Implications for SARS-CoV-2 (COVID-19).

Tobacco smoking has emerged as a risk factor for increasing the susceptibility to infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via increased expression of angiotensin-converting enzyme-2 (ACE2) in the lung, linked to coronavirus disease 2019 (COVID-19) development. Given the modifiable nature of electronic cigarettes and the delivery of high concentrations of nicotine, we investigate whether electronic cigarette vaping has the potential to increase susceptibility to SARS-CoV-2 infection. We exposed BEAS-2B cells (bronchial epithelium transformed with Ad12-SV40 2B) and primary small airway epithelial cells (SAECs) to electronic cigarette aerosol condensates produced from propylene glycol/vegetable glycerin or commercially bought e-liquid (±added nicotine) and cigarette smoke extract to investigate if electronic cigarette exposure, like cigarette smoke, increases the expression of ACE2 in lung epithelial cells. In BEAS-2B cells, cytotoxicity (CCK-8), membrane integrity (LDH), and ACE2 protein expression (immunofluorescence) were measured for both 4- and 24 h treatments in BEAS-2B cells and 4 h in SAECs; ACE2 gene expression was measured using quantitative polymerase chain reaction (qPCR) for 4 h treatment in BEAS-2B cells. Nicotine-free condensates and higher concentrations of nicotine-containing condensates were cytotoxic to BEAS-2B cells. Higher LDH release and reduced membrane integrity were seen in BEAS-2B cells treated for 24 h with higher concentrations of nicotine-containing condensates. ACE2 protein expression was observably increased in all treatments compared to cell controls, particularly for 24 h exposures. ACE2 gene expression was significantly increased in cells exposed to the locally bought e-liquid condensate with high nicotine concentration and cigarette smoke extract compared with cell controls. Our study suggests that vaping alone and smoking alone can result in an increase in lung ACE2 expression. Vaping and smoking are avoidable risk factors for COVID-19, which, if avoided, could help reduce the number of COVID-19 cases and the severity of the disease. This is the first study to utilize electronic cigarette aerosol condensates, novel and developed in our laboratory, for investigating ACE2 expression in human airway epithelial cells.

Clinical Application of Forced Oscillation Technique (FOT) in Early Detection of Airway Changes in Smokers.

The forced oscillation technique (FOT) is a non-invasive method to assess airway function by emitting oscillatory signals into the respiratory tract during tidal ventilation. This opinion piece discusses the current use, trialled modification and future directions in utilizing FOT as a novel diagnostic tool for early detection of small airway changes in smokers. The published evidence to date has shown that FOT parameters could be a sensitive diagnostic tool to detect early respiratory changes in smokers. Multiple frequencies and the frequency dependence of resistance and reactance can provide the most valuable and early information regarding smoking induced changes in airways. Considering its non-invasiveness, lower level of discomfort to patients than spirometry, feasibility, and cost effectiveness, it could be the first-choice diagnostic technique for detection of early respiratory changes in smokers. The finding of FOT could further be supported and correlated with inflammatory markers.

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities.

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship.

The challenge of chronic lung disease in HIV-infected children and adolescents.

Until recently, little attention has been given to chronic lung disease (CLD) in HIV-infected children. As the HIV epidemic matures in sub-Saharan Africa, adolescents who acquired HIV by vertical transmission are presenting to health services with chronic diseases. The most common is CLD, which is often debilitating. This review summarizes the limited data available on the epidemiology, pathophysiology, clinical picture, special investigations and management of CLD in HIV-infected adolescents. A number of associated conditions: lymphocytic interstitial pneumonitis, tuberculosis and bronchiectasis are well described. Other pathologies such as HIV-associated bronchiolitis obliterans resulting in non-reversible airway obstruction, has only recently been described. In this field, there are many areas of uncertainty needing urgent research. These areas include the definition of CLD, pathophysiological mechanisms and common pathologies responsible. Very limited data are available to formulate an effective plan of investigation and management.

Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy.

BACKGROUND: Few large-scale studies have examined inhaled corticosteroid treatment in preschool children with recurrent wheeze. We assessed the effects of ciclesonide in preschool children with recurrent wheeze. METHODS: We included children 2-6 yrs with recurrent wheeze and a positive asthma predictive index or aeroallergen sensitization to, excluding patients with episodic viral wheezing. After a 2-4-week baseline period, patients with ongoing symptoms or rescue medication use were randomised to once-daily ciclesonide 40, 80, 160 µg or placebo for 24 weeks. RESULTS: The number of wheeze exacerbations requiring systemic corticosteroids was unexpectedly low in all groups: 25 (10.2%) in placebo group, as compared to 11 (4.4%), 18 (7.3%), and 17 (6.7%) in ciclesonide 40, 80, and 160 µg, respectively. The difference in time to first exacerbation was not significantly different between groups (p = 0.786), but the difference in exacerbation rates between placebo and the pooled ciclesonide groups was (p = 0.03). Large and significant (p < 0.0001) improvements in symptom scores and rescue medication use occurred in all groups, including placebo. Improvements in FEV(1) and FEF(25-75) (measured in 284 4-6 yr olds) were larger in the ciclesonide than in the placebo group. No differences in safety parameters (adverse events, height growth, serum and urinary cortisol levels) between ciclesonide and placebo were observed. CONCLUSIONS: In preschool children with recurrent wheeze and a positive asthma predictive index, ciclesonide modestly reduces wheeze exacerbation rates and improves lung function. A large placebo response and unexpected selection of patients with mild disease may have affected outcomes, highlighting the heterogeneity of preschool wheezing disorders.