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This study assessed the relationship between peripheral airway function, measured by multiple breath nitrogen washout and oscillometry impedance, and exacerbation history. We found that those with a history of exacerbation in the last year had worse peripheral airway function, whereas those recently treated for an asthma exacerbation had peripheral airway function that was comparable to the stable group. These findings implicate active peripheral airway dysfunction in the pathophysiology of an asthma exacerbation.

Asthma is a common but complex heterogenous inflammatory airway disorder. Despite significant developments in our understanding of the pathophysiology and treatment of asthma, it remains a major cause of mortality and morbidity. Optimal management involves addressing modifiable risk factors, titration of inhaled pharmacotherapy in a stepwise approach and, in severe disease, consideration of biologic agents. Appreciation of the clinical characteristics of asthma and recognition of the immune pathways involved has allowed the development of phenotypic and endotypic subtypes of asthma to be better defined. This has revolutionised asthma management, allowing risk stratification of patients, targeted use of biologic agents to modify cytokine responses that drive asthma and improved patient outcomes. Patient education and engagement are critical to the management of this disease in an era of personalised medicine and a rapidly changing global environment.

Background Asthma epidemics associated with thunderstorms have had catastrophic impacts on individuals and emergency services. Seasonal allergic rhinitis (SAR) is present in the vast majority of people who develop thunderstorm asthma (TA), but there is little evidence regarding risk factors for TA among the SAR population. Objective We sought to identify risk factors for a history of TA and hospital presentation in a cohort of individuals with SAR. Methods This multi-centre study recruited adults from Melbourne (Australia) with a past diagnosis of TA and/or self-reported SAR. Clinical information, spirometry, white blood-cell count, ryegrass pollen specific IgE (RGP-spIgE) and fractional exhaled nitric oxide (FeNO) were measured to identify risk factors for a history of TA in individuals with SAR. Results From a total of 228 individuals with SAR, 35% (80/228) reported SAR only (I-SAR), 37% (84/228) reported TA symptoms but had not attended hospital for treatment (O-TA) and 28% (64/228) had presented to hospital for TA (H-TA). All H-TA patients reported a previous asthma diagnosis. Logistic regression analysis of factors associated with O-TA and H-TA indicated that lower forced expiratory volume in one second (FEV1) and asthma control questionnaire (ACQ) score >1.5 were associated with H-TA. Higher blood RGP-spIgE, eosinophil counts, and FeNO were significantly associated with both O-TA and H-TA. Receiver-operating curve (ROC) analysis showed RGP-spIgE >10·1 kU/L and pre-bronchodilator FEV1 ≤90% to be biomarkers of increased H-TA risk. Conclusion Clinical tests can identify risk for a history of TA in individuals with SAR and thereby inform patient-specific treatment recommendations.

An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking.The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA.A systematic search across standard databases was conducted using specific keywords until May 13, 2021. A meta-analysis was performed to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, patient-reported asthma control) and safety of pre- and post- omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease.In total, 49 studies (n=267) were included in the qualitative synthesis and 14 case series (n=186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate versus pre-treatment (mean difference [MD]: -2.09 [-3.07; -1.11], P0.01). There was a reduction in the OCS use (risk difference [RD]: 0.65 [0.46;0.84], P0.01), an increase in termination of OCS use (RD: 0.53 [0.24;0.82], P0.01), and a reduction in OCS dose (mg/day) (MD: -14.62 [-19.86; -9.39]; P0.01) in ABPA patients receiving omalizumab. Omalizumab improved forced expiratory volume in 1 second (FEV1) % predicted by 11.9% (8.2; 15.6, P0.01) and asthma control, and was well tolerated.Omalizumab treatment reduced exacerbations and OCS use and improved lung function and asthma control in patients with ABPA and was well tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.

Purpose of review Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility. Recent findings PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID. Summary We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.

Epidemic thunderstorm asthma (ETSA) occurs following a thunderstorm due to the interaction of environmental and immunologic factors. Whilst first reported in the 1980s, the world’s largest event in Melbourne, Australia, on November 21, 2016 has led to a wealth of clinical literature seeking to identify its mechanisms, susceptibility risk factors, and management approaches. Thunderstorm asthma (TA) typically presents during an aeroallergen season in individuals sensitized to perennial rye grass pollen (RGP) in Australia, or fungus in the United Kingdom, in combination with meteorological factors such as thunderstorms and lightning activity. It is now well recognized that large pollen grains, which usually lodge in the upper airway causing seasonal allergic rhinitis (SAR), are ruptured during these events, leading to sub-pollen particles respirable to the lower respiratory tract causing acute asthma. The identified risk factors of aeroallergen sensitization, specifically to RGP in Australians with a history of SAR, and individuals born in Australia of South-East Asian descent as a risk factor for TA has been key in selecting appropriate patients for preventative management. Moreover, severity-determining risk factors for ETSA-related asthma admission or mortality, including pre-existing asthma or prior hospitalization, poor inhaled corticosteroid adherence, and outdoor location at the time of the storm are important in identifying those who may require more aggressive treatment approaches. Basic treatments include optimizing asthma control and adherence to inhaled corticosteroid therapy, treatment of SAR, and education regarding TA to increase recognition of at-risk days. Precision treatment approaches may be more beneficial in select individuals, including the use of allergen immunotherapy and even biologic treatment to mitigate asthma severity. Finally, we discuss the importance of environmental health literacy in the context of concerns surrounding the increased frequency of ETSA due to climate change and its implications for the frequency and severity of future events.

There is current interest in the role of ambient pollen in the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or COVID-19) infection risk. The aim of this review is to summarise studies published up until January 2023 investigating the relationship between airborne pollen and the risk of COVID-19 infection. We found conflicting evidence, with some studies showing that pollen may increase the risk of COVID-19 infection by acting as a carrier, while others showed that pollen may reduce the risk by acting as an inhibiting factor. A few studies reported no evidence of an association between pollen and the risk of infection. A major limiting factor of this research is not being able to determine whether pollen contributed to the susceptibility to infection or just the expression of symptoms. Hence, more research is needed to better understand this highly complex relationship. Future investigations should consider individual and sociodemographic factors as potential effect modifiers when investigating these associations. This knowledge will help to identify targeted interventions.

Background: Experimental challenge studies have shown that pollen can have early and delayed effects on the lungs and airways. Here, we qualitatively and quantitatively synthesize the evidence of outdoor pollen exposure on various lung function and airway inflammation markers in community-based studies. Methods: Four online databases were searched: Medline, Web of Science, CINAHL and Google Scholar. The search strategy included terms relating to both exposure and outcomes. Inclusion criteria were human-based studies published in English that were representative of the community. Additionally, we only considered cross-sectional or short-term longitudinal studies which investigated pollen exposure by levels or season. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was conducted using random-effects models. Results: We included 27 of 6551 studies identified from the search. Qualitative synthesis indicated associations between pollen exposure and predominantly type-2 inflammation in both the upper and lower airways, but little evidence for lung function changes. People with ever asthma and/or seasonal allergic rhinitis (SAR) were at higher risk of such airway inflammation. Meta-analysis confirmed a positive relationship between pollen season, eosinophilia and eosinophil cationic protein (ECP) in people with ever SAR but the results between studies were highly variable. Heterogeneity was reduced after further subgrouping by age, and the forest plots indicated that eosinophilic airway inflammation to outdoor pollen exposure increased with age. Conclusion: Among people with ever asthma and ever SAR, exposure to increased ambient pollen triggers type-2 upper and lower airway inflammation rather than a non-specific or innate inflammation. These findings can lead to the formulation of specific pollen immunotherapy for susceptible individuals. Future research should be directed towards investigating lagged associations and effect modifications using larger and more generalized populations.

While the relationship between pollen and respiratory allergies is well-documented, the role of short-term pollen exposure in food allergy and eczema flares has not previously been explored. We aimed to investigate these associations in a population-based sample of children.We investigated 1- (n = 1108) and 6-year-old (n = 675) children in the grass pollen season from the HealthNuts cohort. Grass pollen concentrations were considered on the day of testing (lag 0), up to three days before (lag 1-lag 3) and cumulatively (lag 0-3). Associations between grass pollen and food skin-prick test reactivity (SPT ≥ 2 mm at age 1 year and ≥ 3 mm at age 6 years), eczema flares, challenge-confirmed food allergy, reaction threshold to oral food challenges (OFC), and serum food-specific IgE levels were analyzed using either logistic or quantile regression models. Atopy and family history of allergic disease were considered as potent effect modifiers.Grass pollen at lag 0-3 (every 20 grains/msup3/supincrease) was associated with an up to 1.2-fold increased odds of food SPT reactivity and eczema flares in 6-year-olds. In 1-year-olds, the associations were only observed for peanut in those with a family history of food allergy. Increasing grass pollen concentrations were associated with a lower reaction threshold to OFC and higher serum IgE levels in peanut-allergic 1-year-olds only.Increasing grass pollen concentration was associated with increased risk of food SPT reactivity and eczema flares in children. The associations in peanut-allergic infants may be related to immune activation and/or peanut and grass pollen cross-reactivity leading to a lower reaction threshold.

Epidemic thunderstorm asthma (ETSA) is due to a complex interaction of environmental and individual susceptibility factors, with outbreaks reported globally over the last four decades. Australia has been particularly susceptible with nearly half of episodes reported internationally, culminating in the catastrophic Melbourne 2016 event.Reported ETSA episodes are reviewed for common environmental and meteorological risk factors. Allergen aerobiology interaction with thunderstorm activity and rapid weather condition changes is examined. Assessment of the clinical and immunological data highlights risk factors for ETSA presentation, hospital admission, and intensive care admission. Risk factors associated with ETSA deaths are evaluated. Public health strategies, as well as pharmacological and immunological management approaches to reduce individual susceptibility and prevent ETSA are discussed.Improved understanding of the specific meteorological factors predisposing to the greatest risk of ETSA to improve forecasting is required. Better monitoring of aeroallergen levels in areas of greatest geographic risk, with further research into allergen aerobiology underpinning mechanisms of allergen exposure is needed. The role of climate change in increasing the risk of ETSA outbreaks requires further research. Public awareness and education are required to reduce exposure, and to improve uptake of pharmacological and immunological risk reduction and preventive strategies.

Background The association between grass pollen exposure and early markers of asthma exacerbations such as lung function changes and increase in airway inflammation is limited. We investigated the associations between short-term grass pollen exposure and lung function and airway inflammation in a community-based sample, and whether any such associations were modified by current asthma, current hay fever, pollen sensitization, age, and other environmental factors. Methods Cross-sectional and short-term analyses of data from the Melbourne Atopy Cohort Study (MACS) participants (n = 936). Lung function was assessed using spirometry. Airway inflammation was assessed by fractional exhaled nitric oxide (FeNO) and exhaled breath condensate pH and nitrogen oxides (NOx). Daily pollen counts were collected using a volumetric spore trap. The associations were examined by linear regression. Results Higher ambient levels of grass pollen 2 days before (lag 2) were associated with lower mid-forced expiratory flow (FEF25%-75%) and FEV1/FVC ratio (Coef. [95% CI] = −119 [−226, −11] mL/s and −1.0 [−3.0, −0.03] %, respectively) and also 3 days before (lag 3). Increased levels of grass pollen a day before (lag 1) were associated with increased FeNO (4.35 [−0.1, 8.7] ppb) and also at lag 2. Adverse associations between pollen and multiple outcomes were greater in adults with current asthma, hay fever, and pollen sensitization. Conclusion Grass pollen exposure was associated with eosinophilic airway inflammation 1-2 days after exposure and airway obstruction 2-3 days after exposure. Adults and individuals with asthma, hay fever, and pollen sensitization may be at higher risk.

[Purpose] The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI)., [Methods] Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject’s previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs, [Results] Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12–16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (, [Conclusions] IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI., This study was funded in full by Grifols.

International audience; Severe asthma often remains uncontrolled despite effective treatments and evidence-based guidelines. A group of global experts in asthma and biologic medications from nine countries considered the most relevant clinical variables to manage severe asthma in adult patients and guide treatment choice. The resulting recommendations address the investigation of biomarker levels (blood eosinophil count along with fractional concentration of exhaled nitric oxide [FeNO]), clinical features (oral corticosteroid [OCS] dependency, specific comorbid disease entities associated with severe type 2 asthma), and safety considerations. Current evidence suggests that biomarkers, including both blood or sputum eosinophil counts as well as FeNO, add prognostic and predictive value and should be measured in all patients with severe asthma. OCS use is an important factor in biologic selection, especially given the documented ability of some biologics to reduce OCS dependency. Comorbid diseases and relevant safety considerations to each biologic should also be considered. More data are needed to determine whether biomarker profiles identify patients suited to one biologic versus another as limited data support differential predictors of response. Further prospective head-to-head trials and post hoc analyses of clinical trial data are warranted. The authors believe these recommendations have value as they offer expert opinion to assist health care providers in making difficult decisions regarding the quality of care in severe, type 2 asthma with biologic medications. They remain conditional and are based on limited data owing to a lack of head-to-head comparisons.

Severe asthma affects an estimated 5–10% of the total asthma patient population [1]. Various demographic factors, such as sex, age, obesity and age of onset, have been associated with asthma disease severity [2, 3], and the efficacy of asthma treatments has previously been found to vary depending on patient demographics [4, 5]., Dupilumab treatment versus placebo improved exacerbation rate and lung function outcomes in patients with uncontrolled moderate-to-severe asthma and high type 2 biomarkers at baseline, regardless of baseline characteristics in the phase 3 QUEST study https://bit.ly/3yR7MlD

Background Experimental challenge studies have shown that pollen can affect the lungs and airways. Here, we systematically reviewed community-based studies investigating outdoor pollen exposure, lung function and/or airway inflammation. Methods Four online databases were searched. The search strategy included terms relating to both exposure and outcomes. Inclusion criteria were studies published in English that were representative of the community. We only considered cross-sectional or short-term longitudinal studies which investigated pollen exposure by levels or season. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was conducted using random-effects models. Results We included 27 of 6,551 studies identified from the search. Qualitative synthesis indicated associations between pollen exposure and predominantly type-2 inflammation in both the upper and lower airways, but little evidence for lung function changes. People with ever asthma and/or seasonal allergic rhinitis (SAR) were at higher risk of such airway inflammation. Meta-analysis confirmed a positive relationship between pollen season and eosinophilic airway inflammation in people with ever SAR but the results between studies were highly variable. Heterogeneity was reduced after further subgrouping by age and the forest plots indicated that eosinophilic airway inflammation to outdoor pollen exposure increased with age. Conclusion Among people with ever asthma and ever SAR, exposure to increased ambient pollen triggers type-2 airway inflammation rather than a non-specific or innate inflammation. Key messages This review indicates pollen exposure influences predominantly type-2 airway inflammation, but little evidence on lung function.

Thunderstorm-triggered asthma (TA) is the occurrence of acute asthma attacks immediately following a thunderstorm. Epidemics have occurred across the world during pollen season and have the capacity to rapidly inundate a health care service, resulting in potentially catastrophic outcomes for patients. TA occurs when specific meteorological and aerobiological factors combine to affect predisposed patients. Thunderstorm outflows can concentrate aeroallergens, most commonly grass pollen in TA, at ground level to release respirable allergenic particles after rupture by osmotic shock related to humidity and rainfall. Inhalation of high concentrations of these aeroallergens by sensitized individuals can induce early asthmatic responses which are followed by a late inflammatory phase. Other environmental factors such as rapid temperature change and agricultural practices contribute to the causation of TA. The most lethal TA event occurred in Melbourne, Australia, in 2016. Studies on the affected individuals found TA to be associated with allergic rhinitis, ryegrass pollen sensitization, pre-existing asthma, poor adherence to inhaled corticosteroid preventer therapy, hospital admission for asthma in the previous year and outdoor location at the time of the storm. Patients without a prior history of asthma were also affected. These factors are important in extending our understanding of the etiology of TA and associated clinical indicators as well as possible biomarkers which may aid in predicting those at risk and thus those who should be targeted in prevention campaigns. Education on the importance of recognizing asthma symptoms, adherence to asthma treatment and controlling seasonal allergic rhinitis is vital in preventing TA. Consideration of allergen immunotherapy in selected patients may also mitigate risk of future TA. Epidemic TA events are predicted to increase in frequency and severity with climate change, and identifying susceptible patients and preventing poor outcomes is a key research and public health policy priority.

Grass pollen exposure is a risk factor for childhood asthma hospital attendances. However, its short-term influence on lung function, especially among those with other allergic conditions, has been less well-studied.To investigate this association in a population-based sample of children.Within the HealthNuts cohort, 641 children performed spirometry during the grass pollen season. Grass pollen concentration was considered on the day of testing (lag 0), up to 3 days before (lag 1-lag 3), and cumulatively (lag 0-3). We used linear regression to assess the relevant associations and examined potential interactions with current asthma, hay fever or eczema, and food allergy.Associations were observed only in children with allergic disease (P value for interaction ≤ 0.1). In children with food allergy, grass pollen concentration was associated with a lower ratio of forced expiratory volume in 1 second to forced vital capacity (FEVA proactive approach needs to be enforced to manage susceptible children, especially those with food allergy, before high-grass pollen days.

Background Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. Objective To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. Methods The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. Results Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. Conclusions This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.

ObjectivesThe threat of a pandemic, over and above the disease itself, may have significant and broad effects on a healthcare system. We aimed to describe the impact of the SARS-CoV-2 pandemic (during a relatively low transmission period) and associated societal restrictions on presentations, admissions and outpatient visits.DesignWe compared hospital activity in 2020 with the preceding 5 years, 2015–2019, using a retrospective cohort study design.SettingQuaternary hospital in Melbourne, Australia.ParticipantsEmergency department presentations, hospital admissions and outpatient visits from 1 January 2015 to 30 June 2020, n=896 934 episodes of care.InterventionIn Australia, the initial peak COVID-19 phase was March–April.Primary and secondary outcome measuresSeparate linear regression models were fitted to estimate the impact of the pandemic on the number, type and severity of emergency presentations, hospital admissions and outpatient visits.ResultsDuring the peak COVID-19 phase (March and April 2020), there were marked reductions in emergency presentations (10 389 observed vs 14 678 expected; 29% reduction; pConclusionsAlthough case numbers of COVID-19 were relatively low in Australia during the first 6 months of 2020, the impact on hospital activity was profound.

Respiratory diseases such as asthma, allergic rhinitis (AR) and chronic obstructive pulmonary disease (COPD) affect millions worldwide and pose a significant global public health burden. Over the years, changes in land use and climate have increased pollen quantity, allergenicity and duration of the pollen season, thus increasing its impact on respiratory disease. Many studies have investigated the associations between short-term ambient pollen (i.e., within days or weeks of exposure) and respiratory outcomes. Here, we reviewed the current evidence on the association between short-term outdoor pollen exposure and thunderstorm asthma (TA), asthma and COPD hospital presentations, general practice (GP) consultations, self-reported respiratory symptoms, lung function changes and their potential effect modifiers. The literature suggests strong evidence of an association between ambient pollen concentrations and almost all respiratory outcomes mentioned above, especially in people with pre-existing respiratory diseases. However, the evidence on sub-clinical lung function changes, COPD, and effect modifiers other than asthma, hay fever and pollen sensitisation are still scarce and requires further exploration. Better understanding of the implications of pollen on respiratory health can aid healthcare professionals to implement appropriate management strategies.

Purpose Improved understanding of characteristics that may influence treatment response across phenotypes may help guide treatment decisions. Patients and Methods This was a post hoc analysis of MENSA, a multicenter, randomized, double-blind, placebo-controlled trial (NCT01691521). Patients aged ≥12 years with severe eosinophilic asthma received mepolizumab (75 mg intravenously or 100 mg subcutaneously) or placebo, plus standard of care, every 4 weeks for 32 weeks. Outcomes assessed were the annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire (ACQ)-5 score. Subgroup analyses were performed by baseline blood eosinophil count (17.5 kU/L]), and by house dust mite (HDM) sensitivity. Results Of 576 patients analyzed, 272 were non-atopic, 181 were atopic and 94 were strongly atopic; 29 had missing atopy data. In patients with blood eosinophil counts ≥300 cells/µL, mepolizumab versus placebo reduced clinically significant exacerbations by 74%, 43% and 25% in the non-atopic, atopic and strongly atopic subgroups. Similar reductions were observed in all atopic subgroups in other blood eosinophil count categories where there were sufficient patient numbers for analysis, except for non-atopic patients with baseline blood eosinophil counts of, Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/l92s5nzD3OI

Over recent years, Australians have been subject to an unprecedented number of environmental events materially and visibly affecting air quality, including thunderstorm asthma and bushfire smoke. There is increasing evidence that poor air quality adversely affects health with consequences for mortality and morbidity with measured particulates (PM2.5) in January 2019 frequently exceeding World Health Organization standards. Biological factors can also impact air quality with thunderstorm asthma epidemics evidence of a prime example, the 2016 event being associated with severe impacts on health services. Given these events, consideration needs to be given to environmental health literacy which will support individuals with pre-existing illness to recognise and mitigate as far as possible the effects of adverse air quality. Recognising the impact of poor air quality should also urge physicians to advocate for clean air as a necessity for good health.

Rationale: On November 21, 2016 in Australia, a major thunderstorm-asthma epidemic struck Melbourne with an unprecedented number of emergency presentations, hospital admissions and fatalities. Objectives: We identified affected patients who presented to The Royal Melbourne Hospital, an adult tertiary center in North-West Melbourne. We aimed to characterize individual patient factors associated with hospital admission and identify biomarkers in patient subgroups that are at risk of being severely affected by thunderstorm-asthma. Methods: Cross-sectional, retrospective analysis of demographics of 240 patients presenting to The Royal Melbourne Hospital on November 21 to 22, 2016 post thunderstorm-asthma event and clinical characteristics of 70 of those patients who subsequently attended an outpatient clinic review. Results: Patients were generally young adults (mean age 35 years), with seasonal rhinitis (96%) and universally (100%) sensitized to ryegrass pollen. Forty-four patients (63%) had a known diagnosis of asthma while 20% reported no previous diagnosis but had symptoms consistent with asthma. Patient characteristics associated with hospitalization were: uncontrolled asthma symptoms in the month before the thunderstorm-asthma event, symptomatic allergic rhinitis, high blood eosinophilia and lower lung function. Conclusion: Thunderstorm-asthma affects people with seasonal rhinitis, ryegrass sensitization and can occur without prior history of asthma, with dramatic potential to inundate a healthcare system. Our data suggests that hospitalization, and thus a more severe thunderstorm-asthma exacerbation, was associated with a known history of asthma, prior uncontrolled asthma symptoms, allergic rhinitis, high eosinophil count and lower lung function. These factors may inform strategies to identify those most at risk of thunderstorm-asthma.

Background The world's most catastrophic and deadly thunderstorm asthma epidemic struck Melbourne, Australia, on November 21, 2016. Objective Among thunderstorm-affected patients presenting to emergency rooms (ERs), we investigated risk factors predicting severe attacks requiring admission to hospital. Methods Thunderstorm-affected patients were identified from ER records at the eight major Melbourne health services and interviewed by telephone. Risk factors for hospital admission were analyzed. Results We interviewed 1435/2248 (64%) of thunderstorm-affected patients, of whom 164 (11.4%) required hospital admission. Overall, rhinitis was present in 87%, and current asthma was present in 28%. Odds for hospital admission were higher with increasing age (odds ratio 1.010, 95% CI 1.002, 1.019) and among individuals with current asthma (adjusted odds ratio [aOR] 1.87, 95% CI 1.26, 2.78). Prior hospitalization for asthma in the previous 12 months further increased the odds for hospital admission (aOR 3.16, 95% CI 1.63, 6.12). Among patients of Asian ethnicity, the odds for hospital admission were lower than for non-Asian patients (aOR 0.59, 95% CI 0.38, 0.94), but higher if born in Australia (OR = 5.42, 95% CI 1.56, 18.83). Conclusions In epidemic thunderstorm asthma patients who presented to the ER, higher odds for hospital admission among patients with known asthma were further amplified by recent asthma admission, highlighting the vulnerability conferred by suboptimal disease control. Odds for hospital admission were lower in Asian patients born overseas, but higher in Asian patients born locally, than in non-Asian patients; these observations suggest susceptibility to severe thunderstorm asthma may be enhanced by gene-environment interactions.

Background: A multidisciplinary collaboration investigated the world's largest, most catastrophic epidemic thunderstorm asthma event that took place in Melbourne, Australia, on Nov 21, 2016, to inform mechanisms and preventive strategies. Methods: Meteorological and airborne pollen data, satellite-derived vegetation index, ambulance callouts, emergency department presentations, and data on hospital admissions for Nov 21, 2016, as well as leading up to and following the event were collected between Nov 21, 2016, and March 31, 2017, and analysed. We contacted patients who presented during the epidemic thunderstorm asthma event at eight metropolitan health services (each including up to three hospitals) via telephone questionnaire to determine patient characteristics, and investigated outcomes of intensive care unit (ICU) admissions. Findings: Grass pollen concentrations on Nov 21, 2016, were extremely high (>100 grains/m 3 ). At 1800 AEDT, a gust front crossed Melbourne, plunging temperatures 10°C, raising humidity above 70%, and concentrating particulate matter. Within 30 h, there were 3365 (672%) excess respiratory-related presentations to emergency departments, and 476 (992%) excess asthma-related admissions to hospital, especially individuals of Indian or Sri Lankan birth (10% vs 1%, p

Background: Cashew is a common cause of tree nut allergy in children. To date there have been few studies of diagnostic tests for cashew allergy, and positive predictive values (PPVs) for cashew as well as other tree nuts are largely extrapolated from studies of peanut allergy. How relevant these cutoffs are for cashew has not been formally explored. Objective: We aimed to establish skin prick test (SPT) wheal sizes that correlated to 95% PPV for a positive food challenge for cashew. Methods: We included all cashew oral food challenges (OFCs) conducted as part of the HealthNuts (n = 108; age, 4-6 years) and SchoolNuts (n = 37; age, 10-14 years) studies, both recruited from the community (population cohort). A second cohort of all cashew OFCs conducted at the Royal Children's Hospital (RCH) allergy center (n = 343) (2011-2016) and a private allergy clinic based at RCH (n = 43) was included via electronic medical record review (clinic cohort). The 95% PPV for cashew SPT was calculated for both cohorts. Results: Among the population cohort (n = 145), 62% of cashew OFCs were positive compared with 20% of the clinic cohort (n = 386). The SPT cutoff for 95% PPV derived from the population cohort was 10 mm (95% confidence interval [CI], 7.5-12.0). For the clinic cohort, the 95% PPV was 14 mm (95% CI, 9.5-unknown). An SPT wheal size of 8 mm had a PPV of 89% (95% CI, 79-95) in the population cohort and 62% (95% CI, 45-78) in the clinic cohort. Conclusion: A higher SPT wheal size may be more appropriate than the commonly used 8 mm cutoff to guide clinical decisions around when to perform OFC for cashew.

Allergen immunotherapy (AIT) reduces symptoms and medication use associated with allergic rhinitis with or without conjunctivitis and allergic asthma. Although several AIT guidelines exist, there remain unanswered questions about AIT that are relevant to everyday practice. Our objective was to prepare an evidence-based overview addressing the practical aspects of AIT in clinical practice based on published evidence and the experience of international experts in the field. Topics covered include interpretation and translation of clinical trial data into everyday clinical practice (eg, allergen doses and treatment duration), assessment of risk and treatment of local and systemic allergic reactions, recommendations for improvement of AIT guidelines, and identification of appropriate data for seeking regulatory approval, to name a few. Many informational gaps in AIT practice need further evaluation as products and practices evolve.

Introduction Dupilumab, a fully human VelocImmuner-derived monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on dupilumab 200 mg/300 mg every 2 weeks (q2w) vs placebo reduced severe exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma. Treatment effects were greater in patients with elevated type 2 biomarkers at baseline. This post hoc analysis assessed the effects of dupilumab on pre-bronchodilator FEV1 by baseline disease characteristics in patients with baseline levels of blood eosinophils g150 cells/mL or fractional exhaled nitric oxide (FeNO) g20 ppb, biomarkers of type 2 inflammation.n Methods Least squares (LS) mean changes from baseline to Week 12 in pre-bronchodilator FEV1 were assessed using mixed-effect models with repeated measures. Results Dupilumab 200 mg/300 mg q2w vs placebo improved pre-bronchodilator FEV1 in patients with elevated type 2 biomarkers in subgroups defined by controller medications at randomization, baseline pre-bronchodilator FEV1 (l1.75 L/g1.75 L), number of severe asthma exacerbations (g1, g2, g3) in the previous year, smoking history (never smoked/former smoker with a smoking history l10 pack-years), and age at asthma onset (l40nyears/g40 years) (figure). The effect of dupilumab was significant in all subgroups except for a couple of subgroups of patients with type 2 inflammation on triple asthma controllers and those who were former smokers. Overall, the most frequent dupilumab 200 mg/300 mg vs matched placebo adverse event was injection-site reaction (15%/18% vs 5%/10%). Conclusions Dupilumab significantly improved pre-bronchodilator FEV1 across most baseline disease characteristics in patients with uncontrolled, moderate-to-severe asthma with evidence of type 2 inflammation at baseline. Dupilumab was generally well tolerated.

Background: Epidemic thunderstorm asthma (ETSA) severely affected Melbourne, Australia in November 2016. There is scant literature on the natural history of individuals affected by ETSA. Objective: A multicentre 12-month prospective observational study was conducted assessing symptomatology and behaviors of ETSA-affected individuals. Methods: We used a structured phone questionnaire to assess asthma symptom frequency, inhaled preventer use, asthma action plan ownership and healthcare utilization over 12 months since the ETSA. Analysis of results included subgroup analyses of the "current," "past," "probable," and "no asthma" subgroups defined according to their original 2016 survey responses. Results: Four hundred forty-two questionnaires were analyzed. Eighty percent of individuals reported ongoing asthma symptoms at follow-up, of which 28% were affected by asthma symptoms at least once a week. Risk of persistent asthma symptoms was significantly higher in those with prior asthma diagnosis, current asthma, and probable undiagnosed asthma (all p < 0.01). Of 442 respondents, 53% were prescribed inhaled preventers, of which 51% were adherent at least 5 days a week. Forty-two percent had a written asthma action plan and 16% had sought urgent medical attention for asthma in the preceding year. Conclusions: Following an episode of ETSA, patients experience a pivotal change in asthma trajectory with both loss of asthma control and persistence of de novo asthma. Suboptimal rates of inhaled preventer adherence and asthma action plan ownership may contribute to asthma exacerbation risk and susceptibility to future ETSA episodes. Longer-term follow-up is needed to determine the extent and severity of this apparent change.

Background Asian infants born in Australia are 3 times more likely to develop nut allergy than non-Asian infants and rates of challenge-proven food allergy in infants have been found to be unexpectedly high in metropolitan Melbourne. To further investigate risk factors for nut allergy we assessed the whole of State prevalence distribution of parent-reported nut allergy in 5 year old children entering school. Methods Using the 2010 School Entrant Health Questionnaire administered to all 5 year old children in Victoria, Australia, we assessed the prevalence of parent-reported nut allergy (tree nut and peanut) and whether this was altered by region of residence, socioeconomic status, country of birth or history of migration. Prevalence was calculated as observed proportion with 95% confidence intervals (CI). Risk factors were evaluated using multivariable logistic regression and adjusted for appropriate confounders. Results Parent-reported nut allergy prevalence was 3.1% (95%CI 2.9-3.2) amongst a cohort of nearly 60,000 children. It was more common amongst children of mothers with higher education and socioeconomic index and less prevalent amongst children in regional Victoria than in Melbourne. While children born in Australia to Asian-born mothers (aOR 2.67 95%CI 2.28, 3.27) were more likely to have nut allergy than non-Asian children, children born in Asia who subsequently migrated to Australia were at decreased risk of nut allergy (aOR 0.1 95%CI 0.03, 0.31). Conclusion Migration from Asia after the early infant period appears protective for the development of nut allergy. Additionally, rural regions have lower rates of nut allergy than urban areas. This article is protected by copyright. All rights reserved.

Common variable immunodeficiency is the most prevalent of the primary immunodeficiency diseases, yet its pathogenesis is largely poorly understood. Of the cases that are monogenic, many arise due to pathogenic variants in NFKB1 and NFKB2. Here, we report enteroviral encephalomyelitis as the cause of a fatal neurodegenerative condition in a patient with a novel heterozygous mutation in NFKB2 (c.2543insG, p.P850Sfs36*) that disrupts non-canonical NF-κB signaling. Investigations of primary and secondary lymphoid tissue demonstrated a complete absence of B cells and germinal centers. Despite multiple negative viral PCR testing of cerebrospinal fluid during her disease progression, post-mortem analysis of cerebral tissue revealed a chronic lymphocytic meningoencephalitis, in the presence of Cocksackie A16 virus, as the cause of death. The clinical features, and progression of disease reported here, demonstrate divergent clinical and immunological phenotypes of individuals within a single family. This is the first reported case of fatal enteroviral encephalomyelitis in a patient with NF-κB2 deficiency and mandates a low threshold for early brain biopsy and the administration of increased immunoglobulin replacement in any patient with a defect in this pathway and deterioration of neurological status.

The transforming growth factor (TGF)-β cytokines play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including asthma, COPD, lung cancer and idiopathic pulmonary fibrosis. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact. Although TGF-β inhibition as a therapeutic strategy carries great expectations, the constraints in avoiding compromising the beneficial pleiotropic effects of TGF-β, including the anti-proliferative and immune suppressive effects, have limited the development of effective pharmacological modulators. In this review, we focus on the pathways subserving deleterious and beneficial TGF-β effects to identify strategies for selective modulation of more distal signaling pathways that may result in agents with improved safety/efficacy profiles. Adverse effects of TGF-β inhibitors in respiratory clinical trials are comprehensively reviewed, including those of the marketed TGF-β modulators, pirfenidone and nintedanib. Precise modulation of TGF-β signaling may result in new safer therapies for chronic respiratory diseases.

Background Adolescence is well recognized as a period of increased risk for severe and fatal food-induced anaphylaxis. Current Australian adrenaline autoinjector (AAI) prescription guidelines therefore suggest that consideration be given to AAI prescription in all adolescents with a food allergy. To date, however, few studies have assessed the AAI carriage behavior of adolescents prescribed AAI devices. Objective To determine the carriage behavior of prescribed AAI devices in a population-based sample of young Australian adolescents. Methods Students aged 10 to 14 years (and their parents) from randomly selected schools in metropolitan Melbourne completed self-administered questionnaires regarding the history and management of food allergy, including prescription and carriage of AAI device in different domains of school and social life. Results A total of 9816 students completed the questionnaire (46% response): 620 students were assessed to have likely IgE-mediated food allergy and 234 (38%) of these had been prescribed an AAI. Most students (93%; 95% CI, 89%-96%) who were prescribed AAIs reported that they provided their AAI and anaphylaxis action plan to their school. Adherence to AAI carriage in other domains of social life was poor, with 49% (95% CI, 42%-56%) never carrying their AAI in 1 or more locations. Carriage of the AAI device was particularly poor when students were independent of parental supervision: 32% (95% CI, 25%-39%) never carried it when they were by themselves, 28% (95% CI, 22%-36%) never carried it while out with friends, and 36% (95% CI, 30%-43%) never carried their AAI to sporting activities. Conclusions Carriage of AAI devices is suboptimal in young adolescents prescribed AAIs, particularly when young adolescents are independent of parental supervision.

Item does not contain fulltext Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In approximately 90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-kappaB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105DeltaEx8) is degraded, but is not processed to p50DeltaEx8. Altered NF-kappaB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50-translated from the non-mutated alleles-were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-kappaB1 p50 haploinsufficiency.

Mastocytosis is classified by the World-Health-Organisation (WHO)1 as cutaneous-mastocytosis (CM) and systemic-mastocytosis (SM). CM is subdivided into maculopapular (MPCM), diffuse-CM and mastocytomas. SM is subdivided into indolent (ISM), with-an-associated-haematologic-neoplasm (SM-AHN)2, aggressive (ASM) and mast-cell-leukemia (MCL). This article is protected by copyright. All rights reserved.

Background Despite the rising rates of anaphylaxis in older children and adolescents, risk factors for food allergy among this age group are understudied. Objective The objective of this study was to investigate the risk factors for current adolescent food allergy using a population-based sample. Methods The SchoolNuts study was a questionnaire survey among 10- to 14-year-old adolescents and their parents, followed by clinic evaluation including oral food challenge when food allergy was suspected from questionnaire response. We investigated the association between food allergy and demographic and environmental factors among a total of 4,991 adolescents using multiple logistic regression. Results Males and those with early-onset eczema had a higher risk of current food allergy in adolescence (adjusted odds ratio [aOR], 1.55; 95% confidence interval [CI], 1.12-2.15 and aOR, 14.08; 95% CI, 10.25-19.33). Those with Asian parents had increased risk compared with those with Caucasian parents (aOR, 2.82; 95% CI, 1.91-4.16), whereas being born in Asia compared with being born in Australia had decreased risk (aOR, 0.16; 95% CI, 0.04-0.67). Family history risk was higher for those with multiple members versus only 1 member (aOR, 4.62; 95% CI, 2.75-7.74 and aOR, 2.32; 95% CI, 1.36-3.97, respectively). Dog exposure during the first 5 years of life was associated with a decreased risk (aOR, 0.58; 95% CI, 0.38-0.91). Conclusions Early-onset eczema, Asian background, and family history of allergic disease were associated with an increased risk of food allergy, whereas dog exposure in early life reduced the risk in 10- to14-year-old adolescents. Factors predicting food allergy risk in an adolescent population-based cohort appear remarkably similar to those predicting early-onset food allergy in infancy.

The gender imbalance in medicine has been a topic of increasing interest and discussion. There are increasing proportions of graduating female medical students globally, with 41.1% of Australian doctors, 47% of UK doctors and 46% of US medical residents being female [1, 2]. However, in positions of influence, the proportions change, such that in the US only 21% of medical professors and 16% of medical deans are women [3]. Postulated reasons for this include implicit and unconscious gender bias and fewer promotion opportunities available to women. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Raviskanthan has nothing to disclose. Conflict of interest: Dr. Rees has nothing to disclose. Conflict of interest: Dr. Douglass reports other from Royal Melbourne Hospital, other from Melbourne Allergy, Asthma & Immunology Consultants, other from The Universtiy of Melbourne, personal fees and other from Astra Zeneca, other from Glaxo Smith Kiine, other from Sanofi, other from Grifols, grants and personal fees from Novartis, grants and other from CSL-Behring, other from BioCryst, other from Equilium, outside the submitted work. Conflict of interest: Dr. Sleeman has nothing to disclose. Conflict of interest: Dr. Higginson has nothing to disclose. Conflict of interest: Dr. Smallwood reports holding an unpaid role as the president elect for the Victorian Branch of the Thoracic Society of Australia and New Zealand.

Background Rising rates of food-induced anaphylaxis have recently been shown in the adolescent age group, following earlier descriptions of a rise in children younger than 5 years. However, few population-based studies have examined the prevalence of food allergy in adolescence using objective measures such as oral food challenge (OFC). Objective We sought to determine the prevalence of food allergy among a population-based sample of 10- to 14-year-old adolescents using clinical evaluation including OFC to confirm the diagnosis. Methods Schools were randomly selected from greater metropolitan Melbourne, Australia. Students aged 10 to 14 years, and their parents, were asked to complete a questionnaire regarding the adolescent's food allergy or food-related reactions. Clinic evaluation, which consisted of skin prick tests and OFC where eligible, was undertaken if students were suspected to have current food allergy from parent response. Among 9816 students assessed, 5016 had complete parent response and clinic evaluation when eligible. An additional 4800 students had student questionnaires only. Results The prevalence of clinic-defined current food allergy based on history, sensitization data, and OFC results was 4.5% (95% CI, 3.9-5.1), with the most common food triggers being peanut, 2.7% (95% CI, 2.3-3.2), and tree nut, 2.3% (95% CI, 1.9-2.8). Among the additional group of 4800 adolescents who had only self-reported food allergy status available, the prevalence of self-reported current food allergy was 5.5% (95% CI, 4.9-6.2), with peanut, 2.8% (95% CI, 2.3-3.3), and tree nut, 2.3% (95% CI, 1.9-2.8), the most common. Conclusions Approximately 1 in 20 10- to 14-year-old school students in Melbourne has current food allergy. This high prevalence suggests that the previously reported rise in food-induced anaphylaxis in this age group may reflect an increasing prevalence of food allergy rather than simply increased reporting of anaphylaxis.