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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 1]). IgG subclasses and specific pathogen antibody levels were also measured. 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 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008–0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83–1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. Conclusions: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: Grass pollen at lag 0–3 (every 20 grains/m3 increase) 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

The article describes 2 rare skin conditions not reported to be associated with underlying B-cell chronic lymphocytic leukemia (B-CLL) where specific anti-leukemia treatment successfully eradicated skin lesions. The first case is a 69 year old patient presented with recurrent ulcerated lesions in his lower limbs consistent with pyoderman gangrenosum (PG) and the second case is a 46 year old patient presented in 2008 with generalized painful and itchy urticarial lesions triggered by cold.

Three patients were skin test positive to only goat and sheep milk and four to at least one other milk product from buffalo mozzarella, cow's milk or camel milk. We identified seven adults with new-onset IgE-mediated allergy to orally ingested goat milk products Patients used goat milk skincare products prior to developing allergy, and six had atopic dermatitis Competitive inhibition experiments suggested the skincare products led to transcutaneous sensitization and goat milk allergy To the Editor, Milk allergy is one of the most common food allergies in children, but usually resolves in the first years of life.1 Adult-onset milk allergy is rare. [Extracted from the article]

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. Systematic review registration: CRD42020146981 (PROSPERO). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. We examined patients with acute asthma, who presented to Emergency Rooms during the 2016 Melbourne thunderstorm asthma epidemic. Patients with current asthma had higher odds (1.9) for hospital admission, hospitalization for asthma in the prior 12 months further increased the odds by 3.16. Among patients of Asian ethnicity, odds for hospital admission were lower than for non‐Asian patients (0.59), but higher if born in Australia (5.42), suggesting enhanced susceptibility from gene‐environment interactions. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼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-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 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-κB1 p50 haploinsufficiency. [ABSTRACT FROM AUTHOR]

Background The association between grass pollen exposure and lung function changes and airway inflammation is limited. We investigated these associations in a community-based sample, and whether any such associations were modified by current asthma, current hay fever, pollen sensitization and age. Methods Cross-sectional 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) was 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. Conclusions Grass pollen exposure was associated with eosinophilic airway inflammation 1-2 days after exposure and airway obstruction 2-3 days after exposure. Key messages There is a more delayed effect on lung function compared to airway inflammation. Adults with current asthma, hay fever and grass pollen sensitisation are especially vulnerable. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Thunderstorm asthma is defined as epidemics of asthma occurring shortly after a thunderstorm. While grass pollen has been implicated in thunderstorm asthma events, little is known about the role of fungi and studies have not been synthesised. This systematic review aims to evaluate whether grass pollen is necessary in thunderstorm asthma events and whether fungi also play a part in these associations. We conducted a systematic search using six electronic databases (i.e. CINAHL, Medline (Ovid), Web of Science, ProQuest Central, EMBASE and Google Scholar) and checked reference lists. The search terms used were pollen AND thunderstorm* AND asthma. The inclusion criteria were studies published in English with original human data relating to outdoor pollen and thunderstorm asthma. Twenty of 2198 studies were eligible. Reported findings differed due to variation in methodological approaches and a meta-analysis was not possible. Nonetheless, of the 20 studies included, 15 demonstrated some relationship with nine demonstrating lagged effects up to four days for increasing grass pollen counts associated with increased risk of thunderstorm asthma. Of the 10 studies that examined fungi, nine demonstrated a positive relationship with thunderstorm asthma. The fungal taxa involved varied, depending on whether measurements were recorded before, during or after the thunderstorm. Nevertheless, none of the studies considered fungi as a potential effect modifier for the pollen-thunderstorm asthma association. We found evidence to suggest that grass pollen was a necessary factor for thunderstorm asthma but there are other as yet unrecognised environmental factors that may also be important. Further research is required to examine the role of fungi and other environmental factors such as air quality as potential effect modifiers of the association. • Grass pollen is most commonly associated with thunderstorm asthma. • There is a lagged effect of up to four days. • Grass pollen on its own is not enough to cause thunderstorm asthma. • Fungi is also important, but more studies are required. [ABSTRACT FROM AUTHOR]