Fungi are ubiquitous and form their own kingdom. Up to 80 genera of fungi have been linked to type I allergic disease, and yet, commercial reagents to test for sensitization are available for relatively few species. In terms of asthma, it is important to distinguish between species unable to grow at body temperature and those that can (thermotolerant) and thereby have the potential to colonize the respiratory tract. The former, which include the commonly studied Alternaria and Cladosporium genera, can act as aeroallergens whose clinical effects are predictably related to exposure levels. In contrast, thermotolerant species, which include fungi from the Candida, Aspergillus, and Penicillium genera, can cause a persistent allergenic stimulus independent of their airborne concentrations. Moreover, their ability to germinate in the airways provides a more diverse allergenic stimulus, and may result in noninvasive infection, which enhances inflammation. The close association between IgE sensitization to thermotolerant filamentous fungi and fixed airflow obstruction, bronchiectasis, and lung fibrosis suggests a much more tissue-damaging process than that seen with aeroallergens. This review provides an overview of fungal allergens and the patterns of clinical disease associated with exposure. It clarifies the various terminologies associated with fungal allergy in asthma and makes the case for a new term (allergic fungal airway disease) to include all people with asthma at risk of developing lung damage as a result of their fungal allergy. Lastly, it discusses the management of fungirelated asthma. Key words: Thermotolerant fungi. Allergic fungal airway disease (AFAD). ABPA. SAFS. Asthma. Allergic fungal rhinosinusitis (AFRS). Immune responses. Diagnosis. Treatment. ResumenLos hongos son obicuos y forman su propio reino. Hasta 80 géneros de hongos han sido asociados con la enfermedad alérgica tipo I; sin embargo, los reactivos comerciales para testar las sensibilizaciones a los mismos, se encuentran disponibles para un número relativamente pequeño de especies. En cuanto al asma, es importante distinguir entre especies incapaces de crecer en temperatura ambiente y aquellas que son termotolerantes y que, por lo tanto, tienen una capacidad potencial para colonizar el tracto respiratorio. Los primeros, que incluyen los géneros comúnmente estudiados Alternaria y Cladosporium, pueden actuar como aeroalérgenos y sus efectos clínicos están relacionados con los niveles de exposición. En contraste, las especies termotolerantes, que incluyen hongos del género Candida, Aspergillus y Penicillium, pueden causar un estímulo alergénico persistente independiente de su concentración en el aire. Además, su capacidad para germinar en las vías aéreas da lugar a estímulos alergénicos más diversos y puede dar como resultado infecciones no invasivas que facilitan la inflamación. La estrecha asociación entre sensibilización dependiente de IgE a hongos filamentosos termotolerantes y la obstrucción del flujo aéreo, bronquiectasias y fib...

SummaryBackground Immunological biomarkers are the key to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and fungal sensitisation, but how these relate to clinically relevant outcomes is unclear. Objectives To assess how fungal immunological biomarkers are related to fixed airflow obstruction and radiological abnormalities in moderate to severe asthma. Methods Cross-sectional study of 431 asthmatics. Inflammatory biomarkers, lung function and an IgE fungal panel to colonising filamentous fungi, yeasts and fungal aeroallergens were measured. CT scans were scored for the presence of radiological abnormalities. Factor analysis informed the variables used in a k-means cluster analysis. Fixed airflow obstruction and radiological abnormalities were then mapped to these immunological variables in the cluster analysis. Results 329 (76.3%) subjects were sensitised to ≥ 1 fungi. Sensitisation to Aspergillus fumigatus and/or Penicillium chrysogenum was associated with a lower post-bronchodilator FEV 1 compared with those not sensitised to fungi ((73.0 (95% CI 70.2-76) vs. 82.8 (95% CI 78.5-87.2)% predicted, P < 0.001), independent of atopic status (P = 0.005)), and an increased frequency of bronchiectasis (54.5%, P < 0.001), tree-in-bud (18.7%, P < 0.001) and collapse/consolidation (37.5%, P = 0.002). Cluster analysis identified three clusters: (i) hypereosinophilic (n = 71, 16.5%), (ii) high immunological biomarker load and high frequency of radiological abnormalities (n = 34, 7.9%) and (iii) low levels of fungal immunological biomarkers (n = 326, 75.6%). Conclusions and Clinical Relevance IgE sensitisation to thermotolerant filamentous fungi, in particular A. fumigatus but not total IgE, is associated with fixed airflow obstruction and a number of radiological abnormalities in moderate to severe asthma. All patients with IgE sensitisation to A. fumigatus are at risk of lung damage irrespective of whether they meet the criteria for ABPA.

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Fungi are ubiquitous and form their own kingdom. Up to 80 genera of fungi have been linked to type I allergic disease, and yet, commercial reagents to test for sensitization are available for relatively few species. In terms of asthma, it is important to distinguish between species unable to grow at body temperature and those that can (thermotolerant) and thereby have the potential to colonize the respiratory tract. The former, which include the commonly studied Alternaria and Cladosporium genera, can act as aeroallergens whose clinical effects are predictably related to exposure levels. In contrast, thermotolerant species, which include fungi from the Candida, Aspergillus, and Penicillium genera, can cause a persistent allergenic stimulus independent of their airborne concentrations. Moreover, their ability to germinate in the airways provides a more diverse allergenic stimulus, and may result in noninvasive infection, which enhances inflammation. The close association between IgE sensitization to thermotolerant filamentous fungi and fixed airflow obstruction, bronchiectasis, and lung fibrosis suggests a much more tissue-damaging process than that seen with aeroallergens. This review provides an overview of fungal allergens and the patterns of clinical disease associated with exposure. It clarifies the various terminologies associated with fungal allergy in asthma and makes the case for a new term (allergic fungal airway disease) to include all people with asthma at risk of developing lung damage as a result of their fungal allergy. Lastly, it discusses the management of fungirelated asthma. Key words: Thermotolerant fungi. Allergic fungal airway disease (AFAD). ABPA. SAFS. Asthma. Allergic fungal rhinosinusitis (AFRS). Immune responses. Diagnosis. Treatment. ResumenLos hongos son obicuos y forman su propio reino. Hasta 80 géneros de hongos han sido asociados con la enfermedad alérgica tipo I; sin embargo, los reactivos comerciales para testar las sensibilizaciones a los mismos, se encuentran disponibles para un número relativamente pequeño de especies. En cuanto al asma, es importante distinguir entre especies incapaces de crecer en temperatura ambiente y aquellas que son termotolerantes y que, por lo tanto, tienen una capacidad potencial para colonizar el tracto respiratorio. Los primeros, que incluyen los géneros comúnmente estudiados Alternaria y Cladosporium, pueden actuar como aeroalérgenos y sus efectos clínicos están relacionados con los niveles de exposición. En contraste, las especies termotolerantes, que incluyen hongos del género Candida, Aspergillus y Penicillium, pueden causar un estímulo alergénico persistente independiente de su concentración en el aire. Además, su capacidad para germinar en las vías aéreas da lugar a estímulos alergénicos más diversos y puede dar como resultado infecciones no invasivas que facilitan la inflamación. La estrecha asociación entre sensibilización dependiente de IgE a hongos filamentosos termotolerantes y la obstrucción del flujo aéreo, bronquiectasias y fib...

Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks.

is a gene that produces iron regulatory protein 2 (IRP2), which is critical to intracellular iron homeostasis and which relates to the rate of cellular proliferation. lies in a lung cancer susceptibility locus. The aims were to assess 1) the relationship between iron loading, cell proliferation and IRP2 expression in lung cancer; 2) the potential of iron related pathways as therapeutic targets; and 3) the relevance of IRP2 in operated lung cancer patients.Cells of two nonsmall cell cancer (NSCLC) lines and primary bronchial epithelial cells (PBECs) were cultured with and without iron; and proliferation, apoptosis and migration were assessed. Reverse transcriptase PCR and Western blot were used to assess expression of iron homeostasis genes/proteins. Iron chelation and knockdown of were used to explore therapeutics. A cohort of operated NSCLC patients was studied for markers of systemic iron status, tumour IRP2 staining and survival.Iron loading caused cell proliferation in cancer cell lines, which were less able to regulate expression than PBECs. Iron chelation resulted in a return of proliferation rates to baseline levels; knockdown of had a similar effect. IRP2-positive tumours were larger (p=0.045) and higher percentage staining related to poorer survival (p=0.079).Loss of iron regulation represents a poor prognostic marker in lung cancer.

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