Effectiveness of voriconazole in the treatment of Aspergillus fumigatus–associated asthma (EVITA3 study)

Agbetile, Joshua; Bourne, Michelle; Fairs, Abbie; Hargadon, Beverley; Desai, Dhananjay; Broad, Claire; Morley, J. P.; Bradding, Peter; Brightling, Christopher E.; Green, Ruth H.; Haldar, Pranabashis; Pashley, Catherine H.; Pavord, Ian D.; Wardlaw, Andrew J.

doi:10.1016/j.jaci.2013.09.050

Cited by 78 publications

(60 citation statements)

References 26 publications

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“…Oral itraconazole yielded positive effects in a subset of asthmatic patients with fungal sensitivity 10 and the majority of asthma or ABPA patients that cannot tolerate itraconazole appear to benefit from either posaconazole or voriconazole 11 . In contrast, findings with voriconazole could not be replicated in a prospective study 33 . Although the reasons for the inconsistent performance of anti-fungal antibiotics are not entirely clear, negative studies with voriconazole have been used to argue that positive results with other antifungal antibiotics, especially itraconazole, are due to their ability to promote corticosteroid activity.…”

Section: Discussionmentioning

confidence: 74%

Airway surface mycosis in chronic TH2-associated airway disease

Porter

Lim

Maskatia

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Environmental fungi have been linked to T helper type 2 (Th2) cell-related airway inflammation and the Th2-associated chronic airway diseases asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. Objective To determine the frequency of fungus isolation and fungus-specific immunity in Th2-associated and non-associated airway disease patients. Methods Sinus lavage fluid and blood were collected from sinus surgery patients (n=118) including CRS patients with and without nasal polyps and AFRS and non-CRS/non-asthmatic control patients. Asthma status was deteremined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. Peripheral blood mononuclear cells were restimulated with fungal antigens in an enzyme linked immunocell spot (ELISpot) assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared to fungus-specific IgE levels measured from plasma by ELISA. Results Filamentous fungi were significantly more commonly cultured from Th2-associated airway disease subjects (asthma, CRSwNP, or AFRS: n=68) compared to non-Th2-associated control patients (n=31); 74% vs 16% respectively, p<0.001. Both fungus-specific IL-4 ELISpot (n=48) and specific IgE (n=70) data correlated with Th2-associated diseases (sensitivity 73% and specificity 100% vs. 50% and 77%, respectively). Conclusions The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with Th2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients. Clinical Implications Airway fungi may contribute to the expression of sinusitis with nasal polyps and asthma, suggesting that efforts to eradicate fungi from the airways and environments of these patients should be considered.

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Section: Discussionmentioning

confidence: 74%

Airway surface mycosis in chronic TH2-associated airway disease

Porter

Lim

Maskatia

et al. 2014

Journal of Allergy and Clinical Immunology

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“…Management is avoidance of fungal exposure as far as possible (checking any nebulizer for contamination and avoiding stables) and consideration of antifungal therapy, although it has to be said that the evidence for antifungal therapy is not compelling. 80,81 If itraconazole is used, the potential interaction with budesonide which can lead to iatrogenic Cushing's syndrome should be remembered.…”

Section: Safs: Potential Approachesmentioning

confidence: 99%

Severe asthma in children

2017

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Most children with asthma have their disease easily controlled if low-dose inhaled corticosteroids (ICSs) are regularly and correctly administered. If a child presents with asthma which is apparently resistant to therapy with high-dose ICS and other controllers, then they have problematic severe asthma. However, in light of the UK National Review of Asthma Deaths, definitions of severe asthma based solely on the levels of prescribed treatment are too narrow. A detailed assessment of all such children should be performed. First, the diagnosis of asthma should be confirmed, then co-morbidities assessed. Next, a nurse-led assessment further characterizes the problem, conventionally categorizing the child as either having difficult asthma or severe therapy-resistant asthma. Here, we reassess in particular the interactions between, and management of, these two categories, highlighting that this dichotomous classification may need reconsideration. We use bronchoscopy and an intramuscular steroid injection to determine if the child has steroid-resistant asthma, using a novel, multidomain approach because the adult definition does not apply to around half the children we see. Finally, we highlight some mechanistic data which have emerged from this protocol such as the absence of T-helper 2 (TH2) cytokines even in eosinophilic severe asthma and the potential role of the innate epithelial cytokine IL-33, novel data on lineage negative innate lymphoid cells, which we can measure in induced sputum, and demonstrating that intraepithelial neutrophils are associated with better, not worse asthma outcomes. Severe paediatric asthma is very different from severe asthma in adults, and approaches must not be uncritically extrapolated from adult disease to children.

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“…Four randomized-controlled trials have assessed antifungal treatment in asthma associated with AFAD. Three used itraconazole [117][118][119], the fourth used voriconazole [120]. Although the disease names and inclusion criteria were slightly different in each study, the patient population was essentially the same in all 4.…”

Section: Antifungal Therapymentioning

confidence: 99%

“…The minor benefit of triazole antifungal agents may be due in part to the difficulty in eradicating the fungi from the airways owing to lack of penetration of the drug into the bronchial lumen [122,123]. In the EVITA3 study [120], 40% of patients still had at least 1 positive sputum culture while taking voriconazole. In addition, rates of positive sputum culture returned to baseline values within 2 months of stopping the intervention.…”

Section: Antifungal Therapymentioning

confidence: 99%

Allergic Fungal Airway Disease

Rick¹,

Woolnough²,

Pashley³

et al. 2016

J Investig Allergol Clin Immunol

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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...

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Effectiveness of voriconazole in the treatment of Aspergillus fumigatus–associated asthma (EVITA3 study)

Abstract: We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.

Cited by 78 publications

References 26 publications

Airway surface mycosis in chronic TH2-associated airway disease

Airway surface mycosis in chronic TH2-associated airway disease

Severe asthma in children

Allergic Fungal Airway Disease

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