The role of antifungals in the management of patients with severe asthma

Rapeport, Garth; Ito, Kazuhiro; Denning, David W.

doi:10.1186/s13601-020-00353-8

Cited by 25 publications

(19 citation statements)

References 86 publications

(157 reference statements)

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“…In contrast there are several case series/reports and uncontrolled trials suggesting an improvement in symptoms and outcomes with triazole anti-fungal therapy. 126,127 We observed that two or three subjects in our trial of 32 voriconazole-treated patients with AFAD associated with asthma appeared to gain a clear benefit. These subjects each had a productive cough and grew large amounts of A. fumigatus in their sputum.…”

Section: Dovepressmentioning

confidence: 69%

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease

Wardlaw¹,

Rick²,

Özyiğit³

et al. 2021

JAA

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Allergy to airway-colonising, thermotolerant, filamentous fungi represents a distinct eosinophilic endotype of often severe lung disease. This endotype, which particularly affects adult asthma, but also complicates other airway diseases and sometimes occurs de novo, has a heterogeneous presentation ranging from severe eosinophilic asthma to lobar collapse. Its hallmark is lung damage, characterised by fixed airflow obstruction (FAO), bronchiectasis and lung fibrosis. It has a number of monikers including severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis/mycosis (ABPA/ M), but these exclusive terms constitute only sub-sets of the condition. In order to capture the full extent of the syndrome we prefer the inclusive term allergic fungal airway disease (AFAD), the criteria for which are IgE sensitisation to relevant fungi in association with airway disease. The primary fungus involved is Aspergillus fumigatus, but a number of other thermotolerant species from several genera have been implicated. The unifying mechanism involves germination of inhaled fungal spores in the lung in the context of IgE sensitisation, leading to a persistent and vigorous eosinophilic inflammatory response in association with release of fungal proteases. Most allergenic fungi, including Alternaria and Cladosporium species, are not thermotolerant and cannot germinate in the airways so only act as aeroallergens and do not cause AFAD. Studies of the airway mycobiome have shown that A. fumigatus colonises the normal as much as the asthmatic airway, suggesting it is the tendency to become IgE-sensitised that is the critical triggering factor for AFAD rather than colonisation per se. Treatment is aimed at preventing exacerbations with glucocorticoids and increasingly by the use of anti-T2 biological therapies. Anti-fungal therapy has a limited place in management, but is an effective treatment for fungal bronchitis which complicates AFAD in about 10% of cases.

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Section: Dovepressmentioning

confidence: 69%

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease

Wardlaw¹,

Rick²,

Özyiğit³

et al. 2021

JAA

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“…To address this high burden, there are available safe oral antifungal drugs effective in the control of severe symptoms of asthma. 42 …”

Section: Resultsmentioning

confidence: 99%

“…Changes in the susceptibility to antifungal drugs and the unavailability of routine fungal culture and drug susceptibility testing services have exacerbated the problem of fungal infections. 42 In order to reduce the effect of fungal infections on HIV-related mortality, national and international guidelines have put forward various recommendations on the screening, treatment and prevention of fungal and other opportunistic infections. The WHO guidelines strongly recommend the use of dual therapy for cryptococcal meningitis and routine screening for cryptococcal disease in all patients living with HIV (PLHIV) with a CD4 cell counts less than 100/µl.…”

Section: Discussionmentioning

confidence: 99%

The burden of serious fungal infections in Sierra Leone: a national estimate

Lakoh

Orefuwa

Kamara

et al. 2021

Therapeutic Advances in Infection

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Sierra Leone is a small, resource-limited country that has a low national prevalence of human immunodeficiency virus (HIV) and a very high burden of tuberculosis (TB). Fungal diseases are probably common, but poorly documented. In this article, we reviewed the existing literature on fungal epidemiology in Sierra Leone using national, regional, and international data, identified knowledge gaps, and propose solutions to address the challenges on the prevention and control of fungal diseases in Sierra Leone and similar countries. In advanced HIV disease, we estimate 300 cryptococcal meningitis, 640 Pneumocystis pneumonia, and over 4000 esophageal candidiasis cases annually. Chronic lung disease is common, with an estimated 6000 cases of chronic pulmonary aspergillosis, many mistaken for TB, 5000 adults with allergic bronchopulmonary aspergillosis complicating asthma, and probably over 6600 cases of severe asthma with fungal sensitization. Invasive aspergillosis is estimated at 478 cases. None of these diagnoses are made in Sierra Leone at present. Major burdens are recurrent vulvovaginal candidiasis (85,400) and tinea capitis in children (266,450). Improvement in fungal disease diagnosis in Sierra Leone will enable better estimates to be made and reduce morbidity and mortality.

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“…Af exposure could induce a series of allergic pulmonary disorders, such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) [ 2 ]. It was estimated that ABPA affected approximately 4.8 million people globally [ 3 ], and over 70% of patients with severe asthma were sensitized to at least one fungus [ 4 ]. However, for patients with fungus exposure, conventional treatment using inhaled corticosteroids seems inadequate, and combination therapy such as systemic corticosteroid and antifungal agents has been suggested [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…It was estimated that ABPA affected approximately 4.8 million people globally [ 3 ], and over 70% of patients with severe asthma were sensitized to at least one fungus [ 4 ]. However, for patients with fungus exposure, conventional treatment using inhaled corticosteroids seems inadequate, and combination therapy such as systemic corticosteroid and antifungal agents has been suggested [ 4 , 5 ]. Therefore, it was essential to explore the potential mechanisms for Af-induced allergic lung inflammation to offer promising therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

Ameliorative effects of eosinophil deficiency on immune response, endoplasmic reticulum stress, apoptosis, and autophagy in fungus-induced allergic lung inflammation

Wang

Jiang

et al. 2021

Respir Res

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Background Respiratory fungal exposure is known to be associated with various allergic pulmonary disorders. Eosinophils have been implicated in tissue homeostasis of allergic inflammation as both destructive effector cells and immune regulators. What contributions eosinophils have in Aspergillus fumigatus (Af)-induced allergic lung inflammation is worthy of investigating. Methods We established the Af-exposed animal asthmatic model using eosinophil-deficient mice, ∆dblGATA1 mice. Airway inflammation was assessed by histopathological examination and total cell count of bronchoalveolar lavage fluid (BALF). The protein level in BALF and lung mRNA level of type 2 cytokines IL-4, IL-5, and IL-13 were detected by ELISA and qRT-PCR. We further studied the involvement of endoplasmic reticulum (ER) stress, apoptosis, and autophagy by western blots, qRT-PCR, immunofluorescence, TUNEL, or immunohistochemistry. RNA-Seq analysis was utilized to analyze the whole transcriptome of Af-exposed ∆dblGATA1 mice. Results Hematoxylin and eosin (HE) staining and periodic acid–Schiff staining (PAS) showed that airway inflammation and mucus production were alleviated in Af-challenged ∆dblGATA1 mice compared with wild-type controls. The protein and mRNA expressions of IL-4, IL-5, and IL-13 were reduced in the BALF and lung tissues in Af-exposed ∆dblGATA1 mice. The results demonstrated that the significantly increased ER stress markers (GRP78 and CHOP) and apoptosis executioner caspase proteases (cleaved caspase-3 and cleaved caspase-7) in Af-exposed wild-type mice were all downregulated remarkably in the lungs of ∆dblGATA1 mice with Af challenge. In addition, the lung autophagy in Af-exposed ∆dblGATA1 mice was found elevated partially, manifesting as higher expression of LC3-II/LC3-I and beclin1, lower p62, and downregulated Akt/mTOR pathway compared with Af-exposed wild-type mice. Additionally, lung RNA-seq analysis of Af-exposed ∆dblGATA1 mice showed that biological processes about chemotaxis of lymphocytes, neutrophils, or eosinophils were enriched but without statistical significance. Conclusions In summary, eosinophils play an essential role in the pathogenesis of Af-exposed allergic lung inflammation, whose deficiency may have relation to the attenuation of type 2 immune response, alleviation of ER stress and apoptosis, and increase of autophagy. These findings suggest that anti-eosinophils therapy may provide a promising direction for fungal-induced allergic pulmonary diseases.

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The role of antifungals in the management of patients with severe asthma

Cited by 25 publications

References 86 publications

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease

The burden of serious fungal infections in Sierra Leone: a national estimate

Ameliorative effects of eosinophil deficiency on immune response, endoplasmic reticulum stress, apoptosis, and autophagy in fungus-induced allergic lung inflammation

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