0 citations0 references

Lassoing a chimera: the semantics of allergic fungal airway disease

Clinical & Experimental Allergy2015Vol. 45(12), pp. 1746–1749

Citations Over Time

Andrew J. Wardlaw, Kerry Woolnough, Catherine H. Pashley

Abstract

Fungi are one of the kingdoms of life and represent a diverse group of eukaryotic organisms that occupy every ecological habitat including the healthy human body. From the perspective of human disease in general and allergy in particular, fungi can be divided into two groups: those that are thermotolerant and can therefore colonize humans and those that cannot grow at body temperature, but act as aeroallergens in IgE-sensitized individuals 1. The property of thermotolerance is relevant to those filamentous fungi (moulds), which are involved in decomposition where temperatures are often high and are exemplified by members of the Aspergillus and Penicillium genera, particularly Aspergillus fumigatus. Yeasts, particularly members of the Candida genera, can also be thermotolerant and colonize mucocutaneous surfaces. Generally, yeasts are commensals causing no symptoms, but can become troublesome for example after taking antibiotics or inhaled corticosteroids (IHC). Non-thermotolerant species include plant pathogens such as members of the Alternaria and Cladosporium genera which can cause exacerbations of asthma and rhinitis when spore levels in ambient air are high such as during harvesting. However, they are unable to colonize the human airway and therefore have a limited and predictable impact on human health which is directly related to spore concentrations in inhaled air. Lung host defence is very effective at preventing invasive fungal infection unless there is profound immunosuppression, but lesser degrees of immune vulnerability associated with airways diseases such as asthma, COPD and cystic fibrosis where macrophage function and the mucociliary escalator is compromised can result in semi-invasive infection such as fungal balls in pre-existing cavities, fungal bronchitis, a pneumonitis and fungal associated pleurisy 2. Measurement of adaptive fungal immunity in a clinical setting is generally limited to humoral responses to a limited number of fungi. Th1 responses are typified by raised specific IgG and Th2 responses by a positive skin prick test (or less commonly intradermal test), a raised specific IgE and a raised total IgE. Cell-mediated immunity or innate immune responses although of critical importance are not usually measured unless immunodeficiency is suspected. Considering the number of fungi potentially involved in allergic fungal disease, relatively few reagents are available to measure fungal immunity. Fungal extracts, some of which are bespoke rather than commercially available, are imperfectly standardized and can be unreliable. This may be one reason for the imperfect correspondence between skin tests and in vitro measurements of specific IgE 3. The methodology for culturing fungi from human secretions is often insensitive and at best semi-quantitative 4, 5. Fungal allergens are complex and poorly characterized, and component-resolved approaches to diagnosing fungal allergy are in their infancy 6. The population epidemiology of fungal IgE sensitization is not well described and generally relies on SPT to a limited number of fungi which may underestimate the true level. However, in healthy controls, it is generally quoted as 1000 KU/L in the absence of infection with helminthic parasites almost always denotes fungal sensitization and fungal allergy is a common cause of an apparently idiopathic hypereosinophilic blood count. Taking the above comments into account, it is perhaps not surprising that there has been a long-standing and unresolved debate about how to determine when IgE sensitization to fungi, in particular A. fumigatus, is clinically important. The term allergic bronchopulmonary aspergillosis (ABPA) was first coined in the 1950s to describe a florid form of fungal allergy caused by Aspergillus species in particular A. fumigatus 13. A number of case series and reports, generally involving relatively small numbers of patients, describing the clinical and immunological features of ABPA, over time have become elevated into a set of diagnostic criteria with considerable importance attached to the total serum IgE concentration 14, 15. The features that were regarded as helpful in distinguishing ABPA from sensitization were a diagnosis of asthma or cystic fibrosis, fleeting lung shadows (rarely encountered these days), IgE sensitization to A. fumigatus either by SPT or by specific IgE, A. fumigatus-specific precipitins (now generally measured as specific IgG), a total IgE of >417 IU/L (equivalent to 1000 ng/mL) and a raised peripheral blood eosinophil count. Central or proximal bronchiectasis was recognized as an important feature although a subgroup without bronchiectasis was also described (ABPA-S). Culture of A. fumigatus in sputum was not regarded as a reliable marker of clinically significant disease. The difficulty of telling the difference between ABPA and asthma with sensitization to A. fumigatus was appreciated, and a number of stages of ABPA from mild disease to severe lung damage were described 16. Although based on anecdote, these criteria have been remarkably influential and clinicians have tried to squeeze their patients into the boxes created by these rather arbitrary rules ever since, with limited success. Thus, only about 10% of the patients with severe asthma who are IgE sensitized to A. fumigatus meet all the major criteria for ABPA and inclusion criteria for clinical trials of antifungal agents in ABPA have not been consistent in following these criteria 17-19. Attempts have been made to update the criteria consistent with modern practice. The term allergic bronchopulmonary mycosis (ABPM) has been used to recognize the fact that other fungal genera can result in a clinical picture similar to ABPA. Denning and colleagues coined the term severe asthma with fungal sensitization (SAFS), to describe patients with features suggestive of ABPA in the context of severe asthma, but who had an IgE below 1000 IU/L, a cut-off which has been preferred in recent years to the Patterson–Greenberger cut of 417 IU/L for reasons that are obscure 20. However, many patients with clinically significant fungal allergy do not have obviously severe asthma and SAFS includes asthmatics with sensitization to non-thermotolerant fungi which as noted above are unlikely to cause significant persistent lung disease. Other attempts to revise the criteria for ABPA have been hampered by the lack of a gold standard for what is in essence the florid end of a spectrum of disease. This has resulted in circularity where patients selected on the basis of the criteria are then measured against the same criteria 21. The problems associated with tying down ABPA in relation to fungal sensitization are illustrated by a systematic review of the criteria used to diagnose ABPA in cystic fibrosis (CF) carried out by Maturu and Agarwal and published in this issue 22. Their two main conclusions were that IgE sensitization to A. fumigatus in CF was very common occurring in 40% of patients, although <10% were diagnosed with ABPA and that only 50% of studies (post 2005) followed criteria laid out by the CF foundation for the diagnosis of ABPA in 2003 23. They highlight in their discussion many of the problems associated with diagnosing fungal allergy in CF that have been discussed above. Establishing criteria for ABPA is like trying to lasso a chimera. While there is undoubtedly a group of patients with clear evidence of lung damage in association with a florid immunological response to thermotolerant fungi, the presentation of fungal allergy is too protean to submit to a set of fixed rules. By imposing criteria which have limited specificity and sensitivity in predicting the presence of lung damage (which is the major clinical outcome of fungal lung disease), the majority of people whose problems can be ascribed to fungal allergy are left out. Diagnostic criteria are helpful when they guide a distinct approach to management or predict future harm (risk). Neither apply to ABPA/ABPM which, in the absence of good evidence for a role for antifungal treatment, is not managed much differently from patients with the underlying condition. It is our contention that ABPA as a term has outlived its usefulness confusing rather than clarifying the role of fungal allergy in respiratory disease. An inclusive term such as allergic fungal airway disease qualified in terms of severity and the underlying condition and defined as anyone with airway disease and IgE sensitization to thermotolerant fungi is in our view preferable. The starting point of any discussion about the role of fungi in airway disease should be what are the clinically important pathophysiological abnormalities that relate directly and specifically to fungal allergy? We propose that the hallmark of allergic fungal involvement in airway disease are changes that can be grouped under the term ‘lung damage’ with bronchiectasis, fixed airflow obstruction and upper lobe fibrosis prominent features 24. These are likely to be the result at least in part of chronic mucus plugging of the large and small airways as result of a persistent, multi-allergenic stimulus. Determining the relationship between the immunology of allergic fungal airway disease and clinically relevant outcomes should be based on their relationship to the presence or absence of these features. Until it is recognized that all people with specific IgE to thermotolerant fungi in the context of airway disease are at risk of progressive lung damage, our understanding of why only some people with fungal sensitization develop lung damage and the relative role of antifungal and anti-allergic approaches to its management will continue to be compromised. The authors are supported by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Dr Pashley is the recipient of a fellowship from the Midlands Asthma and Allergy Research Association. The author declares no conflict of interest.

Citations Over Time

Abstract

Related Papers